Science.gov

Sample records for adrenocorticotropic hormone release

  1. Metastatic Pancreatic Neuroendocrine Tumor that Progressed to Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome with Growth Hormone-releasing Hormone (GHRH) Production

    PubMed Central

    Tadokoro, Rie; Sato, Shotaro; Otsuka, Fumiko; Ueno, Makoto; Ohkawa, Shinichi; Katakami, Hideki; Taniyama, Matsuo; Nagasaka, Shoichiro

    2016-01-01

    The patient was a 61-year-old woman who had a well-differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis. After 15 months of octreotide treatment, glucose control deteriorated and pigmentation of the tongue and moon face developed, leading to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome. An abnormal secretion of growth hormone (GH) was identified, and the plasma growth hormone-releasing hormone (GHRH) level was elevated. A tumor biopsy specimen positively immunostained for ACTH and GHRH. Ectopic hormone secretion seems to have evolved along with the progression of the PNET. PMID:27746436

  2. Metastatic Pancreatic Neuroendocrine Tumor that Progressed to Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome with Growth Hormone-releasing Hormone (GHRH) Production.

    PubMed

    Tadokoro, Rie; Sato, Shotaro; Otsuka, Fumiko; Ueno, Makoto; Ohkawa, Shinichi; Katakami, Hideki; Taniyama, Matsuo; Nagasaka, Shoichiro

    The patient was a 61-year-old woman who had a well-differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis. After 15 months of octreotide treatment, glucose control deteriorated and pigmentation of the tongue and moon face developed, leading to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome. An abnormal secretion of growth hormone (GH) was identified, and the plasma growth hormone-releasing hormone (GHRH) level was elevated. A tumor biopsy specimen positively immunostained for ACTH and GHRH. Ectopic hormone secretion seems to have evolved along with the progression of the PNET.

  3. Effects of ghrelin, growth hormone-releasing peptide-6, and growth hormone-releasing hormone on growth hormone, adrenocorticotropic hormone, and cortisol release in type 1 diabetes mellitus.

    PubMed

    de Sá, Larissa Bianca Paiva Cunha; Nascif, Sergio Oliva; Correa-Silva, Silvia Regina; Molica, Patricia; Vieira, José Gilberto Henriques; Dib, Sergio Atala; Lengyel, Ana-Maria Judith

    2010-10-01

    In type 1 diabetes mellitus (T1DM), growth hormone (GH) responses to provocative stimuli are normal or exaggerated, whereas the hypothalamic-pituitary-adrenal axis has been less studied. Ghrelin is a GH secretagogue that also increases adrenocorticotropic hormone (ACTH) and cortisol levels, similarly to GH-releasing peptide-6 (GHRP-6). Ghrelin's effects in patients with T1DM have not been evaluated. We therefore studied GH, ACTH, and cortisol responses to ghrelin and GHRP-6 in 9 patients with T1DM and 9 control subjects. The GH-releasing hormone (GHRH)-induced GH release was also evaluated. Mean fasting GH levels (micrograms per liter) were higher in T1DM (3.5 ± 1.2) than in controls (0.6 ± 0.3). In both groups, ghrelin-induced GH release was higher than that after GHRP-6 and GHRH. When analyzing Δ area under the curve (ΔAUC) GH values after ghrelin, GHRP-6, and GHRH, no significant differences were observed in T1DM compared with controls. There was a trend (P = .055) to higher mean basal cortisol values (micrograms per deciliter) in T1DM (11.7 ± 1.5) compared with controls (8.2 ± 0.8). No significant differences were seen in ΔAUC cortisol values in both groups after ghrelin and GHRP-6. Mean fasting ACTH values were similar in T1DM and controls. No differences were seen in ΔAUC ACTH levels in both groups after ghrelin and GHRP-6. In summary, patients with T1DM have normal GH responsiveness to ghrelin, GHRP-6, and GHRH. The ACTH and cortisol release after ghrelin and GHRP-6 is also similar to controls. Our results suggest that chronic hyperglycemia of T1DM does not interfere with GH-, ACTH-, and cortisol-releasing mechanisms stimulated by these peptides.

  4. Improved response of growth hormone to growth hormone-releasing hormone and reversible chronic thyroiditis after hydrocortisone replacement in isolated adrenocorticotropic hormone deficiency.

    PubMed

    Inagaki, Miho; Sato, Haruhiro; Miyamoto, Yoshiyasu; Hirukawa, Takashi; Sawaya, Asako; Miyakogawa, Takayo; Tatsumi, Ryoko; Kakuta, Takatoshi

    2009-07-20

    We report a 44-year-old Japanese man who showed a reversible blunted response of growth hormone (GH) to GH-releasing hormone (GRH) stimulation test and reversible chronic thyroiditis accompanied by isolated ACTH deficiency. He was admitted to our hospital because of severe general malaise, hypotension, and hypoglycemia. He showed repeated attacks of hypoglycemia, and his serum sodium level gradually decreased. Finally, he was referred to the endocrinology division, where his adrenocorticotropic hormone (ACTH) and cortisol values were found to be low, and his GH level was slightly elevated. An increased value of thyroid stimulating hormone (TSH) and decreased values of free triidothyronine and free thyroxine were observed along with anti-thyroglobulin antibody, suggesting chronic thyroiditis. Pituitary stimulation tests revealed a blunted response of ACTH and cortisol to corticotropin-releasing hormone, and a blunted response of GH to GRH. Hydrocortisone replacement was then started, and this improved the patient's general condition. His hypothyroid state gradually ameliorated and his titer of anti-thyroglobulin antibody decreased to the normal range. Pituitary function was re-evaluated with GRH stimulation test under a maintenance dose of 20 mg/day hydrocortisone and showed a normal response of GH to GRH. It is suggested that re-evaluation of pituitary and thyroid function is useful for diagnosing isolated ACTH deficiency after starting a maintenance dose of hydrocortisone in order to avoid unnecessary replacement of thyroid hormone.

  5. Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms

    SciTech Connect

    Kyllo, J.H.; Collins, M.M.; Vetter, K.L.

    1996-03-29

    Genetic screening techniques using simple sequence repeat polymorphisms were applied to investigate the molecular nature of congenital isolated adrenocorticotropic hormone (ACTH) deficiency. We hypothesize that this rare cause of hypocortisolism shared by a brother and sister with two unaffected sibs and unaffected parents is inherited as an autosomal recessive single gene mutation. Genes involved in the hypothalamic-pituitary axis controlling cortisol sufficiency were investigated for a causal role in this disorder. Southern blotting showed no detectable mutations of the gene encoding pro-opiomelanocortin (POMC), the ACTH precursor. Other candidate genes subsequently considered were those encoding neuroendocrine convertase-1, and neuroendocrine convertase-2 (NEC-1, NEC-2), and corticotropin releasing hormone (CRH). Tests for linkage were performed using polymorphic di- and tetranucleotide simple sequence repeat markers flanking the reported map locations for POMC, NEC-1, NEC-2, and CRH. The chromosomal haplotypes determined by the markers flanking the loci for POMC, NEC-1, and NEC-2 were not compatible with linkage. However, 22 individual markers defining the chromosomal haplotypes flanking CRH were compatible with linkage of the disorder to the immediate area of this gene of chromosome 8. Based on these data, we hypothesize that the ACTH deficiency in this family is due to an abnormality of CRH gene structure or expression. These results illustrate the useful application of high density genetic maps constructed with simple sequence repeat markers for inclusion/exclusion studies of candidate genes in even very small nuclear families segregating for unusual phenotypes. 25 refs., 5 figs., 2 tabs.

  6. Pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome.

    PubMed

    Murakami, Keigo; Nakamura, Yasuhiro; Felizola, Saulo J A; Morimoto, Ryo; Satoh, Fumitoshi; Takanami, Kentaro; Katakami, Hideki; Hirota, Seiichi; Takeda, Yoshiyu; Meguro-Horike, Makiko; Horike, Shin-Ichi; Unno, Michiaki; Sasano, Hironobu

    2016-11-15

    Solitary fibrous tumors occasionally present with hypoglycemia because of the excessive release of insulin-like growth factor II. We report the first case of pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome. An 82-year-old Japanese man presented with lower limb edema, uncontrolled hypertension, hypokalemia, and baseline hypercortisolism. Distal pancreatectomy was performed after the clinical diagnosis of a neuroendocrine tumor with ectopic secretion of adrenocorticotropic hormone. On histological examination, the tumor showed spindle cells in a fascicular arrangement. The diagnosis of the solitary fibrous tumor was confirmed by the identification of the NAB2-STAT6 fusion gene and positive immuno-histochemical staining for STAT6 and CD34. Using quantitative real-time polymerase chain reaction, mRNA that encoded proopiomelanocortin, precursor of adrenocorticotropic hormone, was detected. Proopiomelanocortin production through the demethylation of the promoter region Domain IV was detected. Pancreatic solitary fibrous tumors represent a new cause of ectopic adrenocorticotropic hormone syndrome.

  7. Placental corticotropin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans.

    PubMed Central

    Sasaki, A; Shinkawa, O; Yoshinaga, K

    1989-01-01

    To clarify the physiological role of placental corticotropin-releasing hormone (CRH), we measured plasma CRH, ACTH, and cortisol throughout pregnancy. Cerebrospinal fluid (CSF) CRH levels and ACTH responsiveness to synthetic CRH were also quantified in pregnant and nonpregnant women. Maternal plasma CRH levels, which increased progressively during pregnancy, correlated well with both ACTH and cortisol in early labor, delivery, and postpartum samples, and also with cortisol levels in samples before labor. CSF CRH levels in term pregnant women did not differ from those of nonpregnant women. CRH infusion that attained similar plasma CRH levels to those found in late pregnancy elicited significant ACTH release in vivo and regular CRH test provoked normal ACTH response during early pregnancy but no response during late pregnancy. We concluded that: (a) maternal pituitary-adrenal axis correlates well with plasma CRH levels, which are high enough to provoke ACTH release from maternal pituitary; (b) hypothalamic CRH secretion in term pregnant women is not exaggerated; and (c) maternal pituitary is responsive to synthetic CRH in early but not late pregnancy, suggesting that maternal pituitary-adrenal axis is already activated by high circulating CRH. Placental CRH may be an important stimulator of the maternal pituitary-adrenal axis during pregnancy. Images PMID:2556451

  8. Influence of feeding status, time of the day, and season on baseline adrenocorticotropic hormone and the response to thyrotropin releasing hormone-stimulation test in healthy horses.

    PubMed

    Diez de Castro, E; Lopez, I; Cortes, B; Pineda, C; Garfia, B; Aguilera-Tejero, E

    2014-07-01

    Equine pituitary pars intermedia function can be assessed by the measurement of baseline and thyrotropin releasing hormone (TRH)-induced concentrations of adrenocorticotropic hormone (ACTH); however, these measurements may be affected by the environment. Therefore, a prospective observational study evaluated the influence of feeding, time of the day, and season on baseline and TRH-induced concentrations of ACTH in healthy horses. Baseline ACTH was measured in 50 horses before and 2 h after feeding. Six research horses were subjected to a crossover study in which 6 TRH tests were performed in 2 different seasons, March-April (MA) and July-September (JS), at 2 different times of the day, 8 AM and 8 PM, and, under 2 different conditions relative to feeding status, fasted and 2 h after feeding. Differences between fasted and fed horses were found in baseline ACTH, 17.1 ± 1.8 versus 46.1 ± 7.6 pg/mL (P = 0.003) and TRH-stimulated ACTH: 124.1 ± 21.3 versus 192.6 ± 33.1 pg/mL (P = 0.029) at 10 min, and 40.1 ± 4.9 versus 73.2 ± 13.4 pg/mL (P = 0.018) at 30 min post TRH injection. No differences were found between tests performed at different times of the day. Basal ACTH concentrations were greater in JS than in MA, 17.1 ± 1.8 versus 11.9 ± 0.6 pg/mL (P = 0.006). A seasonal influence was also found in stimulated ACTH values, which were much greater in JS 122.7 ± 36.7 versus 31.2 ± 7.4 pg/mL, at 10 min (P = 0.03) and 39.0 ± 7.2 versus 19.8 ± 3.1 pg/mL, at 30 min (P = 0.03). In addition to season, feeding is a potential confounding factor when measuring baseline or stimulated ACTH in horses. In conclusion, feeding status should be standardized for the diagnosis of equine pituitary pars intermedia dysfunction.

  9. CXCL10/CXCR3 signaling mediates inhibitory action by interferon-gamma on CRF-stimulated adrenocorticotropic hormone (ACTH) release.

    PubMed

    Horiguchi, Kotaro; Fujiwara, Ken; Tsukada, Takehiro; Yoshida, Saishu; Higuchi, Masashi; Tateno, Kozue; Hasegawa, Rumi; Takigami, Shu; Ohsako, Shunji; Yashiro, Takashi; Kato, Takako; Kato, Yukio

    2016-05-01

    Secretion of hormones by the anterior pituitary gland can be stimulated or inhibited by paracrine factors that are produced during inflammatory reactions. The inflammation cytokine interferon-gamma (IFN-γ) is known to inhibit corticotropin-releasing factor (CRF)-stimulated adrenocorticotropin (ACTH) release but its signaling mechanism is not yet known. Using rat anterior pituitary, we previously demonstrated that the CXC chemokine ligand 10 (CXCL10), known as interferon-γ (IFN-γ) inducible protein 10 kDa, is expressed in dendritic cell-like S100β protein-positive (DC-like S100β-positive) cells and that its receptor CXCR3 is expressed in ACTH-producing cells. DC-like S100β-positive cells are a subpopulation of folliculo-stellate cells in the anterior pituitary. In the present study, we examine whether CXCL10/CXCR3 signaling between DC-like S100β-positive cells and ACTH-producing cells mediates inhibition of CRF-activated ACTH-release by IFN-γ, using a CXCR3 antagonist in the primary pituitary cell culture. We found that IFN-γ up-regulated Cxcl10 expression via JAK/STAT signaling and proopiomelanocortin (Pomc) expression, while we reconfirmed that IFN-γ inhibits CRF-stimulated ACTH-release. Next, we used a CXCR3 agonist in primary culture to analyze whether CXCL10 induces Pomc-expression and ACTH-release using a CXCR3 agonist in the primary culture. The CXCR3 agonist significantly stimulated Pomc-expression and inhibited CRF-induced ACTH-release, while ACTH-release in the absence of CRF did not change. Thus, the present study leads us to an assumption that CXCL10/CXCR3 signaling mediates inhibition of the CRF-stimulated ACTH-release by IFN-γ. Our findings bring us to an assumption that CXCL10 from DC-like S100β-positive cells acts as a local modulator of ACTH-release during inflammation.

  10. Isolated adrenocorticotropic hormone deficiency development during chemotherapy for gastric cancer: a case report

    PubMed Central

    2014-01-01

    Introduction Isolated adrenocorticotropic hormone deficiency is an endocrinological disorder characterized by loss of adrenocorticotropic hormone and resultant adrenal insufficiency. Affected patients often present with fatigue, anorexia, and hyponatremia. Although the number of reported cases has been recently increasing, isolated adrenocorticotropic hormone deficiency combined with malignant neoplasia is very rare. Here we describe a patient with gastric cancer who developed unexpected isolated adrenocorticotropic hormone deficiency during chemotherapy. Case presentation A 72-year-old Japanese man was admitted to our hospital because of febrile neutropenia due to chemotherapy for gastric cancer recurrence. Although the neutropenia and fever immediately improved, he became unable to take any oral medications and was bedridden 1 week after admission. His serum sodium level abruptly decreased to 122mEq/L on the fifth day of hospitalization. We performed endocrinological studies to investigate the cause of his hyponatremia and plasma hyposmolality. His plasma adrenocorticotropic hormone and cortisol levels were very low. However, his serum levels of all other anterior pituitary hormones were slightly elevated. We then performed a corticotropin-releasing hormone test, which showed that neither his plasma adrenocorticotropic hormone nor cortisol level responded to corticotropin-releasing hormone stimulation. We definitively diagnosed isolated adrenocorticotropic hormone deficiency based on these findings. Hydrocortisone replacement therapy was begun at 20mg/day, resulting in a marked improvement in his anorexia and general fatigue within a few days. His serum sodium level was also normalized immediately after the administration of hydrocortisone. He was discharged from our hospital on the 50th day of hospitalization. Conclusions The present case is the second report of a patient with concurrent isolated adrenocorticotropic hormone deficiency and gastric cancer and the

  11. Radioactive probes for adrenocorticotropic hormone receptors

    SciTech Connect

    Hofmann, K.; Romovacek, H.; Stehle, C.J.; Finn, F.M.; Bothner-By, A.A.; Mishra, P.K.

    1986-03-25

    Our attempts to develop adrenocorticotropic hormone (ACTH) analogues that can be employed for ACTH receptor identification and isolation began with the synthesis of ACTH fragments containing N epsilon-(dethiobiotinyl)lysine (dethiobiocytin) amide in position 25 to be used for affinity chromatographic purification of hormone-receptor complexes on Sepharose-immobilized avidin resins. Because labeling ACTH or ACTH fragments by conventional iodination techniques destroys biological activity due to oxidation of Met4 and incorporation of iodine into Tyr2, we have prepared (Phe2,Nle4)ACTH1-24, (Phe2,Nle4,biocytin25)ACTH1-25 amide, and (Phe2,Nle4,dethiobiocytin25)ACTH1-25 amide by conventional synthetic techniques. The HPLC profiles and amino acid analyses of the final products indicate that the materials are of a high degree of purity. The amount of tertiary butylation of the Trp residue in the peptides was assessed by NMR and was found to be less than 0.5%. All three peptides are equipotent with the standard ACTH1-24 as concerns their ability to stimulate steroidogenesis and cAMP formation in bovine adrenal cortical cells. Iodination of (Phe2,Nle4)ACTH1-24, with iodogen as the oxidizing agent, has been accomplished without any detectable loss of biological activity. The mono- and diiodo derivatives of (Phe2,Nle4)ACTH1-24 have been prepared, separated by HPLC, and assayed for biological activity. Both peptides have the full capacity to stimulate steroidogenesis and cAMP production in bovine adrenal cortical cells.

  12. Adrenocorticotropic hormone analog use for podocytopathies

    PubMed Central

    Filippone, Edward J; Dopson, Shirley J; Rivers, Denise M; Monk, Rebeca D; Udani, Suneel M; Jafari, Golriz; Huang, Solomon C; Melhem, Arafat; Assioun, Bassim; Schmitz, Paul G

    2016-01-01

    Background Adrenocorticotropic hormone is being increasingly studied for treatment of various glomerulopathies, most notably membranous nephropathy. Less data are available regarding its use in idiopathic nephrotic syndrome (INS) secondary to minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). We report here our experience with H.P. Acthar® Gel (repository corticotropin injection) as first-line or subsequent therapy in patients with INS. Methods Data were taken from three patients with MCD and ten patients with FSGS from around the US, who were treated with Acthar Gel as initial or subsequent therapy. Treatment was solely at the discretion of the primary nephrologist without a specific protocol. A complete response (CR) was defined as final urine protein-to-creatinine ratio <500 mg/g and a partial response (PR) as 50% decrease without rise of serum creatinine. Side effects and tolerability were noted. Results All three patients with MCD received Acthar Gel as second-line or later immunosuppressive (IS) therapy and all responded (one CR and two PRs). Two of the ten patients with FSGS received Acthar Gel as first-line IS therapy, while the other eight had failed multiple agents. Four of the ten patients with FSGS had responses, including two CRs and two PRs. The three patients with MCD tolerated therapy well without side effects. Five patients with FSGS tolerated therapy well, while five had various steroid-like side effects, resulting in therapy discontinuation in two patients. Conclusion Acthar Gel is a viable alternative IS agent for treatment of INS in patients intolerant or resistant to conventional therapy. More data are needed to better define its appropriate place. PMID:27418857

  13. Aberrant luteinizing hormone-releasing hormone-stimulated adrenocorticotropic hormone secretion in a patient with pituitary hyperplasia due to primary hypothyroidism.

    PubMed

    Ban, Y; Ban, Y; Taniyama, M; Hara, H; Abe, T; Katagiri, T

    2000-08-01

    We report a patient with primary hypothyroidism associated with an aberrant ACTH response to the LH-RH test. A 40-year-old woman was admitted to our hospital displaying headache, nausea, and numbness on the left side of her face, upper limbs, and tips of her toes. Computed tomography and magnetic resonance imaging revealed a mass-like lesion in the pituitary. A high serum TSH concentration with concomitant low thyroid hormone concentrations resulted in a diagnosis of primary hypothyroidism. To exclude the possibility of a coexisting pituitary tumor including a TSH-secreting tumor, we performed dynamic TSH secretion tests. TRH testing showed an excessive, delayed TSH response, typical of primary hypothyroidism. Serum TSH decreased not only after administration of CRH, octreotide, or L-DOPA, but also after administration of LH-RH. In this case, LH-RH testing induced ACTH secretion. To determine if aberrant ACTH secretion in response to LH-RH loading is a common phenomenon in severe primary hypothyroidism, we performed the LH-RH test on 4 additional patients with pituitary enlargement due to primary hypothyroidism. Two patients demonstrated aberrant ACTH secretion in response to LH-RH loading, but the others did not. To our knowledge, this is the first report of aberrant LH-RH-stimulated ACTH secretion in primary hypothyroidism.

  14. 21 CFR 862.1025 - Adrenocorticotropic hormone (ACTH) test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Adrenocorticotropic hormone (ACTH) test system. 862.1025 Section 862.1025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  15. 21 CFR 862.1025 - Adrenocorticotropic hormone (ACTH) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Adrenocorticotropic hormone (ACTH) test system. 862.1025 Section 862.1025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  16. 21 CFR 862.1025 - Adrenocorticotropic hormone (ACTH) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Adrenocorticotropic hormone (ACTH) test system. 862.1025 Section 862.1025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  17. 21 CFR 862.1025 - Adrenocorticotropic hormone (ACTH) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Adrenocorticotropic hormone (ACTH) test system. 862.1025 Section 862.1025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  18. 21 CFR 862.1025 - Adrenocorticotropic hormone (ACTH) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Adrenocorticotropic hormone (ACTH) test system. 862.1025 Section 862.1025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical...

  19. Type 2 diabetes mellitus accompanied by isolated adrenocorticotropic hormone deficiency and gastric cancer.

    PubMed

    Kamiya, Yuji; Murakami, Masami

    2009-01-01

    A 69-year-old man with type 2 diabetes mellitus was admitted to our hospital because of appetite loss, nausea and vomiting. Gastroscopy revealed gastric cancer. Levels of plasma cortisol were decreased. Neither adrenocorticotropic hormone (ACTH) nor cortisol levels were adequately increased in response to a mixed intravenous administration of corticotropin-releasing hormone, growth hormone-releasing hormone, thyrotropin-releasing hormone and lutenizing hormone-releasing hormone, although other pituitary hormones were increased adequately. He was diagnosed as having isolated ACTH deficiency (IAD). Anti-pituitary antibody and anti-parietal cell antibody were positive. At least in part, these antibodies may play pathogenic roles of development of IAD and gastric cancer.

  20. Peripheral blood corticotropin-releasing factor, adrenocorticotropic hormone and cytokine (Interleukin Beta, Interleukin 6, tumor necrosis factor alpha) levels after high- and low-dose total-body irradiation in humans

    SciTech Connect

    Girinsky, T.A.; Pallardy, M.; Comoy, E.; Benassi, T.; Roger, R.; Ganem, G.; Socie, G.; Cossett, J.M.; Magdelenat, H.

    1994-09-01

    Total-body irradiation (TBI) induces an increase in levels of granulocytes and cortisol in blood. To explore the underlying mechanisms, we studied 26 patients who had TBI prior to bone marrow transplantation. Our findings suggest that only a high dose of TBI (10 Gy) was capable of activating the hypothalamopituitary area since corticotropin-releasing factor and blood adrenocorticotropic hormone levels increased at the end of the TBI. There was a concomitant increase in the levels of interleukin 6 and tumor necrosis factor in blood, suggesting that these cytokines might activate the hypothalamo-pituitary adrenal axis. Interleukin 1 was not detected. Since vascular injury is a common after radiation treatment, it is possible that interleukin 6 was secreted by endothelial cells. The exact mechanisms of the production of cyctokines induced by ionizing radiation remain to be determined. 25 refs., 1 fig.

  1. Topiramate and adrenocorticotropic hormone (ACTH) as initial treatment for infantile spasms.

    PubMed

    Peltzer, Bradley; Alonso, William D; Porter, Brenda E

    2009-04-01

    Historically, adrenocorticotropic hormone was used as a first-line treatment for infantile spasms; however, there has been increasing use of topiramate as initial therapy. Here, we report a retrospective study of adrenocorticotropic hormone (ACTH) and topiramate as initial treatment for infantile spasms. The neurology patient database at the Children's Hospital of Philadelphia was searched using the International Classification of Diseases, Ninth Revision code for infantile spasms, and 50 patients were randomly chosen for chart review. We identified 31 patients receiving either adrenocorticotropic hormone or topiramate monotherapy (adrenocorticotropic hormone n = 12, topiramate n = 19) as a first-line treatment for infantile spasms. A total of 26 patients were symptomatic and 5 cryptogenic. Six patients treated with adrenocorticotropic hormone had resolution of clinical spasms and hypsarrhythmia within a month, but 3 relapsed. Of the 19 patients treated with topiramate, 4 patients eventually, though over a period of 0, 1, 8, or 69 months, had resolution of spasms and hypsarrhythmia.

  2. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome.

    PubMed

    Choi, Hong Seok; Kim, Min Joo; Moon, Chae Ho; Yoon, Jong Ho; Ku, Ha Ra; Kang, Geon Wook; Na, Im Il; Lee, Seung-Sook; Lee, Byung-Chul; Park, Young Joo; Kim, Hong Il; Ku, Yun Hyi

    2014-03-01

    Ectopic adrenocorticotropic hormone (ACTH) syndrome is caused most frequently by a bronchial carcinoid tumor or by small cell lung cancer. Medullary thyroid carcinoma (MTC) is a rare etiology of ectopic ACTH syndrome. We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.

  3. Metastatic esthesioneuroblastoma secreting adrenocorticotropic hormone in pediatric patients.

    PubMed

    Galioto, Silvestre; Di Petrillo, Alessandro; Pastori, Mauro; Arecchi, Alberto

    2011-09-01

    The purpose of this article was to report a pediatric case of secondary cervical esthesioneuroblastoma involving the parapharyngeal lymph nodes. A 3-year-old boy came to our clinical observation because of a right lymphonodal mass evidenced by nuclear magnetic resonance and a diagnosis of Cushing syndrome associated with ectopic adrenocorticotropic hormone secretion, moon face, central obesity, asthenia, and hirsutism. At the age of 10 months, the patient underwent endoscopic surgery for asportation of the World Health Organization stage IV esthesioneuroblastoma. At 38 months of age, the patient underwent right parapharyngeal lymphadenectomy with surgical access by a double mandibulectomy. After surgery, serum ACTH, cortisolemia, and urinary excretion of cortisol were within the reference range. Blood pressure was recorded at 110/70 mm Hg. Moon face disappeared, as well as central obesity and hirsutism. Clinical report is presented together with brief review of literature.

  4. Effect of price increase of adrenocorticotropic hormone on treatment practices of infantile spasms.

    PubMed

    Wray, Carter D; Benke, Timothy A

    2010-09-01

    Intramuscular adrenocorticotropic hormone putatively constitutes the most efficacious treatment for infantile spasms. Adrenocorticotropic hormone in the United States is an "orphan drug," made by a single manufacturer. The price of adrenocorticotropic hormone increased almost 14-fold on August 27, 2007. We sought to evaluate the impact of this price increase on treatment practices at our institution, using a retrospective chart review of all children with infantile spasms treated during 2007-2009. We identified 97 patients whose spasms were treated using antiepileptic drugs, and we determined the length of stay for those hospitalized to initiate adrenocorticotropic hormone. Patients before the price increase were more likely to have been treated with adrenocorticotropic hormone as first medication, and were hospitalized 2.2 +/- 0.5 S.D. days for initiation. Patients after the price increase were more likely to have been treated initially with oral antiepileptic drugs rather than adrenocorticotropic hormone (P < 0.002). Those commencing adrenocorticotropic hormone after the price increase were hospitalized significantly longer (5.1 +/- 0.6 days S.D., P < 0.001). Treatment choices need to be evidence-based, but other factors often influence them.

  5. Adrenocorticotropic hormone versus prednisolone in the treatment of infantile spasms post vigabatrin failure.

    PubMed

    Jones, Kevin; Snead, O Carter; Boyd, Jennifer; Go, Cristina

    2015-04-01

    The Child Neurology Society/American Academy of Neurology practice parameter has recommended adrenocorticotropic hormone or vigabatrin in the short-term treatment of infantile spasms. When vigabatrin is unavailable or ineffective and adrenocorticotropic hormone is not a treatment option because of the prohibitive cost, other forms of corticosteroids have been considered in the treatment of infantile spasms. This retrospective study reviewed the Hospital for Sick Children's experience with the short-term effectiveness of prednisolone versus adrenocorticotropic hormone in patients with infantile spasms who have failed vigabatrin. The results showed that while adrenocorticotropic hormone was more likely to lead to short-term spasm freedom, there was no difference in the likelihood of longer-term spasm resolution without relapse. These findings can guide clinicians in the treatment of infantile spasms post vigabatrin failure.

  6. Sensitivity of adrenal glands to adrenocorticotropic hormone in animals with alimentary obesity.

    PubMed

    Pankina, T V; Kuzminova, O I; Selyatitskaya, V G

    2008-12-01

    Blood concentration of corticosterone in obese rats did not differ from the control value. In vitro synthesis of progesterone and corticosterone in adrenal slices from obese rats was lower compared to control animals, but these differences disappeared after addition of adrenocorticotropic hormone to the incubation medium. In obese rats, blood content of corticosterone in response to administration of adrenocorticotropic hormone in vivo increased by 8 times, while in control animals this parameter increased by only 4.5 times.

  7. The influence od melatonin receptors antagonists, luzindole and 4-phenyl-2-propionamidotetralin (4-P-PDOT), on melatonin-dependent vasopressin and adrenocorticotropic hormone (ACTH) release from the rat hypothalamo-hypophysial system. In vitro and in vivo studies.

    PubMed

    Juszczak, M; Roszczyk, M; Kowalczyk, E; Stempniak, B

    2014-12-01

    Melatonin exerts its biological role acting via G protein-coupled membrane receptors - MT1 and MT2, as well as through cytoplasmic and/or nuclear receptors. Melatonin has previously been shown to change vasopressin (AVP) and adrenocorticotropic hormone (ACTH) secretion dependently on its concentration. To determine whether the response of vasopressinergic neurones to different concentrations of melatonin is mediated through the membrane MT1 and/or MT2 receptors, the influence of luzindole - an antagonist of both MT1 and MT2 receptors, and 4-phenyl-2-propionamidotetralin (4-P-PDOT) - a selective MT2 receptor antagonist, on melatonin-dependent AVP release from the rat hypothalamo-neurohypophysial (H-NH) system was studied in vitro (melatonin at the concentrations of 10(-9), 10(-7) and 10(-3) M) and in vivo (melatonin at the concentrations of 10(-9) and 10(-7) M). Moreover, the second goal of this study was to find out whether melatonin receptors MT1 and/or MT2 are involved in the regulation of ACTH and corticosterone secretion into the blood. We have demonstrated that melatonin, at the concentrations of 10(-9) and 10(-7) M, significantly inhibited AVP secretion from isolated rat H-NH explants when antagonists solvent (i.e. 0.1% DMSO) was present in the medium. Neither luzindole, nor 4-P-PDOT, applied without melatonin, did influence AVP release in vitro. Luzindole applied together with melatonin (10(-7) M and 10(-9) M) significantly suppressed melatonin-dependent effect, while 4-PPDOT did not eliminate the inhibitory influence of 10(-7) M and 10(-9) M melatonin on AVP secretion from isolated rat H-NH explants. Melatonin at a concentration of 10(-3) M significantly increased AVP release when the H-NH explants were incubated in the medium containing luzindole or 4-P-PDOT. Under present experimental in vivo conditions, infused intracerebroventricularly (i.c.v.) melatonin, at a concentration close to its physiological level in the blood, significantly diminished AVP

  8. Altered expression of adrenocorticotropic hormone in the epileptic gerbil hippocampus following spontaneous seizure.

    PubMed

    Oh, Yun-Jung; Kim, Heung-No; Jeong, Ji-Heon; Park, Dae-Kyoon; Park, Kyung-Ho; Ko, Jeong-Sik; Kim, Duk-Soo

    2013-02-01

    We investigated the temporal alterations of adrenocorticotropic hormone (ACTH) immunoreactivity in the hippocampus after seizure onset. Expression of ACTH was observed within interneurons in the pre-seizure group of seizure sensitive gerbils, whereas its immunoreactivities were rarely detected in seizure resistant gerbil. Three hr after the seizure, ACTH immunoreactivity was significantly increased in interneurons within all hippocampal regions. On the basis of their localization and morphology through immunofluorescence staining, these cells were identified as GABAA α1-containing interneurons. At the 12 hr postictal period, ACTH expression in these regions was down-regulated, in a similar manner to the pre-seizure group of gerbils. These findings support the increase in ACTH synthesis that contributes to a reduction of corticotrophin-releasing factor via the negative feedback system which in turn provides an opportunity to enhance the excitability of GABAergic interneurons. Therefore, ACTH may play an important role in the reduction of excitotoxicity in all hippocampal regions.

  9. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis

    PubMed Central

    Berkovich, Regina; Catania, Anna; Lisak, Robert P; Zaidi, Mone

    2013-01-01

    The therapeutic benefits of adrenocorticotropic hormone in multiple sclerosis are usually ascribed to its corticotropic actions. Evidence is presented that adrenocorticotropic hormone, approved for multiple sclerosis relapses, acts via corticosteroid-independent melanocortin pathways to engender down-modulating actions on immune-system cells and the cytokines they synthesize. Immune response-dampening effects are also brought about by agent-induced neurotransmitters that inhibit immunocytes. The likelihood that adrenocorticotropic hormone promotes microglial quiescence and counteracts glucocorticoid-mediated bone resorption is discussed. PMID:23034287

  10. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis.

    PubMed

    Arnason, Barry G; Berkovich, Regina; Catania, Anna; Lisak, Robert P; Zaidi, Mone

    2013-02-01

    The therapeutic benefits of adrenocorticotropic hormone in multiple sclerosis are usually ascribed to its corticotropic actions. Evidence is presented that adrenocorticotropic hormone, approved for multiple sclerosis relapses, acts via corticosteroid-independent melanocortin pathways to engender down-modulating actions on immune-system cells and the cytokines they synthesize. Immune response-dampening effects are also brought about by agent-induced neurotransmitters that inhibit immunocytes. The likelihood that adrenocorticotropic hormone promotes microglial quiescence and counteracts glucocorticoid-mediated bone resorption is discussed.

  11. Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes.

    PubMed

    Haberlandt, Edda; Weger, Christine; Sigl, Sara Baumgartner; Rauchenzauner, Markus; Scholl-Bürgi, Sabine; Rostásy, Kevin; Karall, Daniela

    2010-01-01

    For treatment of intractable epilepsies, there are no data comparing conventional adrenocorticotropic hormone and pulsatile corticoid therapy with dexamethasone. A retrospective comparison of efficacy was therefore conducted for both forms of application. Between 1989 and 2001, a series of 11 children with West syndrome and 3 with Lennox-Gastaut syndrome were treated with adrenocorticotropic hormone (group 1); between 2003 and 2006, 7 children with West syndrome, 5 with electrical status epilepticus during slow sleep, and 2 with Lennox-Gastaut syndrome were treated with pulsatile corticoid therapy (group 2). In group 1 (n = 14), 9/11 West syndrome patients became seizure free, but none with Lennox-Gastaut syndrome (0/3). In group 2 (n = 14), 4/7 West syndrome patients became seizure-free, 1/2 with Lennox-Gastaut syndrome exhibited seizure-frequency reduction, and 2/5 patients with electrical status epilepticus during slow-wave sleep exhibited significant improvement according to electroencephalograms. In West syndrome, pulsatile corticoid therapy was an effective alternative treatment to adrenocorticotropic hormone, whereas in Lennox-Gastaut syndrome in general steroids did not lead to a significant seizure reduction. In electrical status epilepticus during slow-wave sleep, treatment with pulsatile corticoid therapy seems to be effective and should be investigated in a larger group of patients.

  12. Case of multiple endocrine neoplasia 2B with probable ectopic adrenocorticotropic hormone-secreting liver metastasis from medullary thyroid carcinoma.

    PubMed

    Kurozumi, Akira; Okada, Yosuke; Arao, Tadashi; Nakamoto, Yuji; Togashi, Kaori; Tanaka, Yoshiya

    2013-09-01

    A 31 year old woman was diagnosed with multiple endocrine neoplasia (MEN) 2B at 10 years old. Dark pigmentation gradually developed on her skin and her serum adrenocorticotropic hormone (ACTH) was high, suggesting concurrent ectopic ACTH syndrome (EAS). Corticotropin-releasing hormone (CRH) loading test ruled out Cushing's disease and supported the diagnosis of EAS. Multiple low attenuation mass in the liver was observed in a computed tomography (CT) scan, and was suspected as ectopic ACTH-secreting metastatic tumor from medullary thyroid carcinoma (MTC). ACTH production by MTC is relatively rare, particularly in patients with MEN; patients with ectopic ACTH-secreting liver metastatic tumor from MTC in MEN 2B have never been reported previously.

  13. Using the failure mode and effects analysis model to improve parathyroid hormone and adrenocorticotropic hormone testing

    PubMed Central

    Magnezi, Racheli; Hemi, Asaf; Hemi, Rina

    2016-01-01

    Background Risk management in health care systems applies to all hospital employees and directors as they deal with human life and emergency routines. There is a constant need to decrease risk and increase patient safety in the hospital environment. The purpose of this article is to review the laboratory testing procedures for parathyroid hormone and adrenocorticotropic hormone (which are characterized by short half-lives) and to track failure modes and risks, and offer solutions to prevent them. During a routine quality improvement review at the Endocrine Laboratory in Tel Hashomer Hospital, we discovered these tests are frequently repeated unnecessarily due to multiple failures. The repetition of the tests inconveniences patients and leads to extra work for the laboratory and logistics personnel as well as the nurses and doctors who have to perform many tasks with limited resources. Methods A team of eight staff members accompanied by the Head of the Endocrine Laboratory formed the team for analysis. The failure mode and effects analysis model (FMEA) was used to analyze the laboratory testing procedure and was designed to simplify the process steps and indicate and rank possible failures. Results A total of 23 failure modes were found within the process, 19 of which were ranked by level of severity. The FMEA model prioritizes failures by their risk priority number (RPN). For example, the most serious failure was the delay after the samples were collected from the department (RPN =226.1). Conclusion This model helped us to visualize the process in a simple way. After analyzing the information, solutions were proposed to prevent failures, and a method to completely avoid the top four problems was also developed. PMID:27980440

  14. Effect of adrenocorticotropic hormone (ACTH) and insulin on the phagocytic capacity of Tetrahymena.

    PubMed

    Köhidai, L; Lovas, B; Csaba, G

    1995-06-01

    Adrenocorticotropic hormone (ACTH) and insulin negatively influenced the phagocytic activity of Tetrahymena. The two hormones had diverse effects after 4 hr of treatments on no-test-particle containing, "0-cells". At this time the number of "0 cells" was significantly lower in the ACTH-treated groups, while in the insulin-treated groups there was an increase of "0-cells" compared to the control and to the results of the starting experiment. Considering previous results, when small molecular weight hormones, if did at all, positively influenced phagocytosis in Tetrahymena, the experiments call the attention to the differences caused by the size of the signal molecules. In the light of the literary data on hormone effects to phagocytosis in mammals and men, the similarity of the effects in species being very far from each other in evolution, could be concluded.

  15. The central anorexigenic mechanism of adrenocorticotropic hormone involves the caudal hypothalamus in chicks.

    PubMed

    Shipp, Steven L; Yi, Jiaqing; Dridi, Sami; Gilbert, Elizabeth R; Cline, Mark A

    2015-10-01

    Adrenocorticotropic hormone (ACTH), consisting of 39 amino acids, is most well-known for its involvement in an organism's response to stress. It also participates in satiety, as exogenous ACTH causes decreased food intake in rats. However, its anorexigenic mechanism is not well understood in any species and its effect on appetite is not reported in the avian class. Thus, the present study was designed to evaluate central ACTH's effect on food intake and to elucidate the mechanism mediating this response using broiler chicks. Chicks that received intracerebroventricular (ICV) injection of 1, 2, or 4 nmol of ACTH reduced food intake, under both ad libitum and 180 min fasted conditions. Water intake was also reduced in ACTH-injected chicks under both feeding conditions, but when measured without access to feed it was not affected. Blood glucose was not affected in either feeding condition. Following ACTH injection, c-Fos immunoreactivity was quantified in key appetite-associated hypothalamic nuclei including the ventromedial hypothalamus (VMH), dorsomedial hypothalamus, lateral hypothalamus (LH), arcuate nucleus (ARC) and the parvo- and magno-cellular portions of the paraventricular nucleus. ACTH-injected chicks had increased c-Fos immunoreactivity in the VMH, LH, and ARC. Hypothalamus was collected at 1h post-injection, and real-time PCR performed to measure mRNA abundance of some appetite-associated factors. Neuropeptide Y, pro-opiomelanocortin, glutamate decarboxylase 1, melanocortin receptors 2-5, and urocortin 3 mRNA abundance was not affected by ACTH treatment. However, expression of corticotropin releasing factor (CRF), urotensin 2 (UT), agouti-related peptide (AgRP), and orexin (ORX), and melanocortin receptor 1 (MC1R) mRNA decreased in the hypothalamus of ACTH-injected chicks. In conclusion, ICV ACTH causes decreased food intake in chicks, and is associated with VMH, LH, and ARC activation, and a decrease in hypothalamic mRNA abundance of CRF, UT, AgRP, ORX

  16. Positive gallium scan in the syndrome of opsoclonus-myoclonus treated with adrenocorticotropic hormone

    SciTech Connect

    Gumbinas, M.; Gratz, E.S.; Johnston, G.S.; Schwartz, A.D.

    1984-09-01

    The syndrome of opsoclonus and myoclonus may be the first presenting symptom of neuroblastoma. The disorder is often controlled by treatment with adrenocorticotropic hormone (ACTH). A child with this disorder and treated with ACTH gel had abnormal uptake of /sup 67/Ga in both adrenal glands during studies to attempt to detect an occult neuroblastoma. Repeat /sup 67/Ga scans proved to be normal once the ACTH was discontinued and the patient was treated with prednisone. It is concluded that ACTH stimulation of normal adrenal tissue was responsible for these abnormal findings.

  17. Hypofibrinogenemia caused by adrenocorticotropic hormone for infantile spasms: a case report.

    PubMed

    Kamei, Atsushi; Araya, Nami; Akasaka, Manami; Mizuma, Kanako; Asami, Maya; Tanifuji, Sachiko; Chida, Shoichi

    2015-01-01

    We report the case of a 7-month-old boy who developed hypofibrinogenemia (66.6 mg/dL; reference value, 170-405 mg/dL) during adrenocorticotropic hormone (ACTH) therapy for infantile spasms. Although the patient showed no clinical signs of a bleeding diathesis, we recommend that plasma fibrinogen levels should be monitored during ACTH therapy, which should be discontinued when fibrinogen levels fall below hemostatic levels (60.0mg/dL) or when bleeding tendencies are recognized.

  18. Paraneoplastic Dermatomyositis with Cutaneous and Myopathic Disease Responsive to Adrenocorticotropic Hormone Therapy

    PubMed Central

    Mancuso, Christopher; Lal, Karan; Dicostanzo, Damian; Gropper, Charles

    2017-01-01

    Dermatomyositis is a myopathic or amyopathic autoimmune connective tissue disease that presents with classic dermatologic findings ranging from: poikilodermatous photosensitivity (shawl sign), eyelid edema and violaceous-pigmentation (heliotrope sign), lichenoid eruptions on the knuckles and elbows (Gottron’s sign), periungual telangiectasias, and ragged cuticles (Samitz sign). Up to 30 percent of adult-onset cases of dermatomyositis may represent a paraneoplastic syndrome warranting a thorough work-up for malignancy. The authors present a case report of paraneoplastic dermatomyositis associated with triple negative, BRCA-1 positive, invasive intraductal carcinoma of the breast, whose myopathic and cuteanous symptoms were recalcitrant to high-dose corticosteroid therapy. Herein, the authors describe the first reported case of the use of an injectable adrenocorticotropic hormone agonist gel in a patient with myopathic paraneoplastic disease that achieved clinical resolution of both myopathic and cutaneous symptoms, but subseuqently developed significant hyperpigmentation of her face suspected to be secondary to a chemotherapeutic-induced pigmentary change which was augmented by adrenocorticotropic hormone therapy. PMID:28210382

  19. Isolated adrenocorticotropic hormone deficiency due to probable lymphocytic hypophysitis in a woman

    PubMed Central

    Kacem, Faten Hadj; Charfi, Nadia; Mnif, Mouna Feki; Kamoun, Mahdi; Akid, Faouzi; Mnif, Fatma; Naceur, Basma Ben; Rekik, Nabila; Mnif, Zainab; Abid, Mohamed

    2013-01-01

    We report a 22-year-old woman who presented with asthenia, weight loss and hypotension in which extensive pituitary and adrenal investigations were diagnostic of isolated adrenocorticotropic hormone deficiency (IAD) of pituitary origin. Magnetic resonance imaging of the hypothalamus and pituitary showed a normal-sized pituitary, with no mass lesion. The diagnosis of IAD probably secondary to lymphocytic hypophysitis (LYH) was made. IAD is able to be the way of presentation of LYH, although the disease could or could not turn into a panhypopituitarism. Prompt recognition of this potentially fatal condition is important because of the availability of effective treatment. Indeed, regular endocrine and imaging follow up is important for patients with IAD and normal initial pituitary imaging results to detect early new-onset pituitary hormones deficiencies or imaging abnormalities. PMID:24251125

  20. [Ectopic Adrenocorticotropic Hormone-producing Pulmonary Carcinoid Tumor Presenting as Cushing Syndrome].

    PubMed

    Taniguchi, Daisuke; Sawada, Takahiro; Ebisui, Osamu; Kito, Katsumi; Nagayasu, Takeshi

    2015-02-01

    The patient was a 57-year-old female who felt muscle weakness and visited a physician. Hypokalemia was pointed out, and she was referred to our hospital for detailed examination and treatment. Hormone-related tests and imaging were performed, and the patient was diagnosed as Cushing syndrome. Moreover, an ectopic adrenocorticotropic hormone (ACTH)-producing tumor was suspected. The whole body was examined to find a tumor, but no apparent lesion was found, except for a small nodule of 5-mm in size was present in the right middle pulmonary lobe on chest computed tomography (CT). It was decided to perform surgical resection for both diagnosis and treatment. Pathological diagnosis was a typical carcinoid. On immunostaining, ACTH-positive cells were detected, and the lesion was definitely diagnosed as an ectopic ACTH-producing tumor. Since the ACTH level after surgery returned to normal, the lesion was concluded to be completely excised.

  1. Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing

    PubMed Central

    Faghih, Rose T.; Dahleh, Munther A.; Adler, Gail K.; Klerman, Elizabeth B.; Brown, Emery N.

    2015-01-01

    Pulsatile release of cortisol from the adrenal glands is governed by pulsatile release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. In return, cortisol has a negative feedback effect on ACTH release. Simultaneous recording of ACTH and cortisol is not typical, and determining the number, timing, and amplitudes of pulsatile events from simultaneously recorded data is challenging because of several factors: (I) stimulator ACTH pulse activity, (II) kinematics of ACTH and cortisol, (III) the sampling interval, and (IV) the measurement error. We model ACTH and cortisol secretion simultaneously using a linear differential equations model with Gaussian errors and sparse pulsatile events as inputs to the model. We propose a novel framework for recovering pulses and parameters underlying the interactions between ACTH and cortisol. We recover the timing and amplitudes of pulses using compressed sensing, and employ generalized cross validation for determining the number of pulses. We analyze serum ACTH and cortisol levels sampled at 10-minute intervals over 24 hours from 10 healthy women. We recover physiologically plausible timing and amplitudes for these pulses and model the feedback effect of cortisol. We recover 15 to 18 pulses over 24 hours, which is highly consistent with the results of another cortisol data analysis approach. Modeling the interactions between ACTH and cortisol allows for accurate quantification of pulsatile events, and normal and pathological states. This could lay the basis for a more physiologically-based approach for administering cortisol therapeutically. The proposed approach can be adapted to deconvolve other pairs of hormones with similar interactions. PMID:25935025

  2. Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing.

    PubMed

    Faghih, Rose T; Dahleh, Munther A; Adler, Gail K; Klerman, Elizabeth B; Brown, Emery N

    2015-10-01

    Pulsatile release of cortisol from the adrenal glands is governed by pulsatile release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. In return, cortisol has a negative feedback effect on ACTH release. Simultaneous recording of ACTH and cortisol is not typical, and determining the number, timing, and amplitudes of pulsatile events from simultaneously recorded data is challenging because of several factors: 1) stimulator ACTH pulse activity, 2) kinematics of ACTH and cortisol, 3) the sampling interval, and 4) the measurement error. We model ACTH and cortisol secretion simultaneously using a linear differential equations model with Gaussian errors and sparse pulsatile events as inputs to the model. We propose a novel framework for recovering pulses and parameters underlying the interactions between ACTH and cortisol. We recover the timing and amplitudes of pulses using compressed sensing and employ generalized cross validation for determining the number of pulses. We analyze serum ACTH and cortisol levels sampled at 10-min intervals over 24 h from ten healthy women. We recover physiologically plausible timing and amplitudes for these pulses and model the feedback effect of cortisol. We recover 15 to 18 pulses over 24 h, which is highly consistent with the results of another cortisol data analysis approach. Modeling the interactions between ACTH and cortisol allows for accurate quantification of pulsatile events, and normal and pathological states. This could lay the basis for a more physiologically-based approach for administering cortisol therapeutically. The proposed approach can be adapted to deconvolve other pairs of hormones with similar interactions.

  3. Differential responses of cortisol and corticosterone to adrenocorticotropic hormone (ACTH) in a subterranean rodent (Ctenomys talarum).

    PubMed

    Vera, Federico; Zenuto, Roxana Rita; Antenucci, Carlos Daniel

    2012-03-01

    We aimed to evaluate the responses of cortisol, corticosterone, and blood glucose to adrenocorticotropic hormone (ACTH) in males and females of the subterranean rodent Ctenomys talarum and addressed interannual variations in the plasma levels of both hormones. The most important results indicate that: (1) cortisol positively responds to the ACTH signal but corticosterone does not, even though corticosterone levels were higher than cortisol concentrations, (2) plasma corticosterone concentrations in free-living animals were 20 times higher compared to values reported for the same population during previous annual periods and, as cortisol levels were similar, this resulted in much lower cortisol/corticosterone ratios, (3) cortisol and corticosterone differentiated in their relative proportions in plasma in free-living males and females. These results indicate that cortisol and corticosterone are differentially regulated in our study species and emphasize that a remarkable temporal variation in the relative proportions of these hormones may occur in natural populations. Therefore, the conclusions regarding the presence of cortisol and corticosterone in plasma of wild animals may differ substantially depending on the moment when the study is conducted. Recent data indicate that cortisol and corticosterone are not interchangeable hormones in species of free-living vertebrates. We suggest that, in addition to the classical roles of glucocorticoids (GCs), it is crucial that other physiological functions be kept in mind when interpreting GC data from wild species.

  4. A harmful traditional practice in newborns with adrenocorticotropic hormone resistance syndrome: branding

    PubMed Central

    Baştuğ, Osman; Korkmaz, Levent; Korkut, Sabriye; Halis, Hülya; Güneş, Tamer; Kurtoğlu, Selim

    2016-01-01

    Branding refers to a traditional practice of creating ‘therapeutic’ burns with hot iron rods over the skin in order to treat various diseases. Although branding is a harmful practice for the body, it has been used for various illnesses including physiologic jaundice in newborns, pneumonia, and convulsions. It causes serious morbidity and delays seeking proper medical care in neonates. Innovations of modern medicine and the use of evidence-based medicine should be preferred instead of these traditional practices. We present a branded mature newborn baby who was diagnosed as having adrenocorticotropic hormone resistance syndrome. This problem is very rare in Turkey; however, it is a very important health issue and has social aspects. Therefore, this case is presented to increase awareness. PMID:28123337

  5. NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency

    PubMed Central

    Shi, Chuan; Wang, Fen; Tong, Anli; Zhang, Xiao-Qian; Song, Hong-Mei; Liu, Zheng-Yin; Lyu, Wei; Liu, Yue-Hua; Xia, Wei-Bo

    2016-01-01

    Abstract Background Common variable immunodeficiency (CVID) with central adrenal insufficiency is a recently defined clinical syndrome caused by mutations in the nuclear factor kappa-B subunit 2 (NFKB2) gene. We present the first case of NFKB2 mutation in Asian population. Methods and Results An 18-year-old Chinese female with adrenocorticotropic hormone (ACTH) deficiency was admitted due to adrenal crisis and pneumonia. She had a history of recurrent respiratory infections since childhood and ectodermal abnormalities were noted during physical examination. Immunologic tests revealed panhypogammaglobulinemia and deficient natural killer (NK)-cell function. DNA sequencing of NFKB2 identified a heterozygous nonsense mutation (c.2563 A>T, p.855: Lys>∗) in the patient but not her parents. Conclusion Clinicians should be alert to comorbidities of adrenal insufficiency and ectodermal dysplasia in CVID patients as these might suggest a rare hereditary syndrome caused by NFKB2 mutation. PMID:27749582

  6. Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome

    PubMed Central

    KATO, AKIHISA; HAYASHI, KAZUKI; NAITOH, ITARU; SENO, KYOJI; OKADA, YUKIKO; BAN, TESSHIN; KONDO, HIROMU; NISHI, YUJI; UMEMURA, SHUICHIRO; HORI, YASUKI; NATSUME, MAKOTO; JOH, TAKASHI

    2016-01-01

    Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin. PMID:27330779

  7. A harmful traditional practice in newborns with adrenocorticotropic hormone resistance syndrome: branding.

    PubMed

    Baştuğ, Osman; Korkmaz, Levent; Korkut, Sabriye; Halis, Hülya; Güneş, Tamer; Kurtoğlu, Selim

    2016-12-01

    Branding refers to a traditional practice of creating 'therapeutic' burns with hot iron rods over the skin in order to treat various diseases. Although branding is a harmful practice for the body, it has been used for various illnesses including physiologic jaundice in newborns, pneumonia, and convulsions. It causes serious morbidity and delays seeking proper medical care in neonates. Innovations of modern medicine and the use of evidence-based medicine should be preferred instead of these traditional practices. We present a branded mature newborn baby who was diagnosed as having adrenocorticotropic hormone resistance syndrome. This problem is very rare in Turkey; however, it is a very important health issue and has social aspects. Therefore, this case is presented to increase awareness.

  8. Ectopic Adrenocorticotropic Hormone-Secreting Bronchial Carcinoid Diagnosed by Balloon-Occluded Pulmonary Arterial Sampling.

    PubMed

    Yotsukura, Masaya; Kohno, Mitsutomo; Asakura, Keisuke; Kamiyama, Ikuo; Ohtsuka, Takashi; Hayashi, Yuichiro; Kurihara, Isao; Nakatsuka, Seishi; Asamura, Hisao

    2016-05-01

    We present the case of a 50-year-old man with Cushing syndrome caused by an ectopic adrenocorticotropic hormone (ACTH)-secreting tumor. A small nodule was located in close association with the lateral segmental branch of the pulmonary artery in the left upper lobe. Blood samples were obtained from various branches of the pulmonary artery by balloon-occluded retrograde sampling for the measurement of location-specific serum ACTH levels. After confirmation that the pulmonary nodule was responsible for the increased ACTH secretion, lobectomy was performed. This report demonstrates the usefulness of balloon-occluded retrograde pulmonary arterial sampling for the preoperative diagnosis of an ACTH-producing tumor whose diagnosis is difficult to confirm.

  9. Cardiac Autonomic Dysfunction in Patients With Infantile Spasm and the Effect of Adrenocorticotropic Hormone Treatment.

    PubMed

    Gencpinar, Pinar; Kocabas, Abdullah; Duman, Özgür; Dündar, Nihal Olgaç; Haspolat, Senay; Kardelen, Fırat

    2016-02-01

    Infantile spasm is an age-dependent epileptic-encephalopathy syndrome. Cardiac autonomic function is frequently altered in epilepsy. In this study, we examined heart rate variability in patients with infantile spasm before and after treatment. Nineteen patients with infantile spasm and 13 healthy comparisons were enrolled in the study. Cardiac rhythm was recorded with a Holter device for 24 hours before adrenocorticotropic hormone (ACTH) (Synacthen depot) and B6 vitamin administration and 1 month after treatment. Heart rate variability analysis found lower heart rate variability parameters in patients with infantile spasm at the onset of the syndrome, prior to treatment with ACTH. The time domain parameters of heart rate variability values showed a statistically significant increase following ACTH treatment. Our data suggest that patients with infantile spasm exhibit lower heart rate variability parameters, and the treatment of spasms with ACTH and B6 together diminished the autonomic dysfunction in our cohort.

  10. Isolated double adrenocorticotropic hormone-secreting pituitary adenomas: A case report and review of the literature

    PubMed Central

    PU, JIUJUN; WANG, ZHIMING; ZHOU, HUI; ZHONG, AILING; JIN, KAI; RUAN, LUNLIANG; YANG, GANG

    2016-01-01

    Only a few cases of double or multiple pituitary adenomas have previously been reported in the literature; however, isolated double adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are even more rare. The present study reports a rare case of a 50-year-old female patient who presented with typical clinical features of Cushing's disease and was diagnosed with isolated double ACTH-secreting pituitary adenomas. Endocrinological examination revealed an ACTH-producing pituitary adenoma, and preoperative magnetic resonance imaging (MRI) demonstrated a microadenoma with a lower intensity on the right side of the pituitary gland. The patient underwent endoscopic endonasal transsphenoidal surgery, which revealed another pituitary tumor in the left side of the pituitary gland. The two, clearly separated, pituitary adenomas identified in the same gland were completely resected. Immunohistochemistry and pathology revealed that the clearly separated double pituitary adenomas were positive for ACTH, thyroid-stimulating, growth and prolactin hormones. Postoperatively, the levels of ACTH and cortisol hormone decreased rapidly. The case reported in the present study is considerably rare, due to the presence of a second pituitary adenoma in the same gland, which was not detected by preoperative MRI scan, but was noticed during surgery. Intraoperative evaluation may be important in the identification of double or multiple pituitary adenomas. PMID:27347184

  11. Isolated double adrenocorticotropic hormone-secreting pituitary adenomas: A case report and review of the literature.

    PubMed

    Pu, Jiujun; Wang, Zhiming; Zhou, Hui; Zhong, Ailing; Jin, Kai; Ruan, Lunliang; Yang, Gang

    2016-07-01

    Only a few cases of double or multiple pituitary adenomas have previously been reported in the literature; however, isolated double adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are even more rare. The present study reports a rare case of a 50-year-old female patient who presented with typical clinical features of Cushing's disease and was diagnosed with isolated double ACTH-secreting pituitary adenomas. Endocrinological examination revealed an ACTH-producing pituitary adenoma, and preoperative magnetic resonance imaging (MRI) demonstrated a microadenoma with a lower intensity on the right side of the pituitary gland. The patient underwent endoscopic endonasal transsphenoidal surgery, which revealed another pituitary tumor in the left side of the pituitary gland. The two, clearly separated, pituitary adenomas identified in the same gland were completely resected. Immunohistochemistry and pathology revealed that the clearly separated double pituitary adenomas were positive for ACTH, thyroid-stimulating, growth and prolactin hormones. Postoperatively, the levels of ACTH and cortisol hormone decreased rapidly. The case reported in the present study is considerably rare, due to the presence of a second pituitary adenoma in the same gland, which was not detected by preoperative MRI scan, but was noticed during surgery. Intraoperative evaluation may be important in the identification of double or multiple pituitary adenomas.

  12. Metabolic responses to adrenocorticotropic hormone (ACTH) vary with life-history stage in adult male northern elephant seals.

    PubMed

    Ensminger, David C; Somo, Derek A; Houser, Dorian S; Crocker, Daniel E

    2014-08-01

    Strong individual and life-history variation in serum glucocorticoids has been documented in many wildlife species. Less is known about variation in hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its impact on metabolism. We challenged 18 free-ranging adult male northern elephant seals (NES) with an intramuscular injection of slow-release adrenocorticotropic hormone (ACTH) over 3 sample periods: early in the breeding season, after 70+ days of the breeding fast, and during peak molt. Subjects were blood sampled every 30 min for 2h post-injection. Breeding animals were recaptured and sampled at 48 h. In response to the ACTH injection, cortisol increased 4-6-fold in all groups, and remained elevated at 48 h in early breeding subjects. ACTH was a strong secretagogue for aldosterone, causing a 3-8-fold increase in concentration. Cortisol and aldosterone responses did not vary between groups but were correlated within individuals. The ACTH challenge produced elevations in plasma glucose during late breeding and molting, suppressed testosterone and thyroid hormone at 48 h in early breeding, and increased plasma non-esterified fatty acids and ketoacids during molting. These data suggest that sensitivity of the HPA axis is maintained but the metabolic impacts of cortisol and feedback inhibition of the axis vary with life history stage. Strong impacts on testosterone and thyroid hormone suggest the importance of maintaining low cortisol levels during the breeding fast. These data suggest that metabolic adaptations to extended fasting in NES include alterations in tissue responses to hormones that mitigate deleterious impacts of acute or moderately sustained stress responses.

  13. Pubertal shifts in adrenal responsiveness to stress and adrenocorticotropic hormone in male rats.

    PubMed

    Romeo, Russell D; Minhas, Sumeet; Svirsky, Sarah E; Hall, Baila S; Savenkova, Marina; Karatsoreos, Ilia N

    2014-04-01

    Studies have indicated significant pubertal-related differences in hormonal stress reactivity. We report here that prepubertal (30 days) male rats display a more protracted stress-induced corticosterone response than adults (70 days), despite showing relatively similar levels of adrenocorticotropic hormone (ACTH). Additionally, we show that adrenal expression of the ACTH receptor, melanocortin 2 receptor (Mc2r), is higher in prepubertal compared to adult animals, and that expression of melanocortin receptor accessory protein (Mrap), a molecule that chaperones MC2R to the cell surface, is greater in prepubertal males following stress. Given that these data suggest a pubertal shift in adrenal sensitivity to ACTH, we directly tested this possibility by injecting prepubertal and adult males with 6.25 or 9.375μg/kg of exogenous rat ACTH and measured their hormone levels 30 and 60min post-injection. As these doses resulted in different circulating levels of ACTH at these two ages, we performed regression analyses to assess the relationship between circulating ACTH and corticosterone concentrations. We found no difference between the ages in the correlation between ACTH and corticosterone levels at the 30min time point. However, 60min following the ACTH injection, we found prepubertal rats had significantly higher corticosterone concentrations at lower levels of ACTH compared to adults. These data suggest that prolonged exposure to ACTH leads to greater corticosterone responsiveness prior to puberty, and indicate that changes in adrenal sensitivity to ACTH may, in part, contribute to the protracted hormonal stress response in prepubertal rats.

  14. Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor

    PubMed Central

    Zhou, Xiang; Hang, Junbiao; Che, Jiaming; Chen, Zhongyuan; Qiu, Weicheng; Ren, Jian; Yang, Xiaoqing; Xiang, Jie

    2016-01-01

    Background The study was to review the clinical manifestations and laboratory examinations of ectopic adrenocorticotropic hormone (ACTH) syndrome, and to analyze the efficacy of surgical treatment. Methods The clinical data, surgical therapy, and outcome of 23 cases of ectopic ACTH syndrome accompanied by intra-thoracic tumors were reviewed. The tumors were removed from all the patients according to the principles of radical resection. Results The tumors were confirmed as associated with ectopic ACTH secretion in 19 cases. Hyperglycemia and hypokalemia were recovered, while plasma cortisol, plasma ACTH and 24-hour urinary free cortisol (UFC) levels were significantly reduced after surgery in these 19 cases. Recurrences of the disease were found in six cases during following-up, and five of them died. Conclusions The thoracic cavity should be a focus in routine examinations of patients with symptoms of Cushing’s syndrome (CS), because ectopic ACTH-producing tumors are commonly found in bronchus/lung and mediastinum. Despite the incidence of the pulmonary nodule secondary to opportunistic infection in some cases, surgery is still the first choice if the tumor is localized. The surgical procedure should be performed according to the principles in resection of lung cancer and mediastinal tumor. The surgical efficacy is significant for short-term periods; however, the recurrence of the disease in long-term periods is in great part related to distal metastasis or relapse of the tumor. PMID:27162663

  15. Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine carcinoma of the colon.

    PubMed

    Fujimoto, Kazuyo; Nakashima, Takatoshi; Sasaki, Kazunari; Hayashi, Kenichi; Hanafusa, Masao; Yoshida, Shiei; Myojo, Satoshi; Yoshida, Shun-Ichi; Sawai, Shigeaki; Sano, Nobuya

    A 48-year-old woman with a history of autoimmune hemolytic anemia and taking long-term corticosteroid therapy presented with a 3-month history of general fatigue, abdominal distension, and pigmentation. A computed tomography scan of the abdomen showed a tumor in the sigmoid colon and multiple metastatic nodules in the liver. A colonoscopy revealed an obstructing mass with the presence of an irregular ulcer in the sigmoid colon. Following biopsy and histopathological analysis, the patient was diagnosed with neuroendocrine carcinoma (NEC) of the colon. She received her first cycle of chemotherapy, with carboplatin and etoposide. During hospitalization, her pigmentation and hypertension worsened and hypokalemia was observed, all of which suggsted Cushing's syndrome. Her plasma adrenocorticotropic hormone (ACTH) and cortisol levels were high, and an ectopic ACTH-producing tumor was suspected. After a second chemotherapy cycle, she developed neutropenic fever and subsequently died. At autopsy, two histological types were found in the tumor: small cell carcinoma and large cell NEC. Immunohistochemical analysis revealed ACTH in the large cell NEC. This is the first reported case of an ectopic ACTH syndrome caused by NEC of the colon.

  16. Comparison of Ultraviolet Photodissociation and Collision Induced Dissociation of Adrenocorticotropic Hormone Peptides

    NASA Astrophysics Data System (ADS)

    Robotham, Scott A.; Brodbelt, Jennifer S.

    2015-09-01

    In an effort to better characterize the fragmentation pathways promoted by ultraviolet photoexcitation in comparison to collision induced dissociation (CID), six adrenocorticotropic hormone (ACTH) peptides in a range of charge states were subjected to 266 nm ultraviolet photodissociation (UVPD), 193 nm UVPD, and CID. Similar fragment ions and distributions were observed for 266 nm UVPD and 193 nm UVPD for all peptides investigated. While both UVPD and CID led to preferential cleavage of the Y-S bond for all ACTH peptides [except ACTH (1-39)], UVPD was far less dependent on charge state and location of basic sites for the production of C-terminal and N-terminal ions. For ACTH (1-16), ACTH (1-17), ACTH (1-24), and ACTH (1-39), changes in the distributions of fragment ion types ( a, b, c, x, y, z, and collectively N-terminal ions versus C-terminal ions) showed only minor changes upon UVPD for all charge states. In contrast, CID displayed significant changes in the fragment ion type distributions as a function of charge state, an outcome consistent with the dependence on the number and location of mobile protons that is not prominent for UVPD. Sequence coverages obtained by UVPD showed less dependence on charge state than those determined by CID, with the latter showing a consistent decrease in coverage as charge state increased.

  17. [A Case of an Adrenocorticotropic Hormone-Producing Pituitary Adenoma Removed via Electromagnetic-Guided Neuroendoscopy].

    PubMed

    Tomita, Yusuke; Kurozumi, Kazuhiko; Terasaka, Tomohiro; Inagaki, Kenichi; Otsuka, Fumio; Date, Isao

    2016-06-01

    The use of navigation systems is safe and reliable for neurological surgery. We performed endoscopic transsphenoidal surgery to totally resect an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma associated with oculomotor nerve palsy. A 70-year-old woman developed right ptosis 4 months before admission. She developed anisocoria 2 months later and was referred to the department of neurology from clinic. Brain magnetic resonance imaging(MRI)showed an intrasellar tumor that partially invaded the right cavernous sinus, and she was then referred to our department. She exhibited a round face ("moon face") and central obesity. Laboratory test results showed a high urinary cortisol level and high serum ACTH level, and neither the serum cortisol nor ACTH level was suppressed by a low-dose dexamethasone test. We performed transsphenoidal surgery using high-dimensional endoscopy under electromagnetic navigation. The tumor invading the cavernous sinus was visualized via endoscopy and confirmed on navigation using a flexible needle probe. Postoperative MRI showed total removal of the tumor, and the serum ACTH level recovered to the normal range. The patient's right oculomotor palsy resolved within 1 week postoperatively. In summary, electromagnetic navigation was useful for total resection of a pituitary tumor invading the cavernous sinus, contributing to normalization of the ACTH level and improvement in neurological symptoms.

  18. Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone.

    PubMed

    Mohammadi, Rahim; Yadegarazadi, Mohammad-Javad; Amini, Keyvan

    2014-09-01

    The objective of this study was to assess local effect of adrenocorticotropic hormone (ACTH) on the functional recovery of the sciatic nerve in a transection model. Sixty male healthy white Wistar rats were randomized into four experimental groups of 15 animals each: In the sham-operated group (SHAM), the sciatic nerve was exposed and manipulated. In the transected group (TC), the left sciatic nerve was transected and the cut nerve ends were fixed in the adjacent muscle. In the silicone graft group (SIL) a 10-mm defect was made and bridged using a silicone tube. The graft was filled with phosphated-buffer saline alone. In the treatment group a silicone tube (SIL/ACTH) was filled with 10 μL ACTH (0.1 mg/mL). Each group was subdivided into three subgroups of five animals each and regenerated nerve fibres were studied at 4, 8 and 12 weeks post operation. Behavioral testing, functional, gastrocnemius muscle mass and morphometric indices showed earlier regeneration of axons in SIL/ACTH than in SIL group (p < 0.05). Immunohistochemistry clearly showed more positive location of reactions to S-100 in SIL/ACTH than in SIL group. ACTH improved functional recovery and morphometric indices of sciatic nerve. This finding supports role of ACTH after peripheral nerve repair and may have clinical implications for the surgical management of patients after nerve transection.

  19. Adrenocorticotropic hormone, melanocyte-stimulating hormone, and the melanocortin receptors: revisiting the work of Robert Schwyzer: a thirty-year retrospective.

    PubMed

    Dores, Robert M

    2009-04-01

    In 1977 Dr. Robert Schwyzer wrote the review ACTH: A Short Introductory Review, which provided a reference point for current structure/function studies on the interactions between adrenocorticotropic hormone and alpha-melanocyte-stimulating hormone and the melanocortin receptors. This mini review will evaluate how the predictions made in the 1977 review have held up and also propose a mechanism to explain the ligand selectivity properties of the melanocortin receptors.

  20. Changes in plasma adrenocorticotropic hormone and cortisol levels induced by intracerebroventricular injection of histamine and its related compounds in dogs.

    PubMed

    Tsujimoto, S; Kamei, C; Yoshida, T; Tasaka, K

    1993-08-01

    Changes in plasma adrenocorticotropic hormone (ACTH) and cortisol levels induced by intracerebroventricular injection of histamine (H(i)) were studied in dogs. Intracerebroventricular administration of Hi at doses of 5 and 10 micrograms/kg caused a significant increase in plasma ACTH, while more rapid and more marked increase in plasma cortisol was noticed after Hi injection at doses of 2-10 micrograms/kg. Similar results were obtained when 2-methylhistamine was injected; remarkable increases in both plasma ACTH and cortisol levels were observed at doses of 25 and 50 micrograms/kg. However, no such effect was elicited by 4-methylhistamine even at a dose of 50 micrograms/kg. The rate of plasma cortisol increase induced by either Hi or 2-methylhistamine was significantly faster than that of plasma ACTH. Simultaneous application of pyrilamine (intracerebroventricularly) with H(i) resulted in the significant inhibition of H(i)-induced hormone secretions, but in similar administration neither ACTH nor cortisol were affected by cimetidine. In hypophysectomized dogs, a significant increase in plasma cortisol level was also observed after H(i) injection at a dose of 5 micrograms/kg. Intravenous infusion of hexamethonium continued before and after H(i) injection failed to inhibit the increase in plasma ACTH and cortisol levels induced by H(i). From these findings, it can be concluded that intracerebroventricular injection of H(i) caused an increase in plasma ACTH and cortisol levels via H1-receptor, and it is suggested that to some extent, the cortisol release elicited by H(i) is certainly produced without participation of ACTH.

  1. Effects of adrenocorticotropic hormone challenge and age on hair cortisol concentrations in dairy cattle

    PubMed Central

    del Rosario González-de-la-Vara, Marcela; Valdez, Ricardo Arturo; Lemus-Ramirez, Vicente; Vázquez-Chagoyán, Juan Carlos; Villa-Godoy, Alejandro; Romano, Marta C.

    2011-01-01

    Dairy cattle suffer stress from management and production; contemporary farming tries to improve animal welfare and reduce stress. Therefore, the assessment of long-term hypothalamic-pituitary-adrenal function using non-invasive techniques is useful. The aims in this study were: to measure cortisol concentration in cow and calves hair by radioimmunoassay (RIA), to test cortisol accumulation in bovine hair after adrenocorticotropic hormone (ACTH) challenges, and determine the influence of hair color on cortisol concentrations. Fifteen Holstein heifers were allotted to 3 groups (n = 5 each): in control group (C), just the hair was sampled; in the saline solution group (SS), IV saline solution was administered on days 0, 7, and 14; and the ACTH group was challenged 3 times with ACTH (0.15 UI per kg of body weight) on days 0, 7, and 14. Serum samples from the SS and ACTH groups were obtained 0, 60 and 90 min post-injection. Serum cortisol concentration was greater 60 and 90 min after injection with ACTH. Hair was clipped on days 0, 14, 28, and 44. Hair cortisol was methanol extracted and measured by RIA. Hair cortisol was preserved for 11 mo. Hair cortisol concentrations in the ACTH group were greater than in the saline and control groups on days 14 and 28, but not on day 44. Concentrations were greater in calves than in cows and greater in white hair than in black hair. Cortisol accumulated in bovine hair after ACTH challenges, but the concentration was affected by both age and hair color. If hair color effects are taken into account, assessing cortisol concentration in hair is a potentially useful non-invasive method for assessing stress in cattle. PMID:22210998

  2. Adrenocorticotropic hormone gel in the treatment of systemic lupus erythematosus: A retrospective study of patients.

    PubMed Central

    Li, Xiao; Golubovsky, Josh; Hui-Yuen, Joyce; Shah, Ummara; Olech, Ewa; Lomeo, Rosalia; Singh, Vijay; Busch, Howard; Strandberg, Mary Jane; Strandberg, Kayla; Horowitz, Leslie; Askanase, Anca

    2016-01-01

    Objectives: Acthar Gel is a long-acting formulation of adrenocorticotropic hormone (ACTH) with anti-inflammatory effects thought to be mediated in part through melanocortin receptor activation. This study was initiated to understand the role of Acthar Gel in SLE treatment in rheumatology practices. Methods: This is a retrospective case series of nine adult female patients treated with Acthar Gel for at least six months at five academic centers. Treating physicians completed a one-page questionnaire on lupus medications, disease activity, and outcomes. Clinical response was defined using SLEDAI 2K and improvement in the clinical manifestation(s) being treated. Results: The most common clinical SLE manifestations/indications requiring therapy with Acthar Gel were arthritis, rash, and inability to taper corticosteroids. The mean SLEDAI 2K score at baseline was 5.8 ± 5.0 (range 0-16). Six patients were concomitantly treated with corticosteroids (mean dose 18.3mg/day). All patients were on background SLE medications including immunosuppressives. Seven of nine patients had an overall improvement, with a decrease in SLEDAI 2K from 5.8 ± 5.0 at baseline to 3.5 ± 2.7 (range 0-8); four of five patients had improvement or resolution in arthritis, and one of two patients had resolution of inflammatory rash. Four patients discontinued corticosteroids and one patient tapered below 50% of the initial dose by 3 months of treatment with Acthar Gel. No adverse events were reported. Conclusions: This study suggests a role for Acthar Gel as an alternative to corticosteroids in the treatment of SLE. Acthar Gel appears to be safe and well-tolerated after 6 months of treatment, with a significant reduction in disease activity. PMID:27158444

  3. Effects of adrenocorticotropic hormone challenge and age on hair cortisol concentrations in dairy cattle.

    PubMed

    González-de-la-Vara, Marcela del Rosario; Valdez, Ricardo Arturo; Lemus-Ramirez, Vicente; Vázquez-Chagoyán, Juan Carlos; Villa-Godoy, Alejandro; Romano, Marta C

    2011-07-01

    Dairy cattle suffer stress from management and production; contemporary farming tries to improve animal welfare and reduce stress. Therefore, the assessment of long-term hypothalamic-pituitary-adrenal function using non-invasive techniques is useful. The aims in this study were: to measure cortisol concentration in cow and calves hair by radioimmunoassay (RIA), to test cortisol accumulation in bovine hair after adrenocorticotropic hormone (ACTH) challenges, and determine the influence of hair color on cortisol concentrations. Fifteen Holstein heifers were allotted to 3 groups (n = 5 each): in control group (C), just the hair was sampled; in the saline solution group (SS), IV saline solution was administered on days 0, 7, and 14; and the ACTH group was challenged 3 times with ACTH (0.15 UI per kg of body weight) on days 0, 7, and 14. Serum samples from the SS and ACTH groups were obtained 0, 60 and 90 min post-injection. Serum cortisol concentration was greater 60 and 90 min after injection with ACTH. Hair was clipped on days 0, 14, 28, and 44. Hair cortisol was methanol extracted and measured by RIA. Hair cortisol was preserved for 11 mo. Hair cortisol concentrations in the ACTH group were greater than in the saline and control groups on days 14 and 28, but not on day 44. Concentrations were greater in calves than in cows and greater in white hair than in black hair. Cortisol accumulated in bovine hair after ACTH challenges, but the concentration was affected by both age and hair color. If hair color effects are taken into account, assessing cortisol concentration in hair is a potentially useful non-invasive method for assessing stress in cattle.

  4. Depressive-like behavior in adrenocorticotropic hormone-treated rats blocked by memantine.

    PubMed

    Tokita, Kenichi; Fujita, Yuko; Yamaji, Takayuki; Hashimoto, Kenji

    2012-08-01

    Hyperactivity of the hypothalamic pituitary-adrenal (HPA) axis plays a role in the pathophysiology of major depressive disorder (MDD). Recent studies suggest the role of the glutamatergic system in the pathophysiology of MDD, and N-methyl-D-aspartate (NMDA) receptor antagonists have shown antidepressant effects in both preclinical and clinical studies. However, little is known about the role of adrenocorticotropic hormone (ACTH) specifically in the glutamatergic response to HPA axis activation. Glutamate is an NMDA receptor agonist, and glycine and D-serine act as co-agonists. Here, we measured brain concentrations of these amino acids in rats given repeated administration of ACTH (100 μg/rat/day, sc, for 14 days). Further, we also evaluated behavioral effects of memantine, a non-competitive NMDA antagonist, on immobility time in the forced swimming test and on locomotor activity in ACTH-treated rats. Compared with control rats, glutamine, glycine, L-serine, and D-serine levels were increased in the hippocampus of ACTH-treated rats; glutamate, glutamine, glycine, L-serine, and D-serine were increased in the cerebellum; and glutamine and glycine were increased in the frontal cortex and striatum, all with statistical significance. Remarkably, these increases in agonists and co-agonists might have led to the augmentation of NMDA receptor activity. ACTH treatment increased immobility time in the forced swimming test and decreased locomotor activity in rats. On the contrary, memantine (10 mg/kg, ip) significantly decreased immobility time in the forced swimming test and increased locomotor activity in ACTH-treated rats. Furthermore, imipramine (15 mg/kg, ip) did not alter immobility time in the forced swimming test whereas this drug significantly decreased locomotor activity in ACTH-treated rats. These results suggest that depressive-like behaviors by chronic ACTH treatment could be blocked by memantine.

  5. Differential expression of functional adrenocorticotropic hormone receptors by subpopulations of lymphocytes

    SciTech Connect

    Clarke, B.L.; Bost, K.L.

    1989-07-15

    In an effort to investigate the presence of adrenocorticotropic hormone (ACTH) receptors on rat lymphocytes, cells were separated by a panning procedure into T and B cell populations. By using the radiolabeled ACTH agonist, (/sup 125/I-Tyr23) phenylalanine2-norleucine4-ACTH1-24, substantial numbers of ACTH binding sites were detected on T and B lymphocytes, but not on thymocytes. Scatchard analysis revealed two types of binding sites on each cell population, one with Kd1 = 0.088 +/- 0.025 nM and one with Kd2 = 4.2 +/- 0.6 nM; however, the absolute number of binding sites per cell was different. B lymphocytes expressed approximately three times the number of Kd1 binding sites per cell when compared with T lymphocytes. However, ACTH receptor expression by these cell populations was not static as suggested by the ability to induce receptor expression via mitogens. B or T cells and thymocytes stimulated with the mitogens LPS or Con A, respectively, substantially increased their number of Kd1 binding sites per cell (approximately three-fold). Even more dramatic increases in Kd1 receptor expression (approximately 100-fold) were observed when comparing ''normal'' and stimulated thymocytes. To demonstrate that these ACTH binding sites were in fact functional, cAMP levels were measured in lymphocytes 10 min after exposure to varying concentrations of ACTH. Dose-dependent increases in cAMP levels were observed, with significant stimulation occurring with as little as 0.1 nM ACTH added. Taken together, these studies demonstrate the presence of functional ACTH receptors on normal, rat T and B lymphocytes.

  6. Mapping of enkephalins and adrenocorticotropic hormone in the squirrel monkey brainstem.

    PubMed

    Duque-Díaz, Ewing; Díaz-Cabiale, Zaida; Narváez, José Angel; Coveñas, Rafael

    2017-03-01

    An immunocytochemical technique has been used to study for the first time the distribution of fibers and cell bodies containing leucine-enkephalin (leu-enk), methionine-enkephalin (met-enk) or adrenocorticotropic hormone (ACTH) in the whole brainstem of the squirrel monkey Saimiri sciureus. Cell bodies containing leu-enk or met-enk were found in the superior colliculus and the formatio reticularis tegmenti mesencephali, respectively. No immunoreactive cell bodies containing ACTH were observed. Leu-enk-immunoreactive fibers were observed in 40 brainstem nuclei/tracts/regions, fibers containing met-enk were found in 38 brainstem nuclei/tracts/regions and fibers containing ACTH were found in 26 nuclei/tracts/regions. In the latter case, the density of immunoreactive fibers was always low. A high/moderate density of leu-enk- or met-enk-immunoreactive fibers were found in 18 and 16 brainstem nuclei/tracts/regions, respectively. The distribution of immunoreactive fibers containing leu-enk or met-enk was quite similar, with both leu-enk and met-enk observed in 82.5 % of the squirrel monkey brainstem nuclei/tracts/regions. This relationship is less marked for met-enk and ACTH (60.5 %) and even lower for leu-enk and ACTH (52.5 %). In 42.5 % of the nuclei/tracts/regions of the squirrel monkey brainstem (colliculus superior, substantia grisea centralis, nucleus interpeduncularis, nucleus tractus spinalis nervi trigemini, nucleus tractus solitarii, nucleus parabrachialis, formatio reticularis, substantia nigra), we observed fibers containing all three neuropeptides. The widespread distribution reported here suggests that enkephalins and ACTH can be involved in several physiological functions. The distribution of the immunoreactive fibers reported here is quite similar to that previously reported for enkephalins and ACTH in Macaca species and humans.

  7. Isolated Adrenocorticotropic Hormone or Thyrotropin Deficiency Following Mild Traumatic Brain Injury: Three Cases with Long-Term Follow-Up

    PubMed Central

    Baek, Cho-Ok; Kim, Yu Ji; Kim, Ji Hye

    2015-01-01

    Few studies have examined the clinical features and long-term outcomes of isolated pituitary hormone deficiencies after traumatic brain injury (TBI). Such deficiencies typically present at time intervals after TBI, especially after mild injuries such as concussions, which makes their diagnosis difficult without careful history taking. It is necessary to improve diagnosis and prevent life threatening or morbid conditions such as those that may occur in deficiencies of adrenocorticotropic hormone (ACTH) or thyroid-stimulating hormone (as known as thyrotropin, TSH), the two most important pituitary hormones in hypopituitarism treatment. Here, we report two cases of isolated ACTH deficiency and one case of isolated TSH deficiency. These patients presented at different time points after concussion and underwent long-term follow-ups. PMID:27169080

  8. Isolated Adrenocorticotropic Hormone or Thyrotropin Deficiency Following Mild Traumatic Brain Injury: Three Cases with Long-Term Follow-Up.

    PubMed

    Baek, Cho-Ok; Kim, Yu Ji; Kim, Ji Hye; Park, Ji Hyun

    2015-10-01

    Few studies have examined the clinical features and long-term outcomes of isolated pituitary hormone deficiencies after traumatic brain injury (TBI). Such deficiencies typically present at time intervals after TBI, especially after mild injuries such as concussions, which makes their diagnosis difficult without careful history taking. It is necessary to improve diagnosis and prevent life threatening or morbid conditions such as those that may occur in deficiencies of adrenocorticotropic hormone (ACTH) or thyroid-stimulating hormone (as known as thyrotropin, TSH), the two most important pituitary hormones in hypopituitarism treatment. Here, we report two cases of isolated ACTH deficiency and one case of isolated TSH deficiency. These patients presented at different time points after concussion and underwent long-term follow-ups.

  9. Adrenocorticotropic hormone in serial cerebrospinal fluid in man - Subject to acute regulation by the hypothalamic-pituitary-adrenocortical system?

    PubMed

    Kellner, Michael; Wortmann, Viola; Salzwedel, Cornelie; Kober, Daniel; Petzoldt, Martin; Urbanowicz, Tatiana; Pulic, Mersija; Boelmans, Kai; Yassouridis, Alexander; Wiedemann, Klaus

    2016-05-30

    Acute regulation of adrenocorticotropic hormone (ACTH) in cerebrospinal fluid (CSF) by the hypothalamic-pituitary-adrenocortical system has not been investigated in man. In a pilot study in healthy male volunteers we measured ACTH every twenty minutes in serial CSF for three hours after an intravenous placebo, hydrocortisone (100mg) or insulin (2mg/kg) injection. No acute inhibitory or stimulatory effects of these interventions were discovered. Our results corroborate previous findings in rhesus monkeys. The regulation of CSF ACTH and its potential relevance for behavioral alterations in health and disease (e.g. major depression or anorexia nervosa) in humans need further study.

  10. Treatable Bedridden Elderly―Recovery from Flexion Contracture after Cortisol Replacement in a Patient with Isolated Adrenocorticotropic Hormone Deficiency

    PubMed Central

    Tanaka, Takamasa; Terada, Norihiko; Fujikawa, Yoshiki; Fujimoto, Takushi

    2016-01-01

    Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder with diverse clinical presentations. A 79-year-old man was bedridden for six months due to flexion contractures of the bilateral hips and knees, along with hyponatremia. He was diagnosed with IAD based on the results of endocrine tests. After one month of corticosteroid replacement, he recovered and was able to stand up by himself. Although flexion contracture is a rare symptom of IAD, steroid replacement therapy may be effective, even for seemingly irreversibly bedridden elderly patients. In bedridden elderly patients with flexion contractures, we should consider and look for any signs of adrenal insufficiency. PMID:27746435

  11. Treatable Bedridden Elderly -Recovery from Flexion Contracture after Cortisol Replacement in a Patient with Isolated Adrenocorticotropic Hormone Deficiency.

    PubMed

    Tanaka, Takamasa; Terada, Norihiko; Fujikawa, Yoshiki; Fujimoto, Takushi

    Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder with diverse clinical presentations. A 79-year-old man was bedridden for six months due to flexion contractures of the bilateral hips and knees, along with hyponatremia. He was diagnosed with IAD based on the results of endocrine tests. After one month of corticosteroid replacement, he recovered and was able to stand up by himself. Although flexion contracture is a rare symptom of IAD, steroid replacement therapy may be effective, even for seemingly irreversibly bedridden elderly patients. In bedridden elderly patients with flexion contractures, we should consider and look for any signs of adrenal insufficiency.

  12. Omnigen-AF reduces basal plasma cortisol, AWA cortisol release to adrencocorticotropic hormone or corticotrophin releasing hormone & vasopressin in lactating dairy cows under thermoneutral or acute heat stress conditions.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Differences in the adrenal cortisol response of OmniGen-AF (OG) supplemented dairy cows to a corticotrophin releasing hormone (CRH) and vasopressin (VP) or an adrenocorticotropic hormone (ACTH) challenge when housed at different temperature-humidity indices (THI) were studied. Holstein cows (n=12; 1...

  13. Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone.

    PubMed

    van den Beukel, Johanna C; Grefhorst, Aldo; Quarta, Carmelo; Steenbergen, Jacobie; Mastroberardino, Pier G; Lombès, Marc; Delhanty, Patric J; Mazza, Roberta; Pagotto, Uberto; van der Lely, Aart Jan; Themmen, Axel P N

    2014-11-01

    Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.

  14. [West syndrome: clinical and electroencephalographic follow up of 70 patients and response to its treatment with adrenocorticotropic hormone, prednisone, vigabatrin, nitrazepam and valproate].

    PubMed

    Antoniuk, S A; Bruck, I; Spessatto, A; Halick, S M; de Bruyn, L R; Meister, E; de Paola, D

    2000-09-01

    In a retrospective study we assessed the outcome of the criptogenic and symptomatic forms of West syndrome and evaluated the efficacy of adrenocorticotropic hormone, vigabatrin, prednisone, valproate and nitrazepam in the spasms control. Seventy patients were follwed up by 2 years. Twelve (17%) were criptogenics and 58 (83%) symptomatics. In criptogenic group significantly more patients were in regular school classes and with normal motor development, better control of seizure, less tendency to evoluate to Lennox Gastaut syndrome and 83. 3% had control of spasms (72.4% of patients from symptomatic group had control of spasms). Adrenocorticotropic hormone and vigabatrin were the most efective drugs, with 68.75% and 60% of spasms control, respectivelly, when used as first line of therapy and 75% and 50%, respectivelly, as second line of therapy.

  15. Legionella pneumophila and Pneumocystis jirovecii coinfection in an infant treated with adrenocorticotropic hormone for infantile spasm: case report and literature review.

    PubMed

    Musallam, Nadira; Bamberger, Ellen; Srugo, Isaac; Dabbah, Husein; Glikman, Daniel; Zonis, Zeev; Kessel, Aharon; Genizi, Jacob

    2014-02-01

    We describe an 8-month-old infant with infantile spasms treated with adrenocorticotropic hormone (ACTH) who presented with fatal Legionella pneumophila and Pneumocystis jirovecii infection. Emphasis is placed on the ensuing immunosuppression and infectious sequelae of ACTH therapy. Given that ACTH therapy may increase the risk of fatal infection, patients undergoing such treatment should be closely monitored, with particular attention paid to the functioning of the immune system.

  16. Levels of central oxytocin and glucocorticoid receptor and serum adrenocorticotropic hormone and corticosterone in mandarin voles with different levels of sociability.

    PubMed

    Qiao, Xufeng; Yan, Yating; Tai, Fadao; Wu, Ruiyong; Hao, Ping; Fang, Qianqian; Zhang, Shuwei

    2014-11-01

    Sociability is the prerequisite to social living. Oxytocin and the hypothalamo-pituitary-adrenocortical axis mediate various social behaviors across different social contexts in different rodents. We hypothesized that they also mediate levels of non-reproductive social behavior. Here we explored naturally occurring variation in sociability through a social preference test and compared central oxytocin, glucocorticoid receptors, serum adrenocorticotropic hormone and corticosterone in mandarin voles with different levels of sociability. We found that low-social voles showed higher levels of anxiety-like behavior in open field tests, and had more serum adrenocorticotropic hormone and corticosterone than high-social voles. High-social individuals had more glucocorticoid receptor positive neurons in the hippocampus and more oxytocin positive neurons in the paraventricular nuclei and supraoptic nuclei of the hypothalamus than low-social individuals. Within the same level of sociability, females had more oxytocin positive neurons in the paraventricular nuclei and supraoptic nuclei of the hypothalamus than males. These results indicate that naturally occurring social preferences are associated with higher levels of central oxytocin and hippocampus glucocorticoid receptor and lower levels of anxiety and serum adrenocorticotropic hormone and corticosterone.

  17. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog.

    PubMed

    Shadrina, M I; Dolotov, O V; Grivennikov, I A; Slominsky, P A; Andreeva, L A; Inozemtseva, L S; Limborska, S A; Myasoedov, N F

    2001-08-03

    The proliferation, differentiation and survival of neuronal and glial cells are affected by a number of neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and others. In a previous study, we observed the effects of 'Semax' (Met-Glu-His-Phe-Pro-Gly-Pro), the physiologically active analogue of adrenocorticotropic hormone(4--10), on neuronal cell survival in vitro. We hypothesized that these effects may be mediated by the regulation of expression of some neurotrophic factors. To test this hypothesis we analyzed NGF and BDNF gene expression in glial cells obtained from the basal forebrain of newborn rats, following in vitro treatment with 'Semax'. We observed changes in mRNA levels for both the NGF and BDNF genes. The greatest increase in expression was found after 30 min of 'Semax' administration. At this time, BDNF mRNA level was increased eight-fold in comparison with control, and NGF mRNA level was increased five-fold.

  18. Laparoscopic Unilateral Total and Contralateral Subtotal Adrenalectomy for Bilateral Adrenocorticotropic Hormone-Secreting Pheochromocytoma: Report of a Rare Case

    PubMed Central

    Fukasawa, Masanari; Miyamoto, Tatsuya; Kira, Satoru; Aoki, Tadashi; Zakoji, Hidenori; Mitsui, Takahiko; Takeda, Masayuki

    2016-01-01

    Abstract Background: Bilateral adrenal tumors are not common in clinical practice, but are an important source of ectopic adrenocorticotropic hormone (ACTH) secretion. Standard operative management for bilateral pheochromocytomas might dictate the removal of the involved adrenal gland and the removal of the contralateral adrenal gland. We present a case of bilateral ACTH-secreting pheochromocytoma treated with staged laparoscopic unilateral total and contralateral subtotal adrenalectomy. Case Presentation: A 58-year-old male with elevated hyperglycemia and general fatigue was hospitalized for pneumonia. CT incidentally revealed bilateral adrenal tumor. Biochemical examination was significant for elevated urinary metanephrine and normetanephrines, and plasma catecholamine level. CT scan of the head, neck, thorax, and pelvis was normal. Under the clinical diagnosis of ACTH-dependent pheochromocytoma, laparoscopic right total adrenalectomy was performed. As endocrinologic examination showed residual ACTH-dependent pheochromocytoma after surgery, laparoscopic left subtotal adrenalectomy was performed. Pathology analysis revealed pheochromocytoma with stained ACTH lesions in both adrenal tumors. Conclusion: This is a rare case of ACTH-secreting bilateral pheochromocytoma effectively treated with staged laparoscopic unilateral total and contralateral subtotal adrenalectomy, in which the production of ACTH was confirmed by immunohistochemical staining. PMID:28078325

  19. Do Patients Require Inpatient Admission to Receive Adrenocorticotropic Hormone (ACTH)? A Survey of US-Based Prescribers.

    PubMed

    Joshi, Charuta; Berg, Anne T; Wirrell, Elaine

    2016-02-01

    We aimed to determine variation in treatment of newly diagnosed infantile spasms, focusing on details of adrenocorticotropic hormone (ACTH) administration using a Redcap questionnaire sent to members of the Child Neurology Society. Two hundred fifty-seven members responded. Eighty-four percent prescribers used ACTH to treat infantile spasms. Seventy-six percent always admit patients. There is no difference between prescriber type (epileptologist or other) and prescriber location (state-funded or non-state-funded hospital) for decision to admit. Electroencephalographic (EEG) confirmation of spasms and education for injection were the commonest reasons to admit. Only 45% of prescribers accurately estimated the cost of ACTH. Participants in the hospital vial program were significantly more likely to always admit patients for ACTH than those who did not participate in such a program (P = .02). Although having the hospital sample vial allows time to complete investigation of infantile spasms and eliminates delays in initiating ACTH, it adds significantly to the cost of therapy.

  20. Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells.

    PubMed

    Nakada, Yuki; Kageyama, Kazunori; Sugiyama, Aya; Desaki, Rie; Takayasu, Shinobu; Niioka, Kanako; Murasawa, Shingo; Ishigame, Noriko; Asari, Yuko; Iwasaki, Yasumasa; Daimon, Makoto

    2015-01-01

    Cushing's disease is primarily caused by adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Pituitary tumor-transforming gene 1 (PTTG1) expression, a hallmark of pituitary tumors, stimulates pituitary cell proliferation. Histone deacetylases (HDACs) play an important role in regulating gene transcription and HDAC inhibitors induce cellular differentiation and suppress tumor cell proliferation. HDAC inhibitors also repress PTTG1 mRNA levels. Trichostatin A (TSA) is a potent cell-permeable HDAC inhibitor that blocks cell cycle progression. In the present study, we determined the effect of TSA on ACTH production and cellular proliferation in mouse AtT-20 corticotroph tumor cells. TSA decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and reduced ACTH levels in the culture medium of these cells. The TSA-induced decreases in POMC mRNA levels were not modulated when TSA and dexamethasone were simultaneously administered. Drug treatment also decreased AtT-20 cell proliferation, induced apoptosis, and increased the percentage of cells in G0/G1 phase using flow cytometry. TSA decreased PTTG1 mRNA levels. Furthermore, PTTG1 knockdown inhibited cellular proliferation. Its knockdown also inhibited POMC mRNA and ACTH levels. TSA inhibits ACTH production and corticotroph tumor cell proliferation. TSA may inhibit cellular proliferation, and ACTH synthesis and secretion by decreasing PTTG1 expression.

  1. Growth Hormone-Releasing Hormone in Diabetes

    PubMed Central

    Fridlyand, Leonid E.; Tamarina, Natalia A.; Schally, Andrew V.; Philipson, Louis H.

    2016-01-01

    Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggest that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications. PMID:27777568

  2. Primary intracranial neuroendocrine tumor with ectopic adrenocorticotropic hormone syndrome: A rare and complicated case report and literature review

    PubMed Central

    LIU, HAILONG; ZHANG, MINGSHAN; WANG, XUAN; QU, YANMING; ZHANG, HONGWEI; YU, CHUNJIANG

    2016-01-01

    Neuroendocrine tumors (NETs) and ectopic adrenocorticotropic hormone (ACTH) syndrome are frequent in adult patients. However, primary intracranial NETs, exhibiting immunonegativity for ACTH, high serum ACTH level and treated with anterior skull base reconstruction, are rare and complicated. We herein present a case of a primary intracranial NET immunonegative for ACTH, resulting in ectopic ACTH syndrome. A 40-year-old woman presented with intermittent rhinorrhea, rapid weight gain, polydipsia, polyuria, hypertension, dimness, bilateral exophthalmus, diminution of vision in the left eye and pigmentation of the skin of the face and trunk. Computed tomography (CT) and magnetic resonance imaging scans revealed a sizeable enhancing tumor in the anterior cranial fossa, which infiltrated the sphenoid and ethmoid sinuses bilaterally, the left maxillary sinus and the nasal cavity. Abdominal CT scans revealed bilateral adrenal hyperplasia. The biochemical findings included hypokalemia and high glucose, cortisol, plasma ACTH, 24-h urinary free cortisol and testosterone levels. The neoplasm was exposed through a right frontal craniotomy, while anterior skull base reconstruction was performed during surgery. The intracranial surgery achieved gross removal of the tumor; however, part of the tumor remained in the nasal cavity. Histopathological examination of the surgical specimen confirmed the diagnosis of a low-grade small-cell NET, exhibiting immunonegativity for ACTH. A postoperative abdominal CT scan demonstrated bilateral regression of the adrenal gland hyperplasia and the serum ACTH level returned to normal after 16 days. To the best of our knowledge, there are no previous reports of primary intracranial NETs, immunohistochemically negative for ACTH, resulting in ectopic ACTH syndrome. PMID:27330775

  3. Reduction in glutamine/glutamate levels in the cerebral cortex after adrenocorticotropic hormone therapy in patients with west syndrome.

    PubMed

    Munakata, Mitsutoshi; Togashi, Noriko; Sakamoto, Osamu; Haginoya, Kazuhiro; Kobayashi, Yasuko; Onuma, Akira; Iinuma, Kazuie; Kure, Shigeo

    2014-01-01

    West syndrome (WS), an intractable epileptic encephalopathy of infancy, is refractory to many antiepileptic drugs; however, adrenocorticotropic hormone (ACTH) is an effective treatment for WS. The mechanism behind the efficacy of ACTH is mediated by biochemical processes that remain unknown. We examined the effects of ACTH therapy with tetracosactide (TCS), a synthetic ACTH analogue, on brain metabolism in patients with WS, using (1)H magnetic resonance spectroscopy (¹H-MRS). In six patients with cryptogenic WS, we performed single-voxel ¹H-MRS at the occipital lobe cortex. Measurements were taken prior to TCS treatment, a few days after therapy, and several months after therapy. Data were also compared with subjects having only mild psychomotor delays. The metabolites measured were glutamine plus glutamate (Glx), N-acetylaspartate (NAA), choline (Cho), and myoinositol (mI); each was expressed as a ratio with creatine plus phosphocreatine (total creatine: tCr). The Glx/tCr ratio was significantly reduced after the TCS treatment. The NAA/tCr ratio was also significantly reduced after the treatment compared with the control group, although the change in NAA signal was heterogeneous among patients, correlating with respective outcomes. The Cho/tCr and mI/tCr ratios were not affected by TCS treatment. The reduction in Glx suggests a decrease in the glutamate-glutamine cycle, which plays a pivotal role in synthesizing neurotransmitters such as glutamate and GABA. TCS-induced Glx reduction may induce changes in synaptic signal transduction, thereby accounting for the effect of TCS on WS. The change in NAA indicates altered neuronal activity, which may be correlated with outcome in WS patients.

  4. Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo.

    PubMed

    Murasawa, Shingo; Kageyama, Kazunori; Sugiyama, Aya; Ishigame, Noriko; Niioka, Kanako; Suda, Toshihiro; Daimon, Makoto

    2014-08-25

    Adrenocorticotropic hormone (ACTH) production by pituitary corticotroph adenomas is the main cause of Cushing's disease. A drug that targets pituitary ACTH-secreting adenomas would aid treatment of Cushing's disease. Octreotide, a somatostatin receptor type 2 (SSTR2)-preferring somatostatin analogue, has no effect on ACTH secretion in patients with Cushing's disease. The multiligand SOM230 (pasireotide) displays a much higher affinity for SSTR1 and SSTR5 than octreotide and suppresses ACTH secretion in cultures of human corticotroph tumors to a greater extent than octreotide. In the present in vitro and in vivo study, we determined the effect of SOM230 on ACTH production and cell proliferation of AtT-20 corticotroph tumor cells. SOM230 decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and ACTH levels in the culture medium of these cells, suggesting that SOM230 suppresses ACTH synthesis and secretion in corticotroph tumor cells. SOM230 also decreased cell proliferation and both cyclic adenosine monophosphate response element-binding protein and Akt phosphorylation in AtT-20 cells. SSTR5 knockdown inhibited the SOM230-induced decreases in cell proliferation. Fluorescence-activated cell sorting analyses revealed that SOM230 did not attenuate cell cycle progression. Tumor weight in mice xenografted with AtT-20 cells and treated with SOM230 was significantly lower than in AtT-20-xenografted control mice. SOM230 also significantly decreased plasma ACTH levels, and POMC and pituitary tumor transforming gene mRNA levels in the tumor cells. Thus, SOM230 inhibits ACTH production and corticotroph tumor cell proliferation in vitro and in vivo.

  5. Variability in leptin and adrenal response in juvenile Steller sea lions (Eumetopias jubatus) to adrenocorticotropic hormone (ACTH) in different seasons.

    PubMed

    Mashburn, Kendall L; Atkinson, Shannon

    2008-01-15

    Eight free-ranging juvenile Steller sea lions (SSL; 6 males, 2 females; 14-20 months) temporarily held under ambient conditions at the Alaska SeaLife Center were physiologically challenged through exogenous administration of adrenocorticotropic hormone (ACTH). Four individuals (3 males, 1 female) underwent ACTH challenge in each of two seasons, summer and winter. Following ACTH injection serial blood and fecal samples were collected for up to 3 and 96 h, respectively. A radioimmunoassay (RIA) was validated for leptin, and using a previously validated RIA for cortisol, collected sera were analyzed for both cortisol and leptin. ACTH injection resulted in a 2.9-fold increase (P=0.164) in leptin which preceded a 3.2-fold increase (P=0.0290) in cortisol by 105 min in summer. In winter, a 1.7-fold increase in leptin (P=0.020) preceded a 2.1-fold increase (P=0.001) in serum cortisol by 45 min. Mean fecal corticosteroid maxima were 10.4 and 16.7-fold above baseline 28 and 12 h post-injection and returned to baseline 52 and 32 h post-injection, in summer and winter, respectively. Data indicate acute activity in juvenile adrenal glands is detectable in feces approximately 12-24 h post-stimulus in either season, with a duration of approximately 40 h in summer and 20 h in winter. Changes in serum cortisol proved statistically significant both seasons and elevated concentrations were detected by 30 min post-stimulus (baseline 64.8+/-4.2; peak 209.5+/-18.3 ng/ml: summer; baseline 87.0+/-15.7; peak 237.6+/-10.0 ng/ml: winter), whereas the changes that occurred in serum leptin proved to be significant only in winter (baseline 6.4+/-0.6; peak 18.7+/-7.0 ng/ml: summer; baseline 4.2+/-0.5; peak 7.5+/-0.6 ng/ml: winter). Changes in fecal corticosteroids proved significant only in summer (baseline 117.8+/-36.7; peak 1219.3+/-298.4 ng/g, P=0.038: summer; baseline 71.8+/-13.7; peak 1198.6+/-369.9 ng/g, P=0.053: winter) due to a high degree of individual variability in winter months. The

  6. ACTH (Adrenocorticotropic Hormone) Test

    MedlinePlus

    ... disease and ectopic ACTH from cortisol and ACTH measurement alone. A variety of other tests are often ... as any steroid, oral, inhaled, topical or eye drop may cause abnormal results. Megestrol acetate can also ...

  7. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta

    SciTech Connect

    Robinson, B.G.; Emanuel, R.L.; Frim, D.M.; Majzoub, J.A. )

    1988-07-01

    Primary cultures of purified human cytotrophoblasts have been used to examine the expression of the corticotropin-releasing hormone (CRH) gene in placenta. The authors report here that glucocorticoids stimulate placental CRH synthesis and secretion in primary cultures of human placenta. This stimulation is in contrast to the glucocorticoid suppression of CRH expression in hypothalamus. The positive regulation of CRH by glucocorticoids suggests that the rise in CRH preceding parturition could result from the previously described rise in fetal glucocorticoids. Furthermore, this increase in placental CRH could stimulate, via adrenocorticotropic hormone, a further rise in fetal glucocorticoids, completing a positive feedback loop that would be terminated by delivery.

  8. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta.

    PubMed Central

    Robinson, B G; Emanuel, R L; Frim, D M; Majzoub, J A

    1988-01-01

    Primary cultures of purified human cytotrophoblasts have been used to examine the expression of the corticotropin-releasing hormone (CRH) gene in placenta. We report here that glucocorticoids stimulate placental CRH synthesis and secretion in primary cultures of human placenta. This stimulation is in contrast to the glucocorticoid suppression of CRH expression in hypothalamus. The positive regulation of CRH by glucocorticoids suggests that the rise in CRH preceding parturition could result from the previously described rise in fetal glucocorticoids. Furthermore, this increase in placental CRH could stimulate, via adrenocorticotropic hormone, a further rise in fetal glucocorticoids, completing a positive feedback loop that would be terminated by delivery. Images PMID:2839838

  9. Efficacy of single serum cortisol reading obtained between 9 AM and 10 AM as an index of adrenal function in children treated with glucocorticoids or synthetic adrenocorticotropic hormone.

    PubMed

    Goto, Masahiro; Shibata, Nao; Hasegawa, Yukihiro

    2016-07-01

    To find a simple method to screen for iatrogenic childhood adrenal insufficiency, we retrospectively examined the results of CRH stimulation tests performed 212 times on 111 subjects (68 males; age at commencement of initial treatment ranged 0.0-19.8 yr; median age, 5.8 yr). Before the commencement of this study, 97 subjects had been treated with glucocorticoids and 14 subjects with West syndrome had been treated with synthetic adrenocorticotropic hormone. Duration of the primary treatment ranged from 15 to 2150 days. CRH stimulation tests were conducted between 09:00 AM and 10:00 AM and peak cortisol values less than 15 µg/dL were considered indicative of adrenal insufficiency. The receiver operating characteristic curve showed that the optimal basal serum cortisol cut-off values when screening for adrenal suppression ranged from 5.35 to 5.80 µg/dL depending on the primary disease. All subjects having a serum cortisol value of less than 2.3 µg/dL had insufficient adrenal function while all subjects having greater than 11 µg/dL had intact adrenal function. We concluded that single serum cortisol values obtained between 09:00 AM and 10:00 AM had the potential to serve as an index of adrenal function in children treated with glucocorticoids or synthetic adrenocorticotropic hormone.

  10. Thyroid hormone biosynthesis and release.

    PubMed

    Carvalho, Denise P; Dupuy, Corinne

    2017-01-31

    Thyroid hormones (TH) 3,5,3',5'- tetraiodothyronine or thyroxine (T4) and 3,5,3'- triiodothyronine (T3) contain iodine atoms as part of their structure, and their synthesis occur in the unique structures called thyroid follicles. Iodide reaches thyroid cells through the bloodstream that supplies the basolateral plasma membrane of thyrocytes, where it is avidly taken up through the sodium/iodide symporter (NIS). Thyrocytes are also specialized in the secretion of the high molecular weight protein thyroglobulin (TG) in the follicular lumen. The iodination of the tyrosyl residues of TG preceeds TH biosynthesis, which depends on the interaction of iodide, TG, hydrogen peroxide (H2O2) and thyroid peroxidase (TPO) at the apical plasma membrane of thyrocytes. Thyroid hormone biosynthesis is under the tonic control of thyrotropin (TSH), while the iodide recycling ability is very important for normal thyroid function. We discuss herein the biochemical aspects of TH biosynthesis and release, highlighting the novel molecules involved in the process.

  11. A secretagogin locus of the mammalian hypothalamus controls stress hormone release.

    PubMed

    Romanov, Roman A; Alpár, Alán; Zhang, Ming-Dong; Zeisel, Amit; Calas, André; Landry, Marc; Fuszard, Matthew; Shirran, Sally L; Schnell, Robert; Dobolyi, Árpád; Oláh, Márk; Spence, Lauren; Mulder, Jan; Martens, Henrik; Palkovits, Miklós; Uhlen, Mathias; Sitte, Harald H; Botting, Catherine H; Wagner, Ludwig; Linnarsson, Sten; Hökfelt, Tomas; Harkany, Tibor

    2015-01-02

    A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin's Ca(2+) sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin's loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness.

  12. A secretagogin locus of the mammalian hypothalamus controls stress hormone release

    PubMed Central

    Romanov, Roman A; Alpár, Alán; Zhang, Ming-Dong; Zeisel, Amit; Calas, André; Landry, Marc; Fuszard, Matthew; Shirran, Sally L; Schnell, Robert; Dobolyi, Árpád; Oláh, Márk; Spence, Lauren; Mulder, Jan; Martens, Henrik; Palkovits, Miklós; Uhlen, Mathias; Sitte, Harald H; Botting, Catherine H; Wagner, Ludwig; Linnarsson, Sten; Hökfelt, Tomas; Harkany, Tibor

    2015-01-01

    A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin’s Ca2+ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin’s loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness. PMID:25430741

  13. Ghrelin and obestatin modulate growth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons.

    PubMed

    Feng, Dan D; Yang, Seung-Kwon; Loudes, Catherine; Simon, Axelle; Al-Sarraf, Tamara; Culler, Michael; Alvear-Perez, Rodrigo; Llorens-Cortes, Catherine; Chen, Chen; Epelbaum, Jacques; Gardette, Robert

    2011-09-01

    Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.

  14. Effects of benzyl glucoside and chlorogenic acid from Prunus mume on adrenocorticotropic hormone (ACTH) and catecholamine levels in plasma of experimental menopausal model rats.

    PubMed

    Ina, Hiroji; Yamada, Kenji; Matsumoto, Kosai; Miyazaki, Toshio

    2004-01-01

    To investigate the effectiveness of benzyl beta-D-glucopyranoside (BG) and chlorogenic acid (CA), the constituents of the fruit of Prunus mume, for relieving tension in experimental menopausal model rats (M-rats) caused by ether stress, the effects of BG and CA on adrenocorticotropic hormone (ACTH) and catecholamine (adrenaline, noradrenaline, and dopamine) levels were examined in the plasma of M-rats. Caffeic acid, quinic acid, and rosmarinic acid, which are compounds structurally related to CA, were also examined. BG obviously recovered catecholamine levels decreased by ether stress and increased dopamine to high levels. On the other hand, CA significantly decreased the ACTH level increased by ether stress and showed the greatest effect of all compounds. These results suggest that BG and CA may contribute to relieving the tension in M-rats caused by ether stress.

  15. Adrenocorticotropic hormone therapy for the treatment of idiopathic nephrotic syndrome in children and young adults: a systematic review of early clinical studies with contemporary relevance.

    PubMed

    Lieberman, Kenneth V; Pavlova-Wolf, Anna

    2017-02-01

    Adrenocorticotropic hormone (ACTH) as a treatment for proteinuria due to nephrotic syndrome (NS) has re-emerged over the last decade. Current clinical data are primarily limited to adults with treatment-resistant NS. Largely unknown to today's clinicians is the existence of early clinical studies, following ACTH's introduction in the late 1940s, showing sustained proteinuria response in idiopathic NS in predominantly pediatric, treatment-naïve patients. Before ACTH, patients suffered severe edema and high mortality rates with no reliable or safe treatment. ACTH dramatically altered NS management, initially through recognition of diuresis effects and then through sustained proteinuria remission. This review synthesizes early clinical literature to inform current NS patient management. We undertook a MEDLINE search using MeSH terms "adrenocorticotropic hormone" and "nephrotic syndrome," with limits 1945-1965 and English. Sixty papers totaling 1137 patients were found; 14 studies (9 short-term, five long-term, N = 419 patients) met inclusion criteria. Studies were divided into two groups: short-term (≤28 days) and long-term (>5 weeks; short-term initial daily treatment followed by long-term intermittent)ACTH therapy and results were aggregated. An initial response, defined as a diuresis, occurred in 74 % of patients/treatment courses across nine short-term ACTH studies. Analyzed in eight of these studies, proteinuria response occurred in 56 % of patients/treatment courses. Across five long-term ACTH studies, proteinuria response was shown in 71 % of patients and was sustained up to 4.7 years following treatment. The inventory and re-evaluation of early clinical data broadens the evidence base of clinical experiences with ACTH for implementation of current treatment strategies and aiding the design of future studies.

  16. Nutrient Sensing Overrides Somatostatin and Growth Hormone-Releasing Hormone to Control Pulsatile Growth Hormone Release.

    PubMed

    Steyn, F J

    2015-07-01

    Pharmacological studies reveal that interactions between hypothalamic inhibitory somatostatin and stimulatory growth hormone-releasing hormone (GHRH) govern pulsatile GH release. However, in vivo analysis of somatostatin and GHRH release into the pituitary portal vasculature and peripheral GH output demonstrates that the withdrawal of somatostatin or the appearance of GHRH into pituitary portal blood does not reliably dictate GH release. Consequently, additional intermediates acting at the level of the hypothalamus and within the anterior pituitary gland are likely to contribute to the release of GH, entraining GH secretory patterns to meet physiological demand. The identification and validation of the actions of such intermediates is particularly important, given that the pattern of GH release defines several of the physiological actions of GH. This review highlights the actions of neuropeptide Y in regulating GH release. It is acknowledged that pulsatile GH release may not occur selectively in response to hypothalamic control of pituitary function. As such, interactions between somatotroph networks, the median eminence and pituitary microvasculature and blood flow, and the emerging role of tanycytes and pericytes as critical regulators of pulsatility are considered. It is argued that collective interactions between the hypothalamus, the median eminence and pituitary vasculature, and structural components within the pituitary gland dictate somatotroph function and thereby pulsatile GH release. These interactions may override hypothalamic somatostatin and GHRH-mediated GH release, and modify pulsatile GH release relative to the peripheral glucose supply, and thereby physiological demand.

  17. Effect of blood plasma collected after adrenocorticotropic hormone administration during the preovulatory period in the sow on oocyte in vitro maturation.

    PubMed

    González, R; Sjunnesson, Y C B

    2013-10-01

    Reproduction may be affected by stressful events changing the female endocrine or metabolic profile. An altered environment during oocyte development could influence the delicate process of oocyte maturation. Here, the effect of simulated stress by media supplementation with blood plasma from sows after adrenocorticotropic hormone (ACTH) administration during the preovulatory period was assessed. Oocytes were matured for 46 hours in the presence of plasma from ACTH-treated sows, or plasma from NaCl-treated control sows, or medium without plasma (BSA group). The plasma used had been collected at 36 and 12 hours (±2 hours) before ovulation (for the first 24 hours + last 22 hours of maturation, respectively). Subsequent fertilization and embryo development were evaluated. Actin cytoskeleton and mitochondrial patterns were studied by confocal microscopy both in the oocytes and the resulting blastocysts. Nuclear maturation did not differ between treatments. Subtle differences were observed in the actin microfilaments in oocytes; however, mitochondrial patterns were associated with the treatment (P < 0.001). These differences in mitochondrial patterns were not reflected by in vitro outcomes, which were similar in all groups. In conclusion, an altered hormonal environment provided by a brief exposure to plasma from ACTH-treated sows during in vitro oocyte maturation could induce alterations in actin cytoskeleton and mitochondrial patterns in oocytes. However, these changes might not hamper the subsequent in vitro embryo development.

  18. Effects of cortisol secreted via a 12-h infusion of adrenocorticotropic hormone on mineral homeostasis and bone metabolism in ovariectomized cows.

    PubMed

    Kim, D; Yamagishi, N; Devkota, B; Furuhama, K

    2012-10-01

    To evaluate the effects of endogenously secreted cortisol on mineral homeostasis and bone metabolism in cows, 4 ovariectomized Holstein cows were infused for 12 h with either an adrenocorticotropic hormone (ACTH) solution (0.5 mg/2 L isotonic NaCl solution per cow) or isotonic NaCl solution in a 2×2 crossover design. ACTH infusion stimulated cortisol secretion and increased plasma cortisol concentrations for 18 h (P<0.001), leading to an elevated plasma glucose concentration until 36 h (P<0.001). Plasma calcium and magnesium concentrations in ACTH-infused cows fluctuated within normal ranges, whereas hypophosphatemia was observed unequivocally. The biochemical bone resorption markers tartrate-resistant acid phosphatase 5b and hydroxyproline decreased following ACTH infusion (P<0.001 and P=0.003, respectively). Similarly, the bone formation marker, bone-specific alkaline phosphatase, decreased continuously until 72 h after the ACTH infusion (P<0.001). These results demonstrate that increased secretion of cortisol via a 12-h ACTH infusion disrupted homeostasis of inorganic phosphate and suppressed bone metabolism in ovariectomized cows without involving gonadal steroid hormones.

  19. Release of Multiple Hormones by a Direct Action of Interleukin-1 on Pituitary Cells

    DTIC Science & Technology

    1987-10-23

    monolayer culture was investigated. Recombinant human IL-I beta stimulated the secretion of adrenocorticotropic hormone, luteinizing hormone, growth ... hormone , and thyroid-stimulating hormone. Prolactin secretion by the monolayers was inhibited by similar doses. These concentrations of IL-I are within

  20. Luteinizing hormone (LH)-releasing hormone agonist reduces serum adrenal androgen levels in prostate cancer patients: implications for the effect of LH on the adrenal glands.

    PubMed

    Nishii, Masahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Oyama, Tetsunari; Suzuki, Kazuhiro

    2012-01-01

    Recently, adrenal androgens have been targeted as key hormones for the development of castration-resistant prostate cancer therapeutics. Although circulating adrenal androgens originate mainly from the adrenal glands, the testes also supply about 10%. Although widely used in androgen deprivation medical castration therapy, the effect of luteinizing hormone-releasing hormone (LH-RH) agonist on adrenal androgens has not been fully studied. In this study, changes in testicular and adrenal androgen levels were measured and compared to adrenocorticotropic hormone levels. To assess the possible role of LH in the adrenal glands, immunohistochemical studies of the LH receptor in normal adrenal glands were performed. Forty-seven patients with localized or locally progressive prostate cancer were treated with LH-RH agonist with radiotherapy. Six months after initiation of treatment, testosterone, dihydrotestosterone, and estradiol levels were decreased by 90%-95%, and dehydroepiandrosterone-sulfate, dehydroepiandrosterone, and androstenedione levels were significantly decreased by 26%-40%. The suppressive effect of LH-RH agonist at 12 months was maintained. Adrenocorticotropic hormone levels showed an increasing trend at 6 months and a significant increase at 12 months. LH receptors were positively stained in the cortex cells of the reticular layer of the adrenal glands. The long-term LH-RH agonist treatment reduced adrenal-originated adrenal androgens. LH receptors in the adrenal cortex cells of the reticular layer might account for the underlying mechanism of reduced adrenal androgens.

  1. Mu-opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic-pituitary-adrenal axis adrenocorticotropic hormone stress response to metyrapone.

    PubMed

    Ducat, Elizabeth; Ray, Brenda; Bart, Gavin; Umemura, Yoshie; Varon, Jack; Ho, Ann; Kreek, Mary Jeanne

    2013-03-01

    The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

  2. A possible analytical and clinical role of endogenous antibodies causing discrepant adrenocorticotropic hormone measurement in a case of ectopic Cushing's syndrome.

    PubMed

    Saiegh, Leonard; Odeh, Majed; Chen-Konak, Limor; Elias, Nizar; Sheikh-Ahmad, Mohammad; Reut, Maria; Slobodin, Gleb; Bejar, Jacob; Shechner, Carmela

    2014-07-01

    Heterophilic antibodies are well described, but poorly appreciated interferents and is often not a recognized problem affecting most immunoassays. We report a patient presented with ectopic Cushing's syndrome (CS), but repeated plasma adrenocorticotropic hormone (ACTH) concentrations conducted by immunoassay were inappropriately within the reference range and not elevated, most probably as a result of antibody interference. A 36-year-old woman, presented with large gastric neuroendocrine carcinoma and severe ectopic CS, while repeated plasma ACTH concentrations conducted by immunoassay were inappropriately within the reference range. As we expected ACTH concentration to be higher, we performed several tests to evaluate whether there was any assay interference causing falsely lower than expected ACTH results. We measured ACTH using a different immunoassay, assayed the sample in dilution, assayed the sample after being incubated in heterophilic antibody blocking agent tube and performed recovery studies. Tests indicated the presence of interfering compounds, most probably heterophilic antibodies. When clinicians find ACTH concentrations to be lower than expected, we recommend the laboratory investigate antibody interference.

  3. Mapping the human melanocortin 2 receptor (adrenocorticotropic hormone receptor; ACTHR) gene (MC2R) to the small arm of chromosome 18 (18p11. 21-pter)

    SciTech Connect

    Vamvakopoulos, N.C.; Chrousos, G.P. ); Rojas, K.; Overhauser, J. ); Durkin, A.S.; Nierman, W.C. )

    1993-11-01

    The human adrenocorticotropic hormone receptor (ACTHR) was recently cloned and shown to belong to the superfamily of membrane receptors that couple to guanine nucleotide-binding proteins and adenylyl cyclase. A genetically heterogeneous (including both X-linked and autosomally recessive forms) congenital syndrome of general hereditary adrenal unresponsiveness to ACTH has been documented in several kindreds. This inherited defect affects one of the steps in the cascade of events of ACTH action on glucocorticoid biosynthesis, without altering mineralocorticoid productions. Since candidate targets for pathophysiological manifestations of deficient responsiveness to ACTH include lesions of the ACTHR gene, the authors undertook to map it to a chromosomal location. They first used polymerase chain reaction (PCR) amplification of NIGMS Panel 1 DNA template to assign a 960-bp-long fragment of the human ACTHR gene to chromosome 18. Subsequently, they determined the location of the ACTHR gene within human chromosome 18 by PCR amplification of genomic DNA template from somatic cell hybrids that contain deletions of this chromosome.

  4. Seasonal and sex differences in responsiveness to adrenocorticotropic hormone contribute to stress response plasticity in red-sided garter snakes (Thamnophis sirtalis parietalis).

    PubMed

    Dayger, Catherine A; Lutterschmidt, Deborah I

    2016-04-01

    As in many vertebrates, hormonal responses to stress vary seasonally in red-sided garter snakes (Thamnophis sirtalis parietalis). For example, males generally exhibit reduced glucocorticoid responses to a standard stressor during the spring mating season. We asked whether variation in adrenal sensitivity to adrenocorticotropic hormone (ACTH) explains why glucocorticoid responses to capture stress vary with sex, season and body condition in red-sided garter snakes. We measured glucocorticoids at 0, 1 and 4 h after injection with ACTH (0.1 IU g(-1)body mass) or vehicle in males and females during the spring mating season and autumn pre-hibernation period. Because elevated glucocorticoids can influence sex steroids, we also examined androgen and estradiol responses to ACTH. ACTH treatment increased glucocorticoids in both sexes and seasons. Spring-collected males had a smaller integrated glucocorticoid response to ACTH than autumn-collected males. The integrated glucocorticoid response to ACTH differed with sex during the spring, with males having a smaller glucocorticoid response than females. Although integrated glucocorticoid responses to ACTH did not vary with body condition, we observed an interaction among season, sex and body condition. In males, ACTH treatment did not alter androgen levels in either season, but androgen levels decreased during the sampling period. Similar to previous studies, plasma estradiol was low or undetectable during the spring and autumn, and therefore any effect of ACTH treatment on estradiol could not be determined. These data provide support for a mechanism that partly explains how the hypothalamus-pituitary-adrenal (HPA) axis integrates information about season, sex and body condition: namely, variation in adrenal responsiveness to ACTH.

  5. Blood plasma collected after adrenocorticotropic hormone administration during the preovulatory period in the sow negatively affects in vitro fertilization by disturbing spermatozoa function.

    PubMed

    González, R; Kumaresan, A; Bergqvist, A S; Sjunnesson, Y C B

    2015-04-15

    Successful fertilization is essential for reproduction and might be negatively affected by stressful events, which could alter the environment where fertilization occurs. The aim of the study was to determine whether an altered hormonal profile in blood plasma caused by adrenocorticotropic hormone (ACTH) administration could affect in vitro fertilization in the pig model. In experiment 1, gametes were exposed for 24 hours to plasma from ACTH-treated, non-ACTH-treated sows, or medium with BSA. Fertilization, cleavage, and blastocyst rates were lower in the ACTH group compared with the no ACTH or BSA control groups (P < 0.01). In experiment 2, the exposure of matured oocytes for 1 hour before fertilization to the same treatments did not have an impact on their ability to undergo fertilization or on embryo development. In experiment 3, spermatozoa were incubated for 0, 1, 4, and 24 hours under the same conditions. There was no effect of treatment on sperm viability. The percentage of acrosome-reacted spermatozoa remained higher in the ACTH group compared with the non-ACTH-treated group through the incubation period (P < 0.001). Protein tyrosine phosphorylation (PTP) patterns were also affected by treatment (P < 0.001). The presence of an atypical PTP pattern was higher in the ACTH group at all the analyzed time points compared with the BSA and no ACTH groups (P < 0.001). In conclusion, this altered environment may not affect oocyte competence but might affect the sperm fertilizing ability through alterations in the acrosome reaction and correct sequence of PTP patterns.

  6. Stress Hormones and their Regulation in a Captive Dolphin Population

    DTIC Science & Technology

    2013-09-30

    stimulation experiments, an animal’s hormonal and physiological response to a simulated stressor can be evaluated. Adrenocorticotropic hormone (ACTH) is...1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Stress Hormones and Their Regulation in a Captive...will determine baseline levels of putative stress hormones and evaluate the functional consequences of increased stress in the bottlenose dolphin

  7. Fuel oil-induced adrenal hypertrophy in ranch mink (Mustela vison): effects of sex, fuel oil weathering, and response to adrenocorticotropic hormone.

    PubMed

    Mohr, F C; Lasley, B; Bursian, S

    2010-01-01

    Environmental contamination by petroleum hydrocarbons from anthropogenic sources can be a cause of stress for free-ranging wildlife. The response of wildlife to chemical contaminants requires that the hypothalamic-pituitary-adrenal (HPA) axis be precisely regulated to allow for proper glucocorticoid-mediated adaptive responses. Chronic oral exposure to low concentrations of bunker C fuel oil causes the development of adrenal hypertrophy in male ranch mink (Mustela vison) without increasing serum or fecal glucocorticoid concentrations. This hypertrophy is an adaptive response to fuel oil-induced adrenal insufficiency. To determine if the same phenomenon occurs in female mink or male mink exposed to artificially weathered fuel oil, female mink were fed 0 ppm (mineral oil) or 420 ppm fuel oil and male mink were exposed to 0 ppm, 420 ppm fuel oil, or 480 ppm artificially weathered fuel oil in the diet for 60-62 days. At the end of the exposure, serum glucocorticoid concentrations were assayed along with body and organ weight measurements. Fecal glucocorticoid concentrations were assayed at time points throughout the exposure. Male mink fed fuel oil or weathered fuel oil and female mink fed fuel oil had adrenal enlargement without any significant increases in the serum or fecal concentration of glucocorticoids, which is consistent with fuel oil-induced adrenal insufficiency. To address the physiological consequences of adrenal insufficiency, fuel oil-exposed male mink were administered an adrenocorticotropic hormone (ACTH) stimulation test. Fuel oil-exposed animals had a smaller incremental increase in serum glucocorticoid concentration after ACTH challenge compared to control animals. Our findings provide further evidence that the HPA axis of fuel oil-exposed animals is compromised and, therefore, not able to respond appropriately to the diverse stressors found in the environment.

  8. Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats.

    PubMed

    Kawaura, Kazuaki; Ogata, Yukino; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

    2016-04-01

    We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5-7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti-immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl-p-tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p-chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline α2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D1 receptors and adrenaline α2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH-treated rats.

  9. Adrenocorticotropic hormone but not high-density lipoprotein cholesterol or salivary cortisol was a predictor of adrenal insufficiency in patients with septic shock.

    PubMed

    Festti, Josiane; Grion, Cintia Magalhães Carvalho; Festti, Luciana; Mazzuco, Tânia Longo; Lima-Valassi, Helena Pantelion; Brito, Vinícius Nahime; Barbosa, Décio Sabbatini; Carrilho, Alexandre José Faria

    2014-07-01

    Relative adrenal insufficiency in sepsis has been extensively debated on; however, accurate diagnosis and therapeutic intervention remain controversial. The authors aimed to evaluate adrenocorticotropic hormone (ACTH), salivary cortisol, total cortisol and estimated plasma-free cortisol, cholesterol, and lipoproteins as predictors of adrenal insufficiency in patients within 24 h of septic shock diagnosis. This prospective study evaluated all hospitalized patients older than 18 years who developed septic shock and were using vasoactive drugs within 24 h of diagnosis. Blood and saliva samples were drawn at baseline and 60 min (T60) after 250 μg tetracosactide intravenous injection. Patients were divided into two groups: responders (Δ [T60 minus baseline] total cortisol >9 μg/dL) and nonresponders (Δ total cortisol ≤ 9 μg/dL or baseline total cortisol <10 μg/dL). The latter group was considered to have adrenal insufficiency. A total of 7,324 hospitalized patients were monitored, and 34 subjects with septic shock were included in the analysis. Adrenal insufficiency was found in 32.4%. Total cholesterol, high-density lipoprotein cholesterol, triglycerides, and salivary cortisol did not differ between groups. Estimated plasma-free cortisol was not better than total plasma cortisol in estimating adrenal function. Baseline endogenous ACTH was higher in nonresponders than responders (55.5 pg/mL vs. 18.3 pg/mL, respectively; P = 0.01). The cutoff ACTH value that discriminated patients with adrenal insufficiency was 31.5 pg/mL. Thus, endogenous ACTH measured within 24 h of septic shock diagnosis could predict adrenal response to tetracosactide.

  10. Adrenocorticotropic Hormone and PI3K/Akt Inhibition Reduce eNOS Phosphorylation and Increase Cortisol Biosynthesis in Long-Term Hypoxic Ovine Fetal Adrenal Cortical Cells.

    PubMed

    Newby, Elizabeth A; Kaushal, Kanchan M; Myers, Dean A; Ducsay, Charles A

    2015-08-01

    This study was designed to determine the role of the MEK/ERK1/2 and PI3K/Akt pathways in cortisol production and endothelial nitric oxide synthase (eNOS) phosphorylation (peNOS) in the ovine fetal adrenal in response to long-term hypoxia (LTH). Pregnant ewes were maintained at high altitude (3820 m) for the last 100 days of gestation (dGa). At 138 to 142 dGa, fetal adrenal cortical cells (FACs) were collected from LTH and age-matched normoxic fetuses. Cortisol production and peNOS were measured in response to pretreatment with the MEK/ERK1/2 pathway inhibitor UO126 (UO) and adrenocorticotropic hormone (ACTH) stimulation. UO126 reduced ACTH-stimulated cortisol in both normoxic and LTH FACs. UO126 alone or in combination with ACTH reduced peNOS in the normoxic group, while ACTH alone or ACTH + UO inhibited peNOS in LTH FACs. Additionally, cortisol was measured in response to pretreatment with UO and treatment with 22R-hydroxycholesterol (22R-OHC) or water-soluble cholesterol (WSC) with and without ACTH stimulation. UO126 had no effect on 22R-OHC-treated cells, but reduced cortisol in cells treated with WSC and/or ACTH. Cortisol and peNOS were also measured in response to pretreatment with PI3K/Akt pathway inhibitor Wortmannin (WT) and ACTH stimulation. Wortmannin further increased cortisol under ACTH-stimulated conditions and, like ACTH, reduced peNOS in LTH but not normoxic FACs. Together, these data suggest that in LTH FACs MEK/ERK1/2 does not regulate peNOS but that UO acts downstream from eNOS, possibly at cholesterol transport, to affect cortisol production in LTH FACs, while the PI3K/Akt pathway, along with ACTH, regulates peNOS and plays a role in the fetal adaptation to LTH in FACs.

  11. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

    SciTech Connect

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V. )

    1989-08-01

    Metal complexes related to the cytotoxic complexes cisplatin (cis-diamminedichloroplatinum(II)) and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

  12. Plurihormonal pituitary adenoma with concomitant adrenocorticotropic hormone (ACTH) and growth hormone (GH) secretion: a report of two cases and review of the literature.

    PubMed

    Rasul, Fahid Tariq; Jaunmuktane, Zane; Khan, Akbar Ali; Phadke, Rahul; Powell, Michael

    2014-01-01

    Plurihormonal pituitary adenomas are tumours that show immunoreactivity for more than one hormone that cannot be explained by normal adenohypophysial cytodifferentiation. The most common combinations in these adenomas include growth hormone (GH), prolactin (PRL) and one or more glycoprotein hormone sub-units (β-TSH, β-FSH, β-LH and αSU). The authors report two cases of a plurihormonal pituitary adenoma expressing the rare combination of ACTH and GH. They both underwent successful transphenoidal hypophysectomy (TSH). Long-term post-operative follow-up revealed no evidence of tumour recurrence. Due to the multiple secretions and plurihormonal characteristics clinical diagnosis of composite pituitary adenomas can be difficult. The authors discuss the diagnosis and management of composite pituitary adenomas and review the literature regarding this rare phenomenon.

  13. Action of luteinizing hormone-releasing hormone: involvement of novel arachidonic acid metabolites.

    PubMed Central

    Snyder, G D; Capdevila, J; Chacos, N; Manna, S; Falck, J R

    1983-01-01

    Anterior pituitary cells were incubated in the presence of luteinizing hormone-releasing hormone and one of three inhibitors of arachidonic acid metabolism:indomethacin, an inhibitor of the cyclooxygenase system; nordihydroguaiaretic acid, an antioxidant that inhibits lipoxygenase; and icosatetraynoic acid, an acetylenic analogue of arachidonic acid that blocks all known pathways of arachidonic acid metabolism. Indomethacin was ineffective in blocking luteinizing hormone-releasing hormone-stimulated luteinizing hormone secretion. Nordihydroguaiaretic acid was only marginally capable of inhibiting luteinizing hormone-releasing hormone-stimulated luteinizing hormone secretion. Icosatetraynoic acid at 10 microM completely inhibited stimulated luteinizing hormone secretion. Addition of several epoxygenated arachidonic acid metabolites to cells in vitro resulted in secretion of luteinizing hormone equal to or greater than that induced by 10 nM luteinizing hormone-releasing hormone. The half-maximal effective dose for these compounds was approximately 50 nM. The 5,6-epoxyicosatrienoic acid was the most potent of the compounds tested. These studies suggest that luteinizing hormone-releasing hormone-stimulated luteinizing hormone release is closely coupled with the production of oxidized arachidonic acid metabolites. Moreover, one or more of the epoxygenated arachidonic acid metabolites might be a component of the cascade of reactions initiated by luteinizing hormone-releasing hormone that ultimately results in secretion of luteinizing hormone. PMID:6344087

  14. Long-term bioeffects of 435-MHz radiofrequency radiation on selected blood-borne endpoints in cannulated rats. Volume 2. Plasma ACTH (adrenocorticotropic hormone) and plasma corticosterone. Final report, 20 August 1984-16 February 1986

    SciTech Connect

    Popovic, V.P.; Toler, J.C.; Bonasera, S.J.; Popovic, P.P.; Honeycutt, C.B.

    1987-08-01

    Two hundred adult male white rats with chronically implanted aortic cannulas were randomly divided into two groups. Animals in the first group were exposed to low-level (1.0 mW/cm2) pulsed-wave 435-MHz radiofrequency radiation (RFR) for approximately 22 h daily, 7 days each week, for 6 months. Animals in the second group were maintained under identical conditions, but were not radiated. The cannulas were used to draw microsamples (0.3 mL) of aortic blood from the unrestrained, unanesthetized rats on a cyclic schedule. Plasma adrenocorticotropic hormone (ACTH) and plasma corticosterone concentrations were determined by radioimmunoassays hormone (ACTH) and plasma corticosterone concentrations were determined by radioimmunoassays. Statistical analysis of the results did not indicate increased plasma ACTH and plasma corticosterone concentrations in exposed animals when compared to sham-exposed animals. Exposure to this low-level radiofrequency environment did not induce stresses that were manifested as an alteration in plasma hormones.

  15. Concentrations of the adrenocorticotropic hormone, corticosterone and sex steroid hormones and the expression of the androgen receptor in the pituitary and adrenal glands of male turkeys (Meleagris gallopavo) during growth and development.

    PubMed

    Kiezun, J; Kaminska, B; Jankowski, J; Dusza, L

    2015-01-01

    Androgens take part in the regulation of puberty and promote growth and development. They play their biological role by binding to a specific androgen receptor (AR). The aim of this study was to evaluate the expression of AR mRNA and protein in the pituitary and adrenal glands, to localize AR protein in luteinizing hormone (LH)-producing pituitary and adrenocortical cells, to determine plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone and the concentrations of corticosterone, testosterone (T), androstenedione (A4) and oestradiol (E2) in the adrenal glands of male turkeys at the age of 4, 8, 12, 16, 20, 24 and 28weeks. The concentrations of hormones and the expression of AR varied during development. The expression of AR mRNA and protein in pituitary increased during the growth. The increase of AR mRNA levels in pituitary occurred earlier than increase of AR protein. The percentage of pituitary cells expressing ARs in the population of LH-secreting cells increased in week 20. It suggests that AR expression in LH-producing pituitary cells is determined by the phase of development. The drop in adrenal AR mRNA and protein expression was accompanied by an increase in the concentrations of adrenal androgens. Those results could point to the presence of a compensatory mechanism that enables turkeys to avoid the potentially detrimental effects of high androgen concentrations. Our results will expand our knowledge of the role of steroids in the development of the reproductive system of turkeys from the first month of age until maturity.

  16. The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW.

    PubMed

    Nøhr, Anne Cathrine; Shehata, Mohamed A; Hauser, Alexander S; Isberg, Vignir; Mokrosinski, Jacek; Andersen, Kirsten B; Farooqi, I Sadaf; Pedersen, Daniel Sejer; Gloriam, David E; Bräuner-Osborne, Hans

    2017-01-01

    GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle "similar targets bind similar ligands", we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca(2+)-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9 was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.

  17. Growth hormone (GH)-releasing activity of chicken GH-releasing hormone (GHRH) in chickens.

    PubMed

    Harvey, S; Gineste, C; Gaylinn, B D

    2014-08-01

    Two peptides with sequence similarities to growth hormone releasing hormone (GHRH) have been identified by analysis of the chicken genome. One of these peptides, chicken (c) GHRH-LP (like peptide) was previously found to poorly bind to chicken pituitary membranes or to cloned and expressed chicken GHRH receptors and had little, if any, growth hormone (GH)-releasing activity in vivo or in vitro. In contrast, a second more recently discovered peptide, cGHRH, does bind to cloned and expressed cGHRH receptors and increases cAMP activity in transfected cells. The possibility that this peptide may have in vivo GH-releasing activity was therefore assessed. The intravenous (i.v.) administration of cGHRH to immature chickens, at doses of 3-100 μg/kg, significantly increased circulating GH concentrations within 10 min of injection and the plasma GH levels remained elevated for at least 30 min after the injection of maximally effective doses. The plasma GH responses to cGHRH were comparable with those induced by human (h) or porcine (p) GHRH preparations and to that induced by thyrotropin releasing hormone (TRH). In marked contrast, the i.v. injection of cGHRH-LP had no significant effect on circulating GH concentrations in immature chicks. GH release was also increased from slaughterhouse chicken pituitary glands perifused for 5 min with cGHRH at doses of 0.1 μg/ml or 1.0 μg/ml, comparable with GH responses to hGHRH1-44. In contrast, the perifusion of chicken pituitary glands with cGHRH-LP had no significant effect on GH release. In summary, these results demonstrate that cGHRH has GH-releasing activity in chickens and support the possibility that it is the endogenous ligand of the cGHRH receptor.

  18. Apelin is involved in postprandial responses and stimulates secretion of arginine-vasopressin, adrenocorticotropic hormone, and growth hormone in the ruminant.

    PubMed

    Sato, K; Takahashi, T; Kobayashi, Y; Hagino, A; Roh, S G; Katoh, K

    2012-04-01

    Apelin and its mRNA are expressed in several tissues, including the supraoptic and paraventricular nuclei in the hypothalamus. Although apelin is reported to be involved in the regulation of fluid homeostasis, little is known about the postprandial dynamics of apelin in plasma and its regulatory effects on the anterior pituitary hormones of ruminants. Therefore, the aims of this study were to investigate the following: (1) changes in plasma apelin concentrations in response to food intake under conditions of hydration (free access to water) or dehydration (water restriction), and (2) the effects of intravenous administration of apelin on plasma concentrations of arginine-vasopressin (AVP), ACTH, GH, and insulin. In Experiment 1 with the use of goats, the postprandial plasma apelin concentration was significantly increased under the dehydration condition compared with the hydration condition, and this increase was accompanied by increased plasma concentrations of AVP and ACTH after 24 h of dehydration. In Experiment 2 with the use of sheep and hydration conditions, the intravenous administration of apelin ([Pyr(1)]-apelin-13; 0.5 mg/head) caused a tendency to increase or caused a significant increase in plasma concentrations of AVP, ACTH, GH, insulin, and glucose. On the basis of these findings, we concluded that apelin is involved in the feeding process, and it regulates endocrine functions in the anterior pituitary gland via AVP in ruminant animals.

  19. Luteinizing hormone-releasing hormone agonists in premenopausal hormone receptor-positive breast cancer.

    PubMed

    Tan, Sing-Huang; Wolff, Antonio C

    2007-02-01

    Ovarian function suppression for the treatment of premenopausal breast cancer was first used in the late 19th century. Traditionally, ovarian function suppression had been accomplished irreversibly via irradiation or surgery, but analogues of the luteinizing hormone-releasing hormone (LH-RH) have emerged as reliable and reversible agents for this purpose, especially the LH-RH agonists. Luteinizing hormone-releasing hormone antagonists are in earlier stages of development in breast cancer and are not currently in clinical use. Luteinizing hormonereleasing hormone agonists act by pituitary desensitization and receptor downregulation, thereby suppressing gonadotrophin release. Limited information is available comparing the efficacies of the depot preparations of various agonists, but pharmacodynamic studies have shown comparable suppressive capabilities on estradiol and luteinizing hormone. At present, only monthly goserelin is Food and Drug Administration-approved for the treatment of estrogen receptor-positive, premenopausal metastatic breast cancer in the United States. Luteinizing hormone-releasing hormone agonists have proven to be as effective as surgical oophorectomy in premenopausal advanced breast cancer. They offer similar outcomes compared with tamoxifen, but the endocrine combination appears to be more effective than LH-RH agonists alone. In the adjuvant setting, LH-RH agonists versus no therapy reduce the annual odds of recurrence and death in women aged>50 years with estrogen receptor-positive tumors. Luteinizing hormone-releasing hormone agonists alone or in combination with tamoxifen have shown disease-free survival rates similar to chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil). Outcomes of chemotherapy with or without LH-RH agonists are comparable, though a few trials favor the combination in young premenopausal women (aged<40 years). Adjuvant LH-RH agonists with or without tamoxifen might be as efficacious as tamoxifen alone

  20. Variability of Hormonal Stress Markers and Stress Responses in a Large Cross-Sectional Sample of Elephant Seals

    DTIC Science & Technology

    2012-09-30

    adrenocorticotropic hormone (ACTH) and thyroid stimulating hormone (TSH) challenges and characterize the activation of the hypothalamic-pituitary-adrenal...1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Variability of Hormonal Stress Markers and Stress...number. 1. REPORT DATE 2012 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Variability of Hormonal Stress Markers and Stress

  1. Specific involvement of gonadal hormones in the functional maturation of growth hormone releasing hormone (GHRH) neurons.

    PubMed

    Gouty-Colomer, Laurie-Anne; Méry, Pierre-François; Storme, Emilie; Gavois, Elodie; Robinson, Iain C; Guérineau, Nathalie C; Mollard, Patrice; Desarménien, Michel G

    2010-12-01

    Growth hormone (GH) is the key hormone involved in the regulation of growth and metabolism, two functions that are highly modulated during infancy. GH secretion, controlled mainly by GH releasing hormone (GHRH), has a characteristic pattern during postnatal development that results in peaks of blood concentration at birth and puberty. A detailed knowledge of the electrophysiology of the GHRH neurons is necessary to understand the mechanisms regulating postnatal GH secretion. Here, we describe the unique postnatal development of the electrophysiological properties of GHRH neurons and their regulation by gonadal hormones. Using GHRH-eGFP mice, we demonstrate that already at birth, GHRH neurons receive numerous synaptic inputs and fire large and fast action potentials (APs), consistent with effective GH secretion. Concomitant with the GH secretion peak occurring at puberty, these neurons display modifications of synaptic input properties, decrease in AP duration, and increase in a transient voltage-dependant potassium current. Furthermore, the modulation of both the AP duration and voltage-dependent potassium current are specifically controlled by gonadal hormones because gonadectomy prevented the maturation of these active properties and hormonal treatment restored it. Thus, GHRH neurons undergo specific developmental modulations of their electrical properties over the first six postnatal weeks, in accordance with hormonal demand. Our results highlight the importance of the interaction between the somatotrope and gonadotrope axes during the establishment of adapted neuroendocrine functions.

  2. Inhibitory pathways and the inhibition of luteinizing hormone-releasing hormone release by alcohol

    PubMed Central

    Lomniczi, Alejandro; Mastronardi, Claudio A.; Faletti, Alicia G.; Seilicovich, Adriana; De Laurentiis, Andrea; McCann, Samuel M.; Rettori, Valeria

    2000-01-01

    In this research we examined the mechanisms by which ethanol (EtOH) inhibits luteinizing hormone-releasing hormone (LHRH) release from incubated medial basal hypothalamic explants. EtOH (100 mM) stimulated the release of two inhibitory neurotransmitters: γ-aminobutyric acid (GABA) and β-endorphin. EtOH also inhibited NO production, indicative of a suppression of nitric oxide synthase (NOS) activity. This inhibition was reversed by naltroxone (10−8 M), a μ-opioid receptor blocker, indicating that the inhibition of NOS by EtOH is mediated by β-endorphin. EtOH also blocked N-methyl-d-aspartic acid-induced LHRH release, but the blockade could not be reversed by either the GABA receptor blocker, bicuculline (10−5 M), naltroxone (10−8 M), or both inhibitors added together. However, increasing the concentration of naltrexone (10−6 M) but not bicuculline (10−4 M) reversed the inhibition. When we lowered the concentration of EtOH (50 mM), the EtOH-induced blockade of LHRH release could be reversed by either bicuculline (10−5 M), naltroxone (10−8 M), or the combination of the two blockers. Therefore, GABA is partially responsible for the blockade of N-methyl-d-aspartic acid-induced LHRH release. The block by GABA was exerted by inhibiting the activation of cyclooxygenase by NO, because it was reversed by prostaglandin E2, the product of activation of cyclooxygenase. Because the inhibition caused by the higher concentration of EtOH could not be reduced by bicuculline (10−4 M) but was blocked by naltroxone (10−6 M), the action of alcohol can be accounted for by stimulation of β-endorphin neurons that inhibit LHRH release by inhibition of activation of NOS and stimulation of GABA release. PMID:10688896

  3. Effects of inhaling the vapor of Lavandula burnatii super-derived essential oil and linalool on plasma adrenocorticotropic hormone (ACTH), catecholamine and gonadotropin levels in experimental menopausal female rats.

    PubMed

    Yamada, Kenji; Mimaki, Yoshihiro; Sashida, Yutaka

    2005-02-01

    The effects of inhaling the vapor of Lavandula burnatii super-derived essential oil and one of the main components of lavender oil, linalool on plasma adrenocorticotropic hormone (ACTH), catecholamine and gonadotropin levels in menopausal model rats under ether-inhalation were studied. The increased plasma ACTH levels induced by ether-inhalation tended to decrease by pre-inhalation of Lavandula burnetii super and linalool vapor was induced the decrease of ACTH level. The decrease in adrenaline, noradrenaline and dopamine levels induced by ether-inhalation tended to recover, especially, the dopamine level significantly recovered to the normal level by the inhalation of Lavandula burnetii super and linalool vapor. However, the increased plasma gonadotropin levels in ovariectomized retired female rats (menopausal model rats) was significantly decreased by the inhalation of linalool. These results suggest that lavender oil or one of the main components, linalool may contribute to relieving tension and may be applicable to the treatment of menopausal disorders in human beings.

  4. Gonadotropin-releasing hormone in the ovary.

    PubMed

    Metallinou, Chryssa; Asimakopoulos, Byron; Schröer, Andreas; Nikolettos, Nikos

    2007-12-01

    Gonadotropin-releasing hormone (GnRH) plays a pivotal role in the physiology of reproduction in mammals. GnRH acts by binding to the GnRH receptor (GnRHR). In humans, only 1 conventional GnRH receptor subtype (type I GnRH receptor) has been found. In the human genome, 2 forms of GnRH have been identified, GnRH-I (mammal GnRH) and GnRH-II (chicken GnRH II). Both forms and their common receptor are expressed, apart from the hypothalamus, in various compartments of the human ovary. Gonadal steroids, gonadotropins, and GnRH itself controls the regulation of the GnRH/GnRHR system gene expression in the human ovary. The 2 types of GnRH acting paracrinally/autocrinally influence ovarian steroidogenesis, decrease the proliferation, and induce apoptosis of ovarian cells. In this review, the biology of GnRH/GnRHR system in humans, the potential roles of GnRH, and the direct effects of GnRH analogues in ovarian cells are discussed.

  5. Glucoreceptors located in different areas mediate the hypoglycemia-induced release of growth hormone, prolactin, and adrenocorticotropin in man.

    PubMed

    Vigas, M; Tatár, P; Jurcovicová, J; Jezová, D

    1990-03-01

    In young male volunteers, the changes in growth hormone (GH), prolactin (PRL), and adrenocorticotropic hormone (ACTH) release in response to insulin injection combined with the infusion of saline, glucose, and fructose were evaluated. Glucose infusion in a dose which prevented insulin hypoglycemia completely abolished endocrine responses. Infusion of fructose, which is known not to cross the blood-brain barrier (BBB), did not influence the GH release during hypoglycemia; however, it inhibited PRL secretion. The ACTH response was slightly attenuated and delayed, while the hypoglycemia-induced rise in cortisol levels was not modified by fructose infusion. These data indicate that the glucoreceptors mediating the signals for a complete counterregulatory neuroendocrine response are not located in a single brain structure. Stimuli for GH release are produced in areas of the central nervous system protected by the BBB, while those for PRL release are presumably present in structures not protected by the BBB. Glucoreceptors triggering ACTH release are located both inside and outside the BBB.

  6. Localization of the genes encoding the melanocortin-2 (Adrenocorticotropic hormone) and melanocortin-3 receptors to chromosomes 18p11. 2 and 20q13. 2-q13. 3 by fluorescence in situ hybridization

    SciTech Connect

    Gantz, I.; Tashiro, Takao; Konda, Yoshitaka; Shimoto, Yoshimasa; Miwa, Hiroto; Munzert, G.; Barcroft, C.; Glover, T.; Yamada, Tadataka )

    1993-10-01

    Adrenocorticotropic hormone (ACTH) and [alpha]-, [beta]-, and [gamma]-melanocyte-stimulating hormone (MSH) are products of propiomelanocortin post-translational processing. These compounds are collectively labeled as melanocortins (MC). Aside from their established effects on the regulation of the adrenal cortex (ACTH) and melanocytes ([alpha]-MSH), the melanocortins have been implicated in a broad array of physiological events. Melanocortins mediate their effects through cell membrane receptors belonging to the superfamily of seven transmembrane G-protein-linked receptors. Using the technique of polymerase chain reaction with primers based on conserved areas of the seven transmembrane G-protein-linked receptor family, the authors recently isolated an [open quotes]orphan[close quotes] subfamily of this receptor group. Within the past year, two of these receptors were identified as specific for [alpha]-MSH (MC1) and ACTH (MC2). They have recently described a third melanocortin receptor (MC3) that appears to recognize the core heptapeptide sequence of melanocortins with equal potency and efficacy and identified its presence in the brain, placenta, and gut. Using the FISH technique, they localized the ACTH and the melanocortin-3 receptors to chromosome loci 18p11.2 and 20q12.3-q13.2, respectively. 19 refs., 1 fig.

  7. Luteinizing hormone release and androgen production of avian hybrids in response to luteinizing hormone releasing hormone injection.

    PubMed

    Mathis, G F; Burke, W H; McDougald, L R

    1983-04-01

    The levels of luteinizing hormone (LH) and androgens were measured in sterile avian hybrids. Guinea fowl-chicken and peafowl-guinea fowl hybrids were bled before and after injection with LH- releasing hormone (LHRH). The preinjection LH levels for the guinea fowl-chicken hybrids were below or at the very lower limit of the assay sensitivity and the peafowl-guinea fowl hybrids averaged 1.3 ng/ml. Within 10 min after LHRH injection, LH had increased dramatically in both hybrids and then began to slowly decline. Androgen levels in the guinea fowl-chicken hybrids increased from 16.2 pg/ml to 95.2 pg/ml and continued to increase, reaching 287 pg/ml at the last bleeding 60 min after injection.

  8. Voluntary wheel running modulates glutamate receptor subunit gene expression and stress hormone release in Lewis rats.

    PubMed

    Makatsori, A; Duncko, R; Schwendt, M; Moncek, F; Johansson, B B; Jezova, D

    2003-07-01

    Lewis rats that are known to be addiction-prone, develop compulsive running if they have access to running wheels. The present experiments were aimed 1) to evaluate the activation of stress systems following chronic and acute voluntary wheel running in Lewis rats by measurement of hormone release and gene expression of neuropeptides related to hypothalamic-pituitary-adrenocortical (HPA) axis activity and 2) to test the hypothesis that wheel running as a combined model of addictive behavior and stress exposure is associated with modulation of ionotropic glutamate receptor subunits in the ventral tegmental area. Voluntary running for three weeks but not for one night resulted in a rise in plasma corticosterone and adrenocorticotropic hormone (ACTH) levels (p<0.05) compared to those in control rats. Principal component analysis revealed the relation between POMC gene expression in the intermediate pituitary and running rate. Acute exposure of animals to voluntary wheel running induced a significant decrease in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor GluR1 subunit mRNA levels (p<0.01), while repeated voluntary physical activity increased levels of GluR1 mRNA in the ventral tegmentum (p<0.05). Neither acute nor chronic wheel running influenced N-methyl-D-aspartate (NMDA) receptor subunit NR1 mRNA levels in the ventral tegmental area. Thus, the present study revealed changes in AMPA receptor subunit gene expression in a reward-related brain structure as well as an activation of HPA axis in response to compulsive wheel running in Lewis rats. It may be suggested that hormones of HPA axis and glutamate receptors belong to the factors that substantiate higher vulnerability to addictive behavior.

  9. Effects of hypothalamic dopamine on growth hormone-releasing hormone-induced growth hormone secretion and thyrotropin-releasing hormone-induced prolactin secretion in goats.

    PubMed

    Jin, Jin; Hashizume, Tsutomu

    2015-06-01

    The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on the secretion of growth hormone (GH) in goats. The GH-releasing response to an intravenous (i.v.) injection of GH-releasing hormone (GHRH, 0.25 μg/kg body weight (BW)) was examined after treatments to augment central DA using carbidopa (carbi, 1 mg/kg BW) and L-dopa (1 mg/kg BW) in male and female goats under a 16-h photoperiod (16 h light, 8 h dark) condition. GHRH significantly and rapidly stimulated the release of GH after its i.v. administration to goats (P < 0.05). The carbi and L-dopa treatments completely suppressed GH-releasing responses to GHRH in both male and female goats (P < 0.05). The prolactin (PRL)-releasing response to an i.v. injection of thyrotropin-releasing hormone (TRH, 1 μg/kg BW) was additionally examined in male goats in this study to confirm modifications to central DA concentrations. The treatments with carbi and L-dopa significantly reduced TRH-induced PRL release in goats (P < 0.05). These results demonstrated that hypothalamic DA was involved in the regulatory mechanisms of GH, as well as PRL secretion in goats.

  10. Hormonal and lactational responses to growth hormone-releasing hormone treatment in lactating Japanese Black cows.

    PubMed

    Shingu, H; Hodate, K; Kushibiki, S; Ueda, Y; Touno, E; Shinoda, M; Ohashi, S

    2004-06-01

    Ten multiparous lactating Japanese Black cows (beef breed) were used to evaluate the effects of bovine growth hormone-releasing hormone (GHRH) analog on milk yield and profiles of plasma hormones and metabolites. The cows received 2 consecutive 21-d treatments (a daily s.c. injection of 3-mg GHRH analog or saline) in a 2 (group) x 2 (period) Latin square crossover design. The 5 cows in group A received GHRH analog during period 1 (from d 22 to 42 postpartum) and saline during period 2 (from d 57 to 77 postpartum), and those in group B received saline and GHRH analog during periods 1 and 2, respectively. Mean milk yield decreased in saline treated compared with that during the 1-wk period before treatment 7.4 and 19.1% during periods 1 (group B) and 2 (group A), respectively. Treatment with GHRH analog increased milk yield 17.4% (period 1, group A) and 6.3% (period 2, group B). Treatment with GHRH analog induced higher basal plasma concentrations of growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin, and glucose compared with saline-treated cows. In glucose challenge, the GHRH analog-treated beef cows had greater insulin secretion than the saline-treated beef cows. In insulin challenge, however, there were no significant differences in the areas surrounded by hypothetical lines of basal glucose concentrations and glucose response curves between GHRH analog- and saline-treated cows. These results demonstrate that GHRH analog treatment facilitates endogenous GH secretion in lactating Japanese Black cows, leading to increases in milk yield and plasma concentrations of IGF-1, insulin, and glucose.

  11. Profiling of adrenocorticotropic hormone and arginine vasopressin in human pituitary gland and tumor thin tissue sections using droplet-based liquid-microjunction surface-sampling-HPLC-ESI-MS-MS.

    PubMed

    Kertesz, Vilmos; Calligaris, David; Feldman, Daniel R; Changelian, Armen; Laws, Edward R; Santagata, Sandro; Agar, Nathalie Y R; Van Berkel, Gary J

    2015-08-01

    Described here are the results from the profiling of the proteins arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) from normal human pituitary gland and pituitary adenoma tissue sections, using a fully automated droplet-based liquid-microjunction surface-sampling-HPLC-ESI-MS-MS system for spatially resolved sampling, HPLC separation, and mass spectrometric detection. Excellent correlation was found between the protein distribution data obtained with this method and data obtained with matrix-assisted laser desorption/ionization (MALDI) chemical imaging analyses of serial sections of the same tissue. The protein distributions correlated with the visible anatomic pattern of the pituitary gland. AVP was most abundant in the posterior pituitary gland region (neurohypophysis), and ATCH was dominant in the anterior pituitary gland region (adenohypophysis). The relative amounts of AVP and ACTH sampled from a series of ACTH-secreting and non-secreting pituitary adenomas correlated with histopathological evaluation. ACTH was readily detected at significantly higher levels in regions of ACTH-secreting adenomas and in normal anterior adenohypophysis compared with non-secreting adenoma and neurohypophysis. AVP was mostly detected in normal neurohypophysis, as expected. This work reveals that a fully automated droplet-based liquid-microjunction surface-sampling system coupled to HPLC-ESI-MS-MS can be readily used for spatially resolved sampling, separation, detection, and semi-quantitation of physiologically-relevant peptide and protein hormones, including AVP and ACTH, directly from human tissue. In addition, the relative simplicity, rapidity, and specificity of this method support the potential of this basic technology, with further advancement, for assisting surgical decision-making. Graphical Abstract Mass spectrometry based profiling of hormones in human pituitary gland and tumor thin tissue sections.

  12. Gut hormone release after intestinal resection.

    PubMed Central

    Besterman, H S; Adrian, T E; Mallinson, C N; Christofides, N D; Sarson, D L; Pera, A; Lombardo, L; Modigliani, R; Bloom, S R

    1982-01-01

    To investigate the possible role of gut and pancreatic hormones in the adaptive responses to gut resection, plasma concentrations of the circulating hormones were measured, in response to a test breakfast, in patients with either small or large intestinal resection and in healthy control subjects. In 18 patients with partial ileal resection a significant threefold rise was found in basal and postprandial levels of pancreatic polypeptide, a fourfold increase in motilin, and more than a twofold increase in gastrin and enteroglucagon levels compared with healthy controls. In contrast, nine patients with colonic resection had a threefold rise in levels of pancreatic polypeptide only. One or more of these peptides may have a role in stimulating the adaptive changes found after gut resection. PMID:7117905

  13. Profiling of adrenocorticotropic hormone and arginine vasopressin in human pituitary gland and tumor thin tissue sections using droplet-based liquid-microjunction surface-sampling-HPLC–ESI-MS–MS

    DOE PAGES

    Kertesz, Vilmos; Calligaris, David; Feldman, Daniel R.; ...

    2015-06-18

    Described here are the results from the profiling of the proteins arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) from normal human pituitary gland and pituitary adenoma tissue sections using a fully automated droplet-based liquid microjunction surface sampling-HPLC-ESI-MS/MS system for spatially resolved sampling, HPLC separation, and mass spectral detection. Excellent correlation was found between the protein distribution data obtained with this droplet-based liquid microjunction surface sampling-HPLC-ESI-MS/MS system and those data obtained with matrix assisted laser desorption ionization (MALDI) chemical imaging analyses of serial sections of the same tissue. The protein distributions correlated with the visible anatomic pattern of the pituitary gland.more » AVP was most abundant in the posterior pituitary gland region (neurohypophysis) and ATCH was dominant in the anterior pituitary gland region (adenohypophysis). The relative amounts of AVP and ACTH sampled from a series of ACTH secreting and non-secreting pituitary adenomas correlated with histopathological evaluation. ACTH was readily detected at significantly higher levels in regions of ACTH secreting adenomas and in normal anterior adenohypophysis compared to non-secreting adenoma and neurohypophysis. AVP was mostly detected in normal neurohypophysis as anticipated. This work demonstrates that a fully automated droplet-based liquid microjunction surface sampling system coupled to HPLC-ESI-MS/MS can be readily used for spatially resolved sampling, separation, detection, and semi-quantitation of physiologically-relevant peptide and protein hormones, such as AVP and ACTH, directly from human tissue. In addition, the relative simplicity, rapidity and specificity of the current methodology support the potential of this basic technology with further advancement for assisting surgical decision-making.« less

  14. Profiling of adrenocorticotropic hormone and arginine vasopressin in human pituitary gland and tumor thin tissue sections using droplet-based liquid-microjunction surface-sampling-HPLC–ESI-MS–MS

    SciTech Connect

    Kertesz, Vilmos; Calligaris, David; Feldman, Daniel R.; Changelian, Armen; Laws, Edward R.; Santagata, Sandro; Agar, Nathalie Y. R.; Van Berkel, Gary J.

    2015-06-18

    Described here are the results from the profiling of the proteins arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) from normal human pituitary gland and pituitary adenoma tissue sections using a fully automated droplet-based liquid microjunction surface sampling-HPLC-ESI-MS/MS system for spatially resolved sampling, HPLC separation, and mass spectral detection. Excellent correlation was found between the protein distribution data obtained with this droplet-based liquid microjunction surface sampling-HPLC-ESI-MS/MS system and those data obtained with matrix assisted laser desorption ionization (MALDI) chemical imaging analyses of serial sections of the same tissue. The protein distributions correlated with the visible anatomic pattern of the pituitary gland. AVP was most abundant in the posterior pituitary gland region (neurohypophysis) and ATCH was dominant in the anterior pituitary gland region (adenohypophysis). The relative amounts of AVP and ACTH sampled from a series of ACTH secreting and non-secreting pituitary adenomas correlated with histopathological evaluation. ACTH was readily detected at significantly higher levels in regions of ACTH secreting adenomas and in normal anterior adenohypophysis compared to non-secreting adenoma and neurohypophysis. AVP was mostly detected in normal neurohypophysis as anticipated. This work demonstrates that a fully automated droplet-based liquid microjunction surface sampling system coupled to HPLC-ESI-MS/MS can be readily used for spatially resolved sampling, separation, detection, and semi-quantitation of physiologically-relevant peptide and protein hormones, such as AVP and ACTH, directly from human tissue. In addition, the relative simplicity, rapidity and specificity of the current methodology support the potential of this basic technology with further advancement for assisting surgical decision-making.

  15. Regulation of the Immune System by Hypothalamic Releasing Hormones.

    DTIC Science & Technology

    1987-11-01

    Meyer, W.J. 1987. Decreased mononuclear leukocyte TSH secretion in patients with major depression. Abstr. Society for Neuroscience. 14. Smith, E.M...corticotropin (ACTH). Also, presented are results that the hypothalamic releasing hormones for luteinizing hormone (LH) and thyrotropin ( TSH ) induce...lymphocytes to synthesize immunoreactive LH and TSH , respectively. Finally, we discuss our data that the ACTH receptor on lymphoeytes acts through

  16. Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency

    SciTech Connect

    Lustig, R.H.; Schriock, E.A.; Kaplan, S.L.; Grumbach, M.M.

    1985-08-01

    Five male children who received cranial irradiation for extrahypothalamic intracranial neoplasms or leukemia and subsequently developed severe growth hormone (GH) deficiency were challenged with synthetic growth hormone-releasing factor (GRF-44), in an attempt to distinguish hypothalamic from pituitary dysfunction as a cause of their GH deficiency, and to assess the readily releasable GH reserve in the pituitary. In response to a pulse of GRF-44 (5 micrograms/kg intravenously), mean peak GH levels rose to values higher than those evoked by the pharmacologic agents L-dopa or arginine (6.4 +/- 1.3 ng/mL v 1.5 +/- 0.4 ng/mL, P less than .05). The peak GH value occurred at a mean of 26.0 minutes after administration of GRF-44. These responses were similar to those obtained in children with severe GH deficiency due to other etiologies (peak GH 6.3 +/- 1.7 ng/mL, mean 28.0 minutes). In addition, there was a trend toward an inverse relationship between peak GH response to GRF-44 and the postirradiation interval. Prolactin and somatomedin-C levels did not change significantly after the administration of a single dose of GRF-44. The results of this study support the hypothesis that cranial irradiation in children can lead to hypothalamic GRF deficiency secondary to radiation injury of hypothalamic GRF-secreting neurons. This study also lends support to the potential therapeutic usefulness of GRF-44 or an analog for GH deficiency secondary to cranial irradiation.

  17. Mapping the human corticotropin releasing hormone binding protein gene (CRHBP) to the long arm of chromosome 5 (5q11.2-q13.3)

    SciTech Connect

    Vamvakopoulos, N.C.; Sioutopoulou, T.O.; Durkin, S.A.

    1995-01-01

    Unexpected stimulation or stress activates the heat shock protein (hsp) system at the cellular level and the hypothalamic-pituitary-adrenal (HPA) axis at the level of the whole organism. At the molecular level, these two systems communicate through the functional interaction between hsp90 and glucocorticoid receptor (GR). The corticotropin releasing hormone (CRH) system regulates the mammalian stress response by coordinating the activity of the HPA axis. It consists of the 41-amino-acid-long principal hypothalamic secretagogue for pituitary adrenocorticotropic hormone (ACTH), CRH, its receptor (CRHR), and its binding protein (CRHBP). Because of its central role in the coordination of stress response and whole body homeostasis, the CRH system has been implicated in the pathogenesis of neuroendocrine and psychiatric disease. 19 refs., 1 fig.

  18. Corticotropin-releasing hormone: Mediator of vertebrate life stage transitions?

    PubMed

    Watanabe, Yugo; Grommen, Sylvia V H; De Groef, Bert

    2016-03-01

    Hormones, particularly thyroid hormones and corticosteroids, play critical roles in vertebrate life stage transitions such as amphibian metamorphosis, hatching in precocial birds, and smoltification in salmonids. Since they synergistically regulate several metabolic and developmental processes that accompany vertebrate life stage transitions, the existence of extensive cross-communication between the adrenal/interrenal and thyroidal axes is not surprising. Synergies of corticosteroids and thyroid hormones are based on effects at the level of tissue hormone sensitivity and gene regulation. In addition, in representative nonmammalian vertebrates, corticotropin-releasing hormone (CRH) stimulates hypophyseal thyrotropin secretion, and thus functions as a common regulator of both the adrenal/interrenal and thyroidal axes to release corticosteroids and thyroid hormones. The dual function of CRH has been speculated to control or affect the timing of vertebrate life history transitions across taxa. After a brief overview of recent insights in the molecular mechanisms behind the synergic actions of thyroid hormones and corticosteroids during life stage transitions, this review examines the evidence for a possible role of CRH in controlling vertebrate life stage transitions.

  19. Long-Term Bioeffects of 435MHz Radiofrequency Radiation on Selected Blood-Borne Endpoints in Cannulated Rats. Volume 2. Plasma ACTH (adrenocorticotropic Hormone) and Plasma Corticosterone

    DTIC Science & Technology

    1987-08-01

    stress hormone concentrations. In this study , an increase in plasma corticosterone was observed after barbiturate anesthesia (Fig. 5). Plasma ACTH...C.H., and Schindler, J. In vitro and vivo adrenal corticosterone secretion following stress. Am J Physiol 196:579-582 (1959). 16. Gale, G.C...related thereto. The animals involved in this study were procured, maintained, and used in accordance with the Animal Welfare Act and the "Guide for

  20. Growth hormone release induced by growth hormone-releasing hexapeptide is not mediated by thyrotropin-releasing hormone in neonatal rats.

    PubMed

    Kacsóh, B; Kacsóh, G; Guzzardo, M B; Black, A C; Bisat, T

    1997-02-01

    GH-releasing hexapeptide (GHRP-6) and nursing stimulate GH secretion in rat pups via GH-releasing factors (GRFs: distinct from GH-releasing hormone (GHRH). It was determined whether GH secretion induced by GHRP-6 or nursing was mediated by TSH-releasing hormone (TRH) in 2-d-old rats. In vitro. GHRP-6 and TRH stimulated GH secretion of neonatal pituitary glands. At their maximally effective doses, GHRP-6 and TRH evoked approximately equal GH responses. Treatment with a combination of the maximally effective doses of GHRP-6 and TRH resulted in a GH response comparable to that evoked by either treatment alone. GHRP-6 in vivo induced a greater GH response than did TRH. Treatment in vivo with a combination of the maximally effective doses of GHRP-6 and TRH synergistically increased serum GH levels. Unlike GHRP-6 TRH was an effective stimulus of prolactin secretion either in vitro or in vivo. Nursing was an effective stimulus for GH secretion, but only marginally increased serum prolactin levels. The effects of either of the peptides and nursing on GH secretion were additive. These results suggest that GHRP-6 stimulates GH secretion both by acting directly on the pituitary gland and indirectly via a hypothalamic GRF. The indirect effect appears to be greater. The alternative GRFs released by GHRP-6 or nursing are distinct from each other and from TRH. These findings suggest that alternative GRFs play a significant role in the regulation of GH secretion in neonatal rats.

  1. Search for novel therapies for triple negative breast cancers (TNBC): analogs of luteinizing hormone-releasing hormone (LHRH) and growth hormone-releasing hormone (GHRH).

    PubMed

    Buchholz, Stefan; Seitz, Stephan; Engel, Jörg B; Montero, Alberto; Ortmann, Olaf; Perez, Roberto; Block, Norman L; Schally, Andrew V

    2012-04-01

    Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is clinically negative for the expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). Patients with TNBC have a worse clinical outcome, as measured by time to metastasis and median overall survival. Chemotherapy has been the mainstay of treatment of TNBC but responses are disappointing. A substantial proportion of TNBC expresses luteinizing hormone-releasing hormone (LHRH), receptors for LHRH, in addition to receptors for growth hormone-releasing hormone (GHRH). These receptors represent potential therapeutic targets. Potent antagonists of GHRH and LHRH receptors have been developed in recent years and these antagonists inhibit the growth, tumorigenicity and metastatic potential of various human experimental malignancies. These antagonists could be utilized for the treatment of TNBC. The targeted cytotoxic analog of LHRH, AN-152 (AEZS-108) containing doxorubicin, must also be strongly considered for therapy of TNBC. Experimental studies suggest the merit of clinical trials with LHRH antagonists and AEZS-108 in TNBC patients.

  2. Luteinizing Hormone-Releasing Hormone Distribution in the Anterior Hypothalamus of the Female Rats

    PubMed Central

    Castañeyra-Ruiz, Leandro; González-Marrero, Ibrahim; Castañeyra-Ruiz, Agustín; González-Toledo, Juan M.; Castañeyra-Ruiz, María; de Paz-Carmona, Héctor; Castañeyra-Perdomo, Agustín; Carmona-Calero, Emilia M.

    2013-01-01

    Luteinizing hormone-releasing hormone (LHRH) neurons and fibers are located in the anteroventral hypothalamus, specifically in the preoptic medial area and the organum vasculosum of the lamina terminalis. Most luteinizing hormone-releasing hormone neurons project to the median eminence where they are secreted in the pituitary portal system in order to control the release of gonadotropin. The aim of this study is to provide, using immunohistochemistry and female brain rats, a new description of the luteinizing hormone-releasing hormone fibers and neuron localization in the anterior hypothalamus. The greatest amount of the LHRH immunoreactive material was found in the organum vasculosum of the lamina terminalis that is located around the anterior region of the third ventricle. The intensity of the reaction of LHRH immunoreactive material decreases from cephalic to caudal localization; therefore, the greatest immunoreaction is in the organum vasculosum of the lamina terminalis, followed by the dorsomedial preoptic area, the ventromedial preoptic area, and finally the ventrolateral medial preoptic area, and in fibers surrounding the suprachiasmatic nucleus and subependymal layer on the floor of the third ventricle where the least amount immunoreactive material is found. PMID:25938107

  3. Development of gonadotropin-releasing hormone secretion and pituitary response.

    PubMed

    Glanowska, Katarzyna M; Burger, Laura L; Moenter, Suzanne M

    2014-11-05

    Acquisition of a mature pattern of gonadotropin-releasing hormone (GnRH) secretion from the CNS is a hallmark of the pubertal process. Little is known about GnRH release during sexual maturation, but it is assumed to be minimal before later stages of puberty. We studied spontaneous GnRH secretion in brain slices from male mice during perinatal and postnatal development using fast-scan cyclic voltammetry (FSCV) to detect directly the oxidation of secreted GnRH. There was good correspondence between the frequency of GnRH release detected by FSCV in the median eminence of slices from adults with previous reports of in vivo luteinizing hormone (LH) pulse frequency. The frequency of GnRH release in the late embryonic stage was surprisingly high, reaching a maximum in newborns and remaining elevated in 1-week-old animals despite low LH levels. Early high-frequency GnRH release was similar in wild-type and kisspeptin knock-out mice indicating that this release is independent of kisspeptin-mediated excitation. In vivo treatment with testosterone or in vitro treatment with gonadotropin-inhibitory hormone (GnIH) reduced GnRH release frequency in slices from 1-week-old mice. RF9, a putative GnIH antagonist, restored GnRH release in slices from testosterone-treated mice, suggesting that testosterone inhibition may be GnIH-dependent. At 2-3 weeks, GnRH release is suppressed before attaining adult patterns. Reduction in early life spontaneous GnRH release frequency coincides with the onset of the ability of exogenous GnRH to induce pituitary LH secretion. These findings suggest that lack of pituitary secretory response, not lack of GnRH release, initially blocks downstream activation of the reproductive system.

  4. Suppression of androgen production by D-tryptophan-6-luteinizing hormone-releasing hormone in man.

    PubMed Central

    Tolis, G; Mehta, A; Comaru-Schally, A M; Schally, A V

    1981-01-01

    Four male transsexual subjects were given a superactive luteinizing hormone-releasing hormone (LHRH) analogue, D-tryptophan-6-LHRH at daily doses of 100 micrograms for 3--6 mo. A decrease in beard growth, acne, and erectile potency was noted; the latter was documented objectively with the recordings of nocturnal penile tumescence episodes. Plasma testosterone and dihydrotestosterone levels fell to castrate values; basal prolactin and luteinizing hormone levels showed a small decline, whereas the acutely releasable luteinizing hormone was significantly suppressed. A rise of plasma testosterone from castrate to normal levels was demonstrable with the use of human chorionic gonadotropin. Discontinuation of treatment led to a normalization of erectile potency and plasma testosterone. The suppression of Leydig cell function by D-tryptophan-6-LHRH might have wide application in reproductive biology and in endocrine-dependent neoplasia (where it could replace surgical castration). PMID:6456277

  5. Gonadotropin-releasing hormone analogs: Understanding advantages and limitations.

    PubMed

    Kumar, Pratap; Sharma, Alok

    2014-07-01

    Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) analogs induces both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pituitary gonadotropin secretions are blocked upon desensitization when a continuous GnRH stimulus is provided by means of an agonist or when the pituitary receptors are occupied with a competitive antagonist. GnRH antagonists were not available originally; therefore, prolonged daily injections of agonist with its desensitizing effect were used. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge and thus to cause desensitization. This review provides an overview of the use of GnRH analogs which is potent therapeutic agents that are considerably useful in a variety of clinical indications from the past to the future with some limitations. These indications include management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumours, other than ovulation induction.

  6. Reciprocal regulation of a glucocorticoid receptor-steroidogenic factor-1 transcription complex on the Dax-1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex.

    PubMed

    Gummow, Brian M; Scheys, Joshua O; Cancelli, Victoria R; Hammer, Gary D

    2006-11-01

    Numerous genes required for adrenocortical steroidogenesis are activated by the nuclear hormone receptor steroidogenic factor 1 (SF-1) (NR5A1). Dax-1 (NR0B1), another nuclear hormone receptor, represses SF-1-dependent activation. Glucocorticoid products of the adrenal cortex provide negative feedback to the production of hypothalamic CRH and pituitary ACTH. We hypothesized that glucocorticoids stimulate an intraadrenal negative feedback loop via activation of Dax-1 expression. Reporter constructs show glucocorticoid-dependent synergy between SF-1 and glucocorticoid receptor (GR) in the activation of Dax-1, which is antagonized by ACTH signaling. We map the functional glucocorticoid response element between -718 and -704 bp, required for activation by GR and synergy with SF-1. Of three SF-1 response elements, only the -128-bp SF-1 response element is required for synergy with GR. Chromatin immunoprecipitation (ChIP) assays demonstrate that dexamethasone treatment increases GR and SF-1 binding to the endogenous murine Dax-1 promoter 10- and 3.5-fold over baseline. Serial ChIP assays reveal that that GR and SF-1 are part of the same complex on the Dax-1 promoter, whereas coimmunoprecipitation assay confirms the presence of a protein complex that contains both GR and SF-1. ACTH stimulation disrupts the formation of this complex by abrogating SF-1 binding to the Dax-1 promoter, while promoting SF-1 binding to the melanocortin-2 receptor (Mc2r) and steroidogenic acute regulatory protein (StAR) promoters. Finally, dexamethasone treatment increases endogenous Dax-1 expression and concordantly decreases StAR expression. ACTH signaling antagonizes the increase in Dax-1 yet strongly activates StAR transcription. These data indicate that GR provides feedback regulation of adrenocortical steroid production through synergistic activation of Dax-1 with SF-1, which is antagonized by ACTH activation of the adrenal cortex.

  7. Resistance to growth hormone releasing hormone and gonadotropins in Albright's hereditary osteodystrophy.

    PubMed

    Mantovani, Giovanna; Spada, Anna

    2006-05-01

    Heterozygous inactivating mutations in the Gs alpha gene cause Albright's hereditary osteo-dystrophy (AHO). Consistent with the observation that only maternally inherited mutations lead to resistance to hormone action (pseudohypoparathyroidism type Ia [PHP-Ia), recent studies have provided evidence for a predominant maternal origin of Gs alpha transcripts in endocrine organs, such as thyroid, gonad and pituitary. Accordingly, patients with PHP-Ia display variable degrees of resistance to parathyroid hormone (PTH), thyroid stimulating hormone (TSH), gonadotropins and growth hormone (GH) releasing hormone (GHRH). Although the incidence and the clinical and biochemical characteristics of PTH and TSH resistance have been widely investigated and described, the cause and significance of the reproductive dysfunction in AHO is still poorly understood. The clinical finding of alterations of GH secretion in these patients was described for the first time only 2 years ago. The present report briefly reviews the literature focusing on the actual knowledge about these last two subjects.

  8. Algorithmic complexity of growth hormone release in humans

    SciTech Connect

    Prank, K.; Wagner, M.; Brabant, G.

    1996-12-31

    Most hormones are secreted in an pulsatile rather than in a constant manner. This temporal pattern of pulsatile hormone release plays an important role in the regulation of cellular function and structure. In healthy humans growth hormone (GH) secretion is characterized by distinct pulses whereas patients bearing a GH producing tumor accompanied with excessive secretion (acromegaly) exhibit a highly irregular pattern of GH release. It has been hypothesized that this highly disorderly pattern of GH release in acromegaly arises from random events in the GH-producing tumor under decreased normal control of GH secretion. Using a context-free grammar complexity measure (algorithmic complexity) in conjunction with random surrogate data sets we demonstrate that the temporal pattern of GH release in acromegaly is not significantly different from a variety of stochastic processes. In contrast, normal subjects clearly exhibit deterministic structure in their temporal patterns of GH secretion. Our results support the hypothesis that GH release in acromegaly is due to random events in the GH-producing tumorous cells which might become independent from hypothalamic regulation. 17 refs., 1 fig., 2 tabs.

  9. Central effects of growth hormone-releasing hexapeptide (GHRP-6) on growth hormone release are inhibited by central somatostatin action.

    PubMed

    Fairhall, K M; Mynett, A; Robinson, I C

    1995-03-01

    Growth hormone (GH) release is stimulated by a variety of synthetic secretagogues, of which growth hormone-releasing hexapeptide (GHRP-6) has been most thoroughly studied; it is thought to have actions at both pituitary and hypothalamic sites. To evaluate the central actions of this peptide, we have studied GH release in response to direct i.c.v. injections in anaesthetized guinea pigs. GHRP-6 (0.04-1 microgram) stimulated GH release > 10-fold 30-40 min after i.c.v. injection. The same GH response required > 20-fold more GHRP-6 when given by i.v. injection. GH release could also be elicited by a non-peptide GHRP analogue (L-692,585, 1 microgram i.c.v.), whereas a growth hormone-releasing factor (GRF) analogue (human GRF27Nle(1-29)NH2, 2 micrograms, i.c.v.) was ineffective. A long acting somatostatin analogue (Sandostatin, SMS 201-995, 10 micrograms i.c.v.) (SMS) given 20 min before 200 ng GHRP-6 blocked GH release. This was unlikely to be due to a direct effect of SMS leaking out to the pituitary, since central SMS injections did not affect basal GH release, nor did they block GH release in response to i.v. GRF injections. We conclude that the hypothalamus is a major target for GHRP-6 in vivo. Since the GH release induced by central GHRP-6 injections can be inhibited by a central action of somatostatin, and other data indicate that GHRP-6 activates GRF neurones, we suggest that somatostatin may block this activation via receptors known to be located on or near the GRF cells themselves. Somatostatin may therefore be a functional antagonist of GHRP-6 acting centrally, as well as at the pituitary gland.

  10. Growth hormone secretion from chicken adenohypophyseal cells in primary culture: effects of human pancreatic growth hormone-releasing factor, thyrotropin-releasing hormone, and somatostatin on growth hormone release.

    PubMed

    Perez, F M; Malamed, S; Scanes, C G

    1987-03-01

    A primary culture of chicken adenohypophyseal cells has been developed to study the regulation of growth hormone (GH) secretion. Following collagenase dispersion, cells were exposed for 2 hr to vehicle (control) or test agents. Human pancreatic (tumor) growth hormone-releasing factor (hpGRF) and rat hypothalamic growth hormone-releasing factor stimulated GH release to similar levels. GH release was increased by the presence of dibutyryl cyclic AMP. Thyrotropin-releasing hormone (TRH) alone did not influence GH release; however, TRH plus hpGRF together exerted a synergistic (greater than additive) effect, increasing GH release by 100 to 300% over the sum of the values for each secretagogue acting alone. These relationships between TRH and hpGRF were further examined in cultured cells exposed to secretagogues for two consecutive 2-hr incubations. TRH pretreatment enhanced subsequent hpGRF-stimulated GH release by about 80% over that obtained if no secretagogue was present during the first incubation. In other experiments, somatostatin (SRIF) alone did not alter GH secretion. However, SRIF reduced hpGRF-stimulated GH release to levels found in controls. Furthermore, GH release stimulated by the presence of both TRH and hpGRF was lowered to control values by SRIF. The results of these studies demonstrate that a primary culture of chicken adenohypophyseal cells is a useful model for the study of GH secretion. Indeed, these results suggest that TRH and hpGRF regulate GH secretion by mechanisms which are not identical.

  11. Regulation of growth hormone secretion by the growth hormone releasing hexapeptide (GHRP-6).

    PubMed

    Micic, D; Mallo, F; Peino, R; Cordido, F; Leal-Cerro, A; Garcia-Mayor, R V; Casanueva, F F

    1993-01-01

    Growth hormone (GH) secretion is regulated by a complex system of central and peripheral signals. Recently, a new GH-releasing hexapeptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) called GHRP-6 which specifically releases GH has been studied. In the present work the mechanism of action of GHRP-6 has been addressed in experimental animal models as well as in obese subjects. GHRP-6 releases GH independently of the hypothalamic factors GHRH and somatostatin and is a powerful GH releaser in obesity.

  12. Mouse hypothalamic growth hormone-releasing hormone and somatostatin responses to probes of signal transduction systems.

    PubMed

    Sato, M; Downs, T R; Frohman, L A

    1993-01-01

    Signal transduction mechanisms involved in mouse growth hormone-releasing hormone (GRH) and somatostatin (SRIH) release were investigated using an in vitro perifusion system. Hypothalamic fragments were exposed to depolarizing agents, protein kinase A and C activators, and a calcium ionophore. The depolarizing agents, KCl (60 mM) and veratridine (50 microM), induced similar patterns of GRH and SRIH release. Somatostatin release in response to both agents was twofold greater than that of GRH. Forskolin (10 microM and 100 microM), an adenylate cyclase activator, stimulated both GRH and SRIH release, though with different secretory profiles. The SRIH response was prolonged and persisted beyond removal of the drug from the system, while the GRH response was brief, ending even prior to forskolin removal. Neither GRH nor SRIH were stimulated by 1,9-dideoxy-forskolin (100 microM), a forskolin analog with cAMP-independent actions. A23187 (5 microM), a calcium ionophore, stimulated the release of SRIH to a much greater extent than that of GRH. The GRH and SRIH secretory responses to PMA (1 microM), a protein kinase C activator, were similar, though delayed. The results suggest that 1) GRH and SRIH secretion are regulated by both protein kinase A and C pathways, and 2) depolarizing agents are important for the release of both hormones.

  13. Effect of Chlorotriazine Pesticides on Gonadotrophin Releasing Hormone in the Neuronal GT1-7 Cell Line and Hypothalamic Explants

    EPA Science Inventory

    Gonadotrophin releasing hormone (GnRH) stimulates the release of pituitary luteinizing hormone (LH) and follicle stimulating hormone. These pituitary hormones are necessary for normal reproductive function in both males and females. It is well recognized that disruption of nor...

  14. Sellar gangliocytoma with adrenocorticotropic and prolactin adenoma.

    PubMed

    Kissiedu, Juliana O; Prayson, Richard A

    2016-02-01

    We report a case of a 60-year-old man who presented with weight gain, headaches, dizziness, erectile dysfunction and decreased libido. He was found to have elevated adrenocorticotropic hormone (ACTH) and prolactin serum levels. The imaging studies revealed a 1.4 cm sella/suprasellar mass which was compressing the optic chiasm. Histologic slides of the lesion showed a pituitary adenoma, marked by a proliferation of biphenotypic appearing cells, associated with a gangliocytoma, and marked by a proliferation of atypical appearing neuronal cells arranged against a glial-appearing background. Pituitary adenoma-gangliocytomas are benign combination tumors that rarely occur in the sellar region. Adenomas in this setting are sometimes functional, and rare patients with mixed adenomas (adenomas secreting more than one hormone) have been reported. To our knowledge, there has been only one other report of a combined ACTH and prolactin-producing adenoma with gangliocytoma, reported in a patient who also had acromegaly. In our patient, the immunohistochemical stains demonstrated that the bulk of the adenoma cells stained with prolactin antibody, and scattered clusters of cells within the adenoma stained positively for ACTH. The adenoma did not stain with antibodies to any of the other anterior pituitary hormones. Postoperatively, the elevated prolactin and ACTH levels returned to normal levels and there was no evidence of residual tumor. Adequate sampling and immunohistochemistry are important in rendering a correct diagnosis and in identifying the hormone status of mixed adenoma-gangliocytomas.

  15. Thyrotrophin-releasing hormone induces growth hormone secretion in adult hypothyroid fowl.

    PubMed

    Harvey, S; Scanes, C G; Klandorf, H

    1988-02-01

    While thyrotrophin-releasing hormone (TRH) stimulated growth hormone (GH) secretion in adult anesthetized cockerels, the GH response was blocked in anesthetized birds pretreated with thyroxine (T4) or triiodothyronine (T3). Moreover, whereas GH secretion in conscious adult birds was poorly responsive to TRH stimulation, conscious birds made hypothyroid by goitrogen pretreatment (with propylthiouracil, methimazole, or thiourea) were responsive to TRH challenge. Basal circulating GH concentrations in the goitrogen-pretreated birds were also higher than in the vehicle-injected controls. Surgical thyroidectomy similarly increased the basal GH concentration in adult birds and promoted TRH-induced GH secretion. These results demonstrate inhibitory effects of the thyroid hormones on basal and stimulated GH secretion in adult domestic fowl and suggest that GH release in adults is partly under tonic thyroidal inhibition.

  16. Corticotropin releasing hormone: therapeutic implications and medicinal chemistry developments.

    PubMed

    Keller, P A; Elfick, L; Garner, J; Morgan, J; McCluskey, A

    2000-06-01

    Corticotropin releasing hormone (CRH, sometimes known as CRF) is an endogenous 41 amino acid peptide that has been implicated in the onset of pregnancy, the 'fight or flight' response, in addition to a large number of physiological disorders. Recently, medicinal chemists have developed a number of potent and selective compounds that show promise in a vast array of therapeutic uses. Herein we review the current status of research.

  17. Active immunization to luteinizing hormone releasing hormone to inhibit the induction of mammary tumors in the rat

    SciTech Connect

    Ravdin, P.M.; Jordan, V.C.

    1988-01-01

    Immunization of female rats with a bovine serum albumin-luteinizing hormone releasing hormone conjugate results in suppression of dimethylbenzanthracene mammary tumor incidence. Tumor incidence was 1.3, and 1.29 tumors per rat in bovine serum albumin alone (n = 10) and unimmunized (n = 18) control groups, but no tumors were found in the bovine serum albumin-luteinizing hormone releasing hormone conjugate immunized animals (n = 10). In a second experiment immunization with bovine serum albumin-luteinizing hormone releasing hormone conjugates reduced tumor incidence to 0.3 tumors per rat (n = 10) from the 1.2 tumors per animal seen in the control animals (n = 10) immunized with bovine serum albumin alone. Bovine serum albumin-luteinizing hormone immunization caused the production of anti-LHRH antibodies, an interruption of estrous cycles, lowered serum estradiol and progesterone levels, and atrophy of the ovaries and uteri. Immunization BSA-hormone conjugates is a novel anti-tumor strategy.

  18. Ectopic Adrenocorticotropic Hormone and Corticotropin-Releasing Hormone Co-Secreting Tumors in Children and Adolescents Causing Cushing Syndrome: A Diagnostic Dilemma and How to Solve It

    PubMed Central

    Karageorgiadis, Alexander S.; Papadakis, Georgios Z.; Biro, Juliana; Keil, Meg F.; Lyssikatos, Charalampos; Quezado, Martha M.; Merino, Maria; Schrump, David S.; Kebebew, Electron; Patronas, Nicholas J.; Hunter, Maya K.; Alwazeer, Mouhammad R.; Karaviti, Lefkothea P.; Balazs, Andrea E.; Stratakis, Constantine A.

    2015-01-01

    Context: Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH-secreting tumors are discussed. Setting: A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009–2014. Patients: Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1–21), and 3 are female. Measurements: Clinical, biochemical, radiological features, treatment, and histological findings are described. Results: Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). Patients underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor. Conclusions: Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary. PMID:25291050

  19. Central administration of chicken growth hormone-releasing hormone decreases food intake in chicks.

    PubMed

    Tachibana, Tetsuya; Sugimoto, Ikue; Ogino, Madoka; Khan, Md Sakirul Islam; Masuda, Keiko; Ukena, Kazuyoshi; Wang, Yajun

    2015-02-01

    Growth hormone-releasing hormone (GHRH) is well known as a stimulator of growth hormone (GH) secretion. GHRH not only stimulates GH release but also modifies feeding behavior and energy homeostasis in rodents. In chickens (Gallus gallus domesticus), on the other hand, two types of GHRH, namely, chicken GHRH (cGHRH) and cGHRH-like peptide (cGHRH-LP), have been identified. The purpose of the present study was to investigate the effect of central injection of cGHRH and cGHRH-LP on feeding behavior in chicks. Intracerebroventricular (ICV) injection of both cGHRH and cGHRH-LP (0.04 to 1 nmol) significantly decreased food intake without any abnormal behavior in chicks. Furthermore, the feeding-inhibitory effect was not abolished by co-injection of the antagonist for pituitary adenylate cyclase-activating polypeptide (PACAP) or corticotropin-releasing hormone (CRH) receptors, suggesting that the anorexigenic effect of cGHRH and cGHRH-LP might not be related to the PACAP and CRH systems in the brain of chicks. Finally, 24-h food deprivation increased mRNA expression of cGHRH but not cGHRH-LP in the diencephalon. These results suggest that central cGHRH is related to inhibiting feeding behavior and energy homeostasis in chicks.

  20. Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine tumors of the thymus: 30-year experience with 16 patients at a single institute in the People’s Republic of China

    PubMed Central

    Chen, Ye-ye; Li, Shan-qing; Liu, Hong-sheng; Qin, Ying-zhi; Li, Li; Huang, Cheng; Bi, Ya-lan; Meng, Yun-xiao; He, Jia; Zhou, Xiao-yun; Ma, Dong-jie

    2016-01-01

    Background and purpose Thymic neuroendocrine carcinomas (TNECs) are extremely uncommon. Certain cases of TNECs can produce the adrenocorticotropic hormone (ACTH) and cause ectopic ACTH syndrome (EAS). The current literature on this topic consists mainly of case reports, and therapeutic guidelines are lacking. The aim of this study was to discuss the diagnosis, surgical management, and prognosis of EAS caused by TNECs to improve clinical experience with this rare disease. Methods From June 1984 to June 2014, at the Peking Union Medical College Hospital, the surgical interventions and follow-up outcomes of 16 consecutive patients (eight men and eight women) with EAS caused by TNECs were retrospectively analyzed. Results The median age was 32.5 years (range: 13–47 years), and the median disease duration was 8.5 months (range: 1–150 months). All patients presented with clinical and biochemical evidence indicating a diagnosis of Cushing’s syndrome. Contrast-enhanced thoracic computed tomography scans were critical to locating the ACTH-producing tumor and evaluating the feasibility of resection. All patients underwent surgery. One patient died of septicemia in the intensive care unit 2 weeks after surgery. No other morbidity or mortality occurred during the perioperative period. The median overall survival (OS) was 41 months (95% CI: 30.3–51.7 months), and the progression-free survival was 28 months (95% CI: 21.6–34.3 months). Both overall survival (P=0.002) and progression-free survival (P=0.030) improved significantly after complete resection. Conclusion TNEC is an extremely aggressive disease that should be considered when treating patients with Cushing’s syndrome due to ectopic ACTH secretion. In particular, all suspected patients should undergo contrast-enhanced thoracic computed tomography scans to facilitate early diagnosis. The current first-line treatment is surgical resection, and complete resection is a favorable prognostic factor. However

  1. Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli.

    PubMed Central

    Jaffe, C A; DeMott-Friberg, R; Barkan, A L

    1996-01-01

    The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion. PMID:8613546

  2. Biological activities of thionated thyrotropin-releasing hormone analogs.

    PubMed

    Lankiewicz, L; Bowers, C Y; Reynolds, G A; Labroo, V; Cohen, L A; Vonhof, S; Sirén, A L; Spatola, A F

    1992-04-15

    Analogs of thyrotropin-releasing hormone (Glp-His-Pro-NH2, TRH) have been prepared which contain thioamide moieties in the pyroglutamic acid ring, the carboxyamide proline terminus, and in both positions (dithio). These compounds have been tested for TSH-releasing activities (in vitro and in vivo), and for binding to TRH receptors in rat pituitary and cortex. The monothionated analogs showed no significant differences in TSH-releasing potency from TRH either in vitro or in vivo. However, with two thioamide replacements the potency decreases about 50%. Significantly, in terms of receptor selectivity, thionation has resulted in differentiation between brain receptors (pituitary and cortex). The Pro psi[CSNH2] and dithio analogs were more selective (higher affinity to pituitary receptors) than the parent hormone, while the analog containing a thioamide replacement in the pyroglutamyl ring had lower affinity and was not selective. These results suggest that the subtle exchange of sulphur for oxygen can have an important impact on both receptor selectivity and affinity within a biologically active peptide.

  3. In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue.

    PubMed

    Moradi, Shayli Varasteh; Varamini, Pegah; Steyn, Frederik; Toth, Istvan

    2015-11-10

    In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q(1)][w(6)]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax = 0.11 μg/ml) was reached at 2h (Tmax) following oral administration of the compound at 10mg/kg. The half-life was determined to be 2.6h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 μg/ml and a correlation coefficient of r(2) ≥ 0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases.

  4. [Stimulation test of the adenohypophysis with arginine, gonadotropin-releasing hormone (GRH), and thyrotropin-releasing hormone (TRH) in 45, XO patients with Turner's syndrome (author's transl)].

    PubMed

    Rudolf, K; Kyank, H; Göretzlehner, G; Kunkel, S

    1980-01-01

    Pituitary stimulation tests with arginine, gonadotropin-releasing hormone (GRH) and thyrotropin-releasing hormone (TRH) were performed in five 45, XO patients with Turner's syndrome. Their ages ranged from 12--17 years. Serum levels of LH, FSH, PRL, HGH, and TSH were measured by RIA. The hypothalamo-pituitary system appeared normal in the patients with Turner's syndrome.

  5. Therapeutic uses of gonadotropin-releasing hormone analogs.

    PubMed

    Andreyko, J L; Marshall, L A; Dumesic, D A; Jaffe, R B

    1987-01-01

    Since the discovery and synthesis of gonadotropin-releasing hormone (GnRH) in 1971, numerous long-acting agonistic and antagonistic analogs have been synthesized. Agonistic analogs were found to desensitize pituitary GnRH receptors with chronic use, resulting in decreased gonadotropin secretion and a hypogonadal state. These analogs are being investigated as potential contraceptives and in the treatment of several conditions in which decreased gonadal steroid production is desired. Substantial progress has been made in these areas. The purpose of this review is to provide the clinician with data regarding the potential clinical utility of this class of peptides.

  6. Pulsatile Release of Parathyroid Hormone from an Implantable Delivery System

    PubMed Central

    Liu, Xiaohua; Pettway, Glenda J.; McCauley, Laurie K.; Ma, Peter X.

    2007-01-01

    Intermittent (pulsatile) administration of parathyroid hormone (PTH) is known to improve bone micro-architecture, mineral density and strength. Therefore, daily injection of PTH has been clinically used for the treatment of osteoporosis. However, this regimen of administration is not convenient and is not a favorable choice of patients. In this study, an implantable delivery system has been developed to achieve pulsatile release of PTH. A well-defined cylindrical device was first fabricated with a biodegradable polymer, poly(lactic acid) (PLLA), using a reverse solid free form fabrication technique. Three-component polyanhydrides composed of sebacic acid, 1,3-bis(p-carboxyphenoxy) propane and poly(ethylene glycol) were synthesized and used as isolation layers. The polyanhydride isolation layers and PTH-loaded alginate layers were then stacked alternately within the delivery device. The gap between the stacked PTH-releasing core and the device frame was filled with PLLA to seal. Multi-pulse PTH release was achieved using the implantable device. The lag time between two adjacent pulses were modulated by the composition and the film thickness of the polyanhydride. The released PTH was demonstrated to be biologically active using an in vitro assay. Timed sequential release of multiple drugs has also been demonstrated. The implantable device holds promise for both systemic and local therapies. PMID:17576005

  7. Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland.

    PubMed

    Pyczek, Joanna; Buslei, Rolf; Schult, David; Hölsken, Annett; Buchfelder, Michael; Heß, Ina; Hahn, Heidi; Uhmann, Anja

    2016-04-25

    Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2(+) and Sox9(+) adult pituitary stem cells and to elevated expression levels of adrenocorticotropic hormone (Acth), growth hormone (Gh) and prolactin (Prl) in the adult gland. Inhibition of the pathway by cyclopamine reversed these effects indicating that active Hh signaling positively regulates proliferative processes of adult pituitary stem cells and hormone production in the anterior pituitary. Since hormone producing cells of the adenohypophysis as well as ACTH-, GH- and PRL-immunopositive adenomas express SHH and its target GLI1, we furthermore propose that excess HH signaling is involved in the development/maintenance of hormone-producing pituitary adenomas. These findings advance the understanding of physiological hormone regulation and may open new treatment options for pituitary tumors.

  8. Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland

    PubMed Central

    Pyczek, Joanna; Buslei, Rolf; Schult, David; Hölsken, Annett; Buchfelder, Michael; Heß, Ina; Hahn, Heidi; Uhmann, Anja

    2016-01-01

    Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2+ and Sox9+ adult pituitary stem cells and to elevated expression levels of adrenocorticotropic hormone (Acth), growth hormone (Gh) and prolactin (Prl) in the adult gland. Inhibition of the pathway by cyclopamine reversed these effects indicating that active Hh signaling positively regulates proliferative processes of adult pituitary stem cells and hormone production in the anterior pituitary. Since hormone producing cells of the adenohypophysis as well as ACTH-, GH- and PRL-immunopositive adenomas express SHH and its target GLI1, we furthermore propose that excess HH signaling is involved in the development/maintenance of hormone-producing pituitary adenomas. These findings advance the understanding of physiological hormone regulation and may open new treatment options for pituitary tumors. PMID:27109116

  9. Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women.

    PubMed

    Craig, Michael C; Fletcher, Paul C; Daly, Eileen M; Rymer, Janice; Cutter, William J; Brammer, Mick; Giampietro, Vincent; Wickham, Harvey; Maki, Pauline M; Murphy, Declan G M

    2007-01-01

    Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.

  10. Effects of retinoic acid on growth hormone-releasing hormone receptor, growth hormone secretagogue receptor gene expression and growth hormone secretion in rat anterior pituitary cells.

    PubMed

    Maliza, Rita; Fujiwara, Ken; Tsukada, Takehiro; Azuma, Morio; Kikuchi, Motoshi; Yashiro, Takashi

    2016-06-30

    Retinoic acid (RA) is an important signaling molecule in embryonic development and adult tissue. The actions of RA are mediated by the nuclear receptors retinoic acid receptor (RAR) and retinoid X receptor (RXR), which regulate gene expression. RAR and RXR are widely expressed in the anterior pituitary gland. RA was reported to stimulate growth hormone (GH) gene expression in the anterior pituitary cells. However, current evidence is unclear on the role of RA in gene expression of growth hormone-releasing hormone receptor (Ghrh-r), growth hormone secretagogue receptor (Ghs-r) and somatostatin receptors (Sst-rs). Using isolated anterior pituitary cells of rats, we examined the effects of RA on gene expression of these receptors and GH release. Quantitative real-time PCR revealed that treatment with all-trans retinoic acid (ATRA; 10(-6) M) for 24 h increased gene expression levels of Ghrh-r and Ghs-r; however, expressions of Sst-r2 and Sst-r5 were unchanged. Combination treatment with the RAR-agonist Am80 and RXR-agonist PA024 mimicked the effects of ATRA on Ghrh-r and Ghs-r gene expressions. Exposure of isolated pituitary cells to ATRA had no effect on basal GH release. In contrast, ATRA increased growth hormone-releasing hormone (GHRH)- and ghrelin-stimulated GH release from cultured anterior pituitary cells. Our results suggest that expressions of Ghrh-r and Ghs-r are regulated by RA through the RAR-RXR receptor complex and that RA enhances the effects of GHRH and ghrelin on GH release from the anterior pituitary gland.

  11. Basic understanding of gonadotropin-releasing hormone-agonist triggering.

    PubMed

    Casper, Robert F

    2015-04-01

    A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.

  12. Aging-reversing properties of thyrotropin-releasing hormone.

    PubMed

    Pierpaoli, Walter

    2013-02-01

    Thyrotropin-releasing hormone (TRH) aroused our interest when we were engaged in related experiments, so we decided to study its effects on organs, tissues, and aging-related metabolic and hormonal markers when administered in acute or chronic (oral) doses at various time points in its cyclic circadian pattern. We also wanted to determine what effects, if any, it had on aging processes in two essential systems, namely gonadal-reproductive and kidney-urinary. Our results show positive changes as a result of short-term acute and long-term chronic oral administration of TRH to old mice that included rapid correction to more juvenile levels of most typical aging-related hormonal and metabolic measurements. Remarkably, testes function was maintained by means of a 4-month oral treatment with TRH in aging mice. As we suspected upon seeing a significant increase in testes weight, TRH resulted in maintenance or even reconstitution of testes structure and function when administered in the drinking water. This was demonstrated by the active formation and proliferation of mature spermatogonia and the intensive spermatogenesis in the follicles. The same TRH treatment led to protection for the kidneys from amyloid and hyalin infiltration of tubuli and glomeruli, which typically occurs in aging mice. In fact, we observed massive deposits of amyloid and hyalin material infiltrating the shrunken glomeruli and negatively affecting filtration capacity of the untreated mice, whereas this was barely present in the TRH-treated mice. Advanced hyalin degeneration could also be observed in the tubular vessels of the untreated control mice. These experiments with TRH supplementation show clear aging-delaying and apparently even aging-reversing effects of the neuropeptide, whether it was administered parenterally or orally. TRH, like melatonin, is an anti-aging agent with a broad spectrum of activities that, because of their actions, suggest that TRH has a fundamental role in the regulation

  13. Precocious puberty associated with neurofibromatosis and optic gliomas. Treatment with luteinizing hormone releasing hormone analogue.

    PubMed

    Laue, L; Comite, F; Hench, K; Loriaux, D L; Cutler, G B; Pescovitz, O H

    1985-11-01

    Seven children with central precocious puberty and either neurofibromatosis and/or optic gliomas were referred to the National Institutes of Health, Bethesda, Md, for evaluation and treatment with the long-acting luteinizing hormone releasing hormone analogue (LHRHa) D-Trp6-Pro9-NEt-LHRH. Only six of the seven children chose to receive treatment. Four children presented with neurofibromatosis, three of whom also had optic gliomas; the remaining three children had isolated optic gliomas, without other neurocutaneous stigmas. All had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis. Six months of LHRHa therapy caused suppression of gonadotropin and sex steroid levels, stabilization or regression of secondary sexual characteristics, and decreases in growth velocity and the rate of bone age maturation. We conclude that LHRHa therapy is effective in the treatment of central precocious puberty secondary to neurofibromatosis and/or optic gliomas.

  14. Rationally designed cyclic analogues of luteinizing hormone-releasing hormone: enhanced enzymatic stability and biological properties.

    PubMed

    Laimou, Despina; Katsila, Theodora; Matsoukas, John; Schally, Andrew; Gkountelias, Kostas; Liapakis, George; Tamvakopoulos, Constantin; Tselios, Theodore

    2012-12-01

    This article describes the rational design, synthesis and pharmacological properties of amide-linked cyclic analogues of Luteinizing Hormone-Releasing Hormone (LHRH) with substitutions at positions 1 (Pro), 6 (D-Leu/D-Trp), 9 (Aze) and 10 (BABA/Acp). These LHRH analogues fulfil the conformational requirements that are known in the literature (bend in the 5-8 segment) to be essential for receptor recognition and activation. Although, they are characterised by an overall low binding affinity to the LHRH-I receptor, the cyclic analogues that were studied and especially the cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH, exhibit a profoundly enhanced in vitro and in vivo stability and improved pharmacokinetics in comparison with their linear counterpart and leuprolide. Upon receptor binding, cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH causes testosterone release in C57/B16 mice (in vivo efficacy) that is comparable to that of leuprolide. Testosterone release is an acutely dose dependent effect that is blocked by the LHRH-I receptor antagonist, cetrorelix. The pharmacokinetic advantages and efficacy of cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH render this analogue a promising platform for future rational drug design studies towards the development of non-peptide LHRH mimetics.

  15. Hyperresponse to Thyrotropin-Releasing Hormone Accompanying Small Decreases in Serum Thyroid Hormone Concentrations

    PubMed Central

    Vagenakis, Apostolos G.; Rapoport, Basil; Azizi, Fereidoun; Portnay, Gary I.; Braverman, Lewis E.; Ingbar, Sidney H.

    1974-01-01

    To determine whether pituitary thyrotropin (TSH) responsiveness to thyrotropin-releasing hormone (TRH) is enhanced by small decreases in serum thyroxine (T4) and triiodothyronine (T3), 12 euthyroid volunteers were given 190 mg iodide po daily for 10 days to inhibit T4 and T3 release from the thyroid. Basal serum T4, T3, and TSH concentrations and the serum T4 and TSH responses to 400 μg TRH i.v. were assessed before and at the end of iodide administration. Iodide induced small but highly significant decreases in basal serum T4 (8.0±1.6 vs. 6.6±1.7 μg/100 ml; mean ± SD) and T3 (128±15 vs. 110±22 ng/100 ml) and increases in basal serum TSH (1.3±0.9 vs. 2.1±1.0 μU/ml). During iodide administration, the TSH response to TRH was significantly increased at each of seven time points up to 120 min. The maximum increment in serum TSH after TRH increased from a control mean of 8.8±4.1 to a mean of 13.0±2.8 μU/ml during iodide administration. As evidence of the inhibitory effect of iodide on hormonal release, the increment in serum T3 at 120 min after TRH was significantly lessened during iodide administration (61±42 vs. 33±24 ng/100 ml). These findings demonstrate that small acute decreases in serum T4 and T3 concentrations, resulting in values well within the normal range, are associated both with slight increases in basal TSH concentrations and pronounced increases in the TSH response to TRH. These results demonstrate that a marked sensitivity of TSH secretion and responsiveness to TRH is applicable to decreasing, as well as increasing, concentrations of thyroid hormones. PMID:4214837

  16. Effects of oral chlortetracycline and dietary protein level on plasma concentrations of growth hormone and thyroid hormones in beef steers before and after challenge with a combination of thyrotropin-releasing hormone and growth hormone-releasing hormone.

    PubMed

    Rumsey, T S; McLeod, K; Elsasser, T H; Kahl, S; Baldwin, R L

    1999-08-01

    The objective of this study was to determine the effect of a subtherapeutic level of chlortetracycline (CTC) fed to growing beef steers under conditions of limited and adequate dietary protein on plasma concentrations of GH, thyroid-stimulating hormone (TSH), and thyroid hormones before and after an injection of thyrotropin-releasing hormone (TRH) + GHRH. Young beef steers (n = 32; average BW = 285 kg) were assigned to a 2x2 factorial arrangement of treatments of either a 10 or 13% crude protein diet (70% concentrate, 15% wheat straw, and 15% cottonseed hulls) and either a corn meal carrier or carrier + 350 mg of CTC daily top dressed on the diet. Steers were fed ad libitum amounts of diet for 56 d, and a jugular catheter was then placed in each steer in four groups (two steers from each treatment combination per group) during four consecutive days (one group per day). Each steer was injected via the jugular catheter with 1.0 microg/kg BW TRH + .1 microg/kg BW GHRH in 10 mL of saline at 0800. Blood samples were collected at -30, -15, 0, 5, 10, 15, 20, 30, 45, 60, 120, 240, and 360 min after releasing hormone injection. Plasma samples were analyzed for GH, TSH, thyroxine (T4), and triiodothyronine (T3). After 84 d on trial, the steers were slaughtered and the pituitary and samples of liver were collected and analyzed for 5'-deiodinase activity. Feeding CTC attenuated the GH response to releasing hormone challenge by 26% for both area under the response curve (P<.03) and peak response (P<.10). Likewise, CTC attenuated the TSH response to releasing hormone challenge for area under the response curve by 16% (P<.10) and peak response by 33% (P<.02), and attenuated the T4 response for area under the curve by 12% (P<.08) and peak response by 14% (P<.04). Type II deiodinase activity in the pituitary was 36% less (P<.02) in CTC-fed steers than in steers not fed CTC. The results of this study are interpreted to suggest that feeding subtherapeutic levels of CTC to young

  17. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  18. Endocrine disrupting chemicals affect the gonadotropin releasing hormone neuronal network.

    PubMed

    Mueller, Johanna K; Heger, Sabine

    2014-04-01

    Endocrine disrupting chemicals have been shown to alter the pubertal process. The controlling levels of the Gonadotropin releasing hormone (GnRH) network involve GnRH itself, KiSS1, and the transcriptional regulators enhanced at puberty 1 (EAP1), Thyroid Transcription Factor 1 (TTF1), and Yin Yang 1 (YY1). While Genistein and Bisphenol A (BPA) have been shown to advance the advent of puberty, exposure to Dioxin delayed pubertal onset. Utilizing in vitro approaches, we observed that Genistein and BPA suppress inhibitory and activate stimulatory components of the GnRH network, while Dioxin exhibit an inhibitory effect at all regulatory hierarchical levels of the GnRH network. It repressed KiSS1, Gnrh, Ttf1 and Yy1 transcription via the xenobiotic response element (XRE), while EAP1 was not affected. Therefore, EDCs alter the neuroendocrine GnRH regulatory network at all hierarchical levels.

  19. Gonadotropin-releasing hormone in invertebrates: structure, function, and evolution.

    PubMed

    Tsai, Pei-San

    2006-08-01

    Gonadotropin-releasing hormone (GnRH) is central to the initiation and maintenance of reproduction in vertebrates. GnRH is found in all major groups of Phylum Chordata, including the protochordates. Studies on functional and structural evolution of GnRH have, in the past, focused exclusively on chordates. However, the recent structural elucidation of an octopus GnRH-like molecule and increasing evidence that GnRH-like substances are present in multiple invertebrate phyla suggest GnRH is an ancient peptide that arose prior to the divergence of protostomes and deuterostomes. The extraordinary conservation of GnRH structure and function raises interesting questions regarding the functional role assumed by GnRH over the course of evolution. This review will focus on the current understanding of GnRH structure and function in non-chordate invertebrates. Special emphasis will be placed upon the possible and speculated functions of GnRH in mollusks.

  20. Gonadotropin-Releasing Hormone and Adipokinetic Hormone Signaling Systems Share a Common Evolutionary Origin

    PubMed Central

    Lindemans, Marleen; Janssen, Tom; Beets, Isabel; Temmerman, Liesbet; Meelkop, Ellen; Schoofs, Liliane

    2011-01-01

    Gonadotropin-releasing hormone (GnRH) is a critical and central hormone that regulates vertebrate reproduction. The high conservation of GnRH signaling within the chordates (deuterostomians) raises the important question as to whether its appearance might date back prior to the divergence of protostomian and deuterostomian lineages, about 700 million years ago. This leads to several important questions regarding the evolution of the GnRH family. Has GnRH been retained in most protostomian lineages? And was regulation of reproduction already a function of ancestral GnRH? The first question can undoubtedly be answered affirmatively since several GnRH-like sequences have been found in wide variety of protostomian and deuterostomian phyla. However, based on their different primary functions in different phyla – which implies a less unanimous answer on the second question – consistency in the nomenclature of this peptide family has been lost. A comparative and phylogenetic approach shows that the ecdysozoan adipokinetic hormones (AKHs), lophotrochozoan GnRHs and chordate GnRHs are structurally related and suggests that they all originate from a common ancestor. This review supports the view that the AKH–GnRH signaling system probably arose very early in metazoan evolution, prior to the divergence of protostomians and deuterostomians. PMID:22649364

  1. Corticotropin-releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes

    PubMed Central

    Zouboulis, Christos C.; Seltmann, Holger; Hiroi, Naoki; Chen, WenChieh; Young, Maggie; Oeff, Marina; Scherbaum, Werner A.; Orfanos, Constantin E.; McCann, Samuel M.; Bornstein, Stefan R.

    2002-01-01

    Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal (HPA) axis. Such a pathway has been described and may occur in human skin and lately in the sebaceous glands because they express neuropeptide receptors. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress. To further examine the probability of an HPA equivalent pathway, we investigated the expression of CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R) in SZ95 sebocytes in vitro and their regulation by CRH and several other hormones. CRH, CRH-BP, CRH-R1, and CRH-R2 were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type (CRH-R1/CRH-R2 = 2). CRH was biologically active on human sebocytes: it induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10−7 M and up-regulated mRNA levels of 3β- hydroxysteroid dehydrogenase/Δ5–4 isomerase, although it did not affect cell viability, cell proliferation, or IL-1β-induced IL-8 release. CRH, dehydroepiandrosterone, and 17β-estradiol did not modulate CRH-R expression, whereas testosterone at 10−7 M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h, and growth hormone (GH) switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback. The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin. PMID:12011471

  2. Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes.

    PubMed

    Zouboulis, Christos C; Seltmann, Holger; Hiroi, Naoki; Chen, WenChieh; Young, Maggie; Oeff, Marina; Scherbaum, Werner A; Orfanos, Constantin E; McCann, Samuel M; Bornstein, Stefan R

    2002-05-14

    Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal (HPA) axis. Such a pathway has been described and may occur in human skin and lately in the sebaceous glands because they express neuropeptide receptors. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress. To further examine the probability of an HPA equivalent pathway, we investigated the expression of CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R) in SZ95 sebocytes in vitro and their regulation by CRH and several other hormones. CRH, CRH-BP, CRH-R1, and CRH-R2 were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type (CRH-R1/CRH-R2 = 2). CRH was biologically active on human sebocytes: it induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10(-7) M and up-regulated mRNA levels of 3 beta- hydroxysteroid dehydrogenase/Delta(5-4) isomerase, although it did not affect cell viability, cell proliferation, or IL-1 beta-induced IL-8 release. CRH, dehydroepiandrosterone, and 17 beta-estradiol did not modulate CRH-R expression, whereas testosterone at 10(-7) M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h, and growth hormone (GH) switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback. The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin.

  3. Thyroid Hormone and Estrogen Regulate Exercise-Induced Growth Hormone Release

    PubMed Central

    Ignacio, Daniele Leão; da S. Silvestre, Diego H.; Cavalcanti-de-Albuquerque, João Paulo Albuquerque; Louzada, Ruy Andrade

    2015-01-01

    Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response. PMID:25874614

  4. Establishment and clinical application of enzyme immunoassays for determination of luteinizing hormone releasing hormone and metastin.

    PubMed

    Katagiri, Fumihiko; Tomita, Kenji; Oishi, Shinya; Takeyama, Masaharu; Fujii, Nobutaka

    2007-06-01

    Metastin, a 54-residue peptide, was identified as the cognate ligand of human G-protein-coupled receptor GPR54. Since metastin is a gene product of the human metastasis suppressor gene 'KiSS-1', early studies on metastin were focused on its activity as a tumor metastasis suppressor. Recently, there have been some reports that metastin is found in human plasma and is particularly abundant in the plasma of pregnant women. Dysfunction of the GPR54 receptor causes diseases that are characterized by an insufficient release of gonadotropin and lack or delay of pubertal maturation. This information strongly suggests that metastin is involved in the regulation of reproductive endocrine functions. In order to determine the plasma levels of metastin and luteinizing hormone releasing hormone (LHRH) in an isolated hypogonadotropic hypogonadism (IHH) patient, who received intermittent administrations of LHRH, we tried to establish a sensitive and specific enzyme immunoassay. The plasma LHRH levels of the patient were very high, while plasma metastin levels were at almost the same levels as circadian rhythms of healthy male humans. In the central nervous system, metastin stimulates the neuroendocrine reproductive axis. However, the effects of peripheral metastin are not known. Our result suggested that peripheral metastin had a genesis and activity different from central metastin.

  5. Acceleration of wound healing by growth hormone-releasing hormone and its agonists.

    PubMed

    Dioufa, Nikolina; Schally, Andrew V; Chatzistamou, Ioulia; Moustou, Evi; Block, Norman L; Owens, Gary K; Papavassiliou, Athanasios G; Kiaris, Hippokratis

    2010-10-26

    Despite the well-documented action of growth hormone-releasing hormone (GHRH) on the stimulation of production and release of growth hormone (GH), the effects of GHRH in peripheral tissues are incompletely explored. In this study, we show that GHRH plays a role in wound healing and tissue repair by acting primarily on wound-associated fibroblasts. Mouse embryonic fibroblasts (MEFs) in culture and wound-associated fibroblasts in mice expressed a splice variant of the receptors for GHRH (SV1). Exposure of MEFs to 100 nM and 500 nM GHRH or the GHRH agonist JI-38 stimulated the expression of α-smooth muscle actin (αSMA) based on immunoblot analyses as well as the expression of an αSMA-β-galactosidase reporter transgene in primary cultures of fibroblasts isolated from transgenic mice. Consistent with this induction of αSMA expression, results of transwell-based migration assays and in vitro wound healing (scratch) assays showed that both GHRH and GHRH agonist JI-38 stimulated the migration of MEFs in vitro. In vivo, local application of GHRH or JI-38 accelerated healing in skin wounds of mice. Histological evaluation of skin biopsies showed that wounds treated with GHRH and JI-38 were both characterized by increased abundance of fibroblasts during the early stages of wound healing and accelerated reformation of the covering epithelium at later stages. These results identify another function of GHRH in promoting skin tissue wound healing and repair. Our findings suggest that GHRH may have clinical utility for augmenting healing of skin wounds resulting from trauma, surgery, or disease.

  6. Gonadotrophin-releasing hormone signalling downstream of calmodulin.

    PubMed

    Melamed, P; Savulescu, D; Lim, S; Wijeweera, A; Luo, Z; Luo, M; Pnueli, L

    2012-12-01

    Gonadotrophin-releasing hormone (GnRH) regulates reproduction via binding a G-protein coupled receptor on the surface of the gonadotroph, through which it transmits signals, mostly via the mitogen-activated protein (MAPK) cascade, to increase synthesis of the gonadotrophin hormones: luteinising hormone (LH) and follicle-stimulating hormone (FSH). Activation of the MAPK cascade requires an elevation in cytosolic Ca(2+) levels, which is a result of both calcium influx and mobilisation from intracellular stores. However, Ca(2+) also transmits signals via an MAPK-independent pathway, through binding calmodulin (CaM), which is then able to bind a number of proteins to impart diverse downstream effects. Although the ability of GnRH to activate CaM was recognised over 20 years ago, only recently have some of the downstream effects been elucidated. GnRH was shown to activate the CaM-dependent phosphatase, calcineurin, which targets gonadotrophin gene expression both directly and indirectly via transcription factors such as nuclear factor of activated T-cells and Nur77, the Transducer of Regulated CREB (TORC) co-activators and also the prolyl isomerase, Pin1. Gonadotrophin gene expression is also regulated by GnRH-induced CaM-dependent kinases (CaMKs); CaMKI is able to derepress the histone deacetylase-inhibition of β-subunit gene expression, whereas CaMKII appears to be essential for the GnRH-activation of all three subunit genes. Asides from activating gonadotrophin gene expression, GnRH also exerts additional effects on gonadotroph function, some of which clearly occur via CaM, including the proliferation of immature gonadotrophs, which is dependent on calcineurin. In this review, we summarise these pathways, and discuss the additional functions that have been proposed for CaM with respect to modifying GnRH-induced signalling pathways via the regulation of the small GTP-binding protein, Gem, and/or the regulator of G-protein signalling protein 2.

  7. Hypothalamic hypopituitarism in a patient with a basal encephalocoele--treatment with luteinizing hormone-releasing hormone.

    PubMed Central

    Morris, D. V.; Mason, W. P.; Wilson-Holt, N.; Adams, J.; Keene, M.; Tanner, J.; Jacobs, H. S.

    1984-01-01

    A 20-year-old patient presented with primary amenorrhoea and growth hormone deficiency caused by a basal encephalocoele. She was found to have developed diabetes insipidus in the 8 years following diagnosis. Gonadotrophin release in response to bolus injection of luteinizing hormone-releasing hormone (LHRH) was normal, as was thyrotrophin and adrenocorticotrophin (ACTH) secretion. Pulsatile administration of LHRH by the subcutaneous route resulted in normal ovulation and subsequent menstruation. The investigation and management of patients with basal encephalocoeles are discussed in the light of these findings. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:6384984

  8. Arg-Phe-amide-related peptides influence gonadotropin-releasing hormone neurons

    PubMed Central

    Kelestimur, Haluk; Kacar, Emine; Uzun, Aysegul; Ozcan, Mete; Kutlu, Selim

    2013-01-01

    The hypothalamic Arg-Phe-amide-related peptides, gonadotropin-inhibitory hormone and orthologous mammalian peptides of Arg-Phe-amide, may be important regulators of the hypothalamus-pituitary-gonadal reproductive axis. These peptides may modulate the effects of kisspeptins because they are presently recognized as the most potent activators of the hypothalamus-pituitary-gonadal axis. However, their effects on gonadotropin-releasing hormone neurons have not been investigated. In the current study, the GT1–7 cell line-expressing gonadotropin-releasing hormone was used as a model to explore the effects of Arg-Pheamide-related peptides on kisspeptin activation. Intracellular calcium concentration was quantified using the calcium-sensitive dye, fura-2 acetoxymethyl ester. Gonadotropin-releasing hormone released into the medium was detected via enzyme-linked immunosorbent assay. Results showed that 100 nmol/L kisspeptin-10 significantly increased gonadotropin-releasing hormone levels (at 120 minutes of exposure) and intracellular calcium concentrations. Co-treatment of kisspeptin with 1 μmol/L gonadotropin-inhibitory hormone or 1 μmol/L Arg-Phe-amide-related peptide-1 significantly attenuated levels of kisspeptin-induced gonadotropin-releasing hormone but did not affect kisspeptin-induced elevations of intracellular calcium concentration. Overall, the results suggest that gonadotropin-inhibitory hormone and Arg-Phe-amide-related peptide-1 may have inhibitory effects on kisspeptin-activated gonadotropin-releasing hormone neurons independent of the calcium signaling pathway. PMID:25206468

  9. Arg-Phe-amide-related peptides influence gonadotropin-releasing hormone neurons.

    PubMed

    Kelestimur, Haluk; Kacar, Emine; Uzun, Aysegul; Ozcan, Mete; Kutlu, Selim

    2013-06-25

    The hypothalamic Arg-Phe-amide-related peptides, gonadotropin-inhibitory hormone and orthologous mammalian peptides of Arg-Phe-amide, may be important regulators of the hypothalamus-pituitary-gonadal reproductive axis. These peptides may modulate the effects of kisspeptins because they are presently recognized as the most potent activators of the hypothalamus-pituitary-gonadal axis. However, their effects on gonadotropin-releasing hormone neurons have not been investigated. In the current study, the GT1-7 cell line-expressing gonadotropin-releasing hormone was used as a model to explore the effects of Arg-Pheamide-related peptides on kisspeptin activation. Intracellular calcium concentration was quantified using the calcium-sensitive dye, fura-2 acetoxymethyl ester. Gonadotropin-releasing hormone released into the medium was detected via enzyme-linked immunosorbent assay. Results showed that 100 nmol/L kisspeptin-10 significantly increased gonadotropin-releasing hormone levels (at 120 minutes of exposure) and intracellular calcium concentrations. Co-treatment of kisspeptin with 1 μmol/L gonadotropin-inhibitory hormone or 1 μmol/L Arg-Phe-amide-related peptide-1 significantly attenuated levels of kisspeptin-induced gonadotropin-releasing hormone but did not affect kisspeptin-induced elevations of intracellular calcium concentration. Overall, the results suggest that gonadotropin-inhibitory hormone and Arg-Phe-amide-related peptide-1 may have inhibitory effects on kisspeptin-activated gonadotropin-releasing hormone neurons independent of the calcium signaling pathway.

  10. Interleukin 1. alpha. inhibits prostaglandin E sub 2 release to suppress pulsatile release of luteinizing hormone but not follicle-stimulating hormone

    SciTech Connect

    Rettori, V.; McCann, S.M. ); Gimeno, M.F. ); Karara, A. ); Gonzalez, M.C. )

    1991-04-01

    Interleukin 1{alpha} (IL-1{alpha}), a powerful endogenous pyrogen released from monocytes and macrophages by bacterial endotoxin, stimulates corticotropin, prolactin, and somatotropin release and inhibits thyrotropin release by hypothalamic action. The authors injected recombinant human IL-1{alpha} into the third cerebral ventricle, to study its effect on the pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in conscious, freely moving, ovariectomized rats. Intraventricular injection of 0.25 pmol of IL-1{alpha} caused an almost immediate reduction of plasma LH concentration. To determine the mechanism of the suppression of LH release, mediobasal hypothalamic fragments were incubated in vitro with IL-1{alpha} (10 pM) and the release of LH-releasing hormone (LHRH) and prostaglandin E{sub 2} into the medium was measured by RIA in the presence or absence of nonrepinephrine. 1{alpha} reduced basal LHRH release and blocked LHRH release induced by nonrepinephrine. In conclusion, IL-1{alpha} suppresses LH but not FSH release by an almost complete cessation of pulsatile release of LH in the castrated rat. The mechanism of this effect appears to be by inhibition of prostaglandin E{sub 2}-mediated release of LHRH.

  11. Corticotropin-releasing hormone mediates alpha-melanocyte-stimulating hormone-induced anorexigenic action in goldfish.

    PubMed

    Matsuda, Kouhei; Kojima, Kenji; Shimakura, Sei-Ichi; Wada, Kohei; Maruyama, Keisuke; Uchiyama, Minoru; Kikuyama, Sakae; Shioda, Seiji

    2008-11-01

    alpha-Melanocyte-stimulating hormone (alpha-MSH) and corticotropin-releasing hormone (CRH) both suppress food intake, and the alpha-MSH- or CRH-signaling pathway has possible potency to mediate anorexigenic actions induced by most other neuropeptides in goldfish. Therefore, using specific receptor antagonists, we examined whether the anorexigenic actions of alpha-MSH and CRH mutually interact. The inhibitory effect of ICV injection of the alpha-MSH agonist, melanotan II (MT II), on food intake was abolished by treatment with a CRH 1/2 receptor antagonist, alpha-helical CRH((9-41)), whereas the anorexigenic action of ICV-injected CRH was not affected by treatment with a melanocortin 4 receptor antagonist, HS024. This led us to investigate whether alpha-MSH-containing neurons in the goldfish brain have direct inputs to CRH-containing neurons, using confocal laser scanning microscopy. alpha-MSH- and CRH-like immunoreactivities were distributed throughout the brain, especially in the diencephalon. alpha-MSH-containing nerve fibers or endings lay in close apposition to CRH-containing neurons in a region of the hypothalamus, the nucleus posterioris periventricularis (NPPv). These results indicate that, in goldfish, alpha-MSH-induced anorexigenic action is mediated by the CRH-signaling pathway, and that CRH plays a crucial role in the regulation of feeding behavior as an integrated anorexigenic neuropeptide in this species.

  12. Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis

    PubMed Central

    Tao, Quanwei; Ma, Qunchao; Chen, Huiqiang; Wang, Jian'an

    2016-01-01

    Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues. PMID:27774107

  13. Luteinizing Hormone-Releasing Hormone Enhances T Cell Recovery following Allogeneic Bone Marrow Transplantation1

    PubMed Central

    Goldberg, Gabrielle L.; King, Christopher G.; Nejat, Rebecca A.; Suh, David Y.; Smith, Odette M.; Bretz, Jamison C.; Samstein, Robert M.; Dudakov, Jarrod A.; Chidgey, Ann P.; Chen-Kiang, Selina; Boyd, Richard L.; van den Brink, Marcel R. M.

    2009-01-01

    Posttransplant immunodeficiency, specifically a lack of T cell reconstitution, is a major complication of allogeneic bone marrow transplantation. This immunosuppression results in an increase in morbidity and mortality from infections and very likely contributes to relapse. In this study, we demonstrate that sex steroid ablation using leuprolide acetate, a luteinizing hormone-releasing hormone agonist (LHRHa), increases the number of lymphoid and myeloid progenitor cells in the bone marrow and developing thymocytes in the thymus. Although few differences are observed in the peripheral myeloid compartments, the enhanced thymic reconstitution following LHRHa treatment and allogeneic bone marrow transplantation leads to enhanced peripheral T cell recovery, predominantly in the naive T cell compartment. This results in an increase in T cell function in vivo and in vitro. Graft-versus-host-disease is not exacerbated by LHRHa treatment and graft-versus-tumor activity is maintained. Because LHRHa allows for reversible (and temporary) sex steroid ablation, has a strong safety profile, and has been clinically approved for diseases such as prostate and breast cancer, this drug treatment represents a novel therapeutic approach to reversal of thymic atrophy and enhancement of immunity following immunosuppression. PMID:19380833

  14. Luteinizing hormone--releasing hormone agonists: a quick reference for prevalence rates of potential adverse effects.

    PubMed

    Walker, Lauren M; Tran, Susan; Robinson, John W

    2013-12-01

    Men with prostate cancer (PCa) frequently undergo androgen deprivation therapy (ADT), typically in the form of a depot injection of luteinizing hormone-releasing hormone agonists (LHRHa). LHRHa are associated with many adverse effects (eg, hot flashes, sexual dysfunction, loss of muscle mass, osteopenia, metabolic syndrome), which drastically impact patient quality of life. This literature review, which includes a comprehensive table documenting prevalence rates, provides a quick reference for health care professionals involved in the care of men undergoing ADT with LHRHa. Primary sources were acquired from PubMed using the search terms "androgen deprivation therapy" and each potentially adverse effect (eg, "androgen deprivation therapy and hot flashes"). Commonly cited review articles were also examined for citations of original studies containing prevalence rates. More than 270 articles were reviewed. In contrast to many existing reviews, rates are cited exclusively from original sources. The prevalence rates, obtained from original sources, suggest that more than half of documented adverse effects are experienced by as many as 40% or more of patients. A critique of the literature is also provided. Although there is a vast literature of both original and review articles on specific adverse effects of LHRHa, the quality of research on prevalence rates for some adverse effects is subpar. Many review articles contain inaccuracies and do not cite original sources. The table of prevalence rates will serve as a quick reference for health care providers when counseling patients and will aid in the development of evidence-based patient education materials.

  15. Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

    PubMed Central

    Yoshida, Natsu; Maejima, Yuko; Sedbazar, Udval; Ando, Akihiko; Kurita, Hideharu; Damdindorj, Boldbaatar; Takano, Eisuke; Gantulga, Darambazar; Iwasaki, Yusaku; Kurashina, Tomoyuki; Onaka, Tatsushi; Dezaki, Katsuya; Nakata, Masanori; Mori, Masatomo; Yada, Toshihiko

    2010-01-01

    A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses. PMID:20966530

  16. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

    PubMed Central

    Jaszberenyi, Miklos; Rick, Ferenc G.; Popovics, Petra; Block, Norman L.; Zarandi, Marta; Cai, Ren-Zhi; Vidaurre, Irving; Szalontay, Luca; Jayakumar, Arumugam R.; Schally, Andrew V.

    2014-01-01

    The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells. PMID:24379381

  17. Decapeptides as effective agonists from L-amino acids biologically equivalent to the luteinizing hormone-releasing hormone.

    PubMed Central

    Folkers, K; Bowers, C Y; Tang, P F; Kubota, M

    1986-01-01

    Apparently, no agonist has been found that is comparable in potency to the luteinizing hormone-releasing hormone (LHRH) for release of LH and follicle-stimulating hormone (FSH) without substitutions with unnatural or D forms of natural amino acids. Of 139 known "agonist analogs" of LHRH, two were active in the range of 65%. The four LHRHs known to occur in nature involve a total of six amino acids (Tyr, His, Leu, Trp, Arg, Gln) in positions 5, 7, and 8. There are 16 possible peptides with these six amino acids in positions 5, 7, and 8, of which 4 are the known LHRHs, and 2 more were synthesized. We have synthesized the 10 new peptides and assayed 11 in vivo and in vitro, and we found not only 1 but a total of 5 that have activity equivalent to or greater than that of LHRH for the release of LH and/or FSH under at least one assay condition. These five are as follows: [His5,Trp7,Gln8]LHRH; [His5,Trp7,Leu8]LHRH; [His5,Trp7]LHRH; [Trp7]LHRH; [His5]LHRH. Two of these five agonists variably released relatively more FSH than LH. One or more of these five agonists may occur in nature and one may be follicle-stimulating hormone-releasing hormone. The two peptides with Gln8 and Leu8, if occurring in nature, may have different receptors according to radioreceptor assays and to the ratio of LH/FSH release in vivo. These structures are a basis for the design of antagonists without Arg8 toward avoiding histamine release. Complete inhibition of LH and FSH release in vivo may be induced by joint use of Arg8 and Gln8 or Leu8 antagonists. These potent agonists, related to LHRH, may be therapeutically useful in disorders of reproduction, the central nervous system, and for the control of hormone-dependent carcinomas. PMID:3081889

  18. Pheromonal stimulation of spawning release of gametes by gonadotropin releasing hormone in the chiton, Mopalia sp.

    PubMed

    Gorbman, Aubrey; Whiteley, Arthur; Kavanaugh, Scott

    2003-03-01

    The chiton Mopalia sp., a mollusc, was exposed to various dilutions of gonadotropin releasing hormone (GnRH) in sea water to determine whether this peptide is capable of acting as a pheromone that could stimulate release of ripe gametes (spawning). Two of the peptides, lamprey GnRH-1 and tunicate GnRH-2, had this action at a higher concentration (1.0 mg/L) but dilutions to 50 microg/L no longer were effective. Three other GnRHs: lamprey GnRH-3, tunicate GnRH-1, and a modified chicken GnRH-2, had no such action under the same test conditions. Since the spawning response could be produced by some GnRHs and not by others, it would appear that some kind of molecular recognition is involved, possibly by specific binding to a receptor. In earlier preliminary experiments tunicate GnRH-2 rapidly stimulated gamete release in a hemichordate, Saccoglossus. Thus it is suggested that GnRHs, in at least some invertebrates, may function as pheromones, serving to stimulate simultaneous spawning of individuals in a population of animals, and in this way assure more successful fertilization in species that must release their gametes into the water in which they live.

  19. Thyrotropin-releasing hormone (TRH) reverses hyperglycemia in rat

    SciTech Connect

    Luo Luguang Luo, John Z.Q. Jackson, Ivor M.D.

    2008-09-12

    Hyperglycemia in thyrotropin-releasing hormone (TRH) null mice indicates that TRH is involved in the regulation of glucose homeostasis. Further, TRH levels in the pancreas peak during the stages of late embryonic and early neonatal {beta} cell development. These observations are consistent in linking TRH to islet cell proliferation and differentiation. In this study, we examined the effect of TRH administration in damaged pancreatic rat (streptozotocin, STZ) to determine whether TRH could improve damaged pancreatic {beta} cells function. We hypothesize that TRH is able to reverse STZ-induced hyperglycemia by increasing pancreatic islet insulin content, preventing apoptosis, and potentially induce islet regeneration. It was found that following intra-peritoneal (ip) injection, TRH (10 {mu}g/kg body weight (bwt)) reverses STZ (65 mg/kg bwt)-induced hyperglycemia (TRH given 3 days after STZ injection). Increased circulating insulin levels and insulin content in extracted pancreas suggests that TRH reversed STZ-induced hyperglycemia through improving pancreatic islet {beta} cell function. Further studies show a significantly lower level of apoptosis in islets treated with TRH as well as the presence of proliferation marker nestin and Brdu, suggesting that the TRH has the potential to prevent apoptosis and stimulate islet proliferation.

  20. Redefining the gonadotrophin-releasing hormone neurone dendrite.

    PubMed

    Campbell, R E; Suter, K J

    2010-07-01

    Gonadotrophin-releasing hormone (GnRH) neurones are the final output neurones of the complex synaptic network responsible for the central control of fertility. This scattered population of neurones has been shown to have remarkably long dendritic processes by cell-filling of GnRH neurones in situ with low-molecular weight dyes. This review focuses on how the functional significance of these long dendritic extensions is being explored through dual somatic-dendritic electrophysiological recordings, computational modelling, immunolabelling for specific channels and multiple modes of microscopy and imaging. Remarkably, recent work has discovered that GnRH neurone dendrites not only actively propagate action potentials, but also comprise the primary site of action potential initiation. These findings, along with the discovery of regionalized expression of active conductances, highlight dendrites of single GnRH neurones as being central sites of signal integration. Moreover, imaging studies have shown that the long dendrites of GnRH neurones intertwine and bundle with one another. The presence of shared synaptic input to bundling dendrites, coupled with their active properties and the increased potency of distally placed synaptic inputs, is suggestive of a novel mechanism of GnRH neurone synchronisation, a feature critical for mammalian reproduction. Together, these discoveries of the GnRH neurone dendrite structure and function are changing the way that we view the central regulation of fertility.

  1. Sympathomimetic pressor responses to thyrotropin-releasing hormone in rats

    SciTech Connect

    Mattila, J.; Bunag, R.D.

    1986-07-01

    Cardiovascular responses to centrally administered thyrotropin-releasing hormone (TRH) were studied in urethan-anesthetized rats to allow continuous recording of attendant changes in sympathetic nerve activity. Intracerebroventricular infusions of TRH consistently increased not only blood pressure and heart rate, but also spike frequency in splanchnic, renal, or cervical sympathetic nerves. Parasympathetic inhibition seemed unlikely because TRH responses were unaltered by cholinergic blockade with atropine, and efferent vagal nerve firing, instead of being reduced, was actually increased by TRH. An increased secretion of endogenous vasopressin also appeared unlikely, since TRH responses were essentially unaffected by either hypophysectomy or pretreatment with a vasopressin antagonist. Inasmuch as pharmacological ganglion blockade with pentolinium eliminated increases in splanchnic nerve firing but reduced the attendant tachycardia by only 50%, residual tachycardia after ganglion blockade was considered partly due to persistent sympathetic cardioaccelerator tone. On the other hand, because pressor responses to TRH were always accompanied by increased sympathetic nerve firing and were completely abolished after pentolinium-induced ganglioplegia, they were attributed solely to sympathetic hyperactivity.

  2. Corticotropin-releasing hormone, stress and human reproduction: an update.

    PubMed

    Kalantaridou, S N; Zoumakis, E; Makrigiannakis, A; Lavasidis, L G; Vrekoussis, T; Chrousos, G P

    2010-05-01

    The stress system has suppressive effects on female and male reproductive function. Corticotrophin-releasing hormone (CRH), the principal regulator of stress, has been identified in the female and male reproductive system. Reproductive CRH participates in various reproductive functions that have an inflammatory component, where it serves as an autocrine and paracrine modulator. These include ovarian and endometrial CRH, which may participate in the regulation of steroidogenesis and the inflammatory processes of the ovary (ovulation and luteolysis) and the endometrium (decidualization and blastocyst implantation) and placental CRH, which is secreted mostly during the latter half of pregnancy and is responsible for the onset of labor. It has been suggested that there is a "CRH placental clock" which determines the length of gestation and the timing of parturition and delivery. The potential use of CRH-antagonists is presently under intense investigation. CRH-R1 antagonists have been used in animal studies to elucidate the role of CRH in blastocyst implantation and invasion, early fetal immunotolerance and premature labor. The present review article focuses on the potential roles of CRH on the physiology and pathophysiology of reproduction and highlights its participation in crucial steps of pregnancy, such as implantation, fetal immune tolerance, parturition and fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis.

  3. Predicted primary and antigenic structure of canine corticotropin releasing hormone.

    PubMed

    Mol, J A; van Wolferen, M; Kwant, M; Meloen, R

    1994-07-01

    Although the dog has been recognized as a useful model for the study of the cerebrospinal and peripheral actions of corticotropin releasing hormone (CRH) the exact amino acid composition of canine CRH is still unknown. In the present study the structure of canine CRH was predicted from the partial sequence of the gene encoding canine CRH. The CRH gene was amplified from genomic DNA obtained from white blood cells by a polymerase chain reaction and subsequently sequenced using the dideoxy method. The likely structure of canine CRH is: SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII-NH2, which is identical to the structure of human, rat and equine CRH. PEPSCAN analysis of 3 different CRH antisera predicted an antiserum raised against a conjugate of human CRH and CNBr -activated thyroglobulin to be the antiserum of choice for the measurement of CRH in the dog. Preliminary data confirmed the existence of the highest cross-reactivity of a canine hypothalamus extract, known to have a high content of CRH, with antisera directed against human, rat CRH. As a result of the present study immunological tools for CRH estimations are characterized. Also, a homologous DNA probe for in situ hybridizations has become available for further investigations.

  4. Clinical uses of gonadotropin-releasing hormone analogues.

    PubMed Central

    Casper, R F

    1991-01-01

    Gonadotropin-releasing hormone (Gn-RH) analogues are synthetic derivatives of the native hypothalamic peptide with alterations in their chemical structure that result in changes in biologic activity. Several Gn-RH agonists are available for clinical use, and all act through the same mechanism: first to stimulate and then to inhibit gonadotropin and gonadal steroid secretion by downregulating the pituitary Gn-RN receptors. This review should provide clinicians with a working knowledge of the physiologic and pharmacokinetic features of Gn-RH agonists. Although over 2000 articles concerning Gn-RH analogues have been published I chose to review only those that were the first to report a novel clinical application. Gn-RH agonists have proved to be extremely efficacious in treating gonadal steroid-dependent problems such as endometriosis, uterine leiomyoma, precocious puberty and prostate and breast cancers, and they have resulted in very few side effects. Long-term use may, however, lead to skeletal calcium loss in women as a consequence of hypoestrogenism. Further research is needed to prevent this and maintain clinical efficacy. PMID:1986827

  5. Placental corticotrophin-releasing hormone, local effects and fetomaternal endocrinology.

    PubMed

    King, B R; Nicholson, R C; Smith, R

    2001-12-01

    The human placenta produces corticotrophin-releasing hormone (CRH) in exponentially increasing amounts during pregnancy with peak levels during labour. CRH in human pregnancy appears to be involved in many aspects of pregnancy including placental bloodflow, placental prostaglandin production, myornetrial function, fetal pituitary and adrenal function and the maternal stress axis. Since fetal cortisol levels are associated with pulmonary development and maturity, placental CRH may have an indirect role in fetal development.Although the precise role of placental CRH in the regulation of gestational length and timing of parturition is unclear it appears to be involved in a placental clock. While glucocorticoids inhibit hypothalamic CRH production they stimulate CRH gene expression in the placenta.This difference may allow the fetal and maternal stress axes to influence this placental clock.Maternal CRH levels are elevated in many pathological conditions of pregnancy where fetal well-being is compromised, and in these situations it may act to maintain a stable intrauterine environment. Therefore, CRH appears to link placental function, maternal well-being, fetal well-being and fetal development to the duration of gestation and the timing of parturition.

  6. Changes in serum growth hormone and prolactin levels, and in hypothalamic growth hormone-releasing hormone, thyrotropin-releasing hormone and somatostatin content, after superior cervical sympathectomy in rats.

    PubMed

    Cardinalí, D P; Esquifino, A I; Arce, A; Vara, E; Ariznavarreta, C; Tresguerres, J A

    1994-01-01

    After bilateral superior cervical ganglionectomy (SCGx) of adult male rats, norepinephrine (NE) content of the medial basal hypothalamus (MBH) decreased significantly by 39-47% from 16 h to 7 days after surgery. During this time the levels of serum growth hormone (GH) and prolactin (PRL) and of MBH GH-releasing hormone (GRH), thyrotropin-releasing hormone (TRH) and somatostatin were measured by RIA. In sham-operated controls, serum PRL increased and serum GH decreased 16-24 h after surgery, attaining pre-surgical levels later on. In SCGx rats, significantly lower serum GH and PRL and higher MBH GRH and TRH content as compared to controls was observed 16-24 h after surgery, during the wallerian degeneration phase after SCGx. MBH somatostatin concentration decreased in SCGx rats 20 h after surgery. Two injections of the alpha 1-adrenoceptor blocker prazosin 45 and 90 min before sacrifice, alone or together with the beta-blocker propranolol, prevented the changes in MBH hypophysiotropic hormone content, as well as in serum GH and PRL levels, found in SCGx rats 20 h after surgery. Propranolol treatment did not affect hormone levels. Neither drug modified the decrease in MBH NE content observed after SCGx. The results argue in favor of the existence of physiologically relevant projections from superior cervical ganglion neurons to the MBH controlling hypophysiotropic hormone release.

  7. Neither bovine somatotropin nor growth hormone-releasing factor alters expression of thyroid hormone receptors in liver and mammary tissues.

    PubMed

    Capuco, A V; Binelli, M; Tucker, H A

    2011-10-01

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine to specific nuclear receptors. Organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, have been hypothesized to target the action of thyroid hormones on the mammary gland and play a role in mediating or augmenting a galactopoietic response to bovine somatotropin (bST). Additionally, tissue responsiveness to thyroid hormones may be altered by changes in the number or affinity of nuclear receptors for thyroid hormones. In the present study, effects of bST and bovine growth hormone-releasing factor (bGRF) on thyroid hormone receptors in liver and mammary gland were studied. Lactating Holstein cows received continuous infusions of bST or bGRF for 63 d or served as uninfused controls. Nuclei were isolated from harvested mammary and liver tissues and incubated with [(125)I]-triiodothyronine. Treatments did not alter the capacity or affinity of specific binding sites for triiodothyronine in liver or mammary nuclei. Evaluation of transcript abundance for thyroid hormone receptors showed that isoforms of thyroid hormone receptor or retinoid receptor (which may influence thyroid receptor action) expressed in the mammary gland were not altered by bST or bGRF treatment. Data do not support the hypothesis that administration of bST or bGRF alters sensitivity of mammary tissue by changing expression of thyroid hormone receptors.

  8. Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release.

    PubMed Central

    Hartman, M L; Pincus, S M; Johnson, M L; Matthews, D H; Faunt, L M; Vance, M L; Thorner, M O; Veldhuis, J D

    1994-01-01

    Pulses of growth hormone (GH) release in acromegaly may arise from hypothalamic regulation or from random events intrinsic to adenomatous tissue. To distinguish between these possibilities, serum GH concentrations were measured at 5-min intervals for 24 h in acromegalic men and women with active (n = 19) and inactive (n = 9) disease and in normal young adults in the fed (n = 20) and fasted (n = 16) states. Daily GH secretion rates, calculated by deconvolution analysis, were greater in patients with active acromegaly than in fed (P < 0.05) but not fasted normal subjects. Significant basal (nonpulsatile) GH secretion was present in virtually all active acromegalics but not those in remission or in fed and fasted normal subjects. A recently introduced scale- and model-independent statistic, approximate entropy (ApEn), was used to test for regularity (orderliness) in the GH data. All but one acromegalic had ApEn values greater than the absolute range in normal subjects, indicating reduced orderliness of GH release; ApEn distinguished acromegalic from normal GH secretion (fed, P < 10(-12); fasted, P < 10(-7)) with high sensitivity (95%) and specificity (100%). Acromegalics in remission had ApEn scores larger than those of normal subjects (P < 0.0001) but smaller than those of active acromegalics (P < 0.001). The coefficient of variation of successive incremental changes in GH concentrations was significantly lower in acromegalics than in normal subjects (P < 0.001). Fourier analysis in acromegalics revealed reduced fractional amplitudes compared to normal subjects (P < 0.05). We conclude that GH secretion in acromegaly is highly irregular with disorderly release accompanying significant basal secretion. Images PMID:8083369

  9. Long-term effects of human growth hormone-releasing hormone and photoperiod on hormone release and puberty in dairy heifers.

    PubMed

    Ringuet, H; Pelletier, G; Brazeau, P; Gaudreau, P; Guilbault, L A; Morisset, J; Couture, Y; Petitclerc, D

    1994-10-01

    Forty-eight Holstein dairy heifers (98.9 kg BW; 3 mo old) were subjected for 246 d to twice-daily s.c. injections of saline (CTL) or human growth hormone-releasing hormone (GRH; 5 micrograms/kg BW) and to photoperiods of 8 h of light (L): 16 h of dark (D) or 16L:8D according to a 2 x 2 factorial arrangement of treatments. Jugular blood samples were collected from 16 heifers at 3, 4, 8, and 11 mo of age to monitor prolactin, growth hormone, and estradiol-17 beta. Plasma progesterone concentrations were monitored weekly in all heifers as an index of puberty (> 1 ng/mL). Growth hormone release was induced by GRH (P < .001) throughout the trial; area under the GH curve (AUC) averaged 1,582 vs 3,643 ng.min-1.mL-1 in CTL vs GRH heifers. However, GRH-induced GH response was less (P < .05) after the second daily injection. There was also an interaction (P = .08) between GRH, photoperiod, and days of treatment on GRH-induced GH response; AUC was greater in GRH-16L:8D than in GRH-8L:16D heifers at 3 mo but less at 8 mo of age. The PRL concentrations were similar for both photoperiods at 3 mo (36.4 vs 41.7 ng/mL) and 8 mo (16.2 vs 12.8 ng/mL) of age but were greater in 16L:8D vs 8L:16D heifers at 4 mo (18.4 vs 39.3 ng/mL) and 11 mo (26.3 vs 44.1 ng/mL) of age (photoperiod x day interaction, P < .001). Photoperiod of 16L:8D vs 8L:16D reduced (P < .01) weight at puberty in CTL heifers (251 vs 303 kg BW) and to a lesser extent in GRH-treated heifers (271 vs 284 kg BW; GRH x photoperiod interaction, P = .10). In conclusion, GH response is maintained throughout 8 mo of GRH treatment, and a 16L:8D photoperiod will reduce age and weight at puberty in heifers. Furthermore, refractoriness to photoperiod-induced PRL changes was detected.

  10. Efficacy of switching therapy of luteinizing hormone-releasing hormone analogue for advanced prostate cancer.

    PubMed

    Shen, Yuan-Chi; Kang, Chih-Hsiung; Chiang, Po-Hui

    2016-11-01

    This study was conducted to determine the efficacy of switching therapy with a second-line luteinizing hormone-releasing hormone (LHRH) analogue after prostate-specific antigen (PSA) progression for advanced prostate cancer. We enrolled 200 patients, from December 2005 to September 2013, with nodal positive, metastatic prostate cancer or disease progression after definite treatment receiving continuous LHRH analogue therapy with monthly depot leuprorelin(sc) acetate 3.75 mg/vial (LA) or goserelin acetate(sc) 3.6 mg/vial (GA). If the patients had castration-resistant prostate cancer, the treatment choice of switching therapy (from LA to GA or from GA to LA) prior to starting chemotherapy was given. The LH, testosterone level, and PSA change were recorded. The records showed that there were 127 patients receiving LA as initial ADT therapy, whereas the other 73 patients were in GA therapy. A total of 92 patients received LHRH analogue switching therapy (54 patients switched from LA to GA and 38 switched from GA to LA). The effect of LH and testosterone reduction prior to and after switching therapy was comparable between the two groups, and increased PSA level after 3 months of treatment was seen in both groups (median PSA: 15.7-67.7 ng/mL in the LA to GA group; 15.2-71.4 ng/mL in the GA to LA group). This study concluded that switching therapy for patients with PSA progression after ADT has no efficacy of further PSA response.

  11. Corticotropin Releasing Hormone and Imaging, Rethinking the Stress Axis

    PubMed Central

    Contoreggi, Carlo

    2015-01-01

    The stress system provides integration of both neurochemical and somatic physiologic functions within organisms as an adaptive mechanism to changing environmental conditions throughout evolution. In mammals and primates the complexity and sophistication of these systems has surpassed other species in triaging neurochemical and physiologic signaling to maximize chances of survival. Corticotropin releasing hormone (CRH) and its related peptides and receptors have been identified over the last three decades and are fundamental molecular initiators of the stress response. They are crucial in the top down regulatory cascade over a myriad of neurochemical, neuroendocrine and sympathetic nervous system events. From neuroscience, we’ve seen that stress activation impacts behavior, endocrine and somatic physiology and influences neurochemical events that one can capture in real time with current imaging technologies. To delineate these effects one can demonstrate how the CRH neuronal networks infiltrate critical cognitive, emotive and autonomic regions of the central nervous system (CNS) with somatic effects. Abundant preclinical and clinical studies show inter-regulatory actions of CRH with multiple neurotransmitters/peptides. Stress, both acute and chronic has epigenetic effects which magnify genetic susceptibilities to alter neurochemistry; stress system activation can add critical variables in design and interpretation of basic and clinical neuroscience and related research. This review will attempt to provide an overview of the spectrum of known functions and speculative actions of CRH and stress responses in light of imaging technology and its interpretation. Metabolic and neuroreceptor positron emission/single photon tomography (PET/SPECT), functional magnetic resonance imaging (fMRI), anatomic MRI, diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (pMRS) are technologies that can delineate basic mechanisms of neurophysiology and pharmacology

  12. Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency.

    PubMed

    Muglia, L J; Jacobson, L; Luedke, C; Vogt, S K; Schaefer, M L; Dikkes, P; Fukuda, S; Sakai, Y; Suda, T; Majzoub, J A

    2000-05-01

    Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis.

  13. Physiological control of growth hormone secretion by thyrotrophin-releasing hormone in the domestic fowl.

    PubMed

    Klandorf, H; Harvey, S; Fraser, H M

    1985-06-01

    Immature cockerels (4- to 5-weeks old) were passively immunized, with antiserum raised in sheep, against thyrotrophin-releasing hormone (TRH). The administration of TRH antiserum (anti-TRH) at doses of 0.5, 1.0 or 2.0 ml/kg lowered, within 1 h, the basal concentration of plasma GH for at least 24 h. The administration of normal sheep serum had no significant effect on the GH concentration in control birds. Although the GH response to TRH (1.0 or 10.0 micrograms/kg) was not impaired in birds treated 1 h previously with anti-TRH, prior incubation (at 39 degrees C for 1 h) of TRH (20 micrograms/ml) with an equal volume of anti-TRH completely suppressed the stimulatory effect of TRH (10 micrograms/kg) on GH secretion in vivo. These results suggest that TRH is physiologically involved in the hypothalamic control of GH secretion in the domestic fowl.

  14. Proteins and insulin release: A dual role of amino-acids and intestinal hormones

    PubMed Central

    Jarrett, R. J.; Graver, H. J.; Cohen, N. M.

    1969-01-01

    In two subjects concurrent infusion of amino-acids and the hormones secretin and pancreozymin provoked much higher plasma insulin levels than did administration of amino-acids or hormones individually. It is suggested that this may be a physiological phenomenon, augmenting the release of insulin from the pancreas after a meal containing protein. PMID:5356549

  15. Long-term suppression of ovarian function by a luteinizing-hormone releasing hormone agonist implant in patients with endometriosis.

    PubMed

    Fraser, H M; Sandow, J; Cowen, G M; Lumsden, M A; Haining, R; Smith, S K

    1990-01-01

    Ten endometriosis patients received luteinizing hormone releasing hormone (LH-RH) agonist (buserelin) implant injections (6.6 mg subcutaneously) at days 0, 42, 84 and 126. Serum LH and follicle-stimulating hormone (FSH) were lowered by day 14. Luteinizing hormone remained at basal concentrations while FSH returned to values in the low-normal range of the menstrual cycle by day 35. At the end of the luteal phase during which treatment commenced, estrone and pregnanediol declined and remained at postmenopausal or early follicular phase values until days 305 to 460. Time to first ovulation ranged from 321 to 481 days after starting treatment. After the initial menstruation, only three instances of bleeding occurred during treatment. Pelvic pain was relieved or markedly reduced by day 42 and remained absent throughout the period of ovarian suppression. These results indicate the potential of a long-acting LH-RH agonist implant to form the basis for the treatment of symptomatic endometriosis.

  16. Reproductive characteristics of grass-fed, luteinizing hormone-releasing hormone-immunocastrated Bos indicus bulls.

    PubMed

    Hernandez, J A; Zanella, E L; Bogden, R; de Avila, D M; Gaskins, C T; Reeves, J J

    2005-12-01

    Two field trials were conducted in Brazil to evaluate LHRH immunocastration of Bos indicus bulls (d 0 = 2 yr of age). In Study I, 72 bulls were assigned randomly to one of three treatment groups: LHRH0-immunized, castrated, and intact. Immunized animals (n = 25) received a primary and two booster injections of ovalbumin-LHRH-7 and thioredoxin-LHRH-7 fusion proteins on d 0, 141, and 287. Twenty-three bulls were surgically castrated on d 141, and 24 served as intact controls. All animals were slaughtered on d 385, at approximately 3 yr of age. In Study II, 216 bulls were assigned randomly to the same three treatments as in Study I; however, because of a drought in the area, bulls were kept on pasture an additional year, and a fourth treatment was added, in which one-half the LHRH-immunized bulls received an additional booster on d 639 (fourth immunization). All animals in Study II were slaughtered on d 741 (4 yr of age). Luteinizing hormone-releasing hormone antibodies increased following each immunization for immunized bulls, but they were not detectable in castrate or intact animals in either study. Consequently, scrotal circumference was suppressed in immunized bulls compared with intact controls in both studies. By d 287, serum concentrations of testosterone in LHRH-immunized bulls were decreased compared with intact controls (P < 0.01). In both studies, testes and epididymal weights at slaughter were greater (P < 0.01) for intact (500 +/- 17 and 60 +/- 2 g, respectively) than for immunized bulls (173 +/- 22 and 26 +/- 2 g, respectively) and fourth immunization bulls (78 +/- 23 and 20 +/- 2 g, respectively; Study II). At the end of each study, BW was greater (P < 0.01) for intact bulls than for castrated and LHRH-immunized animals. In these two studies, the efficacy of the LHRH fusion proteins to induce an effect similar to that of surgical castration was considered 92 and 93%, respectively. These data support the concept that immunocastration of bulls at 2 yr of

  17. Effects of luteinizing hormone-releasing hormone and arginine-vasotocin on the sperm-release response of Günther's Toadlet, Pseudophryne guentheri

    PubMed Central

    2010-01-01

    Background Luteinizing hormone-releasing hormone (LHRH) is an exogenous hormone commonly used to induce spermiation in anuran amphibians. Over the past few decades, the LHRH dose administered to individuals and the frequency of injection has been highly variable. The sperm-release responses reported have been correspondingly diverse, highlighting a need to quantify dose-response relationships on a species-specific basis. This study on the Australian anuran Pseudophryne guentheri first evaluated the spermiation response of males administered one of five LHRHa doses, and second, determined whether AVT administered in combination with the optimal LHRHa dose improved sperm-release. Methods Male toadlets were administered a single dose of 0, 1, 2, 4 or 8 micrograms/g body weight of LHRHa. A 4 micrograms/g dose of AVT was administered alone or in combination with 2 micrograms/g LHRHa. Spermiation responses were evaluated at 3, 7 and 12 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Results LHRHa administration was highly effective at inducing spermiation in P. guentheri, with 100% of hormone-treated males producing sperm during the experimental period. The number of sperm released in response to 2 micrograms/g LHRHa was greater than all other doses administered and sperm viability was highest in the 1 microgram/g treatment. The administration of AVT alone or in combination with LHRHa resulted in the release of significantly lower sperm numbers. Conclusion Overall, results from this study suggest that in P. guentheri, LHRHa is effective at inducing spermiation, but that AVT inhibits sperm-release. PMID:21059269

  18. Suprachiasmatic nuclei may regulate the rhythm of leptin hormone release in Syrian hamsters (Mesocricetus auratus).

    PubMed

    Karakas, Alper; Gündüz, Bülent

    2006-01-01

    The suprachiasmatic nuclei (SCN) generate the circadian rhythm of many hormones. The hormone leptin is a metabolic signal that informs the brain about fat and energy stores of the body. We investigated whether the rhythm of leptin hormone release in Syrian hamsters is directly controlled by the SCN. Three experiments were performed: in the first, hamsters were SCN-lesioned; in the second, hamsters were exposed to different feeding regimes; and in the third, hamsters were adrenalectomized and implanted with cortisol capsules to maintain constant glucocorticoid release. Blood samples were collected before and after the experiments at different clock times and examined for leptin levels by enzyme-linked immunosorbant assay (ELISA). Different feeding regimes and constant glucocorticoid release did not alter the rhythm of leptin release; whereas, SCN lesions abolished the rhythm. The results of the present study suggest the rhythm in leptin release in Syrian hamsters may be controlled by the SCN.

  19. Single-Cell Phenotypic Characterization of Human Pituitary GHomas and Non-Functioning Adenomas Based on Hormone Content and Calcium Responses to Hypothalamic Releasing Hormones.

    PubMed

    Senovilla, Laura; Núñez, Lucía; de Campos, José María; de Luis, Daniel A; Romero, Enrique; García-Sancho, Javier; Villalobos, Carlos

    2015-01-01

    Human pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non-functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs.

  20. Prolactin, thyrotropin, and growth hormone release during stress associated with parachute jumping.

    PubMed

    Noel, G L; Dimond, R C; Earll, J M; Frantz, A G

    1976-05-01

    Prolactin, growth hormone, and thyrotropin (TSH) release during the stress of parachute jumping has been evaluated in 14 male subjects. Subjects were studied at several times before and immediately after their first military parachute jump. All three hormones had risen significantly 1 to 14 min after the jump, compared to mean levels measured immediately beforehand. Earlier studies of physical exercise by ourselves and others would suggest that emotional stress played a role in producing changes of this magnitude. We conclude that prolactin, TSH, and growth hormone are released in physiologically significant amounts in association with the stress of parachute jumping.

  1. Extrathyroidal release of thyroid hormones from thyroglobulin by J774 mouse macrophages.

    PubMed Central

    Brix, K; Herzog, V

    1994-01-01

    Thyroglobulin appears in the circulation of vertebrates at species-specific concentrations. We have observed that the clearance of thyroglobulin from the circulation occurs in the liver by macrophages. Here we show that the thyroid hormones T3 and T4 were released by incubation of mouse macrophages (J774) with thyroglobulin. Thyroid hormone release was a fast process, with an initial rate of approximately 20 pmol T4/mg per min and approximately 0.6 pmol T3/mg per min, indicating that macrophages preferentially release T4. The bulk of released thyroid hormones appeared after 5 min of incubation of macrophages with thyroglobulin, whereas degradation of the protein was detectable only after several hours. During internalization of thyroglobulin, endocytic vesicles and endosomes were reached at 5 min and lysosomes at 60 min. T4 release started extracellularly by secreted proteases and continued along the endocytic pathway of thyroglobulin, whereas T3 release occurred mainly intracellularly when thyroglobulin had reached the lysosomes. This shows that the release of both hormones occurred at distinct cellular sites. Our in vitro observations suggest that macrophages in situ represent an extrathyroidal source for thyroid hormones from circulating thyroglobulin. Images PMID:8163643

  2. Normal pituitary hormone response to thyrotrophin and gonadotrophin releasing hormones in subjects exposed to elemental mercury vapour.

    PubMed Central

    Erfurth, E M; Schütz, A; Nilsson, A; Barregård, L; Skerfving, S

    1990-01-01

    Exposure to elemental mercury (Hg) vapour results in an accumulation of Hg in the pituitary, the thyroid, and the testis. In this study, basal serum concentrations of pituitary hormones (thyrotrophin (TSH), prolactin (PRL), follicle stimulating hormone (FSH), and luteinising hormone (LH] or their response after administration of thyrotrophin and gonadotrophin releasing hormones did not differ between 11 male workers (mean urinary Hg (U Hg) concentration 26 nmol/mmol creatinine) and nine male dentists (U Hg concentration 1.3 nmol/mmol creatinine) exposed to elemental Hg vapour when compared with matched referent groups (U Hg concentration 0.6 and 0.4 nmol/mmol creatinine). Thus there was no evidence of an effect of Hg on the pituitary. Neither was there any association between exposure to Hg and serum concentrations of free thyroid hormones (S FT3, S FT4), testosterone, or cortisol. Increased plasma concentrations of selenium (Se) were associated with increased basal serum concentrations of TSH, decreased concentrations of basal serum cortisol, and decreased release of FSH. PMID:2119795

  3. In vitro release study of mono-PEGylated growth hormone-releasing peptide-6 from PLGA microspheres.

    PubMed

    Park, Eun Ji; Na, Dong Hee; Lee, Kang Choon

    2007-10-01

    The purpose of this study was to investigate in vitro release property of mono-PEGylated growth hormone-releasing peptide-6 (GHRP-6) microspheres. The microspheres encapsulating native GHRP-6 or mono-PEG-GHRP-6 were prepared using the single oil-in-water emulsion solvent evaporation method. In vitro release study was performed in 0.1M phosphate buffer, pH 7.4, containing 0.02% Tween 80 and sodium azide at 37 or 55 degrees C. The mono-PEG-GHRP-6 microspheres showed a lower initial burst compared with native GHRP-6 microspheres and zero-order release profile for a 1-month period. The release period was dependent on the PEG size attached to the GHRP-6 with more rapid drug release being observed with the smaller PEG size. This study suggests that PEGylated peptide has good potential as a source for a sustained release microsphere delivery system.

  4. Growth Hormone Response after Administration of L-dopa, Clonidine, and Growth Hormone Releasing Hormone in Children with Down Syndrome.

    ERIC Educational Resources Information Center

    Pueschel, Seigfried M.

    1993-01-01

    This study of eight growth-retarded children with Down's syndrome (aged 1 to 6.5 years) found that administration of growth hormone was more effective than either L-dopa or clonidine. Results suggest that children with Down's syndrome have both anatomical and biochemical hypothalamic derangements resulting in decreased growth hormone secretion and…

  5. Secretory pattern of GH, TSH, thyroid hormones, ACTH, cortisol, FSH, and LH in patients with fibromyalgia syndrome following systemic injection of the relevant hypothalamic-releasing hormones.

    PubMed

    Riedel, W; Layka, H; Neeck, G

    1998-01-01

    To study the hormonal perturbations in FMS patients we injected sixteen FMS patients and seventeen controls a cocktail of the hypothalamic releasing hormones: Corticotropin-releasing hormone (CRH), Thyrotropin-releasing hormone (TRH), Growth hormone-releasing hormone (GHRH), and Luteinizing hormone-releasing hormone (LHRH) and observed the hormonal secretion pattern of the pituitary together with the hormones of the peripheral endocrine glands. We found in FMS patients elevated basal values of ACTH and cortisol, lowered basal values of insulin-like growth factor I (IGF-I) and of triiodothyronine (T3), elevated basal values of follicle-stimulating hormone (FSH) and lowered basal values of estrogen. Following injection of the four releasing-hormones, we found in FMS patients an augmented response of ACTH, a blunted response of TSH, while the prolactin response was exaggerated. The effects of LHRH stimulation were investigated in six FMS patients and six controls and disclosed a significantly blunted response of LH in FMS. We explain the deviations of hormonal secretion in FMS patients as being caused by chronic stress, which, after being perceived and processed by the central nervous system (CNS), activates hypothalamic CRH neurons. CRH, on the one hand, activates the pituitary-adrenal axis, but also stimulates at the hypothalamic level somatostatin secretion which, in turn, causes inhibition of GH and TSH at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH by its ability to inhibit hypothalamic LHRH release, although it could act also directly on the ovary by inhibiting FSH-stimulated estrogen production. We conclude that the observed pattern of hormonal deviations in FMS patients is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.

  6. Decapeptides as effective agonists from L-amino acids biologically equivalent to the luteinizing hormone-releasing hormone

    SciTech Connect

    Folkers, K.; Bowers, C.Y.; Tang, P.L.; Kubota, M.

    1986-02-01

    Apparently, no agonist has been found that is comparable in potency to the luteinizing hormone-releasing hormone (LHRH) for release of LH and follicle-stimulating hormone (FSH) without substitutions with unnatural or D forms of natural amino acids. Of 139 known agonist analogs of LHRH, two were active in the range of 65%. The four LHRHs known to occur in nature involve a total of six amino acids (Tyr, His, Leu, Trp, Arg, Gln) in positions 5, 7, and 8. There are 16 possible peptides with these six amino acids in positions 5, 7, and 8, of which 4 are the known LHRHs, and 2 more were synthesized. The authors have synthesized the 10 new peptides and assayed 11 in vivo and in vitro, and they found not only 1 but a total of 5 that have activity equivalent to or greater than that of LHRH for the release of LH and/or FSH under at least one assay condition. These five are as follows: (HisV,TrpX,GlnY)LHRH; (HisV,TrpX,LeuY)LHRH; (HisV,TrpX)LHRH; (TrpX)LHRH; (HisV)LHRH. These structures are a basis for the design of antagonists without ArgY toward avoiding histamine release. Complete inhibition of LH and FSH release in vivo may be induced by joint use of ArgY and GlnY or LeuY antagonists. These potent agonists, related to LHRH, may be therapeutically useful in disorders of reproduction, the central nervous system, and for the control of hormone-dependent carcinomas. Radioreceptor assays and radioimmunoassays were utilized.

  7. A potassium current evoked by growth hormone-releasing hormone in follicular oocytes of Xenopus laevis.

    PubMed Central

    Yoshida, S; Plant, S

    1991-01-01

    1. Electrophysiological properties of the growth hormone-releasing hormone (GRH) receptor were studied in Xenopus oocytes with an intact follicle cell layer (i.e. follicular oocytes) by measuring whole-cell current using the two-electrode voltage-clamp method. 2. A slow transient outward current was elicited in oocytes, clamped at -60 mV, by the application of rat GRH but not bovine, porcine, or human GRH. 3. The response to GRH was not suppressed by blockers known to inhibit other endogenous receptors present in follicular Xenopus oocytes; blockers used were timolol (2 microM; beta-adrenergic blocker), theophylline (0.1 mM; purinergic blocker) and atropine (100 nM; muscarinic blocker). 4. The current response evoked by rat GRH occurred in a dose-dependent manner. The concentrations of GRH for threshold and maximum responses were 1 and 100 nM respectively and the estimated EC50 (half-maximal effective concentration) was approximately 7 nM. The amplitude and conductance of the response became larger and the latency, time-to-peak and half-decay time were shortened when the concentration of GRH was increased. 5. The GRH response was reversibly inhibited by a K+ channel blocker, tetraethylammonium+ (TEA+; 20 mM). The reversal potential for the GRH response was around -100 mV and was compatible with the reported value for a K+ current in Xenopus oocytes. Furthermore, a depolarizing shift of 40 mV in the reversal potential was observed when the external K+ concentration was increased from 2 to 10 mM, agreeing with the Nernst equation. In contrast, no significant shift in the reversal potential was observed by changing the external concentration of Na+ or Cl-. 6. The GRH response was not suppressed in oocytes treated with an acetoxy-methyl ester of bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA/AM; 10 microM) which penetrates the cell membrane and chelates internal Ca2+. 7. The GRH response was potentiated by pre-treatment with forskolin (0.4 microM; 5 min

  8. Progression of intracranial meningioma during luteinizing hormone-releasing hormone agonist treatment for prostate cancer: case report.

    PubMed

    Anda, Takeo; Honda, Masaru; Ishihara, Tokuhiro; Kamei, Toshiaki

    2014-01-01

    The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.

  9. Myogenic expression of an injectable protease-resistant growth hormone-releasing hormone augments long-term growth in pigs

    NASA Technical Reports Server (NTRS)

    Draghia-Akli, R.; Fiorotto, M. L.; Hill, L. A.; Malone, P. B.; Deaver, D. R.; Schwartz, R. J.

    1999-01-01

    Ectopic expression of a new serum protease-resistant porcine growth hormone-releasing hormone, directed by an injectable muscle-specific synthetic promoter plasmid vector (pSP-HV-GHRH), elicits growth in pigs. A single 10 mg intramuscular injection of pSP-HV-GHRH DNA followed by electroporation in three-week-old piglets elevated serum GHRH levels by twofold to fourfold, enhanced growth hormone secretion, and increased serum insulin-like growth factor-I by threefold to sixfold over control pigs. After 65 days the average body weight of the pigs injected with pSP-HV-GHRH was approximately 37% greater than the placebo-injected controls and resulted in a significant reduction in serum urea concentration, indicating a decrease in amino acid catabolism. Evaluation of body composition indicated a uniform increase in mass, with no organomegaly or associated pathology.

  10. Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels.

    PubMed

    Aleppo, G; Moskal, S F; De Grandis, P A; Kineman, R D; Frohman, L A

    1997-03-01

    Repeated stimulation of pituitary cell cultures with GH-releasing hormone (GHRH) results in diminished responsiveness, a phenomenon referred to as homologous desensitization. One component of GHRH-induced desensitization is a reduction in GHRH-binding sites, which is reflected by the decreased ability of GHRH to stimulate a rise in intracellular cAMP. In the present study, we sought to determine if homologous down-regulation of GHRH receptor number is due to a decrease in GHRH receptor synthesis. To this end, we developed and validated a quantitative RT-PCR assay system that was capable of assessing differences in GHRH-R messenger RNA (mRNA) levels in total RNA samples obtained from rat pituitary cell cultures. Treatment of pituitary cells with GHRH, for as little as 4 h, resulted in a dose-dependent decrease in GHRH-R mRNA levels. The maximum effect was observed with 0.1 and 1 nM GHRH, which reduced GHRH-R mRNA levels to 49 +/- 4% (mean +/- SEM) and 54 +/- 11% of control values, respectively (n = three separate experiments; P < 0.05). Accompanying the decline in GHRH-R mRNA levels was a rise in GH release; reaching 320 +/- 31% of control values (P < 0.01). Because of the possibility that the rise in medium GH level is the primary regulator of GHRH-R mRNA, we pretreated pituitary cultures for 4 h with GH to achieve a concentration comparable with that induced by a maximal stimulation with GHRH (8 micrograms GH/ml medium). Following pretreatment, cultures were stimulated for 15 min with GHRH and intracellular cAMP accumulation was measured by RIA. GH pretreatment did not impair the ability of GHRH to induce a rise in cAMP concentrations. However, as anticipated, GHRH pretreatment (10 nM) significantly reduced subsequent GHRH-stimulated cAMP to 46% of untreated controls. These data suggest that GHRH, but not GH, directly reduces GHRH-R mRNA levels. To determine whether this effect was mediated through cAMP, cultures were treated with forskolin, a direct stimulator of

  11. Regulation of the Immune System by Hypothalamic Releasing Hormones.

    DTIC Science & Technology

    1986-07-14

    mechanisms of lymphokine induction. @• Depletion of macrophages from human peripheral blood mononuclear cells (PBMC) caused a marked decrease in...Harbour- McMenamin , D.V., E.M. Smith and J.E. Blalock. 1985. Endotoxin induction of leukocyte-derived proopiomelanocortin related peptides. Infect. immun...48:813-817. 3. Blalock, J.E., D.V. McMenamin , and E.M. Smith. 1985. Peptide hormones shared by the neuroendocrine and immune systems. J Immunol. 135

  12. Taurine and the control of basal hormone release from rat neurohypophysis.

    PubMed

    Song, Zhilin; Hatton, Glenn I

    2003-10-01

    Pituicytes of pituitary neural lobe are rich in the amino acid taurine, which they release upon hypoosmotic stimulation. As a generally inhibitory amino acid, taurine is thought to activate receptors on neural lobe nerve terminals and exert some control over hormone release. Previous work has shown the presence of glycine and GABA(A) receptors in neural lobe, both of which have affinity for taurine. Using a perifused explant system, we studied the effects of taurine activation of glycine and GABA(A) receptors on basal hormone release. Somewhat surprisingly, taurine induced increases in basal release of both vasopressin and oxytocin. Taurine-induced increases in oxytocin release were blocked by bicuculline, suggesting involvement of GABA(A) receptors. Increases in vasopressin release were not blocked by bicuculline, indicating involvement of receptors other than GABA(A). Although combined bicuculline and strychnine, an antagonist at most glycine receptors, also did not block increased vasopressin release, picrotoxin (a Cl(-) channel blocker) was effective in blocking increases in both vasopressin and oxytocin release. The other receptor(s) involved in taurine actions is postulated to be strychnine-insensitive glycine receptors. Thus, taurine in neural lobe may act via both a GABA(A) receptor and one or more types of glycine receptors to depolarize nerve terminal membranes under basal conditions. Taurine-induced partial depolarization resulting in Na(+) channel inactivation is probably responsible for its previously observed inhibition of stimulated hormone release from neural lobe.

  13. Developmental changes in hypothalamic Kiss1 expression during activation of the pulsatile release of luteinising hormone in maturing ewe lambs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Onset of puberty is characterized by a marked increase in the frequency of release of gonadotrophin-releasing hormone (GnRH) and luteinizing hormone (LH). The KISS1 gene plays a critical role in pubertal development and its product, kisspeptin, stimulates GnRH and LH release. In the study reported h...

  14. Thyroid hormone modulation of the hypothalamic growth hormone (GH)-releasing factor-pituitary GH axis in the rat.

    PubMed Central

    Miki, N; Ono, M; Hizuka, N; Aoki, T; Demura, H

    1992-01-01

    Both thyroid hormone and hypothalamic growth hormone (GH)-releasing factor (GRF) facilitate pituitary somatotroph function. However, the pathophysiological role of thyroid hormone in GRF secretion is less well understood. Thyrotoxicosis, induced by administration of thyroxine (T4) in rats, inhibited both pituitary GH levels and immunoreactive GRF secretion from incubated hypothalamus. At the highest dose of T4 given for 12 d, GRF secretion and pituitary GH decreased by 50 and 39%, respectively. Hypothyroidism induced by thyroidectomy (Tx) enhanced GRF secretion approximately twofold while depleting pituitary GH by greater than 99%. Both of these hypothalamic and pituitary effects were reversed by replacement of T4 but not human GH for 7 or 14 d. Human GH was as potent as T4 in restoring decreased body weight gains or serum insulin-like growth factor-1 levels in Tx rats. These results indicate that at both physiological and pathological concentrations in serum, thyroid hormone acts as an inhibitory modulator of GRF secretion, probably not involving a feedback mechanism through GH. A biphasic effect of thyroid hormone on pituitary GH levels appears to derive from the difference in primary target tissues of hyper- and hypothyroidism, the hypothalamus and the pituitary, respectively. PMID:1634603

  15. Efficacy and Safety of Sustained-Release Recombinant Human Growth Hormone in Korean Adults with Growth Hormone Deficiency

    PubMed Central

    Kim, Youngsook; Hong, Jae Won; Chung, Yoon-Sok; Kim, Sung-Woon; Cho, Yong-Wook; Kim, Jin Hwa; Kim, Byung-Joon

    2014-01-01

    Purpose The administration of recombinant human growth hormone in adults with growth hormone deficiency has been known to improve metabolic impairment and quality of life. Patients, however, have to tolerate daily injections of growth hormone. The efficacy, safety, and compliance of weekly administered sustained-release recombinant human growth hormone (SR-rhGH, Declage™) supplement in patients with growth hormone deficiency were evaluated. Materials and Methods This trial is 12-week prospective, single-arm, open-label trial. Men and women aged ≥20 years with diagnosed growth hormone deficiency (caused by pituitary tumor, trauma and other pituitary diseases) were eligible for this study. Each subject was given 2 mg (6 IU) of SR-rhGH once a week, subcutaneously for 12 weeks. Efficacy and safety at baseline and within 30 days after the 12th injection were assessed and compared. Score of Assessment of Growth Hormone Deficiency in Adults (AGHDA score) for quality of life and serum IGF-1 level. Results The IGF-1 level of 108.67±74.03 ng/mL was increased to 129.01±68.37 ng/mL (p=0.0111) and the AGHDA QoL score was decreased from 9.80±6.51 to 7.55±5.76 (p<0.0001) at week 12 compared with those at baseline. Adverse events included pain, swelling, erythema, and warmth sensation at the administration site, but many adverse events gradually disappeared during the investigation. Conclusion Weekly administered SR-rhGH for 12 weeks effectively increased IGF-1 level and improved the quality of life in patients with GH deficiency without serious adverse events. PMID:24954335

  16. Differential Activation in Amygdala and Plasma Noradrenaline during Colorectal Distention by Administration of Corticotropin-Releasing Hormone between Healthy Individuals and Patients with Irritable Bowel Syndrome.

    PubMed

    Tanaka, Yukari; Kanazawa, Motoyori; Kano, Michiko; Morishita, Joe; Hamaguchi, Toyohiro; Van Oudenhove, Lukas; Ly, Huynh Giao; Dupont, Patrick; Tack, Jan; Yamaguchi, Takuhiro; Yanai, Kazuhiko; Tashiro, Manabu; Fukudo, Shin

    2016-01-01

    Irritable bowel syndrome (IBS) often comorbids mood and anxiety disorders. Corticotropin-releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis, but it is not clear how CRH agonists change human brain responses to interoceptive stimuli. We tested the hypothesis that brain activation in response to colorectal distention is enhanced after CRH injection in IBS patients compared to healthy controls. Brain H215O- positron emission tomography (PET) was performed in 16 male IBS patients and 16 age-matched male controls during baseline, no distention, mild and intense distention of the colorectum using barostat bag inflation. Either CRH (2 μg/kg) or saline (1:1) was then injected intravenously and the same distention protocol was repeated. Plasma adrenocorticotropic hormone (ACTH), serum cortisol and plasma noradrenaline levels were measured at each stimulation. At baseline, CRH without colorectal distention induced more activation in the right amygdala in IBS patients than in controls. During intense distention after CRH injection, controls showed significantly greater activation than IBS patients in the right amygdala. Plasma ACTH and serum cortisol secretion showed a significant interaction between drug (CRH, saline) and distention. Plasma noradrenaline at baseline significantly increased after CRH injection compared to before injection in IBS. Further, plasma noradrenaline showed a significant group (IBS, controls) by drug by distention interaction. Exogenous CRH differentially sensitizes brain regions of the emotional-arousal circuitry within the visceral pain matrix to colorectal distention and synergetic activation of noradrenergic function in IBS patients and healthy individuals.

  17. Role of thyrotropin-releasing hormone in prolactin-producing cell models.

    PubMed

    Kanasaki, Haruhiko; Oride, Aki; Mijiddorj, Tselmeg; Kyo, Satoru

    2015-12-01

    Thyrotropin-releasing hormone (TRH) is a hypothalamic hypophysiotropic neuropeptide that was named for its ability to stimulate the release of thyroid-stimulating hormone in mammals. It later became apparent that it exerts a number of species-dependent hypophysiotropic activities that regulate other pituitary hormones. TRH also regulates the synthesis and release of prolactin, although whether it is a physiological regulator of prolactin that remains unclear. Occupation of the Gq protein-coupled TRH receptor in the prolactin-producing lactotroph increases the turnover of inositol, which in turn activates the protein kinase C pathway and the release of Ca(2+) from storage sites. TRH-induced signaling events also include the activation of extracellular signal-regulated kinase (ERK) and induction of MAP kinase phosphatase, an inactivator of activated ERK. TRH stimulates prolactin synthesis through the activation of ERK, whereas prolactin release occurs via elevation of intracellular Ca(2+). We have been investigating the role of TRH in a pituitary prolactin-producing cell model. Rat pituitary somatolactotroph GH3 cells, which produce and release both prolactin and growth hormone (GH), are widely used as a model for the study of prolactin- and GH-secreting cells. In this review, we describe the general action of TRH as a hypophysiotropic factor in vertebrates and focus on the role of TRH in prolactin synthesis using GH3 cells.

  18. Differential sensitivity of growth hormone-releasing hormone and somatostatin release from perifused mouse hypothalamic fragments in response to glucose deficiency.

    PubMed

    Sato, M; Frohman, L A

    1993-06-01

    The effects of glucose deficiency on growth hormone (GH)-releasing hormone (GRH) and somatostatin (SRIH) release from mouse hypothalamic fragments were investigated using an in vitro perifusion system. Fragments were perifused with Krebs-Ringer bicarbonate solution (KRB) containing 5.6 mM glucose for 3 h followed by reduced glucose concentrations in KRB for the next 2 h. GRH release was simulated by 0.7-2.8 mM glucose in an inverse concentration-dependent manner. In contrast, SRIH release was not stimulated by glucose at concentrations of 2.8 and 1.4 mM; only at 0.7 mM was there a modest stimulation of SRIH release that was comparable to the effect of 2.8 mM glucose on GRH release. The maximal stimulation of GRH and SRIH release by 0.7 mM glucose was 221 and 150%, respectively, of controls. Glucose concentrations of 11.2 and 22.4 mM inhibited GRH release but did not alter SRIH release. The glucose analog 2-deoxy-D-glucose (2-DG; 5.6-39.2 mM) also stimulated GRH release in a dose-dependent manner, and SRIH release was less sensitive to 2-DG than was GRH. The maximal stimulation of GRH and SRIH release by 39.2 mM 2-DG was 190 and 147%, respectively, of controls. Increases in GRH and SRIH release stimulated by 30 mM KCl 1 h after exposure to low glucose or 2-DG were not significantly different from those after exposure to 5.6 mM glucose. However, the SRIH response to K(+)-induced depolarization was much greater than that of GRH. The glucose intermediate pyruvate (4.9 and 9.8 mM) partially inhibited both GRH and SRIH release induced by 0.7 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. In vitro effect of. Delta. sup 9 -tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E sub 2

    SciTech Connect

    Rettori, V.; Aguila, M.C.; McCann, S.M. ); Gimeno, M.F.; Franchi, A.M. )

    1990-12-01

    Previous in vivo studies have shown that {Delta}{sup 9}-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E{sub 2} (PGE{sub 2}) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE{sub 2} suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE{sub 2} synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.

  20. Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs.

    PubMed

    Moradi, Shayli Varasteh; Varamini, Pegah; Toth, Istvan

    2015-09-01

    The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protected the peptide from proteolytic degradation and increased the peptides' half-lives in human plasma, rat kidney membrane enzymes, and liver homogenate markedly. Among all seven modified analogs, compound 1 (Lac-[Q(1)][w(6)]LHRH) and compound 6 (GS(4)-[w(6)]LHRH) were stable in human plasma during 4 h of experiment. The half-lives of compounds 1 and 6 improved significantly in kidney membrane enzymes (from 3 min for LHRH to 68 and 103 min, respectively). The major cleavage sites for most of the glycosylated compounds were found to be at Trp(3)-Ser(4) and Ser(4)-Tyr(5) in compounds 1-5. Compound 6 was hydrolyzed at Ser(4)-Tyr(5) and the sugar conjugation site. The antiproliferative activity of the glycopeptides was evaluated on LHRH receptor-positive prostate cancer cells. The glycosylated LHRH derivatives had a significant growth inhibitory effect on the LNCaP cells after a 48-h treatment. It was demonstrated that compound 1 significantly increased the release of luteinizing hormone (LH) at 5 and 10 nM concentrations and compound 5 (GS-[Q(1)]LHRH) stimulated the release of follicle-stimulating hormone (FSH) at 5 nM concentration in dispersed rat pituitary cells (p < 0.05). In our studies, compound 1-bearing lactose and D-Trp was the most stable and active and is a promising candidate for future preclinical investigations in terms of in vitro biological activity and metabolic stability.

  1. Lithium stimulates the release of human parathyroid hormone in vitro.

    PubMed

    Birnbaum, J; Klandorf, H; Giuliano, A; Van Herle, A

    1988-06-01

    The effect of lithium on PTH release from human parathyroid tissue was studied using a perifusion system and an immunoradiometric assay for intact human PTH. Tissue was obtained from three patients undergoing surgery for thyroid disease, three patients with secondary hyperparathyroidism due to chronic renal insufficiency, and four patients with primary hyperparathyroidism due to a parathyroid adenoma. Addition of lithium in concentrations equivalent to the therapeutic serum levels normally attained in man (1.3 mmol/L) resulted in a significant (P less than 0.05) increase in PTH release under normocalcemic (1.15 mmol/L) conditions from normal and hyperplastic tissues. The magnitude of the lithium-induced response of PTH release ranged from a 1.4- to 5.3-fold increase above basal levels (perifusion with 1.15 mmol/L calcium alone) and was comparable to the response during a low calcium (0.42 mmol/L) perifusion. Although the response to lithium was delayed compared to that of hypocalcemia, PTH returned to basal levels immediately after removal of either stimulator. In contrast, parathyroid adenomas did not respond to either lithium or hypocalcemia in a characteristic manner, but, rather, functioned in an autonomous fashion with repeated pulsatile bursts of PTH release that were not suppressible even under hypercalcemic (1.70 mmol/L) conditions. These in vitro studies suggest that lithium therapy may elevate serum PTH levels in some patients and could, thus, be responsible for hypercalcemia in them.

  2. Effect of ovarian suppression with gonadotropin-releasing hormone agonist on glucose disposal and insulin secretion.

    PubMed

    Toth, Michael J; Cooper, Brian C; Pratley, Richard E; Mari, Andrea; Matthews, Dwight E; Casson, Peter R

    2008-06-01

    Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after 2 mo of treatment with gonadotropin-releasing hormone agonist (GnRHa; n = 7) or placebo (n = 6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., (13)C and (2)H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution, or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative, or nonoxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second-phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy, eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels.

  3. Seasonal effect of gonadotrophin inhibitory hormone on gonadotrophin-releasing hormone-induced gonadotroph functions in the goldfish pituitary.

    PubMed

    Moussavi, M; Wlasichuk, M; Chang, J P; Habibi, H R

    2013-05-01

    We have shown that native goldfish gonadotrophin inhibitory hormone (gGnIH) differentially regulates luteinsing hormone (LH)-β and follicle-stimulating hormone (FSH)-β expression. To further understand the functions of gGnIH, we examined its interactions with two native goldfish gonadotrophin-releasing hormones, salmon gonadotrophin-releasing hormone (sGnRH) and chicken (c)GnRH-II in vivo and in vitro. Intraperitoneal injections of gGnIH alone reduced serum LH levels in fish in early and mid gonadal recrudescence; this inhibition was also seen in fish co-injected with either sGnRH or cGnRH-II during early recrudescence. Injection of gGnIH alone elevated pituitary LH-β and FSH-β mRNA levels at early and mid recrudescence, and FSH-β mRNA at late recrudescence. Co-injection of gGnIH attenuated the stimulatory influences of sGnRH on LH-β in early recrudescence, and LH-β and FSH-β mRNA levels in mid and late recrudescence, as well as the cGnRH-II-elicited increase in LH-β, but not FSH-β, mRNA expression at mid and late recrudescence. sGnRH and cGnRH-II injection increased pituitary gGnIH-R mRNA expression in mid and late recrudescence but gGnIH reduced gGnIH-R mRNA levels in late recrudescence. gGnIH did not affect basal LH release from perifused pituitary cells and continual exposure to gGnIH did not alter the LH responses to acute applications of GnRH. However, a short 5-min GnIH treatment in the middle of a 60-min GnRH perifusion selectively reduced the cGnRH-II-induced release of LH. These novel results indicate that, in goldfish, gGnIH and GnRH modulate pituitary GnIH-R expression and gGnIH differentially affects sGnRH and cGnRH-II regulation of LH secretion and gonadotrophin subunit mRNA levels. Furthermore, these actions are manifested in a reproductive stage-dependent manner.

  4. Role of calcium in gonadotropin releasing hormone-induced luteinizing hormone secretion from the bovine pituitary

    SciTech Connect

    Kile, J.P.

    1986-01-01

    The hypothesis was tested that GnRH acts to release LH by increasing calcium uptake by gonadotroph which in turn stimulates calcium-calmodulin activity and results in LH release from bovine pituitary cells as it does in the rat. Pituitary glands of calves (4-10 months of age) were enzymatically dispersed (0.2% collagenase) and grown for 5 days to confluency in multiwell plates (3 x 10/sup 5//well). Cells treated with GnRH Ca/sup + +/ ionophore A23187, and ouabain all produced significant releases of LH release in a pronounced all or none fashion, while thorough washing of the cells with 0.5 mM EGTA in Ca/sup + +/-free media prevented the action of GnRH. GnRH caused a rapid efflux of /sup 45/Ca/sup + +/. Both GnRH-stimulated /sup 45/Ca efflux and LH release could be partially blocked by verapamil GnRH-induced LH release could also be blocked by nifedipine and tetrodotoxin, although these agents did not affect /sup 45/Ca efflux. The calmodulin antagonists calmidazolium and W7 were found to block GnRH induced LH release, as well as LH release induced by theophylline, KC PGE/sub 2/ and estradiol. These data indicated that: (1) calcium is required for GnRH action, but extracellular Ca/sup + +/ does not regulate LH release; (2) GnRH elevates intracellular Ca/sup + +/ by opening both voltage sensitive and receptor mediated Ca/sup + +/ channels; (3) activation of calmodulin is one mechanism involved in GnRH-induced LH release.

  5. Attenuated tubal and endometrial urocortin 1 and corticotropin-releasing hormone receptor expression in ectopic pregnancy.

    PubMed

    Borges, L E; Horne, A W; McDonald, S E; Shaw, J L V; Lourenco, P C; Petraglia, F; Critchley, H O D

    2011-03-01

    Fallopian tube (FT) and endometrial urocortin 1 (Ucn1) and corticotropin-releasing hormone (CRH)-receptor (CRH-R1/CRH-R2) expression were examined using quantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry in nonpregnant and pregnant women (intrauterine, IUP; ectopic pregnancy, EP). Tubal Ucn1 messenger RNA (mRNA) expression was higher in luteal compared to follicular phase (P < .01) and equivalent to follicular phase in FT from EP. Tubal CRH-R1/CRH-R2 mRNA was lower in luteal phase (P < .05) and in FT from EP compared to follicular phase (P < .01). Ucn1 mRNA was lower in endometrium from EP compared to IUP (P < .05). Corticotropin-releasing hormone-R1 mRNA was higher in endometrium from EP compared to viable IUP (P < .05). No differences were observed in CRH-R2 expression. Corticotropin-releasing hormone-R1 protein was primarily localized to epithelium of FT and endometrium. Quantitative analysis of tubal CRH-R1 protein expression reflected that seen at the mRNA level but endometrial expression was equivocal. The demonstration of attenuated tubal/endometrial Ucn1/CRH-R expression in EP further supports a role of the CRH-family in embryo implantation.

  6. Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers.

    PubMed

    Perez, Roberto; Schally, Andrew V; Vidaurre, Irving; Rincon, Ricardo; Block, Norman L; Rick, Ferenc G

    2012-09-01

    This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA-602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INFγ, IL-1α, IL-4, IL-6, IL-8, IL-10, and TNFα, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers.

  7. Acute Effect of Manganese on Hypothalamic Luteinizing Hormone Releasing Hormone Secretion in Adult Male Rats: Involvement of Specific Neurotransmitter Systems

    PubMed Central

    Prestifilippo, Juan Pablo; Fernández-Solari, Javier; De Laurentiis, Andrea; Mohn, Claudia Ester; de la Cal, Carolina; Reynoso, Roxana; Dees, W. Les; Rettori, Valeria

    2008-01-01

    Manganese chloride (MnCl2) is capable of stimulating luteinizing hormone releasing hormone (LHRH) secretion in adult male Sprague-Dawley rats through the activation of the hypothalamic nitric oxide/cyclic guanosine monophosphate (cGMP)/protein kinase G pathway. The present study aimed to determine the involvement of specific neurotransmitters involved in this action. Our results indicate that dopamine, but not glutamic acid and prostaglandinds, mediates the MnCl2 stimulated secretion of LHRH from medial basal hypothalami in vitro, as well as increases the activity of nitric oxide synthase. Furthermore, a biphasic response was observed in that gamma aminobutyric acid (GABA) release was also increased, which acts to attenuate the MnCl2 action to stimulate LHRH secretion. Although it is clear that manganese (Mn+2) can acutely induce LHRH secretion in adult males, we suggest that the additional action of MnCl2 to release GABA, a LHRH inhibitor, may ultimately contribute to suppressed reproductive function observed in adult animals following exposure to high chromic levels of Mn+2. PMID:18603625

  8. Growth hormone (GH) and GH-releasing hormone (GHRH): Co-localization and action in the chicken testis.

    PubMed

    Martínez-Moreno, Carlos G; López-Marín, Luz M; Carranza, Martha; Giterman, Daniel; Harvey, Steve; Arámburo, Carlos; Luna, Maricela

    2014-04-01

    Growth hormone (GH) gene expression is not confined to the pituitary gland and occurs in many extrapituitary tissues, including the chicken testis. The regulation and function of GH in extrapituitary tissues is, however, largely unknown. The possibility that chicken testicular GH might be regulated by GH-releasing hormone (GHRH), as in the avian pituitary gland, was investigated in the present study. GHRH co-localized with GH in the germinal epithelium and in interstitial zones within the chicken testes, particularly in the spermatogonia and spermatocytes. In testicular cell cultures, exogenous human GHRH1-44 induced (at 1, 10 and 100nM) a dose-related increase in GH release. Western blot analysis showed a heterogeneous pattern in the GH moieties released during GHRH stimulation. 26kDa monomer GH was the most abundant moiety under basal conditions, but 15 and 17kDa isoforms were more abundant after GHRH stimulation. GHRH treatment also increased the abundance of PCNA (proliferating cell nuclear antigen) immunoreactivity in the testes. This may have been GH-mediated, since exogenous GH similarly increased the incorporation of ((3)H)-thymidine into cultured testicular cells and increased their metabolic activity, as determined by increased MTT reduction. Furthermore, GH and GHRH immunoneutralization blocked GHRH-stimulated proliferative activity. In summary, these results indicate that GHRH stimulates testicular GH secretion in an autocrine or paracrine manner. Data also demonstrate proliferative actions of GHRH on testicular cell number and suggest that this action is mediated by local GH production.

  9. Use of Gonadotropin-Releasing Hormone for Intractable Seizures in a Girl with Precocious Puberty without Hypothalamic Hamartoma.

    PubMed

    Govil-Dalela, Tuhina; Kumar, Ajay; Moltz, Kathleen C; Chugani, Harry T

    2016-07-01

    The use of gonadotropin-releasing hormone analogs has been reported in the treatment of gelastic seizures and precocious puberty associated with hypothalamic hamartomas, but not in other seizure types without hypothalamic hamartoma. We describe a 7.5 year-old girl whose seizures subsided after gonadotropin-releasing hormone analog implant, administered for precocious puberty.

  10. Evidence to suggest that gonadotropin-releasing hormone inhibits its own secretion by affecting hypothalamic amino acid neurotransmitter release.

    PubMed

    Feleder, C; Jarry, H; Leonhardt, S; Moguilevsky, J A; Wuttke, W

    1996-10-01

    The mediobasal hypothalamus of rats contains gonadotropin-releasing hormone (GnRH) receptors. These hypothalamic neurons also express the GnRH corresponding gene. Under these circumstances, the possibility exists that these GnRH receptors could be localized in other neurons, which are GnRH-receptive, unknowing the neurotransmitter quality. Therefore, we studied the in vitro effects of the GnRH agonist buserelin on GnRH, glutamate, gamma-amino-butyric acid (GABA) and taurine release from explanted superfused hypothalami of untreated and buserelin-pretreated (down-regulated) male rats. When buserelin was added to the superfusion medium it inhibited promptly the release of GnRH and the excitatory amino acid neurotransmitter glutamate, but stimulated the release of the inhibitory neurotransmitters, GABA and taurine. Hypothalamic release of GnRH from hypothalami collected from buserelin-treated (30 micrograms/100 g b.w. twice daily for 4 days) male rats released significantly less GnRH, glutamate and more GABA and taurine. The inhibitory effect of buserelin was maintained when the superfusion medium continuously contained the GnRH analog. When superfusion of hypothalami from buserelin-pretreated animals was performed in the absence of buserelin, GnRH and glutamate release increased significantly within 45-60 min, whereas GABA and taurine release decreased at this time point. When buserelin was added to the superfusion medium 2 h after buserelin-free superfusion, GnRH and glutamate release decreased whereas GABA and taurine release increased instantaneously. Buserelin-treated rats showed significantly low values of LH and testosterone than the untreated rats. These results suggest that GnRH receptors may not only be present in GnRH axon terminals in the median eminence, but also on glutamatergic, GABAergic and taurinergic neurons by which GnRH may exert an autoinhibitory ultrashort loop feedback on its own secretion. This effect appears to be connected with glutamatergic

  11. The effect of luteinizing hormone releasing hormone analog regime and stage of oocyte maturity for induced ovulation of channel catfish Ictalurus punctatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effective LHRHa (luteinizing hormone releasing hormone analog) dose based on the gonadal maturity of channel catfish, Ictalurus punctatus to optimize channel x blue hybrid catfish production was evaluated in 4 trials (twice in early part of the season and twice in the peak spawning season) in a ...

  12. A 66-bp deletion in growth hormone releasing hormone gene 5'-flanking region with largemouth bass recessive embryonic lethal.

    PubMed

    Ma, D M; Han, L Q; Bai, J J; Li, S J; Fan, J J; Yu, L Y; Quan, Y C

    2014-06-01

    Growth hormone releasing hormone (GHRH) regulates the secretion of growth hormone (GH) in the pituitary gland. A 66-bp deletion (c.-923_-858del) was detected in the 5'-flanking sequence of the largemouth bass (Micropterus salmoides) GHRH gene. In two cultured random populations of adult individuals (A: n = 170 and B: n = 150), the genotype ratios of +/+:+/- were 2.5:1 and 2.8:1 respectively. Only one -/- fish was detected. A Largemouth bass family was constructed with two heterozygous individuals (+/-) as parents. The genotype ratio of +/+:+/-:-/- in the filial generation embryos was 1:1.6:0.1 at the neurula and 1:2:0 at hatched larvae stages. This indicated that the 66-bp deletion was a recessive lethal site and that homozygous individuals (-/-) died off in embryonic development. The growth traits (body weight, body length and body depth) were measured, and the GHRH mRNA expression levels in brain tissue were detected using real-time PCR. The effects of genotype (+/-) on growth traits and GHRH mRNA expression were not significant. Although the cause of death was not clear, the results hint that the 66-bp deletion site in GHRH 5'-flanking sequence significantly affects the livability in largemouth bass embryonic development.

  13. Topographical localization of the receptors for luteinizing hormone- releasing hormone on the surface of dissociated pituitary cells

    PubMed Central

    1977-01-01

    A derivative of the hypothalamic peptide luteinizing hormone-releasing hormone (LHRH) has been coupled to ferritin and the conjugate purified by gel chromatography. In its ability to stimulate the secretion of luteinizing hormone from pituitary cells in vitro, the conjugate has the same potency and specificity as the native peptide. When dissociated pituitary cells maintained in short-term culture are lightly fixed with formaldehyde and then incubated with the conjugate, examination in the electron microscope shows an even distribution of ferritin particles over the free cell surface of the gonadotrophin cells. This binding appears to be specific for the LHRH receptor since it is prevented by a 10-fold excess of native peptide. In addition to the gonadotrophin cells, some somatotrophin and thyrotrophin cells bind conjugate on their free surfaces under similar conditions. If living cells are incubated with the conjugate for 15 min, the bound conjugate becomes aggregated and then concentrated in one localized area of the cell surface. In this area, which lies immediately above the juxtanuclear Golgi complex, the plasma membrane is frequently invaginated in a manner which suggests that the bound, aggregated conjugate is internalized by endocytosis. PMID:233747

  14. Gonadotrophin releasing hormone-based vaccine, an effective candidate for prostate cancer and other hormone-sensitive neoplasms.

    PubMed

    Junco, Jesús A; Basalto, Roberto; Fuentes, Franklin; Bover, Eddy; Reyes, Osvaldo; Pimentel, Eulogio; Calzada, Lesvia; Castro, Maria D; Arteaga, Niurka; López, Yovisleidis; Hernández, Héctor; Bringas, Ricardo; Garay, Hilda; Peschke, Peter; Bertot, José; Guillén, Gerardo

    2008-01-01

    Prostate growth, development, functions, and neoplastic transformation is androgen dependent. Estrogens have similar effects in the ovary and breast. Previous studies using gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate (PC) and breast cancer (BC). We have synthesized a peptide mutated at position 6 and attached to the 830-844 tetanic toxoid (TT) helper T cell sequence in the same synthesis process. After repeated pig immunizations, we have demonstrated a vaccine that significantly decreased testes size (p < 0.001), prostate (p < 0.01), seminal vesicles (p < 0.01), and testosterone (T) castration [0.05 nM ml(-1) (p < 0. 01)]. Similar results were obtained in adult male and female healthy dogs and Macaca fascicularis models. These data indicate that this GnRHm1-TT vaccine is safe and able to induce significant tumor growth inhibition in the Dunning R3327-H rat androgen responsive prostate tumor model. In these rats, the immunization induced high anti-GnRH titers concomitant with T castration reduction (p < 0.01) in 90% of the animals tested. In addition, 70% of the responders exhibited tumor growth inhibition (p = 0.02) and a survival rate approximately three times longer that those of untreated rats. These data indicate that GnRHm1-TT vaccine may be a potential candidate in the treatment of PC, BC, and other hormone-dependent cancers.

  15. Space weightlessness and hormonal changes in human subjects and experimental animals

    NASA Technical Reports Server (NTRS)

    Grindeland, R. E.

    1982-01-01

    Data from spaceflight and bed rest studies are briefly described and the difficulties in interpreting these results are discussed. Growth hormone, prolactin, adrenocorticotropic hormone, cortisol, insulin, aldosterone, and other hormones are addressed.

  16. Comparison of the effects of human and chicken ghrelin on chicken ovarian hormone release.

    PubMed

    Sirotkin, Alexander V; Harrath, Abdel Halim; Grossmann, Roland

    2016-11-01

    The aim of the present experiments was to examine the species-specific and cell-specific effects of ghrelin on chicken ovarian hormone release. For this purpose, we compared the effects of chicken and human ghrelin on the release of estradiol (E), testosterone (T), progesterone (P) and arginine-vasotocin (AVT) by cultured fragments of chicken ovarian follicles and on the release of T and AVT by cultured ovarian granulosa cells. In cultured chicken ovarian fragments, both human and chicken ghrelin promoted E release. T output was stimulated by chicken ghrelin but not by human ghrelin. No effect of either human or chicken ghrelin on P release was observed. Human ghrelin promoted but chicken ghrelin suppressed AVT release by chicken ovarian fragments. In cultured ovarian granulosa cells, human ghrelin inhibited while chicken ghrelin stimulated T release. Both human and chicken ghrelin suppressed AVT output by chicken granulosa cells. These data confirm the involvement of ghrelin in the control of ovarian secretory activity and demonstrate that the effect of ghrelin is species-specific. The similarity of avian ghrelin on avian ovarian granulosa cells and ovarian fragments (containing both granulosa and theca cells) suggests that ghrelin can influence chicken ovarian hormones primarily by acting on granulosa cells.

  17. Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

    SciTech Connect

    Romshe, C.A.; Zipf, W.B.; Miser, A.; Miser, J.; Sotos, J.F.; Newton, W.A.

    1984-02-01

    We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subject's bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.

  18. Differential gene expression of growth hormone (GH)-releasing hormone (GRH) and GRH receptor in various rat tissues.

    PubMed

    Matsubara, S; Sato, M; Mizobuchi, M; Niimi, M; Takahara, J

    1995-09-01

    Growth hormone (GH)-releasing hormone (GRH) acts on specific receptors in the anterior pituitary to stimulate the synthesis and release of GH. Recent reports suggest that GRH is also synthesized in extrahypothalamic tissues. To evaluate the potential roles of extrahypothalamic GRH, we studied the gene expression of GRH and GRH receptors in various rat tissues by reverse transcribed (RT)-polymerase chain reaction (PCR). Total RNA was extracted from twenty-three rat organs and RT-PCR was performed with GRH and GRH receptor primers. Highly-sensitive RT-PCR-Southern blotting showed that GRH and GRH receptor mRNA coexist in the widespread tissues (14 of 25 tissues). GRH mRNA was relatively abundant in the cerebral cortex, brain stem, testis, and placenta, while GRH receptor mRNA was abundant in renal medulla and renal pelvis. Northern blot hybridization using poly A+ RNA indicated that the transcript of GRH receptor gene found in the renal medulla was similar to the longer transcript (about 4 Kb) of pituitary GRH receptor in the size. These results suggest that GRH plays a potential role not only in the neuroendocrine axis, but also in the autocrine and paracrine systems in extrahypothalamic tissues.

  19. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    PubMed Central

    Vamvakopoulos, Nicholas V.

    1995-01-01

    This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2) a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system. PMID:18475634

  20. Differential involvement of signaling pathways in the regulation of growth hormone release by somatostatin and growth hormone-releasing hormone in orange-spotted grouper (Epinephelus coioides).

    PubMed

    Wang, Bin; Qin, Chaobin; Zhang, Cong; Jia, Jirong; Sun, Caiyun; Li, Wensheng

    2014-02-15

    Somatostatin is the most effective inhibitor of GH release, and GHRH was recently identified as one of the primary GH-releasing factors in teleosts. In this study, we analyzed the possible intracellular transduction pathways that are involved in the mechanisms induced by SRIF and GHRH to regulate GH release. Using a pharmacological approach, the blockade of the PLC/IP/PKC pathway reversed the SRIF-induced inhibition of GH release but did not affect the GHRH-induced stimulation of GH release. Furthermore, SRIF reduced the GH release induced by two PKC activators. Inhibitors of the AC/cAMP/PKA pathway reversed both the SRIF- and GHRH-induced effects on GH release. Moreover, the GH release evoked by forskolin and 8-Br-cAMP were completely abolished by SRIF. The blockade of the NOS/NO pathway attenuated the GHRH-induced GH release but had minimal effects on the inhibitory actions of SRIF. In addition, inhibitors of the sGC/cGMP pathway did not modify the SRIF- or GHRH-induced regulation of GH release. Taken together, these findings indicate that the SRIF-induced inhibition of GH release is mediated by both the PLC/IP/PKC and the AC/cAMP/PKA pathways and not by the NOS/NO/sGC/cGMP pathway. In contrast, the GHRH-induced stimulation of GH secretion is mediated by both the AC/cAMP/PKA and the NOS/NO pathways and is independent of the sGC/cGMP pathway and the PLC/IP/PKC system.

  1. Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

    SciTech Connect

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V. )

    1989-08-01

    The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, (D-Mel{sup 6})LH-RH (SB-05) and (Ac-D-Nal(2){sup 1},D-Phe(pCl){sup 2},D-Pal(3){sup 3},Arg{sup 5},D-Mel{sup 6},D-Ala{sup 10})LH-RH (SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine) possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel{sup 6} analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

  2. Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

    PubMed Central

    Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

    1989-01-01

    The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells. PMID:2548207

  3. Catecholestrogens and release of anterior pituitary gland hormones. I. Luteinizing hormone.

    PubMed

    Rodriguez-Sierra, J F; Blake, C A

    1982-02-01

    We investigated the effects of peripheral administration of 17 beta-estradiol (E2), estrone (E1), and the catecholestrogens, 2-hydroxyestradiol (2-OHE2) and 2-hydroxyestrone (2-OHE1), on anterior pituitary gland LH release in the prepuberal rat. Steroids in oil were injected sc into 25-day-old female and 35- to 40-day-old male rats. The injection of E2, E1, or 2-OHE2 caused a surge in serum LH levels in female rats 48 h later, during the after hours. Only E1 induced a LH surge 24 h after injection. The positive effects of 2-OHE2 in the females were only observed if a massive dose was administered, the steroid was injected on 2 consecutive days, or E2 or progesterone was given to 2-OHE2-primed rats. The 2-OHE1 was totally ineffective in causing a serum LH surge under a variety of experimental protocols. In male rats, the injection of any one of the four steroids decreased serum LH levels. Even the injection of E2 or 2-OHE2 for 2 days or the injection of E2 in 2-OHE2-primed rats failed to elevate the serum LH concentration in male rats. The results suggest that 2-OHE2 and E1 could play a role in the preovulatory release of LH in the female; 2-OHE2 and 2-OHE1 could play a role in the negative feedback control of LH release in the male.

  4. Copper amplification of prostaglandin E/sub 2/ stimulation of the release of luteinizing hormone-releasing hormone is a postreceptor event

    SciTech Connect

    Barnea, A.; Cho, G.

    1987-01-01

    The authors have shown that copper amplifies prostaglandin E/sub 2/ (PGE/sub 2/) stimulation of luteinizing hormone-releasing hormone (LH-RH) from explants of the median eminence area (MEA) and that this process is calcium-dependent. Since a Ca-cAMP pathway has been implicated in PGE/sub 2/ action on the LH-RH neuron, in this study the authors wished to ascertain if copper exerts its effect on the PGE/sub 2/ receptor or on a postreceptor component involved in PGE/sub 2/ action. MEA of adult male rats were incubated for 5 min with 200 ..mu..M Cu/histidine and then incubated for 15 min either with 10 ..mu..M PGE/sub 2/ (Cu/PGE/sub 2/), 100 ..mu..M forskolin (Cu/forskolin), or 1 mM 8-bromoadenosine 3',5'-cyclic monophosphate (Cu/cAMP). Basal release of LH-RH was 4.6 +/- 0.45 pg/15 min per MEA determined by radioimmunoassay. Net stimulated release during the 15-min exposure to PGE/sub 2/, forskolin, or 8-bromoadenosine 3',5'-cyclic monophosphate was 3.6 +/- 0.52, 3.1 +/- 0.39, and 1.6 +/- 0.42 pg/15 min per MEA, respectively. Net stimulated release after exposure to Cu/PGE/sub 2/, Cu/forskolin, or Cu/cAMP indicated that copper amplifies the action of PGE/sub 2/ and forskolin but not cAMP action. When MEA were exposed to a mixture of PGE/sub 2/ and forskolin for 15 min, the effects of these two secretagogues on LH-RH release were not additive. In contrast to PGE/sub 2/ and forskolin, copper did not amplify K/sup +/ stimulation of OH-RH release. These results are supportive of the proposition that PGE/sub 2/ stimulation of OH-RH release is mediated by the Ca-cAMP pathway and that copper amplification of PGE/sub 2/ action is a postreceptor event.

  5. Combination growth hormone and gonadotropin releasing hormone analog therapy in 11beta-hydroxylase deficiency.

    PubMed

    Bajpai, Anurag; Kabra, Madhulika; Menon, P S N

    2006-06-01

    Diagnosis of 11beta-hydroxylase deficiency was made in a boy at the age of 2 1/2 years on the basis of peripheral precocious puberty, growth acceleration (height standard deviation score +4.4) with advanced skeletal maturation (bone age 8.4 years) and elevated deoxycortisol levels. Glucocorticoid supplementation led to normalization of blood pressure but was associated with progression to central precocious puberty and increase in bone age resulting in decrease in predicted adult height to 133.7 cm (target height 163 cm). The child was started on GnRH analog (triptorelin 3.75 mg every 28 days), which led to improvement in predicted adult height by 3.1 cm over 15 months. Addition of growth hormone (0.1 IU/kg/day) resulted in improvement in predicted adult height (151 cm) and height deficit (12 cm) over the next 3.6 years. Final height (151 cm) exceeded predicted height at the initiation of GnRH analog treatment by 17.3 cm. This report suggests that combination GH and GnRH analog treatment may be useful in improving height outcome in children with 11beta-hydroxylase deficiency and compromised final height.

  6. Single-Cell Phenotypic Characterization of Human Pituitary GHomas and Non-Functioning Adenomas Based on Hormone Content and Calcium Responses to Hypothalamic Releasing Hormones

    PubMed Central

    Senovilla, Laura; Núñez, Lucía; de Campos, José María; de Luis, Daniel A.; Romero, Enrique; García-Sancho, Javier; Villalobos, Carlos

    2015-01-01

    Human pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non-functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs. PMID:26106585

  7. Allosteric Modulation of Hormone Release from Thyroxine and Corticosteroid-binding Globulins*

    PubMed Central

    Qi, Xiaoqiang; Loiseau, François; Chan, Wee Lee; Yan, Yahui; Wei, Zhenquan; Milroy, Lech-Gustav; Myers, Rebecca M.; Ley, Steven V.; Read, Randy J.; Carrell, Robin W.; Zhou, Aiwu

    2011-01-01

    The release of hormones from thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG) is regulated by movement of the reactive center loop in and out of the β-sheet A of the molecule. To investigate how these changes are transmitted to the hormone-binding site, we developed a sensitive assay using a synthesized thyroxine fluorophore and solved the crystal structures of reactive loop cleaved TBG together with its complexes with thyroxine, the thyroxine fluorophores, furosemide, and mefenamic acid. Cleavage of the reactive loop results in its complete insertion into the β-sheet A and a substantial but incomplete decrease in binding affinity in both TBG and CBG. We show here that the direct interaction between residue Thr342 of the reactive loop and Tyr241 of the hormone binding site contributes to thyroxine binding and release following reactive loop insertion. However, a much larger effect occurs allosterically due to stretching of the connecting loop to the top of the D helix (hD), as confirmed in TBG with shortening of the loop by three residues, making it insensitive to the S-to-R transition. The transmission of the changes in the hD loop to the binding pocket is seen to involve coherent movements in the s2/3B loop linked to the hD loop by Lys243, which is, in turn, linked to the s4/5B loop, flanking the thyroxine-binding site, by Arg378. Overall, the coordinated movements of the reactive loop, hD, and the hormone binding site allow the allosteric regulation of hormone release, as with the modulation demonstrated here in response to changes in temperature. PMID:21325280

  8. Treatment of canine pyometra with the gonadotropin-releasing hormone antagonist acyline: a case series.

    PubMed

    Batista, Pablo R; Blanco, Paula G; Gobello, Cristina

    2015-03-01

    To describe the effect of the third-generation gonadotropin-releasing hormone antagonist acyline in the treatment of 4 diestrous bitches with the cystic endometrial hyperplasia-pyometra complex. The 4 bitches were treated with 330 μg/kg of subcutaneous acyline on day 0 and antibiotics, and followed up for 2 weeks. One closed-cervix case showed cervical dilatation 36 hours after treatment, and all the 4 animals showed resolution of clinical signs starting on day 3 posttreatment. Ultrasonographic uterine diameters and luminal contents decreased in the bitches having high progesterone serum concentrations before treatment but not in those with low levels. Serum progesterone importantly decreased from high to basal concentrations in the 3 "ultrasonographically cured" animals. No local or systemic side effects related to the treatment were observed. The gonadotropin-releasing hormone antagonist acyline may have a promising place for the medical treatment of cystic endometrial hyperplasia-pyometra complex in dogs.

  9. Estradiol Attenuates Multiple Tetrodotoxin-Sensitive Sodium Currents in Isolated Gonadotropin-releasing Hormone Neurons

    PubMed Central

    Wang, Yong; Garro, Mona; Kuehl-Kovarik, M. Cathleen

    2010-01-01

    Secretion from gonadotropin-releasing hormone (GnRH) neurons is necessary for the production of gametes and hormones from the gonads. Subsequently, GnRH release is regulated by steroid feedback. However, the mechanisms by which steroids, specifically estradiol, modulate GnRH secretion are poorly understood. We have previously shown that estradiol administered to the female mouse decreases inward currents in fluorescently-labeled GnRH neurons. The purpose of this study was to examine the contribution of sodium currents in the negative feedback action of estradiol. Electrophysiology was performed on GnRH neurons dissociated from young, middle-aged, or old female mice. All mice were ovariectomized; half were estradiol replaced. The amplitude of the sodium current underlying the action potential was significantly decreased in GnRH neurons from young estradiol-treated animals. In addition, in vivo estradiol significantly decreased the transient sodium current amplitude, but prolonged the sodium current inactivation time constant. Estradiol decreased the persistent sodium current amplitude, and induced a significant negative shift in peak current potential. In contrast to results obtained from cells from young reproductive animals, estradiol did not significantly attenuate the sodium current underlying the action potential in cells isolated from middle-aged or old mice. Sodium channels can modulate cell threshold, latency of firing, and action potential characteristics. The reduction of sodium current amplitude by estradiol suggests a negative feedback on GnRH neurons, which could lead to a downregulation of cell excitability and hormone release. The attenuation of estradiol regulation in peripostreproductive and postreproductive animals could lead to dysregulated hormone release with advancing age. PMID:20580637

  10. Production of corticotrophin releasing hormone by the isolated hypothalamus of the rat.

    PubMed Central

    Buckingham, J C; Hodges, J R

    1977-01-01

    1. The ability of the rat hypothalamus to produce corticotrophin releasing hormone (CRH) in vitro was studied in the presence and absence of neurotransmitter substances, angiotensin and corticosterone. 2. Acetylcholine, 5-hydroxytryptamine (5-HT) and angiotensin II increased hypothalamic CRH release and content. 3. Noradrenaline and glycine decreased the spontaneous release of CRH from the hypothalamus but neither of these substances affected hypothalamic CRH content. 4. Dopamine, GABA, adrenaline, melatonin, histamine, glutamic acid and corticosterone did not affect the basal CRH activity of the hypothalamus in vitro. 5. Noradrenaline, GABA and corticosterone reduced the acetylcholine- and 5-HT-induced increases in the release of CRH from the hypothalamus. The rises in CRH content induced by acetylcholine and 5-HT were also reduced by noradrenaline and GABA but increased by corticosterone. 6. The physiological significance of the results and the potential value of the technique are discussed. PMID:304104

  11. Electrical synapses connect a network of gonadotropin releasing hormone neurons in a cichlid fish

    PubMed Central

    Ma, Yunyong; Hu, Caroline K.; Huguenard, John R.; Fernald, Russell D.

    2015-01-01

    Initiating and regulating vertebrate reproduction requires pulsatile release of gonadotropin-releasing hormone (GnRH1) from the hypothalamus. Coordinated GnRH1 release, not simply elevated absolute levels, effects the release of pituitary gonadotropins that drive steroid production in the gonads. However, the mechanisms underlying synchronization of GnRH1 neurons are unknown. Control of synchronicity by gap junctions between GnRH1 neurons has been proposed but not previously found. We recorded simultaneously from pairs of transgenically labeled GnRH1 neurons in adult male Astatotilapia burtoni cichlid fish. We report that GnRH1 neurons are strongly and uniformly interconnected by electrical synapses that can drive spiking in connected cells and can be reversibly blocked by meclofenamic acid. Our results suggest that electrical synapses could promote coordinated spike firing in a cellular assemblage of GnRH1 neurons to produce the pulsatile output necessary for activation of the pituitary and reproduction. PMID:25775522

  12. Central stimulation of hormone release and the proliferative response of lymphocytes in humans.

    PubMed

    Juránková, E; Jezová, D; Vigas, M

    1995-01-01

    The central nervous system (CNS) may communicate with the immune system by direct innervation of lymphoid organs and/or by neurotransmitters and changes in neuroendocrine functioning and hormone release. The consequences of selective transient changes in circulating hormones on immune functioning in humans have not yet been studied. To address this problem, the authors evaluated the lymphoproliferative responses to optimal and suboptimal concentrations of phytohemagglutinin (PHA) and pokeweek mitogen (PWM) under selective enhancement of circulating growth hormone, prolactin, or norepinephrine. The authors failed to demonstrate any effect of elevated growth hormone levels after clonidine challenge on the lymphoproliferative response to mitogens. Similarly, the results did not show any effect of elevated prolactin concentrations induced by domperidone administration on the immune test. Exposure of volunteers to cold resulted in elevation of plasma norepinephrine levels without changes in growth hormone, epinephrine, or cortisol secretion. Cold exposure induced elevation of plasma norepinephrine and reduction of the lymphoproliferative response to the suboptimal dosage of PHA. The reduction was significant 180 and 240 min after exposure. These results are indicative of a relationship between norepinephrine and immunity.

  13. Pituitary response to thyrotropin releasing hormone in children with overweight and obesity

    PubMed Central

    Rijks, Jesse; Penders, Bas; Dorenbos, Elke; Straetemans, Saartje; Gerver, Willem-Jan; Vreugdenhil, Anita

    2016-01-01

    Thyroid stimulating hormone (TSH) concentrations in the high normal range are common in children with overweight and obesity, and associated with increased cardiovascular disease risk. Prior studies aiming at unravelling the mechanisms underlying these high TSH concentrations mainly focused on factors promoting thyrotropin releasing hormone (TRH) production as a cause for high TSH concentrations. However, it is unknown whether TSH release of the pituitary in response to TRH is affected in children with overweight and obesity. Here we describe TSH release of the pituitary in response to exogenous TRH in 73 euthyroid children (39% males) with overweight or (morbid) obesity. Baseline TSH concentrations (0.9–5.5 mU/L) were not associated with BMI z score, whereas these concentrations were positively associated with TSH concentrations 20 minutes after TRH administration (r2 = 0.484, p < 0.001) and the TSH incremental area under the curve during the TRH stimulation test (r2 = 0.307, p < 0.001). These results suggest that pituitary TSH release in response to TRH stimulation might be an important factor contributing to high normal serum TSH concentrations, which is a regular finding in children with overweight and obesity. The clinical significance and the intermediate factors contributing to pituitary TSH release need to be elucidated in future studies. PMID:27485208

  14. Hormonal Regulation of Lateral Bud (Tiller) Release in Oats (Avena sativa L.) 1

    PubMed Central

    Harrison, Marcia A.; Kaufman, Peter B.

    1980-01-01

    Stem segments containing a single node and quiescent lateral bud (tiller) were excised from the bases of oat shoots (cv. `Victory') and used to study the effects of plant hormones on release of lateral buds and development of adventitious root primordia. Kinetin (10−5 and 10−6 molar) stimulates development of tillers and inhibits development of root primordia, whereas indoleacetic acid (IAA) (10−5 and 10−6 molar) causes the reverse effects. Abscisic acid strongly inhibits kinetin-induced tiller bud release and elon-gation and IAA-induced adventitious root development. IAA, in combination with kinetin, also inhibits kinetin-induced bud prophyll (outermost leaf of the axillary bud) elongation. The IAA oxidase cofactor p-coumaric acid stimulates lateral bud release; the auxin transport inhibitor 2,3,5-triiodo-benzoic acid and the antiauxin α (p-chlorophenoxy)-isobutyric acid inhibit IAA-induced adventitious root formation. Gibberellic acid is synergistic with kinetin in the elongation of the bud prophyll. In intact oat plants, tiller release is induced by shoot decapitation, geostimulation, or the emergence of the inflorescence. Results shown support the apical dominance theory, namely, that the cytokinin to auxin ratio plays a decisive role in determining whether tillers are released or adventitious roots develop. They also indicate that abscisic acid and possibly gibberellin may act as modulator hormones in this system. PMID:16661589

  15. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

    PubMed

    Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David

    2013-11-01

    Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep.

  16. Centrifugal acceleration to 3Gz is related to increased release of stress hormones and decreased mood in men and women.

    PubMed

    Schneider, Stefan; Guardiera, Simon; Kleinert, Jens; Steinbacher, Anja; Abel, Thomas; Carnahan, Heather; Strüder, Heiko K

    2008-09-01

    It has been suggested that the central and peripheral neural processes (CPNP) are affected by gravitational changes. Based on the previous experiments during parabolic flights, central and peripheral changes may not only be due to the changed gravitational forces but also due to neuroendocrine reactions related to the psycho-physiological consequences of gravitational changes. The present study focuses on the interaction of neuroendocrine changes and the physical and mental states after acceleration to three-time terrestrial gravity (3Gz). Eleven participants (29.4+/-5.1 [SD] years (male (n=8): 30+/-5.1 years; female (n=3): 27.7+/-2.1 years) underwent a 15 min acceleration to 3Gz in a human centrifuge. Before and after the acceleration to 3Gz circulating stress hormone concentrations (cortisol, adrenocorticotropic hormone (ACTH), prolactin, epinephrine, norepinephrine) and perceived physical and mental states were recorded. A second control group of 11 participants underwent the same testing procedure in a laboratory session. Serum cortisol concentration during exposure to the centrifugal acceleration increased by 70%, plasma concentration of ACTH increased threefold, prolactin twofold, epinephrine by 70% and norepinephrine by 45%, whereas the perceived physical well-being decreased. These findings demonstrate that psycho-physiological changes have to be regarded as a relevant factor for the changes in CPNP during phases of hypergravity exposure.

  17. Structural and functional divergence of growth hormone-releasing hormone receptors in early sarcopterygians: lungfish and Xenopus.

    PubMed

    Tam, Janice K V; Chow, Billy K C; Lee, Leo T O

    2013-01-01

    The evolutionary trajectories of growth hormone-releasing hormone (GHRH) receptor remain enigmatic since the discovery of physiologically functional GHRH-GHRH receptor (GHRHR) in non-mammalian vertebrates in 2007. Interestingly, subsequent studies have described the identification of a GHRHR(2) in chicken in addition to the GHRHR and the closely related paralogous receptor, PACAP-related peptide (PRP) receptor (PRPR). In this article, we provide information, for the first time, on the GHRHR in sarcopterygian fish and amphibians by the cloning and characterization of GHRHRs from lungfish (P. dolloi) and X. laevis. Sequence alignment and phylogenetic analyses demonstrated structural resemblance of lungfish GHRHR to their mammalian orthologs, while the X. laevis GHRHR showed the highest homology to GHRHR(2) in zebrafish and chicken. Functionally, lungfish GHRHR displayed high affinity towards GHRH in triggering intracellular cAMP and calcium accumulation, while X. laevis GHRHR(2) was able to react with both endogenous GHRH and PRP. Tissue distribution analyses showed that both lungfish GHRHR and X. laevis GHRHR(2) had the highest expression in brain, and interestingly, X. laevis(GHRHR2) also had high abundance in the reproductive organs. These findings, together with previous reports, suggest that early in the Sarcopterygii lineage, GHRHR and PRPR have already established diverged and specific affinities towards their cognate ligands. GHRHR(2), which has only been found in xenopus, zebrafish and chicken hitherto, accommodates both GHRH and PRP.

  18. Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

    PubMed Central

    Ludwig, Barbara; Rotem, Avi; Schmid, Janine; Weir, Gordon C.; Colton, Clark K.; Brendel, Mathias D.; Neufeld, Tova; Block, Norman L.; Yavriyants, Karina; Steffen, Anja; Ludwig, Stefan; Chavakis, Triantafyllos; Reichel, Andreas; Azarov, Dimitri; Zimermann, Baruch; Maimon, Shiri; Balyura, Mariya; Rozenshtein, Tania; Shabtay, Noa; Vardi, Pnina; Bloch, Konstantin; de Vos, Paul; Schally, Andrew V.; Bornstein, Stefan R.; Barkai, Uriel

    2012-01-01

    Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation. PMID:22393012

  19. Is radiation-induced ovarian failure in rhesus monkeys preventable by luteinizing hormone-releasing hormone agonists?: Preliminary observations

    SciTech Connect

    Ataya, K.; Pydyn, E.; Ramahi-Ataya

    1995-03-01

    With the advent of cancer therapy, increasing numbers of cancer patients are achieving long term survival. Impaired ovarian function after radiation therapy has been reported in several studies. Some investigators have suggested that luteinizing hormone-releasing hormone agonists (LHRHa) can prevent radiation-induced ovarian injury in rodents. Adult female rhesus monkeys were given either vehicle or Leuprolide acetate before, during, and after radiation. Radiation was given in a dose of 200 rads/day for a total of 4000 rads to the ovaries. Frequent serum samples were assayed for estradiol (E{sub 2}) and FSH. Ovariectomy was performed later. Ovaries were processed and serially sectioned. Follicle count and size distribution were determined. Shortly after radiation started, E{sub 2} dropped to low levels, at which it remained, whereas serum FSH level, which was low before radiation, rose soon after starting radiation. In monkeys treated with a combination of LHRHa and radiation, FSH started rising soon after the LHRHa-loaded minipump was removed (after the end of radiation). Serum E{sub 2} increased after the end of LHRHa treatment in the non-irradiated monkey, but not in the irradiated monkey. Follicle counts were not preserved in the LHRHa-treated monkeys that received radiation. The data demonstrated no protective effect of LHRHa treatment against radiation-induced ovarian injury in this rhesus monkey model. 58 refs., 2 figs., 1 tab.

  20. Targeted chemotherapy of endometrial, ovarian and breast cancers with cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH).

    PubMed

    Engel, J B; Schally, A V; Buchholz, S; Seitz, S; Emons, G; Ortmann, O

    2012-08-01

    Receptors luteinizing hormone-releasing hormone (LHRH) are expressed in about 80 % of human endometrial and ovarian cancers and account for more than 50 % of breast cancers including triple negative breast cancers. Apart from the pituitary and reproductive organs, no other organs or hematopoietic stem cells express LHRH (GnRH) receptors. Thus, these receptors can be regarded as an ideal target for a personalized medicine approach in cancer therapy. AEZS-108 (formerly known as AN-152) in which doxorubin is linked to the LHRH agonist [D: -Lys(6)]LHRH, appears to be the most advanced compound in late stage clinical development. Results of phase I and phase II clinical trials in patients with gynecological cancers demonstrated anticancer activity without any cardiotoxicity even in highly pretreated patients. AEZS-108 is therefore being considered for phase II trials in triple negative breast cancers and phase III studies in advanced endometrial cancers positive for LHRH-receptor. EP-100 is a membrane-disrupting peptide targeted to LHRH receptors, which is undergoing early clinical studies in ovarian cancer patients.

  1. Role of growth hormone-releasing hormone in sleep and growth impairments induced by upper airway obstruction in rats.

    PubMed

    Tarasiuk, A; Berdugo-Boura, N; Troib, A; Segev, Y

    2011-10-01

    Upper airway obstruction (UAO) can lead to abnormal growth hormone (GH) homeostasis and growth retardation but the mechanisms are unclear. We explored the effect of UAO on hypothalamic GH-releasing hormone (GHRH), which has a role in both sleep and GH regulation. The tracheae of 22-day-old rats were narrowed; UAO and sham-operated animals were sacrificed 16 days post-surgery. To stimulate slow-wave sleep (SWS) and GH secretion, rats were treated with ritanserin (5-HT(2) receptor antagonist). Sleep was measured with a telemetric system. Hypothalamic GHRH, hypothalamic GHRH receptor (GHRHR) and GH receptor, and orexin were analysed using ELISA, real-time PCR and Western blot. UAO decreased hypothalamic GHRH, GHRHR and GH receptor levels, while orexin mRNA increased (p<0.01). In UAO rats, the duration of wakefulness was elevated and the duration of SWS, paradoxical sleep and slow-wave activity was reduced (p<0.001). Ritanserin alleviated these effects, i.e. normalised hypothalamic GHRH content, decreased wake duration, increased duration and depth of SWS, and attenuated growth impairment (p<0.001). Here, we present evidence that growth retardation in UAO is associated with a reduction in hypothalamic GHRH content. Our findings show that abnormalities in the GHRH/GH axis underlie both growth retardation and SWS-disorder UAO.

  2. Distribution of luteinizing hormone-releasing hormone in the upper brainstem and diencephalon of the cat: an immunocytochemical study.

    PubMed

    Belda, M; Coveñas, R; Narváez, J A; Aguirre, J A; Tramu, G

    2000-03-01

    The distribution of luteinizing hormone-releasing hormone (LH-RH)-immunostained cell bodies and fibres was studied in the brainstem and diencephalon of the cat using an indirect immunoperoxidase technique. The brainstem and the thalamus were devoid of immunostained cell bodies, whereas in the hypothalamus immunopositive perikarya were observed in the supraoptic nucleus, the anterior hypothalamus, the preoptic region and in the arcuate nucleus. Our findings also showed that the hypothalamus is richer in immunostained fibres, and that in this region such fibres are more widely distributed than in the thalamus and upper brainstem. No immunopositive fibres were observed in the lower brainstem. Our results point to a more widespread distribution of LH-RH-immunostained perikarya in the cat hypothalamus than that previously reported in the cat; a similar distribution to that found in the rat, and a more restricted distribution than in primates. Additionally, our study shows a more widespread distribution of immunostained fibres in the cat brainstem and diencephalon than that previously described for other mammals. In this context, our results describe for the first time in the mammals central nervous system fibres containing LH-RH located in the stria medullaris of the thalamus, the supramammillary decussation, the laterodorsal and lateroposterior thalamic nuclei, the nucleus reuniens, the supraoptic nucleus, and the optic chiasm. Thus, our findings reveal that LH-RH-immunostained structures are widely distributed in the upper brainstem and in the diencephalon of the cat, suggesting that the peptide may be involved in several physiological functions.

  3. Dexamethasone increases growth hormone (GH)-releasing hormone (GRH) receptor mRNA levels in cultured rat anterior pituitary cells.

    PubMed

    Tamaki, M; Sato, M; Matsubara, S; Wada, Y; Takahara, J

    1996-06-01

    To examine the effects of glucocorticoid (GC) on growth hormone (GH)-releasing hormone (GRH) receptor gene expression, a highly-sensitive and quantitative reverse-transcribed polymerase chain reaction (RT-PCR) method was used in this study. Rat anterior pituitary cells were isolated and cultured for 4 days. The cultured cells were treated with dexamethasone for 2, 6, and 24 h. GRH receptor mRNA levels were determined by competitive RT-PCR using a recombinant RNA as the competitor. Dexamethasone significantly increased GRH receptor mRNA levels at 5 nM after 6- and 24 h-incubations, and the maximal effect was found at 25 nM. The GC receptor-specific antagonist, RU 38486 completely eliminated the dexamethasone-induced enhancement of GRH receptor mRNA levels. Dexamethasone did not alter the mRNA levels of beta-actin and prolactin at 5 nM for 24 h, whereas GH mRNA levels were significantly increased by the same treatment. The GH response to GRH was significantly enhanced by the 24-h incubation with 5 nM dexamethasone. These findings suggest that GC stimulates GRH receptor gene expression through the ligand-activated GC receptors in the rat somatotrophs. The direct effects of GC on the GRH receptor gene could explain the enhancement of GRH-induced GH secretion.

  4. Discordant effects of endogenous and exogenous somatostatin on growth hormone-releasing hormone secretion from perifused mouse hypothalami.

    PubMed

    Pecori Giraldi, F; Frohman, L A

    1995-05-01

    The role of somatostatin (SRIF) on growth hormone-releasing hormone (GRH) secretion has been controversial because of discordant findings that may be model dependent. We have examined possible explanations for these findings by altering endogenous and exogenous SRIF tone in a mouse hypothalamic perifusion system. Four mediobasal hypothalamic fragments were perifused in a single chamber for 6 h. After a 2-hour equilibration period, test substances were introduced and maintained throughout the perifusion. After an additional 2 h, fragments were submaximally stimulated with 30 mM K+. Depletion of tissue SRIF by 10(-3) M cysteamine increased K(+)-stimulated GRH release 2-fold without altering basal GRH secretion. Removal of endogenous SRIF tone by anti-SRIF serum also augmented the GRH response to K+. Perifusion of SRIF at concentrations ranging from 10(-12) to 10(-8) M significantly increased the GRH response to K+ in a dose-dependent manner. A significant increase was also observed during the perifusion of 10(-9) M octreotide. Simultaneous perifusion with anti-SRIF serum and 10(-9) M octreotide (to which the antibody does not bind) resulted in a response of GRH to K+ that was similar to that observed with anti-SRIF serum alone. Combined perifusion with cysteamine and 10(-9) M SRIF also resulted in a GRH response to K+ that did not differ from the response observed during cysteamine alone. The enhancement of GRH secretion by reduction of endogenous SRIF tone or tissue content implies an inhibitory role of endogenous SRIF on GRH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Effects of ionizing radiation and pretreatment with (D-Leu6,des-Gly10) luteinizing hormone-releasing hormone ethylamide on developing rat ovarian follicles

    SciTech Connect

    Jarrell, J.; YoungLai, E.V.; McMahon, A.; Barr, R.; O'Connell, G.; Belbeck, L.

    1987-10-01

    To assess the effects of a gonadotropin-releasing hormone agonist, (D-Leu6,des-Gly10) luteinizing hormone-releasing hormone ethylamide, in ameliorating the damage caused by ionizing radiation, gonadotropin-releasing hormone agonist was administered to rats from day 22 to 37 of age in doses of 0.1, 0.4, and 1.0 microgram/day or vehicle and the rats were sacrificed on day 44 of age. There were no effects on estradiol, progesterone, luteinizing, or follicle-stimulating hormone, nor an effect on ovarian follicle numbers or development. In separate experiments, rats treated with gonadotropin-releasing hormone agonist in doses of 0.04, 0.1, 0.4, or 1.0 microgram/day were either irradiated or sham irradiated on day 30 and all groups sacrificed on day 44 of age. Irradiation produced a reduction in ovarian weight and an increase in ovarian follicular atresia. Pretreatment with the agonist prevented the reduction in ovarian weight and numbers of primordial and preantral follicles but not healthy or atretic antral follicles. Such putative radioprotection should be tested on actual reproductive performance.

  6. Central administration of growth hormone-releasing hormone triggers downstream movement and schooling behavior of chum salmon (Oncorhynchus keta) fry in an artificial stream.

    PubMed

    Ojima, Daisuke; Iwata, Munehico

    2009-03-01

    Anadromous salmonids migrate downstream to the ocean (downstream migration). The neuroendocrine mechanism of triggering the onset of downstream migration is not well known. We investigated the effects of 14 chemicals, including neuropeptides, pineal hormones, neurotransmitters, and neuromodulators (growth hormone-releasing hormone: GHRH, thyrotropin-releasing hormone, corticotropin-releasing hormone: CRH, gonadotropin-releasing hormone, melatonin, N-acetyl serotonin, serotonin, beta-endorphin, enkephalin, dopamine, norepinephrine, epinephrine, acetylcholine, and histamine) on the onset of downstream migration in chum salmon (Oncorhynchus keta) fry. We defined downstream migration as a downstream movement (negative rheotaxis) with schooling behavior and counted the number of downstream movements and school size in experimental circulation tanks. An intracerebroventricular injection of GHRH, CRH, melatonin, N-acetyl serotonin, or serotonin stimulated the number of downstream movements. However, GHRH was the only chemical that also stimulated an increase in schooling behavior. These results suggest that CRH, melatonin, N-acetyl serotonin, and serotonin are involved in the stimulation of downstream movement in chum salmon, while GHRH stimulates both downstream movement and schooling behavior.

  7. Neuropeptide W stimulates adrenocorticotrophic hormone release via corticotrophin-releasing factor but not via arginine vasopressin.

    PubMed

    Yogo, Kosuke; Oki, Yutaka; Iino, Kazumi; Yamashita, Miho; Shibata, Shoko; Hayashi, Chiga; Sasaki, Shigekazu; Suenaga, Toshiko; Nakahara, Daiichiro; Nakamura, Hirotoshi

    2012-01-01

    Neuropeptide W (NPW) was isolated as an endogenous ligand for NPBWR1, an orphan G protein-coupled receptor localized in the rat brain, including the paraventricular nucleus. It has been reported that central administration of NPW stimulates corticosterone secretion in rats. We hypothesized that NPW activates the hypothalamic-pituitary-adrenal (HPA) axis via corticotrophin-releasing factor (CRF) and/or arginine vasopressin (AVP). NPW at 1 pM to 10 nM did not affect basal or ACTH-induced corticosterone release from dispersed rat adrenocortical cells, or basal and CRF-induced ACTH release from dispersed rat anterior pituitary cells. In conscious and unrestrained male rats, intravenous administration of 2.5 and 25 nmol NPW did not affect plasma ACTH levels. However, intracerebroventricular (icv) administration of 2.5 and 5.0 nmol NPW increased plasma ACTH levels in a dose-dependent manner at 15 min after stimulation (5.0 vs. 2.5 nmol NPW vs. vehicle: 1802 ± 349 vs. 1170 ± 204 vs. 151 ± 28 pg/mL, respectively, mean ± SEM). Pretreatment with astressin, a CRF receptor antagonist, inhibited the increase in plasma ACTH levels induced by icv administration of 2.5 nmol NPW at 15 min (453 ± 176 vs. 1532 ± 343 pg/mL, p<0.05) and at 30 min (564 ± 147 vs. 1214 ± 139 pg/mL, p<0.05) versus pretreatment with vehicle alone. However, pretreatment with [1-(β-mercapto-β, β-cyclopentamethylenepropionic acid), 2-(Ο-methyl)tyrosine]-arg-vasopressin, a V1a/V1b receptor antagonist, did not affect icv NPW-induced ACTH release at any time (p>0.05). In conclusion, we suggest that central NPW activates the HPA axis by activating hypothalamic CRF but not AVP.

  8. Binding properties of solubilized gonadotropin-releasing hormone receptor: role of carboxylic groups

    SciTech Connect

    Hazum, E.

    1987-11-03

    The interaction of /sup 125/I-buserelin, a superactive agonist of gonadotropin-releasing hormone (GnRH), with solubilized GnRH receptor was studied. The highest specific binding of /sup 125/I-buserelin to solubilized GnRH receptor is evident at 4/sup 0/C, and equilibrium is reached after 2 h of incubation. The soluble receptor retained 100% of the original binding activity when kept at 4 or 22/sup 0/C for 60 min. Mono- and divalent cations inhibited, in a concentration-dependent manner, the binding of /sup 125/I-buserelin to solubilized GnRH receptor. Monovalent cations require higher concentrations than divalent cations to inhibit the binding. Since the order of potency with the divalent cations was identical with that of their association constants to dicarboxylic compounds, it is suggested that there are at least two carboxylic groups of the receptor that participate in the binding of the hormone. The carboxyl groups of sialic acid residues are not absolutely required for GnRH binding since the binding of /sup 125/I-buserelin to solubilized GnRH receptor was only slightly affected by pretreatment with neuraminidase and wheat germ agglutinin. The finding that polylysines stimulate luteinizing hormone (LH) release from pituitary cell cultures with the same efficacy as GnRH suggest that simple charge interactions can induce LH release. According to these results, the authors propose that the driving force for the formation of the hormone-receptor complex is an ionic interaction between the positively charged amino acid arginine in position 8 and the carboxyl groups in the binding site.

  9. Circadian and sleep-dependent regulation of hormone release in humans

    NASA Technical Reports Server (NTRS)

    Czeisler, C. A.; Klerman, E. B.

    1999-01-01

    Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian

  10. Basic fibroblast growth factor priming increases the responsiveness of immortalized hypothalamic luteinizing hormone releasing hormone neurones to neurotrophic factors.

    PubMed

    Gallo, F; Morale, M C; Tirolo, C; Testa, N; Farinella, Z; Avola, R; Beaudet, A; Marchetti, B

    2000-10-01

    The participation of growth factors (GFs) in the regulation of luteinizing hormone releasing hormone (LHRH) neuronal function has recently been proposed, but little is known about the role played by GFs during early LHRH neurone differentiation. In the present study, we have used combined biochemical and morphological approaches to study the ability of a number of GFs normally expressed during brain development, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) to induce survival, differentiation, proliferation, and phenotypic expression of immortalized (GT1-1) LHRH neurones in vitro, at early (3-days in vitro, 3-DIV) and late (8-DIV) stages of neuronal differentiation. Comparison of GF-treated vs untreated neurones grown in serum-deprived (SD) medium demonstrated bFGF to be the most potent, and insulin the least active in promoting neuronal differentiation. Thus, at both 3-DIV and 8-DIV, but especially at 8-DIV, bFGF induced the greatest increase in the total length and number of LHRH processes/cell and in growth cone surface area. bFGF was also the most active at 3-DIV, and IGF-I at 8-DIV, in counteracting SD-induced cell death, whereas EGF was the most potent in increasing [3H]thymidine incorporation. All GFs studied decreased the spontaneous release of LHRH from GT1-1 cells when applied at 3-DIV or 8-DIV, except for insulin which was inactive at both time-points and bFGF which was inactive at 8-DIV. Pre-treatment of GT1-1 cells with a suboptimal ('priming') dose of bFGF for 12 h followed by application of the different GFs induced a sharp potentiation of the neurotrophic and proliferative effects of the latter and particularly of those of IGF-I. Moreover, bFGF priming counteracted EGF-induced decrease in LHRH release and significantly stimulated LHRH secretion following IGF-I or insulin application, suggesting that bFGF may sensitize LHRH neurones to differentiating effects of

  11. Gonadotropin-releasing hormone stimulates prolactin release from lactotrophs in photoperiodic species through a gonadotropin-independent mechanism.

    PubMed

    Henderson, Helen L; Hodson, David J; Gregory, Susan J; Townsend, Julie; Tortonese, Domingo J

    2008-02-01

    Previous studies have provided evidence for a paracrine interaction between pituitary gonadotrophs and lactotrophs. Here, we show that GnRH is able to stimulate prolactin (PRL) release in ovine primary pituitary cultures. This effect was observed during the breeding season (BS), but not during the nonbreeding season (NBS), and was abolished by the application of bromocriptine, a specific dopamine agonist. Interestingly, GnRH gained the ability to stimulate PRL release in NBS cultures following treatment with bromocriptine. In contrast, thyrotropin-releasing hormone, a potent secretagogue of PRL, stimulated PRL release during both the BS and NBS and significantly enhanced the PRL response to GnRH during the BS. These results provide evidence for a photoperiodically modulated functional interaction between the GnRH/gonadotropic and prolactin axes in the pituitary gland of a short day breeder. Moreover, the stimulation of PRL release by GnRH was shown not to be mediated by the gonadotropins, since immunocytochemical, Western blotting, and PCR studies failed to detect pituitary LH or FSH receptor protein and mRNA expressions. Similarly, no gonadotropin receptor expression was observed in the pituitary gland of the horse, a long day breeder. In contrast, S100 protein, a marker of folliculostellate cells, which are known to participate in paracrine mechanisms within this tissue, was detected throughout the pituitaries of both these seasonal breeders. Therefore, an alternative gonadotroph secretory product, a direct effect of GnRH on the lactotroph, or another cell type, such as the folliculostellate cell, may be involved in the PRL response to GnRH in these species.

  12. Simultaneous measurement of hormone release and secretagogue binding by individual pituitary cells

    SciTech Connect

    Smith, P.F.; Neill, J.D.

    1987-08-01

    The quantitative relationship between receptor binding and hormone secretion at the single-cell level was investigated in the present study by combining a reverse hemolytic plaque assay for measurement of luteinizing hormone (LH) secretion from individual pituitary cells with an autoradiographic assay of /sup 125/I-labeled gonadontropin-releasing hormone (GnRH) agonist binding to the same cells. In the plaque assay, LH secretion induces complement-mediated lysis of the LH-antibody-coated erythrocytes around the gonadotropes, resulting in areas of lysis (plaques). LH release from individual gonadotropes was quantified by comparing radioimmunoassayable LH release to hemolytic area in similarly treated cohort groups of cells; plaque area was linearly related to the amount of LH secreted. Receptor autoradiography was performed using /sup 125/I-labeled GnRH-A (a superagonist analog of GnRH) both as the ligand and as the stimulant for LH release in the plaque assay. The grains appeared to represent specific and high-affinity receptors for GnRH because (i) no pituitary cells other than gonadotropes bound the labeled ligand and (ii) grain development was progressively inhibited by coincubation with increasing doses of unlabeled GnRH-A. The authors conclude that GnRH receptor number for any individual gonadotrope is a weak determinant of the amount of LH it can secrete; nevertheless, full occupancy of all its GnRH receptors is required for any gonadotrope to reach its full LH-secretory capacity. Apparently the levels of other factors comprising the steps along the secretory pathway determine the secretory capacity of an individual cell.

  13. Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid.

    PubMed Central

    Lin, L L; Lin, A Y; Knopf, J L

    1992-01-01

    Cytosolic phospholipase A2 (cPLA2) binds to natural membrane vesicles in a Ca(2+)-dependent fashion, resulting in the selective release of arachidonic acid, thus implicating cPLA2 in the hormonally regulated production of eicosanoids. Here we report that the treatment of Chinese hamster ovary (CHO) cells overexpressing cPLA2 with ATP or thrombin resulted in an increased release of arachidonic acid as compared with parental CHO cells, demonstrating the hormonal coupling of cPLA2. In contrast, CHO cells overexpressing a secreted form of mammalian PLA2 (sPLA2-II) failed to show any increased hormonal responsiveness. Interestingly, we have noted that the activation of cPLA2 with a wide variety of agents stimulates the phosphorylation of cPLA2 on serine residues. Pretreatment of cells with staurosporin blocked the ATP-mediated phosphorylation of cPLA2 and strongly inhibited the activation of the enzyme. Increased cPLA2 activity was also observed in lysates prepared from ATP-treated cells and was sensitive to phosphatase treatment. These results suggest that in addition to Ca2+, the phosphorylation of cPLA2 plays an important role in the agonist-induced activation of cPLA2. Images PMID:1631101

  14. The role of gonadotropin-releasing hormone antagonists in in vitro fertilization.

    PubMed

    Diedrich, K; Ludwig, M; Felberbaum, R E

    2001-09-01

    Gonadotropin-releasing hormone (GnRH)-antagonists can suppress the pituitary hormone secretion completely within a few hours, allowing the avoidance of premature luteinization within controlled ovarian hyperstimulation (COH) for assisted reproductive technologies (ART) by midcycle administration. Two different protocols were described, which were widely used in COH in several phase II and III studies as well as in clinical practice since the GnRH-antagonists Cetrorelix (Cetrotidesound recording copyright sign; Serono International S.A., Geneva, Switzerland) and Ganirelix (Orgalutansound recording copyright sign, Antagonsound recording copyright sign; Organon, Oss, The Netherlands) are available on the market. Cetrorelix was applied in single- and multiple-dose protocols; Ganirelix was used until now only according to the multiple-dose protocol. Fertilization rates of >60% as well as clinical pregnancy rates of about 30% per transfer sound most promising. Estradiol secretion is not compromised by the GnRH-antagonists using recombinant follicle-stimulating hormone (FSH) for COH. The incidence of a premature leutinizing hormone (LH) surge is far below 2% while the pituitary response remains preserved, allowing the induction of ovulation by GnRH or GnRH-agonists. However, luteal phase support remains mandatory. The incidence of severe ovarian hyperstimulation syndrome (OHSS) seems to be lower under antagonist treatment than in the long agonistic protocol. Treatment time is significantly shortened. Without any doubt GnRH-antagonists have the potential to become the new standard for controlled ovarian hyperstimulation.

  15. Interrelationship between feeding level and the metabolic hormones leptin, ghrelin and obestatin in control of chicken egg laying and release of ovarian hormones.

    PubMed

    Sirotkin, Alexander V; Grossmann, Roland

    2015-06-01

    The aim of the present experiment is to examine the role of nutritional status, metabolic hormones and their interrelationships in the control of chicken ovarian ovulatory and secretory activity. For this purpose, we identified the effect of food restriction, administration of leptin, ghrelin 1-18, obestatin and combinations of food restriction with these hormones for 3days on chicken ovulation (egg laying) rate and ovarian hormone release. The release of progesterone (P), testosterone (T), estradiol (E) and arginine-vasotocin (AVT) by isolated and cultured ovarian fragments was determined by EIA. It was observed that food restriction significantly reduced the egg-laying rate, T, E and AVT release and promoted P output by ovarian fragments. Leptin, administrated to ad libitum-fed chickens, did not change these parameters besides promoting E release. Nevertheless, administration of leptin was able to prevent the effect of food restriction on ovulation, T and E (but not P or AVT) release. Ghrelin 1-18 administration to ad libitum-fed birds did not affect the measured parameters besides a reduction in P release. Ghrelin 1-18 administration prevented the food restriction-induced decrease in ovarian T, E and AVT, but it did not change P output or egg laying. Obestatin administrated to control chicken promoted their ovarian P, E and inhibited ovarian AVT release but did not affect egg laying. It was able to promote the effect of food restriction on P, T and AVT, but not E release or egg laying. Our results (1) confirm an inhibitory effect of food restriction on chicken ovulation rate; (2) shows that food restriction-induced reduction in egg laying is associated with a decrease in ovarian T, E and AVT and an increase in ovarian P release; (3) confirm the involvement of metabolic hormones leptin, ghrelin and obestatin in the control of chicken ovarian hormones output; and (4) the ability of metabolic hormones to mimic/antagonize or prevent/promote the effects of food

  16. Multi-responsiveness of single anterior pituitary cells to hypothalamic-releasing hormones: A cellular basis for paradoxical secretion

    PubMed Central

    Villalobos, Carlos; Núñez, Lucía; Frawley, L. Stephen; García-Sancho, Javier; Sánchez, Ana

    1997-01-01

    The classic view for hypothalamic regulation of anterior pituitary (AP) hormone secretion holds that release of each AP hormone is controlled specifically by a corresponding hypothalamic-releasing hormone (HRH). In this scenario, binding of a given HRH (thyrotropin-, growth hormone-, corticotropin-, and luteinizing hormone-releasing hormones) to specific receptors in its target cell increases the concentration of cytosolic Ca2+ ([Ca2+]i), thereby selectively stimulating the release of the appropriate hormone. However, “paradoxical” responses of AP cells to the four well-established HRHs have been observed repeatedly with both in vivo and in vitro systems, raising the possibility of functional overlap between the different AP cell types. To explore this possibility, we evaluated the effects of HRHs on [Ca2+]i in single AP cells identified immunocytochemically by the hormone they stored. We found that each of the five major AP cell types contained discrete subpopulations that were able to respond to several HRHs. The relative abundance of these multi-responsive cells was 59% for lactotropes, 33% for thyrotropes, and in the range of 47–55% for gonadotropes, corticotropes, and somatotropes. Analysis of prolactin release from single living cells revealed that each of the four HRHs tested were able to induce hormone release from a discrete lactotrope subpopulation, the size of which corresponded closely to that in which [Ca2+]i changes were induced by the same secretagogues. When viewed as a whole, our diverse functional measurements of multi-responsiveness suggest that hypothalamic control of pituitary function is more complicated than previously envisioned. Moreover, they provide a cellular basis for the so-called “paradoxical” behavior of pituitary cells to hypothalamic hypophysiotropic agents. PMID:9391165

  17. Luteinizing Hormone Secretion during Gonadotropin-Releasing Hormone Stimulation Tests in Obese Girls with Central Precocious Puberty

    PubMed Central

    Lee, Hae Sang; Yoon, Jong Seo; Hwang, Jin Soon

    2016-01-01

    Objective: Girls with precocious puberty have high luteinizing hormone (LH) levels and advanced bone age. Obese children enter puberty at earlier ages than do non-obese children. We analyzed the effects of obesity on LH secretion during gonadotropin-releasing hormone (GnRH) tests in girls with precocious puberty. Methods: A total of 981 subjects with idiopathic precocious puberty who had undergone a GnRH stimulation testing between 2008 and 2014 were included in the study. Subjects were divided into three groups based on body mass index (BMI). Auxological data and gonadotropin levels after the GnRH stimulation test were compared. Results: In Tanner stage 2 girls, peak stimulated LH levels on GnRH test were 11.9±7.5, 10.4±6.4, and 9.1±6.1 IU/L among normal-weight, overweight, and obese subjects, respectively (p=0.035 for all comparisons). In Tanner stage 3 girls, peak stimulated LH levels were 14.9±10.9, 12.8±7.9, and 9.6±6.0 IU/L, respectively (p=0.022 for all comparisons). However, in Tanner stage 4 girls, peak stimulated LH levels were not significantly different among normal, overweight, and obese children. On multivariate analysis, BMI standard deviation score was significantly and negatively associated with peak LH (β=-1.178, p=0.001). Conclusion: In girls with central precocious puberty, increased BMI was associated with slightly lower peak stimulated LH levels at early pubertal stages (Tanner stages 2 and 3). This association was not valid in Tanner stage 4 girls. PMID:27215137

  18. Treatment of nitrosamine-induced pancreatic tumors in hamsters with analogs of somatostatin and luteinizing hormone-releasing hormone

    SciTech Connect

    Paz-Bouza, J.I.; Redding, T.W.; Schally, A.V.

    1987-02-01

    Pancreatic ductal adenocarcinoma was induced in female Syrian golden hamsters by injecting N-nitrosobis(2-oxopropyl)amine (BOP) once a week at a dose of 10 mg per kg of body weight for 18 weeks. Hamsters were then treated with somatostatin analog (RC-160) or with (6-D-tryptophan)luteinizing hormone-releasing hormone ((D-Trp/sup 6/)LH-RH) delayed delivery systems. After 18 weeks of BOP administration, the hamsters were divided into three groups of 10-20 animals each. Group I consisted of untreated controls, group II was injected with RC-160, and group III was injected with (D-Trp/sub 2/)LH-RH. A striking decrease in tumor weight and volume was obtained in animals treated with (D-Trp/sup 6/)LH-RH or with the somatostatin analog RC-160. After 45 days of treatment with either analog, the survival rate was significantly higher in groups II and III (70%), as compared with the control group (35%). The studies, done by light microscopy, high-resolution microscopy, and electron microscopy, showed a decrease in the total number of cancer cells and changes in the epithelium, connective tissue, and cellular organelles in groups II and III treated with the hypothalamic analogs as compared to controls. These results in female hamsters with induced ductal pancreatic tumors confirm and extend the authors findings, obtained in male animals with transplanted tumors, that (D-Trp/sub 6/)LH-RH and somatostatin analogs inhibit the growth of pancreatic cancers.

  19. Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers

    PubMed Central

    Letsch, Markus; Schally, Andrew V.; Busto, Rebeca; Bajo, Ana M.; Varga, Jozsef L.

    2003-01-01

    The antiproliferative effects of an antagonist of growth hormone-releasing hormone (GHRH) JV-1-38 were evaluated in nude mice bearing s.c. xenografts of LNCaP and MDA-PCa-2b human androgen-sensitive and DU-145 androgen-independent prostate cancers. In the androgen-sensitive models, JV-1-38 greatly potentiated the antitumor effect of androgen deprivation induced by surgical castration, but was ineffective when given alone. Thus, in castrated animals bearing MDA-PCa-2b cancers, the administration of JV-1-38 for 35 days virtually arrested tumor growth (94% inhibition vs. intact control, P < 0.01; and 75% vs. castrated control, P < 0.05). The growth of LNCaP tumors was also powerfully suppressed by JV-1-38 combined with castration (83% inhibition vs. intact control, P < 0.01; and 68% vs. castrated control, P < 0.05). However, in androgen-independent DU-145 cancers, JV-1-38 alone could inhibit tumor growth by 57% (P < 0.05) after 45 days. In animals bearing MDA-PCa-2b and LNCaP tumors, the reduction in serum prostate-specific antigen levels, after therapy with JV-1-38, paralleled the decrease in tumor volume. Inhibition of MDA-PCa-2b and DU-145 cancers was associated with the reduction in the expression of mRNA and protein levels of vascular endothelial growth factor. The mRNA expression for GHRH receptor splice variants was found in all these models of prostate cancer. Our results demonstrate that GHRH antagonists inhibit androgen-independent prostate cancers and, after combination with androgen deprivation, also androgen-sensitive tumors. Thus, the therapy with GHRH antagonist could be considered for the management of both androgen-dependent or -independent prostate cancers. PMID:12538852

  20. The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas

    PubMed Central

    Busto, Rebeca; Schally, Andrew V.; Varga, Jozsef L.; Garcia-Fernandez, M. Olga; Groot, Kate; Armatis, Patricia; Szepeshazi, Karoly

    2002-01-01

    Splice variants (SVs) of receptors for growth hormone-releasing hormone (GHRH) have been found in primary human prostate cancers and diverse human cancer cell lines. GHRH antagonists inhibit growth of various experimental human cancers, including pancreatic and colorectal, xenografted into nude mice or cultured in vitro, and their antiproliferative action could be mediated in part through SVs of GHRH receptors. In this study we examined the expression of mRNA for GHRH and for SVs of its receptors in tumors of human pancreatic, colorectal, and gastric cancer cell lines grown in nude mice. mRNA for both GHRH and SV1 isoform of GHRH receptors was expressed in tumors of pancreatic (SW1990, PANC-1, MIA PaCa-2, Capan-1, Capan-2, and CFPAC1), colonic (COLO 320DM and HT-29), and gastric (NCI-N87, HS746T, and AGS) cancer cell lines; mRNA for SV2 was also present in Capan-1, Capan-2, CFPAC1, HT-29, and NCI-N87 tumors. In proliferation studies in vitro, the growth of pancreatic, colonic, and gastric cancer cells was stimulated by GHRH(1–29)NH2 and inhibited by GHRH antagonist JV-1–38. The stimulation of some gastroenteropancreatic cancer cells by GHRH was followed by an increase in cAMP production, and GHRH antagonist JV-1–38 competitively inhibited this effect. Our study indicates the presence of an autocrine/paracrine stimulatory loop based on GHRH and SV1 of GHRH receptors in human pancreatic, colorectal, and gastric cancers. The finding of SV1 receptor in human cancers provides an approach to an antitumor therapy based on the blockade of this receptor by specific GHRH antagonists. PMID:12186980

  1. Gonadotropin-releasing hormone analogue treatment for precocious puberty. Twenty years of experience.

    PubMed

    Heger, Sabine; Sippell, Wolfgang G; Partsch, Carl-Joachim

    2005-01-01

    Central precocious puberty (CPP) is the premature onset of puberty due to a precocious activation of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. This condition results in accelerated development of secondary sex characteristics, accelerated bone maturation, impaired final height with disproportioned body appearance and can have a disturbing impact on the psychosocial behavior of children suffering from CPP. It is therefore necessary to assess the hormonal status of children who show pubertal signs before the age 8 years in girls and 9 years in boys. The indication for treatment should be made after evaluating pubertal progression, progression of bone age maturation and final height prognosis, development of reproductive function, and psychosocial adjustment and well-being. This paper summarizes the experience of GnRH agonist treatment, which is momentarily the treatment of choice for central precocious puberty in children.

  2. Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion.

    PubMed

    Lefebvre, S; De Paepe, L; Abs, R; Rahier, J; Selvais, P; Maiter, D

    1995-09-01

    Diagnosis of ectopic acromegaly was made in a 21-year-old female patient who 3 years before had undergone a right pneumectomy for a disseminated bronchial carcinoid. Plasma growth hormone-releasing hormone (GHRH) concentrations were markedly elevated (6440 ng/l; normal value < 100 ng/l), as were serum GH (187 micrograms/l; normal < 5 micrograms/l) and plasma insulin-like growth factor I (IGF-I) levels (6.7 U/ml; normal < 2 U/ml). Retrospective immunohistochemical examination of the carcinoid tumor was positive for GHRH and the tumoral content of GHRH was 2130 ng/g wet weight. Subcutaneous treatment with octreotide was begun and first resulted in a profound inhibition of GH hypersecretion, normalization of plasma IGF-I and only partial reduction of GHRH concentrations. However, the initial dose of 3 x 100 micrograms had to be increased gradually to 4 x 750 micrograms because of a progressive deterioration of the hormonal control. After 15 months of intermittent therapy, octreotide was administered by continuous sc infusion. This treatment improved compliance, allowed the daily dose of octreotide to be reduced to 1500 micrograms and normalized serum GH levels. A near-normalization of the plasma IGF-I concentrations was also obtained, whereas the suppression of plasma GHRH concentrations remained incomplete. Despite favorable evolution of the endocrine parameters, intramedullar metastases were diagnosed and required radiation therapy. This observation emphasizes the superiority of continuous over intermittent administration of octreotide in the treatment of ectopic acromegaly. It also shows that the somatostatin analog acts more at the pituitary level to inhibit GH secretion than at the site of the neuroendocrine tumor.

  3. Estradiol Regulates GH Releasing-Peptide's Interactions with GH-Releasing Hormone and Somatostatin in Postmenopausal Women

    PubMed Central

    Norman, Catalina; Rollene, Nanette L.; Erickson, Dana; Miles, John M.; Bowers, Cyril Y.; Veldhuis, Johannes D.

    2013-01-01

    Objective Estrogen stimulates pulsatile secretion of growth hormone (GH), albeit via mechanisms that are largely unknown. An untested hypothesis is that estradiol (E2) drives GH secretion by amplifying interactions among GH-releasing hormone (GHRH), somatostatin (SS) and GH-releasing peptide (GHRP). Design The design comprised double-blind randomized prospective administration of transdermal E2 vs placebo to healthy postmenopausal women (N=24) followed by pulsatile GHRH or SS infusions for 13 hr overnight with or without continuous GHRP-2 stimulation. Methods Endpoints were mean GH concentration, deconvolved GH secretion, and GH ApEn (a regularity measure). Results By generalized ANOVA models, E2 vs placebo supplementation: (1) augmented mean (13-hr) GH concentrations (P=0.023), GHRH-induced pulsatile GH secretion over the first 3.0 hr (P=0.0085) and pulsatile GH secretion over the next 10 hr (P=0.054); (2) increased GHRP- (P=0.022) and SS- (P<0.001) modulated GH ApEn; and (3) did not amplify GHRH/GHRP synergy on pulsatile GH secretion. By linear regression, E2 concentrations correlated positively with GH secretion during GHRP-2 infusion (P=0.022), whereas BMI correlated negatively with GH secretion during GHRH (P=0.006) and combined GHRH/GHRP (P=0.015) stimulation. E2 and BMI jointly determined triple (combined L-arginine, GHRH, GHRP-2) stimulation of GH secretion after saline (R2=0.44, P=0.003) and pulsatile GHRH (R2=0.39, P=0.013) infusions. Conclusion In summary, in postmenopausal individuals, E2 supplementation augments the amount (mass) and alters the pattern (regularity) of GH secretion via interactions among GHRH, SS, GHRP, and BMI. These outcomes introduce a more complex model of E2 supplementation in coordinating GH secretion in aging women. PMID:24114435

  4. Localization of immunoreactive lamprey gonadotropin-releasing hormone in the rat brain.

    PubMed

    Dees, W L; Hiney, J K; Sower, S A; Yu, W H; McCann, S M

    1999-12-01

    A highly specific antiserum against lamprey gonadotropin-releasing hormone (GnRH) was used to localize 1-GnRH in areas of the rat brain associated with reproductive function. Immunoreactive 1-GnRH-like neurons were observed in the ventromedial preoptic area (POA), the region of the diagonal band of Broca and the organum vasculosum lamina terminalis, with fiber projections to the rostral wall of the third ventricle and the organum vasculosum lamina terminalis. Another population of 1-GnRH-like neurons was localized in the dorsomedial and lateral POA, with nerve fibers projecting caudally and ventrally to terminate in the external layer of the median eminence. Other fibers apparently projected caudally and circumventrically to terminate around the cerebral aqueduct in the mid-brain central gray. By using a highly specific antiserum directed against mammalian luteinizing hormone-releasing hormone (m-LHRH), the localization of the LHRH neuronal system was compared to that of the 1-GnRH system. There were no LHRH neurons in the dorsomedial or the lateral region of the POA that contained the 1-GnRH neurons. As expected, there was a large population of LHRH neurons in the ventromedial POA associated with the diagonal band of Broca and organum vasculosum lamina terminalis. In both of these regions, there were many more LHRH neurons than 1-GnRH neurons and the LHRH neurons extended more dorsally and laterally than the 1-GnRH neurons. The LHRH neurons seemed to project to the median eminence in the same areas as those that were innervated by the 1-GnRH neurons. Absorption studies indicated that 1-GnRH cell bodies were eliminated by adding 1 microg of either 1-GnRH-I or 1-GnRH-III, but not m-LHRH to the antiserum before use. Fibers were largely eliminated by the addition of 1 microg 1-GnRH-III to the antiserum. No chicken GnRH-II neurons or nerve fibers could be visualized by immunostaining. Because the antiserum recognized GnRH-I and GnRH-III equally, we have visualized an 1

  5. Gonadotropin-releasing hormone receptor system: modulatory role in aging and neurodegeneration

    PubMed Central

    Wang, Liyun; Chadwick, Wayne; Park, Soo-Sung; Zhou, Yu; Silver, Nathan; Martin, Bronwen; Maudsley, Stuart

    2010-01-01

    Receptors for hormones of the hypothalamic-pituitary-gonadal axis are expressed throughout the brain. Age-related decline in gonadal reproductive hormones cause imbalances of this axis and many hormones in this axis have been functionally linked to neurodegenerative pathophysiology. Gonadotropin-releasing hormone (GnRH) plays a vital role in both central and peripheral reproductive regulation. GnRH has historically been known as a pituitary hormone; however, in the past few years, interest has been raised in GnRH actions at non-pituitary peripheral targets. GnRH ligands and receptors are found throughout the brain where they may act to control multiple higher functions such as learning and memory function and feeding behavior. The actions of GnRH in mammals are mediated by the activation of a unique rhodopsin-like G protein-coupled receptor that does not possess a cytoplasmic carboxyl terminal sequence. Activation of this receptor appears to mediate a wide variety of signaling mechanisms that show diversity in different tissues. Epidemiological support for a role of GnRH in central functions is evidenced by a reduction in neurodegenerative disease after GnRH agonist therapy. It has previously been considered that these effects were not via direct GnRH action in the brain, however recent data has pointed to a direct central action of these ligands outside the pituitary. We have therefore summarized the evidence supporting a central direct role of GnRH ligands and receptors in controlling central nervous physiology and pathophysiology. PMID:20632963

  6. Childhood lead toxicity and impaired release of thyrotropin-stimulating hormone

    SciTech Connect

    Huseman, C.A.; Moriarty, C.M.; Angle, C.R.

    1987-04-01

    Decreased stature of children is epidemiologically associated with increased blood lead independent of multiple socioeconomic and nutritional variables. Since endocrine dysfunction occurs in adult lead workers, they studied two girls, 2 years of age, before and after calcium disodium edetate chelation for blood leads (PbB) of 19-72 ..mu..g/dl. The height of both children had crossed from the 50th to below the 10th percentile during the course of chronic lead toxicity. Basal free T/sub 4/, T/sub 4/, T/sub 3/, cortisol, somatomedin C, and sex steroids were normal. A decrease in the growth hormone response and elevation of basal prolcatin and gonadotropins were noted in one. Both children demonstrated blunted thyrotropin-stimulating hormone (TSH) responses to thyrotropin-releasing hormone (TRH) in six of seven challenges. This prompted in vitro studies of cultured cells from rat pituitarities. After incubation of pituitary cells with 0.1-10 ..mu..M Pb/sup 2 +/ for 2 hr, followed by the addition of TRH, there was a dose-dependent inhibition of TSH release Lead did not interfere with the assay of TSH. To investigate the interaction of lead and calcium, /sup 45/Ca/sup 2 +/ kinetic analyses were done on rat pituitary slices after 1 hr incubation with 1.0 ..mu..M lead. The impaired late efflux was consistent with a decrease in the size and exchangeability of the tightly bound pool of intracellular microsomal or mitochondrial calcium. The rat pituitary cell model provides a model for the decreased TSH release of lead poisoning, supports the biological plausibility of a neuroendocrine effect on growth, and suggests that interference with calcium-mediated intracellular responses is a basic mechanism of lead toxicity.

  7. Cerebral hypoperfusion as a stimulus for growth hormone release in man.

    PubMed

    Kellerová, E; Vigas, M

    1980-01-01

    In healthy male volunteers the effect of a short-term cerebral ischemia due to an acute orthostatic hypotension, on the release of growth hormone (HGH) was studied. Peroral administration of guanethidine 12.5 mg t.i.d. for 3 days plus 25 mg before the experiment was used to block peripheral vascular reflexes and thus to provoke orthostatic intolerance. An extreme increase of HGH serum levels (on average from 0.8 to 13.6 ng/ml; p < 0.001) was found in subjects who developed clinical signs of syncope after assuming upright posture. The possible mechanisms of this finding are discussed.

  8. Application of hydrogel polymers for development of thyrotropin releasing hormone-loaded adhesive buccal patches.

    PubMed

    Chinwala, Maimoona G; Lin, Senshang

    2010-06-01

    To utilize hydrogels for fabricating thyrotropin releasing hormone (TRH) adhesive buccal patches, type of hydrogels such as polyacrylic acids (Polycarbophil AA1, Carbopols 934P, 974P and 971P), celluloses (HPMC K4M, K4MCR and K15M), polysaccharide (sodium alginate) and polyacrylic acid combinations with either cellulose or polysaccharide were evaluated for adhesion force, water uptake and swelling capacity. Upon the characterization of hydrogel polymers, TRH-loading of patches fabricated from these hydrogels was evaluated at various polymer concentrations, combinations and ratios and then in vitro release kinetics of TRH from these patches were studied. Results indicated that maximum adhesion force was shown by polyacrylic acids. Adhesive force of polymer combination mainly resulted from combination of adhesive force, according to ratio proportion used, of each polymer without any superimposed effect of polymer combination. Polycarbophil AA1 showed highest water uptake and swelling capacity. Maximum TRH-loading was obtained with sodium alginate and Polycarbophil AA1 and sodium alginate combination. TRH release profiles revealed that release was sustained from Polycarbophil AA1 and its combination with celluloses or polysaccharide at 2:1 level of polymer ratio. Based on adhesion, loading and release characteristics, patches of Polycarbophil AA1 with K4M, K4MCR and sodium alginate were concluded to be suitable for further development.

  9. Heterozygous gsp mutation renders ion channels of human somatotroph adenoma cells unresponsive to growth hormone-releasing hormone.

    PubMed

    Yasufuku-Takano, J; Takano, K; Takei, T; Fukumoto, S; Teramoto, A; Takakura, K; Yamashita, N; Fujita, T

    1999-05-01

    Ionic mechanisms play an important role in the regulation of hormone secretion. The GHRH-induced GH release by human GH-secreting cells is transmitted through protein kinase A (PKA), which activates nonselective cation current (NSCC) and induces membrane depolarization, intracellular Ca2+ increase, and GH secretion. To evaluate whether ionic mechanisms have pathophysiological significance in GH oversecretion of GH-secreting pituitary adenomas, we examined four adenomas with constitutively active Gs alpha mutation (gsp mutation) and compared with three gsp-negative adenomas. In primary-cultured cells of gsp-positive adenomas, GHRH did not increase the NSCC under voltage-clamp experiments. Detailed examination showed that NSCC was maximally activated at the basal level and application of GHRH did not increase the current in these adenomas. Furthermore, by using single-cell RT-PCR method, we demonstrated for the first time at the single cell level that gsp mutation is heterozygous in GH-secreting pituitary adenomas. These indicate that heterozygous gsp mutation fully activates NSCC at the basal level, which may account for the GH oversecretion in gsp-positive GH-secreting pituitary adenomas.

  10. Different effects of growth hormone-releasing hormone (GRH) and somatostatin on growth hormone and stable metabolite of prostaglandin E2, 13, 14-dihydro-15-keto-prostaglandin E2 (PGE2-M) in normal subjects.

    PubMed

    Zacharieva, S; Muchá, I; Popova, J; Andonova, K

    1992-01-01

    Twenty four healthy subjects were placed in two treatment groups: 1. The first group consisted of twelve subjects in whom growth releasing hormone (GRH) (1 microgram/kg.BW) resulted in a marked and sustained elevation of serum growth hormone (GH) and a slight and delayed increase in plasma prostaglandin E2-M. In the second group, consisting also of twelve subjects, somatostatin infusion (500 micrograms/250 ml) was initiated and maintained for 60 min. Serum GH significantly decreased at 30 and 60 min during infusion and 15 min thereafter. We did not observe any changes in plasma prostaglandin E2-M during or after somatostatin infusion. The results obtained confirm previous in vitro studies and suggest a possible link between growth releasing hormone and prostaglandin E2 in their action on growth hormone secretion. It seems that somatostatin does not play a role in the control of prostaglandin E2 release.

  11. Molecular analysis of the koala reproductive hormones and their receptors: gonadotrophin-releasing hormone (GnRH), follicle-stimulating hormone β and luteinising hormone β with localisation of GnRH.

    PubMed

    Busby, E R; Soeta, S; Sherwood, N M; Johnston, S D

    2014-12-01

    During evolution, reproductive hormones and their receptors in the brain-pituitary-gonadal axis have been altered by genetic mechanisms. To understand how the neuroendocrine control of reproduction evolved in mammals, it is important to examine marsupials, the closest group to placental mammals. We hypothesised that at least some of the hormones and receptors found in placental mammals would be present in koala, a marsupial. We examined the expression of koala mRNA for the reproductive molecules. Koala cDNAs were cloned from brain for gonadotrophin-releasing hormones (GnRH1 and GnRH2) or from pituitary for GnRH receptors, types I and II, follicle-stimulating hormone (FSH)β and luteinising hormone (LH)β, and from gonads for FSH and LH receptors. Deduced proteins were compared by sequence alignment and phylogenetic analysis with those of other vertebrates. In conclusion, the koala expressed mRNA for these eight putative reproductive molecules, whereas at least one of these molecules is missing in some species in the amniote lineage, including humans. In addition, GnRH1 and 2 are shown by immunohistochemistry to be expressed as proteins in the brain.

  12. From nose to brain: development of gonadotrophin-releasing hormone-1 neurones.

    PubMed

    Wray, S

    2010-07-01

    Gonadotrophin-releasing hormone-1 (GnRH-1) is essential for mammalian reproduction, controlling release of gonadotrophins from the anterior pituitary. GnRH-1 neurones migrate from the nasal placode into the forebrain during development. Although first located within the nasal placode, the embryonic origin/lineage of GnRH-1 neurones is still unclear. The migration of GnRH-1 cells is the best characterised example of neurophilic/axophilic migration, with the cells using a subset of olfactory-derived vomeronasal axons as their pathway and numerous molecules to guide their movement into the forebrain. Exciting work in this area is beginning to identify intersecting pathways that orchestrate the movement of these critical neuroendocrine cells into the central nervous system, both spatially and temporally, through a diverse and changing terrain. Once within the forebrain, little is known about how the axons target the median eminence and ultimately secrete GnRH-1 in a pulsatile fashion.

  13. Characterization of a Novel Subtype of Hippocampal Interneurons That Express Corticotropin-Releasing Hormone

    PubMed Central

    Hooper, Andrew; Maguire, Jamie

    2017-01-01

    A subset of corticotropin-releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV-Flex-ChR2-tdTomato reveal dense back-projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function. PMID:26135556

  14. Characterization of a novel subtype of hippocampal interneurons that express corticotropin-releasing hormone.

    PubMed

    Hooper, Andrew; Maguire, Jamie

    2016-01-01

    A subset of corticotropin-releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV-Flex-ChR2-tdTomato reveal dense back-projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function.

  15. Internalization and recycling of receptor-bound gonadotropin-releasing hormone agonist in pituitary gonadotropes

    SciTech Connect

    Schvartz, I.; Hazum, E.

    1987-12-15

    The fate of cell surface gonadotropin-releasing hormone (GnRH) receptors on pituitary cells was studied utilizing lysosomotropic agents and monensin. Labeling of pituitary cells with a photoreactive GnRH derivative, (azidobenzoyl-D-Lys6)GnRH, revealed a specific band of Mr = 60,000. When photoaffinity-labeled cells were exposed to trypsin immediately after completion of the binding, the radioactivity incorporated into the Mr = 60,000 band decreased, with a concomitant appearance of a proteolytic fragment (Mr = 45,000). This fragment reflects cell surface receptors. Following GnRH binding, the hormone-receptor complexes underwent internalization, partial degradation, and recycling. The process of hormone-receptor complex degradation was substantially prevented by lysosomotropic agents, such as chloroquine and methylamine, or the proton ionophore, monensin. Chloroquine and monensin, however, did not affect receptor recycling, since the tryptic fragment of Mr = 45,000 was evident after treatment with these agents. This suggests that recycling of GnRH receptors in gonadotropes occurs whether or not the internal environment is acidic. Based on these findings, we propose a model describing the intracellular pathway of GnRH receptors.

  16. Assessing placental corticotrophin-releasing hormone disruption by hexestrol in a cell model.

    PubMed

    Zhu, Yun; Qin Tan, Yan; Leung, Lai K

    2016-12-01

    Studies have shown that corticotrophin-releasing hormone (CRH) and relaxin are associated with early delivery. Our lab previously has shown the mycotoxin zeranol increases placental CRH expression. The mycotoxin is used in the farming industry to promote cattle growth, and some synthetic hormones are also used for the same purposes. In order to complete the picture of these growth promoting agents, we attempted to examine the synthetic hormones on the placental gene expression in the current study. Among the tested compounds, hexestrol induced the CRH mRNA and protein expression at 100nM in JEG-3 cells. As signal transduction pathways have been described in the transcriptional control previously, the activations of several protein kinases were determined. P38, PKCβ and JNK were activated upon hexestrol treatment. Since the P38-inhibitor SB203580 prevented hexestrol from inducing CRH in a subsequent experiment, P38 was likely involved in the transcriptional regulation. Electrophoretic mobility shift assay revealed an increase in the CRE binding activity in CRH promoter. This study showed that hexestrol exposure might be a concern for pregnant women.

  17. Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH) neurons

    PubMed Central

    Cortés-Campos, Christian; Letelier, Joaquín; Ceriani, Ricardo; Whitlock, Kathleen E.

    2015-01-01

    ABSTRACT Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons. PMID:26209533

  18. Pharmacophore development for corticotropin-releasing hormone: new insights into inhibitor activity.

    PubMed

    Keller, P A; Bowman, M; Dang, K H; Garner, J; Leach, S P; Smith, R; McCluskey, A

    1999-07-01

    Corticotropin-releasing hormone (CRH) is an endogenous 41-amino acid peptide involved in a wide ranging series of systems including the brain, the coordination of the body's overall response to stress, and more recently as a crucial initiator in the onset of labor, also known as the placental clock. Although more physiological data on CRH is emerging shedding more light on the processes involved and their integration, the mode of action of the hormone and the postulated binding site(s) remain unknown. Recently, a number of small-molecular-weight ligands have emerged as potent antagonists but, as therapeutics, suffer from a lack of solubility. Additionally, despite a number of exhaustively large patents, the lack of structural diversity with these antagonists has enabled little scope for comprehensive and wide ranging studies into the structure of the binding sites of this hormone. As part of a program investigating new, structurally diverse antagonists and agonists of CRH, we have developed a preliminary pharmacophore based on the known small-molecular-weight ligands as an initial step in our program. This pharmacophore was validated by comparison with some of the compounds we postulated to be active.

  19. Identification of the growth hormone-releasing hormone analogue [Pro1, Val14]-hGHRH with an incomplete C-term amidation in a confiscated product.

    PubMed

    Esposito, Simone; Deventer, Koen; Van Eenoo, Peter

    2014-01-01

    In this work, a modified version of the 44 amino acid human growth hormone-releasing hormone (hGHRH(1-44)) containing an N-terminal proline extension, a valine residue in position 14, and a C-terminus amidation (sequence: PYADAIFTNSYRKVVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2 ) has been identified in a confiscated product by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Investigation of the product suggests also an incomplete C-term amidation. Similarly to other hGHRH analogues, available in black markets, this peptide can potentially be used as performance-enhancing drug due to its growth hormone releasing activity and therefore it should be considered as a prohibited substance in sport. Additionally, the presence of partially amidated molecule reveals the poor pharmaceutical quality of the preparation, an aspect which represents a big concern for public health as well.

  20. Purification of a high-molecular-weight somatoliberin (growth-hormone-releasing factor) from pig hypothalami.

    PubMed Central

    Sykes, J E; Lowry, P J

    1983-01-01

    Preliminary observations [Sykes & Lowry (1980) J. Endocrinol. 85, 42P-43P] had suggested that the major hypothalamic somatoliberin (growth-hormone-releasing factor) was a larger peptide than the other characterized hypothalamic factors, with an elution position on Sephadex G-50 between those of neurophysin and corticotropin. The present paper reports the isolation and preliminary characterization of pig hypothalamic somatoliberin. Acid extracts of pig stalk median eminence were purified by gel filtration and preparative and analytical high-pressure liquid chromatography to yield a preparation that was specific in the release of somatotropin (growth hormone) in vitro, giving a steep dose--response curve at doses in the range 0.20-3.0 ng. Amino acid analysis revealed a non-cysteine-containing peptide with a high number of glutamate (or glutamine) and aspartate (or asparagine) residues. The peptide had about 56-57 amino acid residues and an apparent molecular weight of 6400, in keeping with its elution position on a column of Sephadex G-50. PMID:6409074

  1. Molecular diversity of corticotropin-releasing hormone mRNA-containing neurons in the hypothalamus.

    PubMed

    Romanov, Roman A; Alpár, Alán; Hökfelt, Tomas; Harkany, Tibor

    2017-03-01

    Hormonal responses to acute stress rely on the rapid induction of corticotropin-releasing hormone (CRH) production in the mammalian hypothalamus, with subsequent instructive steps culminating in corticosterone release at the periphery. Hypothalamic CRH neurons in the paraventricular nucleus of the hypothalamus are therefore considered as 'stress neurons'. However, significant morphological and functional diversity among neurons that can transiently produce CRH in other hypothalamic nuclei has been proposed, particularly as histochemical and molecular biology evidence associates CRH to both GABA and glutamate neurotransmission. Here, we review recent advances through single-cell RNA sequencing and circuit mapping to suggest that CRH production reflects a state switch in hypothalamic neurons and thus confers functional competence rather than being an identity mark of phenotypically segregated neurons. We show that CRH mRNA transcripts can therefore be seen in GABAergic, glutamatergic and dopaminergic neuronal contingents in the hypothalamus. We then distinguish 'stress neurons' of the paraventricular nucleus that constitutively express secretagogin, a Ca(2+) sensor critical for the stimulus-driven assembly of the molecular machinery underpinning the fast regulated exocytosis of CRH at the median eminence. Cumulatively, we infer that CRH neurons are functionally and molecularly more diverse than previously thought.

  2. Oxytocin/vasopressin and gonadotropin-releasing hormone from cephalopods to vertebrates.

    PubMed

    Minakata, Hiroyuki

    2010-07-01

    Recent advances in peptide search methods have revealed two peptide systems that have been conserved through metazoan evolution. Members of the oxytocin/vasopressin-superfamily have been identified from protostomian and deuterostomian animals, indicating that the oxytocin/vasopressin hormonal system represents one of the most ancient systems. In most protostomian animals, a single member of the superfamily shares oxytocin-like and vasopressin-like actions. Co-occurrence of two members has been discovered in modern cephalopods, octopus, and cuttlefish. We propose that cephalopods have developed two peptides in the molluscan evolutionary lineage like vertebrates have established two lineages in the oxytocin/vasopressin superfamily. The existence of gonadotropin-releasing hormone (GnRH) in protostomian animals was initially suggested by immunohistochemical analysis using chordate GnRH antibodies. A peptide with structural features similar to those of chordate GnRHs was originally isolated from octopus, and an identical peptide has been characterized from squid and cuttlefish. Novel forms of GnRH-like molecules from other molluscs, an annelid, arthropods, and nematodes demonstrate somewhat conserved structures at the N-terminal regions; but structures of the C-terminal regions critical to gonadotropin-releasing activity are diverse. These findings may be important for the study of the molecular evolution of GnRH in protostomian animals.

  3. Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments.

    PubMed

    Barra de la Tremblaye, P; Plamondon, H

    2016-07-01

    Although it is well accepted that changes in the regulation of the hypothalamic-pituitary adrenal (HPA) axis may increase susceptibility to affective disorders in the general population, this link has been less examined in stroke patients. Yet, the bidirectional association between depression and cardiovascular disease is strong, and stress increases vulnerability to stroke. Corticotropin-releasing hormone (CRH) is the central stress hormone of the HPA axis pathway and acts by binding to CRH receptors (CRHR) 1 and 2, which are located in several stress-related brain regions. Evidence from clinical and animal studies suggests a role for CRH in the neurobiological basis of depression and ischemic brain injury. Given its importance in the regulation of the neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation to stress, CRH is likely associated in the pathophysiology of post stroke emotional impairments. The goals of this review article are to examine the clinical and experimental data describing (1) that CRH regulates the molecular signaling brain circuit underlying anxiety- and depression-like behaviors, (2) the influence of CRH and other stress markers in the pathophysiology of post stroke emotional and cognitive impairments, and (3) context and site specific interactions of CRH and BDNF as a basis for the development of novel therapeutic targets. This review addresses how the production and release of the neuropeptide CRH within the various regions of the mesocorticolimbic system influences emotional and cognitive behaviors with a look into its role in psychiatric disorders post stroke.

  4. Effect of antenatal administration of thyrotrophin releasing hormone on fetal flow velocity waveforms

    PubMed Central

    Bajoria, R.; Stagiannis, K.; Fisk, N.

    1997-01-01

    AIM—To determine whether antenatal administration of thyrotrophin releasing hormone (TRH), to promote lung maturation, alters blood flow through the fetal middle cerebral, umbilical artery, or ductus arteriosus and through the maternal uterine arteries.
METHODS—The effect of transplacentally administered TRH on the fetal circulation was prospectively evaluated in 30 patients between 24 and 34 weeks' gestation. TRH (400 µg) was given to the mother intravenously either as a bolus or an infusion. Fetal effects were determined by measuring the maximum velocity and pulsatility index (PI) in middle cerebral artery, ductus arteriosus, uterine artery and umbilical artery Doppler waveforms. Measurements were made immediately before, and 10 and 60 minutes after maternal TRH administration.
RESULTS—Intravenous injection of TRH had no significant effect on PI in the uterine, umbilical, or middle cerebral artery and the ductus arteriosus within 60 minutes of administration in either group.
CONCLUSION—The antenatal use of TRH in conjunction with steroids for fetal lung maturity does not affect utero-placental or fetal haemodynamic variables, as measured by Doppler. These findings, therefore, do not support the suggestion that antenatal intravenous administration of TRH either as bolus or infusion may have immediate adverse vascular effects in the fetus.

 Keywords: thyrotrophin releasing hormone; fetal middle cerebral artery; ductus arteriosus; utero-placental circulation; fetal Doppler PMID:9377135

  5. The hypothalamic-pituitary response in SLE. Regulation of prolactin, growth hormone and cortisol release.

    PubMed

    Rovenský, J; Blazícková, S; Rauová, L; Jezová, D; Koska, J; Lukác, J; Vigas, M

    1998-01-01

    It has been suggested that neuroendocrine regulation plays an important role in the pathogenesis and activation of autoimmune diseases. The aim of this investigation was to clarify the hypothalamic-pituitary response to a well-defined stimulus under standardised conditions in patients with SLE. Plasma concentrations of prolactin (PRL), growth hormone (GH) and cortisol were determined in venous blood drawn through an indwelling cannula during insulin-induced hypoglycaemia (0.1 U/kg b.w., i.v.) in ten patients and in 12 age-, gender- and weight-matched healthy subjects. Basal PRL concentrations were higher in patients vs healthy controls (12 vs 6 ng/ml, P < 0.01), though still within the physiological range. Insulin-induced plasma PRL and GH were significantly increased both in patients and healthy subjects; however, the increments or areas under the curves were not different in the two groups. Plasma cortisol response showed moderate attenuation in patients. Sensitivity of pituitary lactotrothrops to thyrotropin-releasing hormone (TRH) administration (200 microg, i.v.) was the same in patients and control subjects. In SLE patients with low activity of the disease the sensitivity of pituitary PRL release to TRH administration remained unchanged. The hypothalamic response to stress stimulus (hypoglycaemia) was comparable in patients and healthy subjects.

  6. Disrupting the circadian photo-period alters the release of follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol in maternal and fetal sheep

    PubMed Central

    GAO, Qinqin; LV, Juanxiu; LI, Weisheng; ZHANG, Pengjie; TAO, Jianying; XU, Zhice

    2016-01-01

    Although a large number of studies show that photo-period disruption potentially affects hormone secretion in mammals, information about the effects of circadian photo-period disruption during pregnancy on fetal blood reproductive hormone levels is scarce. This study used ewes and their fetuses to determine the effects of circadian photo-period disruption (deprivation of darkness) on follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone in maternal and fetal circulation at late gestation. Pregnant ewes (gestational age: 135 ± 3 days) were randomly placed into control and dark deprivation groups. The control (N = 5) and dark deprivation (N = 5) groups were exposed to a fixed 12 h light/12 h dark cycle and a 24 h constant light cycle, respectively, for 2 days. Dark deprivation up-regulated follicle-stimulating hormone and estradiol levels and down-regulated progesterone levels in both maternal and fetal circulation, and up-regulated luteinizing hormone levels in fetal but not maternal circulation. These results provide new information about how circadian photo-period disruption during pregnancy could alter the release of certain reproductive hormones into fetal blood, which may influence the development of fetal organs in utero, as well as long-term health. PMID:27319751

  7. Preparation and characterization of luteinising-hormone releasing hormone nanoliposomal microbubbles specifically targeting ovarian cancer cells in vitro.

    PubMed

    Zhang, Jinyi; Liu, Sisun; Zhu, Yuanfang; Zhang, Liping; Li, Wenjuan; Wang, Fen; Huang, Shuying

    2014-07-01

    The aim of the present study was to prepare luteinizing-hormone releasing hormone (LHRH) nanoliposomal microbubbles specifically targeting ovarian cancer cells. The lyophilization/sonication method was used to prepare non-targeting nanoliposomal microbubbles (N-N-Mbs). Using the biotin-avidin bridge method, conjugated LHRH antibodies to N-N-Mbs generated LHRH nanoliposomal microbubbles (LHRH-N-Mbs) specifically targeting ovarian cancer cells. The morphology and physicochemical properties of the microbubbles was detected using an optical microscope and zeta detector. The binding affinity between the secondary antibody and LHRH-N-Mbs or N-N-Mbs was determined by flow cytometry. The binding of LHRH-N-Mb to human ovarian cancer cells (OVCAR-3) was detected by light microscopy. The rounded and uniformly distributed N-N-Mbs and LHRH-N-Mbs were successfully generated. The particle size ranged from 295-468 nm with a mean of 360 nm for N-N-Mbs or 369-618 nm with a mean of 508 nm for LHRH-N-Mbs. There was a significant difference in size between the two groups (P<0.05), although the surface potential of the two microbubbles remained the same (-14.6 mV). Following being kept at room temperature for 14 days, no significant difference in the physicochemical properties of the LHRH-N-Mbs was detected compared with that of freshly prepared microbubbles. The secondary antibody binding rate of LHRH-N-Mbs and N-N-Mbs was 75.6 and 0.83%, respectively. Furthermore, the formation of a rosette-like structure surrounding OVCAR-3 cells was observed after the cells were incubated with LHRH-N-Mbs, whereas pre-incubation with LHRH antibody blocked this rosette formation. In conclusion, LHRH-N-Mbs specifically targeting ovarian cancer cells were successfully prepared through biotin-avidin mediation and the lyophilization/sonication method. The key feature of LHRH-N-Mbs is their small size, stability and high efficiency in targeting human OVCAR-3 cells in vitro.

  8. Pregnancy rates to timed artificial insemination in dairy cows treated with gonadotropin-releasing hormone or porcine luteinizing hormone.

    PubMed

    Colazo, M G; Gordon, M B; Rajamahendran, R; Mapletoft, R J; Ambrose, D J

    2009-07-15

    We compared the effects of porcine luteinizing hormone (pLH) versus gonadotropin-releasing hormone (GnRH) on ovulatory response and pregnancy rate after timed artificial insemination (TAI) in 605 lactating dairy cows. Cows (mean+/-SEM: 2.4+/-0.08 lactations, 109.0+/-2.5 d in milk, and 2.8+/-0.02 body condition score) at three locations were assigned to receive, in a 2x2 factorial design, either 100 microg GnRH or 25mg pLH im on Day 0, 500 microg cloprostenol (PGF) on Day 7, and GnRH or pLH on Day 9, with TAI 14 to 18h later. Ultrasonographic examinations were performed in a subset of cows on Days 0, 7, 10, and 11 to determine ovulations, presence of corpus luteum, and follicle diameter and in all cows 32 d after TAI for pregnancy determination. In 35 cows, plasma progesterone concentrations were determined 0, 3, 4, 5, 6, 7, and 12 d after ovulation. The proportion of noncyclic cows and cows with ovarian cysts on Day 0 were 12% and 6%, respectively. Ovulatory response to first treatment was 62% versus 44% for pLH and GnRH and 78% versus 50% for noncyclic and cyclic cows (P<0.01). Location, ovulatory response to first pLH or GnRH, cyclic status, presence of an ovarian cyst, and preovulatory follicle size did not affect pregnancy rate. Plasma progesterone concentrations after TAI did not differ among treatments. Pregnancy rate to TAI was greater (P<0.01) in the GnRH/PGF/pLH group (42%) than in the other three groups (28%, 30%, and 26% for GnRH/PGF/GnRH, pLH/PGF/GnRH, and pLH/PGF/pLH, respectively). Although only 3% of cows given pLH in lieu of GnRH on Day 9 lost their embryo versus 7% in those subjected to a conventional TAI using two GnRH treatments, the difference was not statistically significant. In summary, pLH treatment on Day 0 increased ovulatory response but not pregnancy rate. Cows treated with GnRH/PGF/pLH had the highest pregnancy rate to TAI, but progesterone concentrations after TAI were not increased. In addition, preovulatory follicle diameter did not

  9. Effects of the growth hormone-releasing hormone (GH-RH) antagonist on brain functions in mice.

    PubMed

    Telegdy, Gyula; Tanaka, Masaru; Schally, Andrew V

    2011-10-10

    The growth hormone-releasing hormone (GH-RH) antagonist MZ-4-71 has been shown to suppress secretion of GH and insulin-like growth factor-1 (IGF-1) secretion. These findings suggested that GH-RH antagonists could be used for the therapy of disorders characterized by excessive GH secretion. A number of GH-RH antagonists has been synthesized, and shown to suppress the growth of various tumors. However, little is known about the possible action of GR-RH antagonists on brain functions. In the present work, the influence of MZ-4-71 on different aspects of brain function was studied in mice, following its administration into the lateral brain ventricle. The effects tested included the action of MZ-4-71 on passive avoidance learning and on the impairment of the consolidation of a passive avoidance reflex caused by beta-amyloid 25-35, antidepressive action in a forced swimming test, and anxiolytic action on plus-maze and open-field behavior. MZ-4-71 facilitated the consolidation of passive avoidance learning. Beta-amyloid 25-35 administered immediately after the learning trial impaired the consolidation of passive avoidance learning. MZ-4-71 fully blocked this impairment when given simultaneously with or 30min following beta-amyloid 25-35 administration icv. In the forced swimming tests, MZ-47-1 demonstrated antidepressive-like action and in the plus-maze, depending on the dose used it elicited mild anxiolytic action, however, in open-field behavior tests, it displayed no action on locomotion, rearing or grooming. The results demonstrate that MZ-4-71 affects the brain functions: by improving memory consolidation in passive avoidance learning and correcting the impairment of the memory consolidation caused by beta-amyloid 25-35. MZ-4-71 also elicits anxiolytic and antidepressive effects, but it does not influence the open-field activity. Further experimental work with MZ-4-71 is necessary, to determine the possible mechanism of action. The results imply a possible merit of

  10. Five gonadotrophin-releasing hormone receptors in a teleost fish: isolation, tissue distribution and phylogenetic relationships.

    PubMed

    Moncaut, Natalia; Somoza, Gustavo; Power, Deborah M; Canário, Adelino V M

    2005-06-01

    Gonadotrophin-releasing hormone (GnRH) is the main neurohormone controlling gonadotrophin release in all vertebrates, and in teleost fish also of growth hormone and possibly of other adenohypophyseal hormones. Over 20 GnRHs have been identified in vertebrates and protochoordates and shown to bind cognate G-protein couple receptors (GnRHR). We have searched the puffer fish, Fugu rubripes, genome sequencing database, identified five GnRHR genes and proceeded to isolate the corresponding complementary DNAs in European sea bass, Dicentrachus labrax. Phylogenetic analysis clusters the European sea bass, puffer fish and all other vertebrate receptors into two main lineages corresponding to the mammalian type I and II receptors. The fish receptors could be subdivided in two GnRHR1 (A and B) and three GnRHR2 (A, B and C) subtypes. Amino acid sequence identity within receptor subtypes varies between 70 and 90% but only 50-55% among the two main lineages in fish. All European sea bass receptor mRNAs are expressed in the anterior and mid brain, and all but one are expressed in the pituitary gland. There is differential expression of the receptors in peripheral tissues related to reproduction (gonads), chemical senses (eye and olfactory epithelium) and osmoregulation (kidney and gill). This is the first report showing five GnRH receptors in a vertebrate species and the gene expression patterns support the concept that GnRH and GnRHRs play highly diverse functional roles in the regulation of cellular functions, besides the "classical" role of pituitary function regulation.

  11. Corticotropin-releasing factor neurogenesis during midlife development in salmon: genetic, environmental and thyroid hormone regulation.

    PubMed

    Ebbesson, L O E; Nilsen, T O; Helvik, J V; Tronci, V; Stefansson, S O

    2011-08-01

    Salmon parr-smolt transformation (smoltification) is a mid-life transitional stage between life in freshwater and seawater that entails a wide range of neural, endocrine and physiological modifications. In salmon, the neuroendocrine corticotropin-releasing factor (CRF) system regulates pituitary adrenocorticotrophic hormone and thyrotrophin release. Four experimental groups of Atlantic salmon, Salmo salar, were used to investigated CRF neurogenesis and its regulation during smoltification. We compared: (i) developmental stages (parr and early-smolt) in anadromous controls; (ii) a developmentally arrested model: anadromous reared under continuous light (LL) with anadromous controls; (iii) a natural hypoendocrine/incomplete smolt development salmon model (landlocked) with anadromous controls; and (iv) landlocked treated with thyroxine to anadromous control smolt levels. CRF neurogenesis between groups was studied with bromodeoxyuradine (BrdU) incorporation followed by double-labelling CRF and BrdU immunhistochemistry. The rate of CRF neurogenesis in the preoptic area (POA) increased from parr to early-smolts in anadromous salmon. By contrast, neurogenesis was inhibited in the LL group and reduced in the landlocked salmon. The administration of thyroxine in landlocked salmon to match anadromous levels increased the rate of CRF neurogenesis to anadromous levels. In conclusion, newly-formed CRF cells in the POA during smoltification are associated with increased retinal innervation to the POA and endocrine responsiveness to increased photoperiod. Both genetic and environmental factors influence the degree of salmon brain development. Thyroid hormones increase CRF neurogenesis during this critical period of development in salmon. We hypothesise that a positive-feedback of thyroid hormones on CRF neurogenesis may be an important event in reaching the developmental climax during critical periods.

  12. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist.

    PubMed

    Dittrich, R; Binder, H; Cupisti, S; Hoffmann, I; Beckmann, M W; Mueller, A

    2005-12-01

    In transsexual people, cross-sex hormone therapy is an important component of medical treatment. In male-to-female transsexuals, feminizing effects should be achieved before irreversible sex reassignment surgery (SRS) is considered. The most common treatment regimen in male-to-female transsexuals is a combination of ethinyl oestradiol and cyproterone acetate, with the exception of transdermal oestradiol-17beta in individuals over the age of 40. The mortality and morbidity rates with this treatment regimen have been reported in more than 800 patients. Typical side effects include venous thrombosis, elevated liver enzymes, symptomatic gallstones, hyperprolactinaemia and depression. Sixty male-to-female transsexuals were treated with monthly injections of gonadotropin-releasing hormone agonist (GnRHa) and oral oestradiol-17beta valerate for 2 years to achieve feminisation until SRS. There was a significant decline in gonadotropins, total testosterone and calculated free testosterone. In general, the treatment regimen was well accepted. An equal increase in breast size was achieved compared to common hormone therapy. Two side effects were documented. One, venous thrombosis, occurred in a patient with a homozygous MTHFR mutation. One patient was found to be suffering from symptomatic preexisting gallstones. No other complications were documented. Liver enzymes, lipids, and prolactin levels were unchanged. Significantly increased oestradiol and SHBG serum levels were detectable. In addition, an increase in bone mass density, in the femoral neck and lumbar spine, was recorded. We conclude that cross-sex hormone treatment of male-to-female transsexuals using GnRHa and oestradiol-17beta valerate is effective, and side effects and complication rates can be reduced using the treatment regimen presented here.

  13. Gonadotropin-releasing hormone: regulation of the GnRH gene.

    PubMed

    Lee, Vien H Y; Lee, Leo T O; Chow, Billy K C

    2008-11-01

    As the key regulator of reproduction, gonadotropin-releasing hormone (GnRH) is released by neurons in the hypothalamus, and transported via the hypothalamo-hypophyseal portal circulation to the anterior pituitary to trigger gonadotropin release for gonadal steroidogenesis and gametogenesis. To achieve appropriate reproductive function, mammals have precise regulatory mechanisms; one of these is the control of GnRH synthesis and release. In the past, the scarcity of GnRH neurons and their widespread distribution in the brain hindered the study of GnRH gene expression. Until recently, the development of GnRH-expressing cell lines with properties similar to those of in vivo GnRH neurons and also transgenic mice facilitated GnRH gene regulation research. This minireview provides a summary of the molecular mechanisms for the control of GnRH-I and GnRH-II gene expression. These include basal transcription regulation, which involves essential cis-acting elements in the GnRH-I and GnRH-II promoters and interacting transcription factors, and also feedback control by gonadotropins and gonadal sex steroids. Other physiological stimuli, e.g. insulin and melatonin, will also be discussed.

  14. Elevation of growth hormone-releasing hormone receptor messenger ribonucleic acid expression in growth hormone-secreting pituitary adenoma with Gsalpha protein mutation.

    PubMed

    Sakai, Naoyuki; Kim, Kyongsong; Sanno, Naoko; Yoshida, Daizo; Teramoto, Akira; Shibasaki, Tamotsu

    2008-01-01

    Growth hormone-releasing hormone (GHRH) stimulates not only the synthesis and secretion of GH but also the proliferation of normal somatotrophs. The expression of GHRH receptor (GHRHR) is regulated by GHRH, both of which are known to be expressed in human GH-secreting pituitary adenoma cells. Somatic mutations in the subunit of Gsalpha protein (gsp), lead to the constitutive activation of adenylyl cyclase in pituitary adenomas that secrete GH. It has not been examined how gsp mutations influence GHRHR expression in GH-secreting adenomas. We therefore analyzed the expression levels of GHRHR messenger ribonucleic acid (mRNA) in GH-secreting pituitary adenomas focusing on a gsp mutation. Furthermore, we investigated the effect of GHRH on the expression of GHRHR mRNA in primary cultures of GH-secreting pituitary adenoma cells. GHRHR mRNA expression levels were significantly elevated in gsp mutation-positive GH-secreting adenomas compared with those in gsp mutation-negative ones. In primary-cultured GH-secreting adenoma cells, the increase of GH secretion in response to GHRH was shown in both gsp mutation-positive and -negative adenoma cells with a significantly higher response in the latter adenoma cells. GHRH increased GHRHR mRNA expression level in gsp mutation-negative adenoma cells while it was not influenced by GHRH in gsp mutation-positive adenoma cells. These results suggest that gsp mutations up-regulate GHRHR mRNA expression in GH-secreting pituitary adenoma cells, and that gsp mutations desensitize the adenoma cells to GHRH in terms of their GHRHR mRNA expression probably because of their saturation of GHRH signaling.

  15. Gonadotropin-releasing hormone, estradiol, and inhibin regulation of follicle-stimulating hormone and luteinizing hormone surges: implications for follicle emergence and selection in heifers.

    PubMed

    Haughian, James M; Ginther, O J; Diaz, Francisco J; Wiltbank, Milo C

    2013-06-01

    Mechanisms regulating gonadotropin surges and gonadotropin requirements for follicle emergence and selection were studied in heifers. Experiment 1 evaluated whether follicular inhibins regulate the preovulatory luteinizing hormone (LH)/follicle-stimulating hormone (FSH) surges elicited by gonadotropin-releasing hormone (GnRH) injection (Hour = 0) and the subsequent periovulatory FSH surge. Treatments included control (n = 6), steroid-depleted bovine follicular fluid (bFF) at Hour -4 (n = 6), and bFF at Hour 6 (n = 6). Gonadotropins in blood were assessed hourly from Hours -6 to 36, and follicle growth tracked by ultrasound. Consistent with inhibin independence, bFF at Hour -4 did not impact the GnRH-induced preovulatory FSH surge, whereas treatment at Hour 6 delayed onset of the periovulatory FSH surge and impeded growth of a new follicular wave. Experiment 2 examined GnRH and estradiol (E2) regulation of the periovulatory FSH surge. Treatment groups were control (n = 8), GnRH-receptor antagonist (GnRHr-ant, n = 8), and E2 + GnRHr-ant (n = 4). GnRHr-ant (acyline) did not reduce the concentrations of FSH during the periovulatory surge and early follicle development (<7.0 mm) was unaffected, although subsequent growth of a dominant follicle (>8.0 mm) was prevented by GnRHr-ant. Addition of E2 delayed both the onset of the periovulatory FSH surge and emergence of a follicular wave. Failure to select a dominant follicle in the GnRHr-ant group was associated with reduced concentrations of LH but not FSH. Maximum diameter of F1 in controls (13.3 ± 0.5 mm) was greater than in both GnRHr-ant (7.7 ± 0.3 mm) and E2 + GnRHr-ant (6.7 ± 0.8 mm) groups. Results indicated that the periovulatory FSH surge stems from removal of negative stimuli (follicular E2 and inhibin), but is independent of GnRH stimulation. Emergence and early growth of follicles (until about 8 mm) requires the periovulatory FSH surge but not LH pulses. However, follicular deviation and late-stage growth of

  16. NEURONAL ACTIVITY AND STRESS DIFFERENTIALLY REGULATE HIPPOCAMPAL AND HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE EXPRESSION IN THE IMMATURE RAT

    PubMed Central

    HATALSKI, C. G.; BRUNSON, K. L.; TANTAYANUBUTR, B.; CHEN, Y.; BARAM, T. Z.

    2011-01-01

    Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone’s abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide’s levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide’s expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration. Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide’s expression in the hypothalamus is influenced by neuroendocrine challenges. PMID:11113306

  17. Receptors for luteinizing hormone-releasing hormone (GnRH) as therapeutic targets in triple negative breast cancers (TNBC).

    PubMed

    Kwok, C W; Treeck, O; Buchholz, S; Seitz, S; Ortmann, O; Engel, J B

    2015-09-01

    Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50% of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 ± 0.21 and 58.50 ± 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated.

  18. Gonadotropin-releasing hormone II (GnRH II) mediates the anorexigenic actions of α-melanocyte-stimulating hormone (α-MSH) and corticotropin-releasing hormone (CRH) in goldfish.

    PubMed

    Kang, Ki Sung; Shimizu, Kanako; Azuma, Morio; Ui, Yuhta; Nakamura, Kouta; Uchiyama, Minoru; Matsuda, Kouhei

    2011-01-01

    Intracerebroventricular (ICV) administration of gonadotropin-releasing hormone II (GnRH II), which plays a crucial role in the regulation of reproduction in vertebrates, markedly reduces food intake in goldfish. However, the neurochemical pathways involved in the anorexigenic action of GnRH II and its interaction with other neuropeptides have not yet been identified. Alpha-melanocyte-stimulating hormone (α-MSH), corticotropin-releasing hormone (CRH) and CRH-related peptides play a major role in feeding control as potent anorexigenic neuropeptides in goldfish. However, our previous study has indicated that the GnRH II-induced anorexigenic action is not blocked by treatment with melanocortin 4 receptor (MC4R) and CRH receptor antagonists. Therefore, in the present study, we further examined whether the anorexigenic effects of α-MSH and CRH in goldfish could be mediated through the GnRH receptor neuronal pathway. ICV injection of the MC4R agonist, melanotan II (80 pmol/g body weight; BW), significantly reduced food intake, and its anorexigenic effect was suppressed by ICV pre-administration of the GnRH type I receptor antagonist, antide (100 pmol/gBW). The CRH-induced (50 pmol/gBW) anorexigenic action was also blocked by treatment with antide. ICV injection of CRH (50 pmol/gBW) induced a significant increase of the GnRH II mRNA level in the hypothalamus, while ICV injection of melanotan II (80 pmol/gBW) had no effect on the level of GnRH II mRNA. These results indicate that, in goldfish, the anorexigenic actions of α-MSH and CRH are mediated through the GnRH type I receptor-signaling pathway, and that the GnRH II system regulates feeding behavior.

  19. Neither bST nor Growth Hormone Releasing Factor Alter Expression of Thyroid Hormone Receptors in Liver and Mammary Tissues

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine, to specific nuclear receptors. It has been hypothesized that organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, target the action of thyroid hormones to the mammary...

  20. Mink aging is associated with a reduction in ovarian hormone release and the response to FSH and ghrelin.

    PubMed

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karina; Lauričik, Jozef; Morovič, Martin; Harrath, Abdel Halim; Kotwica, Jan

    2016-09-15

    The endocrine mechanisms of mink ovarian hormones release and reproductive aging are poorly investigated. The aims of our study were to: (1) identify hormones produced by mink ovaries (the steroids progesterone [P] and estradiol [E], the peptide hormone oxytocin [OT], and the prostaglandin F [PGF] and prostaglandin E [PGE]); (2) examine the effect of FSH and ghrelin on the release of the hormones listed previously; and (3) understand whether these hormones can be involved in the control of mink reproductive aging, i.e., whether aging can be associated with changes (a) in the basal release of P, E, OT, PGF, or PGE and (b) their response to FSH and ghrelin. Fragments of ovaries of young (yearlings) and old (3-5 years of age) minks were cultured with and without FSH and ghrelin (0, 1, 10, or 100 ng/mL), and the release of hormones was analyzed by EIA/RIA. We found that isolated ovaries were able to release P, E, OT, PGF, and PGE, and the levels of P produced in the ovaries of old animals were lower than those produced in the ovaries of young animals, whereas the levels of other hormones did not differ. FSH was able to stimulate P and E and suppress OT and PGF and did not affect PGE release. Aging was associated with the inhibition of the effect of FSH on ovarian P and E, the appearance of the inhibitory action of FSH on OT, and the disappearance of this action on ovarian PGF. PGE was not affected by FSH, irrespective of animal age. Ghrelin was able to promote E (but not P) and suppress OT, PGF, and PGE output. Aging was associated with the appearance of an inhibitory influence of ghrelin on ovarian OT and PGE and with the disappearance of this influence on PGF output. Aging did not affect the action of ghrelin on ovarian P and E. Our observations (1) confirm the production of P and E and show that OT, PGF, and PGE are released from mink ovaries, (2) confirm the involvement of FSH and demonstrate the involvement of ghrelin in the control of mink ovarian hormone

  1. Towards more physiological manipulations of hormones in field studies: comparing the release dynamics of three kinds of testosterone implants, silastic tubing, time-release pellets and beeswax.

    PubMed

    Quispe, Rene; Trappschuh, Monika; Gahr, Manfred; Goymann, Wolfgang

    2015-02-01

    Hormone manipulations are of increasing interest in the areas of physiological ecology and evolution, because hormones are mediators of complex phenotypic changes. Often, however, hormone manipulations in field settings follow the approaches that have been used in classical endocrinology, potentially using supra-physiological doses. To answer ecological and evolutionary questions, it may be important to manipulate hormones within their physiological range. We compare the release dynamics of three kinds of implants, silastic tubing, time-release pellets, and beeswax pellets, each containing 3mg of testosterone. These implants were placed into female Japanese quail, and plasma levels of testosterone measured over a period of 30 days. Testosterone in silastic tubing led to supraphysiological levels. Also, testosterone concentrations were highly variable between individuals. Time-release pellets led to levels of testosterone that were slightly supraphysiological during the first days. Over the period of 30 days, however, testosterone concentrations were more consistent. Beeswax implants led to a physiological increase in testosterone and a relatively constant release. The study demonstrated that hormone implants in 10mm silastic tubing led to a supraphysiological peak in female quail. Thus, the use of similar-sized or even larger silastic implants in males or in other smaller vertebrates needs careful assessment. Time-release pellets and beeswax implants provide a more controlled release and degrade within the body. Thus, it is not necessary to recapture the animal to remove the implant. We propose beeswax implants as an appropriate procedure to manipulate testosterone levels within the physiological range. Hence, such implants may be an effective alternative for field studies.

  2. Cloning and characterization of mouse growth hormone-releasing hormone (GRH) complementary DNA: increased GRH messenger RNA levels in the growth hormone-deficient lit/lit mouse.

    PubMed

    Frohman, M A; Downs, T R; Chomczynski, P; Frohman, L A

    1989-10-01

    We have isolated and cloned the full length cDNA for mouse GH-releasing hormone (mGRH) from mouse hypothalamus using a recently described strategy involving the polymerase chain reaction technique (PCR). Degenerate oligonucleotide primers were selected based on short (six amino acids) conserved regions in the human and rat GRH peptides that would recognize DNA sequences encoding similar amino acids regardless of codon usage. Primer-extended cDNA was amplified by PCR on cDNA templates prepared by reverse transcribing total mouse hypothalamic RNA. After cloning and sequencing the initial product, the 3' and 5' ends of mGRH were generated using a separate PCR strategy (RACE protocol). The mGRH cDNA encodes a 103-amino acid reading frame, structurally similar to the human and rat GRH genes, containing a signal sequence, a 42-residue GRH peptide, and a 31-residue C-terminal region. Although the structures of mouse and rat GRH are highly conserved in the signal peptide and C-terminal region, there is considerable diversity in the GRH region, which exhibits nearly comparable homology with the rat (68%) and human (62%) structures. Differences between mouse and rat GRH were also found in the amino acid cleavage sites at the 5' and 3' ends of the mature peptide and at the polyadenylation signal.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Melanin concentrating hormone induces hippocampal acetylcholine release via the medial septum in rats.

    PubMed

    Lu, Zhi-Hong; Fukuda, Satoru; Minakawa, Yoichi; Yasuda, Atsushi; Sakamoto, Hidetoshi; Sawamura, Shigehito; Takahashi, Hidenori; Ishii, Noriko

    2013-06-01

    Among various actions of melanin concentrating hormone (MCH), its memory function has been focused in animal studies. Although MCH neurons project to various areas in the brain, one main target site of MCH is hippocampal formation for memory consolidation. Recent immunohistochemical study shows that MCH neurons directly project to the hippocampal formation and may indirectly affect the hippocampus through the medial septum nucleus (MS). It has been reported that sleep is necessary for memory and that hippocampal acetylcholine (ACh) release is indispensable for memory consolidation. However, there is no report how MCH actually influences the hippocampal ACh effluxes in accordance with the sleep-wake cycle changes. Thus, we investigated the modulatory function of intracerebroventricular (icv) injection of MCH on the sleep-wake cycle and ACh release using microdialysis techniques. Icv injection of MCH significantly increased the rapid eye movement (REM) and non-REM episode time and the hippocampal, not cortical, ACh effluxes. There was a significant correlation between REM episode time and hippocampal ACh effluxes, but not between REM episode time and cortical ACh effluxes. Microinjection of MCH into the MS increased the hippocampal ACh effluxes with no influence on the REM episode time. It appears that the effect sites of icv MCH for prolongation of REM episode time may be other neuronal areas than the cholinergic neurons in the MS. We conclude that MCH actually increases the hippocampal ACh release at least in part through the MS in rats.

  4. The corticotropin-releasing hormone test in normal short children: comparison of plasma adrenocorticotropin and cortisol responses to human corticotropin-releasing hormone and insulin-induced hypoglycemia.

    PubMed

    Goji, K

    1989-03-01

    The human corticotropin-releasing hormone (hCRH) tests were performed in twelve normal short children, and the responses of plasma ACTH and cortisol to iv administration of 1 micrograms/kg hCRH were compared with those to insulin-induced hypoglycemia. After administration of hCRH, the mean plasma ACTH level rose from a basal value of 3.3 +/- 0.4 pmol/l (mean +/- SEM) to a peak value of 9.2 +/- 0.8 pmol/l at 30 min, and the mean plasma cortisol level rose from a basal value of 231 +/- 25 nmol/l to a peak value of 546 +/- 30 nmol/l at 30 min. The ACTH response after insulin-induced hypoglycemia was greater than that after hCRH administration; the mean peak level (P less than 0.01), the percent maximum increment (P less than 0.01), and the area under the ACTH response curve (P less than 0.01) were all significantly greater after insulin-induced hypoglycemia than those after hCRH administration. Although the mean peak cortisol level after insulin-induced hypoglycemia was about 1.3-fold higher than that after hCRH administration (P less than 0.01), neither the percent maximum increment in plasma cortisol nor the area under the cortisol response curve after insulin-induced hypoglycemia was significantly different from that after hCRH administration. Consequently, the acute increases in plasma ACTH after the administration of 1 microgram/kg hCRH stimulated the adrenal gland to almost the same cortisol response as that obtained with a much greater increase in plasma ACTH after insulin-induced hypoglycemia. These results suggest that a plasma ACTH peak of 9-11 pmol/l produces near maximum acute stimulation of adrenal steroidogenesis.

  5. Expression of gonadotropin-releasing hormone receptor and effect of gonadotropin-releasing hormone analogue on proliferation of cultured gastric smooth muscle cells of rats

    PubMed Central

    Chen, Lei; He, Hong-Xuan; Sun, Xu-De; Zhao, Jing; Liu, Li-Hong; Huang, Wei-Quan; Zhang, Rong-Qing

    2004-01-01

    AIM: To investigate the expression of gonadotropin-releasing hormone (GnRH) receptor and the effects of GnRH analog (alarelin) on proliferation of cultured gastric smooth muscle cells (GSMC) of rats. METHODS: Immunohistochemical ABC methods and in situ hybridization methods were used to dectect protein and mRNA expression of GnRH receptor in GSMC, respectively. Techniques of cell culture, OD value of MTT test, measure of 3H-TdR incorporation, average fluorescent values of proliferating cell nuclear antigen (PCNA) and flow cytometric DNA analysis were used in the experiment. RESULTS: The cultured GSMC of rats showed immunoreactivity for GnRH receptor; positive staining was located in cytoplasm. GnRH receptor mRNA hybridized signals were also detected in cytoplasm. When alarelin (10-9, 10-7, 10-5 mol/L) was administered into the medium and incubated for 24 h, OD value of MTT, 3H-TdR incorporation and average fluorescent values of PCNA all decreased significantly as compared with the control group (P < 0.05). The maximum inhibitory effect on cell proliferation was achieved a concentration of 10-5 mol/L and it acted in a dose-dependent manner. Flow cytometric DNA analysis revealed that alarelin could significantly enhance ratio of G1 phase and decrease ratio of S phase of GSMC of rats (P < 0.05).The maximum inhibitory effect on ratio of S phase was at the concentration of 10-5 mol/L and also acted in a dose-dependent manner. CONCLUSION: Our data suggest that GnRH receptor can be expressed by GSMC of rats. GnRH analogue can directly inhibit proliferation and DNA synthesis of rat GSMC through GnRH receptors. PMID:15188505

  6. Thyrotropin-Releasing Hormone is not Required for Thyrotropin Secretion in the Perinatal Rat

    PubMed Central

    Theodoropoulos, Theodor; Braverman, Lewis E.; Vagenakis, Apostolos G.

    1979-01-01

    To determine the role of thyrotropin-releasing hormone (TRH) in the regulation of thyroid-stimulating hormone (TSH) secretion in the perinatal period, a physiological approach of neutralizing circulating TRH in the fetal and early neonatal rat was employed. TRH-antiserum (TRH-AS) raised in rabbits and administered daily to low iodine-propylthiouracil (LID-PTU)-fed pregnant rats from days 12 to 19 of gestation markedly impaired the rise in serum TSH to LID-PTU when compared with normal rabbit serum-treated controls. In contrast, fetal serum TSH was unaffected by TRH-AS. The binding capacity of TRH-AS in the fetal serum (111 ng/ml) far exceeded circulating TRH in the fetus. Similarly, acute TRH-AS administration to the pregnant rat fed LID-PTU markedly decreased the serum TSH concentration in the mother, but not in the fetus, 60 min after TRH-AS administration. Chronic TRH-AS administration to neonatal rats whose nursing mothers were fed LID-PTU was in-effective in decreasing the elevated serum TSH in the neonate through day 8 of life, whereas a slight but significant decrease in serum TSH was observed on day 10. Chronic daily TRH-AS administration to neonatal rats through day 10 of life had no effect on the later development of the hypothalamic-pituitary-thyroid axis. These findings suggest that TRH does not participate in TSH regulation during the perinatal life in the rat and that thyroid hormones are probably the main regulators of TSH secretion during this period. Placental TRH is not important in regulating TSH secretion in the fetal rat. Furthermore, TRH “deprivation” during neonatal life does not prevent normal later development of the hypothalamic-pituitary-thyroid axis. PMID:108290

  7. How does growth hormone releasing hexapeptide self-assemble in nanotubes?

    PubMed

    Santana, Héctor; Avila, Cesar L; Cabrera, Ingrid; Páez, Rolando; Falcón, Viviana; Pessoa, Adalberto; Ventosa, Nora; Veciana, Jaume; Itri, Rosangela; Barbosa, Leandro Ramos Souza

    2014-12-14

    Growth hormone releasing peptide, GHRP-6, a hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2, MW = 872.44 Da) that belongs to a class of synthetic growth hormone secretagogues, can stimulate growth hormone secretion from somatotrophs in several species including humans. In the present study, we demonstrate that GHRP-6 dispersed in aqueous solution, at pH 7.0, room temperature of 22 °C, is able to form long nanotubes, which is evidenced by combining small angle X-ray scattering (SAXS), transmission electron microscopy and molecular dynamics simulation results. Such nanotubes possess inner and outer cross-sections equal to 6.7(2) nm and 13.4(5) nm, respectively. The mechanism of peptide self-assembly was determined by molecular dynamics simulations revealing that the peptides self-assemble like amphiphilic molecules in aqueous solution in a partially interdigitated structure. In this case, the position of the positively charged amino terminus is located at the peptide-water interface, whereas the neutral NH2-capped carboxy terminus remains buried at the hydrophobic core. In contrast, the long side chain of Lys-6 stretches out of the hydrophobic core positioning its positive charge near the cylinder surface. The peptide configuration in the nanotube wall comes from the interplay between the hydrophobic interactions of the aromatic side chains of GHRP-6 and the electrostatic repulsion of its cationic charges. On increasing the peptide concentration, the long nanotubes self-arrange in solution displaying a bi-dimensional hexagonal-like packing in the SAXS curves, with a center-to-center distance of ∼15 nm. Further, we also show that the nanostructure formed in solution is quite stable and is preserved following transfer to a solid support.

  8. Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin releasing hormone agonist depot

    PubMed Central

    de Brito, V. N; Latronico, A.; Arnhold, I.; Lo, L.; Domenice, S.; Albano, M.; Fragoso, M.; Mendonca, B.

    1999-01-01

    The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was −0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.

 PMID:10325702

  9. Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue: studies in the rat and dog.

    PubMed

    Rigamonti, Antonello E; Cella, Silvano G; Giordani, Claudio; Bonomo, Sara M; Giunta, Marialuisa; Sartorio, Alessandro; Muller, Eugenio

    2006-01-01

    Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.c., daily x 12 days) in the dog markedly reduced the canine GH (cGH) responses stimulated by EP51216, a GH secretagogue (GHS), evaluated after 3 and 5 daily rhGH injections, and that the inhibition was still present a few days after rhGH discontinuation. The aim of the present study was to evaluate in the dog the GH response to EP51216 (125 mug/kg i.v.) in a condition of enhanced androgenic function (i.e. acute injection or 15-day treatment with testosterone at the dose of 2 mg/kg i.m. on alternate days), and in the hypophysectomized rat the hypothalamic and hippocampal expression of ghrelin, the receptor of GHSs (GHS-R), GH-releasing hormone (GHRH) and somatostatin (SS) after specific hormonal replacement therapies (testosterone, 1 mg/kg/day s.c.; hydrocortisone, 500 mug/kg/day s.c.; rhGH, 400 mug/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; x11 days). In the dog experiments, under baseline conditions, a single injection of EP51216 elicited an abrupt rise of plasma cGH. Twenty-four hours from the acute bolus injection of testosterone, C(max) and AUC(0-90) of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values. Short-term treatment with testosterone markedly reduced the GHS-stimulated cGH responses evaluated during (5th bolus) and at the end (8th bolus) of testosterone treatment. Four and 8 days after testosterone withdrawal, the EP51216-stimulated cGH response was still significantly reduced when compared with that under baseline conditions. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were stable until the 5th bolus of testosterone and

  10. Regulation of feeding behavior and psychomotor activity by corticotropin-releasing hormone (CRH) in fish

    PubMed Central

    Matsuda, Kouhei

    2013-01-01

    Corticotropin-releasing hormone (CRH) is a hypothalamic neuropeptide belonging to a family of neuropeptides that includes urocortins, urotensin I, and sauvagine in vertebrates. CRH and urocortin act as anorexigenic factors for satiety regulation in fish. In a goldfish model, intracerebroventricular (ICV) administration of CRH has been shown to affect not only food intake, but also locomotor and psychomotor activities. In particular, CRH elicits anxiety-like behavior as an anxiogenic neuropeptide in goldfish, as is the case in rodents. This paper reviews current knowledge of CRH and its related peptides derived from studies of teleost fish, as representative non-mammals, focusing particularly on the role of the CRH system, and examines its significance from a comparative viewpoint. PMID:23754974

  11. The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases

    PubMed Central

    Daimon, Caitlin M.; Chirdon, Patrick; Maudsley, Stuart; Martin, Bronwen

    2013-01-01

    Thyrotropin releasing hormone (TRH) is primarily known as the central regulator of the hypothalamic-pituitary-thyroid (HPT) axis. However, TRH also exerts a variety of central nervous system effects independent from its activity in the HPT axis. With advancing age, decreases in TRH synthesis, expression, and activity have been demonstrated. Associated with this emerging evidence suggests that TRH is implicated in neurodegenerative diseases of aging, including Alzheimer’s disease and Parkinson’s disease. TRH and its synthetic analogs have been recognized as trophic factors in neurons of the diencephalon and spinal cord, and as neuroprotectants against oxidative stress, glutamate toxicity, caspase-induced cell death, DNA fragmentation, and inflammation. In this review, we will provide an overview of some of the roles of TRH, outside of the HPT axis, associated with pathological aging and neurodegeneration and we shall discuss the potential of TRH and TRH analogs for the treatment of neurodegenerative diseases. PMID:24199031

  12. Growth hormone-releasing peptide-6 inhibits cerebellar cell death in aged rats.

    PubMed

    Pañeda, Covadonga; Arroba, Ana I; Frago, Laura M; Holm, Anne Mette; Rømer, John; Argente, Jesús; Chowen, Julie A

    2003-08-26

    Insulin-like growth factor (IGF)-I is essential for cerebellar granule neuron survival and a decline in IGF-I is implicated in various age-dependent processes. Here we show that IGF-I mRNA levels are decreased in the cerebellum of old rats compared with young rats and this was associated with increased cell death and activation of caspases 3 and 9. Growth hormone-releasing peptide (GHRP)-6, a synthetic ligand for the ghrelin receptor, increased IGF-I mRNA levels, decreased cell death and inhibited caspase 3 and 9 activation in the cerebellum of aged rats. These results suggest that increasing IGF-I expression in the cerebellum can decrease cell death in aged rats via inhibition of caspase 3 and 9 activation.

  13. Pseudotumour Cerebri Presentation in a Child Under the Gonadotropin-Releasing Hormone Agonist Treatment

    PubMed Central

    Gül, Ülkü; Kaçar Bayram, Ayşe; Kendirci, Mustafa; Hatipoğlu, Nihal; Okdemir, Deniz; Gümüş, Hakan; Kurtoğlu, Selim

    2016-01-01

    Gonadotropin-releasing hormone analogues are common treatment option in central precocious puberty in childhood as well as in endometriosis, infertility, and prostate cancer in adults. Pseudotumor cerebri is a rare side effect observed in adults. We present the case of a girl with precocious puberty treated with triptorelin acetate who developed pseudotumor cerebri after the 4th dose. She had headaches, and her blood pressure was detected to be above the 99 percentile. There were no causes underlying of hypertension such as cardiac, renal, or endocrine. Neurological examination was normal except bilateral papilledema. Cranial magnetic resonance imaging was normal. Cerebrospinal fluid (CSF) opening pressure was elevated. Triptorelin therapy was ceased and acetazolamide was applied; CSF pressure returned to normal. We observed pseudotumor cerebri after precocious puberty treatment, a finding for the first time ever seen in childhood. PMID:27087351

  14. Effect of thyrotrophin releasing hormone on opiate receptors of the rat brain

    SciTech Connect

    Balashov, A.M.; Shchurin, M.R.

    1987-01-01

    It has recently been shown that the hypothalamic thyrotropin releasing hormone (TRH) has the properties of a morphine antagonist, blocking its inhibitory action on respiration and, to a lesser degree, its analgesic action. This suggests that the antagonistic effects of TRH are mediated through its interaction with opiate receptors. The aim of this paper is to study this hypothesis experimentally. Tritium-labelled enkephalins in conjunction with scintillation spectroscopy were used to assess the receptor binding behavior. The results indicate the existence of interconnections between the opiate systems and TRH. Although it is too early to reach definite conclusions on the mechanisms of this mutual influence and its physiological significance it can be tentatively suggested that TRH abolishes the pharmacological effects of morphine by modulating the functional state of opiate reception.

  15. Expression of gonadotropin-releasing hormone receptor in cerebral cortical neurons of embryos and adult rats.

    PubMed

    Quintanar, J Luis; Salinas, Eva; González, Rodolfo

    2007-01-03

    Mammalian gonadotropin-releasing hormone (GnRH) was initially isolated from hypothalamus and its receptor from anterior pituitary, although extrapituitary GnRH receptors have been reported. The aim of the present study was to investigate whether GnRH receptor and its mRNA are expressed in cerebral cortical neurons of rat embryos and adult rats using immunohistochemical and reverse transcriptase polymerase chain reaction (RT-PCR) techniques. The immunohistochemistry and RT-PCR analysis showed expression of GnRH receptor and presence of its mRNA, in both cerebral cortical neurons of rat embryos and cerebral cortical tissues of adult rats. Additional experiments showed a decrease in the receptor mRNA expression when cultured neurons of rat embryos were treated with GnRH. It is possible that the presence of GnRH receptors in cortical neurons of rat may be involved in other physiological roles such as neurohormone or neuromodulator.

  16. Gonadotropin-releasing hormone reduces the severity of experimental autoimmune encephalomyelitis, a model of multiple sclerosis.

    PubMed

    Quintanar, J Luis; Salinas, Eva; Quintanar-Stephano, Andrés

    2011-02-01

    It has been reported that the spinal cord possesses Gonadotropin-releasing hormone (GnRH) receptor and that GnRH has neurotrophic properties. Experimental autoimmune encephalomyelitis (EAE) causes neurodegeneration in spinal cord. Thus, the present study was designed to determine whether administration of GnRH reduces the severity of EAE. The clinical signs of locomotion, axonal morphometry and neurofilaments (NFs) expression were evaluated. Clinical signs remained significantly lower in EAE rats with GnRH administration compared to animals without treatment. Morphometric analysis, there were more axons of larger areas in the spinal cord of EAE+GnRH group compared to EAE animals. Western blot analysis demonstrated that GnRH administration significantly increased the expression of NFs of 68, 160 and 200kDa in the spinal cord of EAE animals. Our results indicate that GnRH administration reduces the severity of EAE in the rat.

  17. A simple pharmacokinetic model linking plasma progesterone concentrations with the hormone released from bovine intravaginal inserts.

    PubMed

    Mariano, R N; Turino, L N; Cabrera, M I; Scándolo, D E; Maciel, M G; Grau, R J A

    2010-10-01

    On the basis of pharmacokinetic modeling, this study provides some insights into predicting in vivo plasma progesterone concentrations when using bovine intravaginal inserts for systemic progesterone delivery. More significantly, this contribution is the first attempt to build a simple pharmacokinetic model that links plasma progesterone concentrations with the hormone released from bovine intravaginal inserts. After evaluating three rival pharmacokinetic models and considering some phenomena involved in the intravaginal administration of progesterone, a primary pharmacokinetic model having a good data fitting capability with only two adjustable parameters is proposed to the above mentioned task. Kinetic parameters are given for lactating Holstein dairy cows with two levels of daily milk yields; and non-pregnant, non-lactating Holstein-Friesian cattle. Model predictions indicate the occurrence of a preferential distribution of the intravaginally administered progesterone dose through a first uterine pass effect.

  18. Gonadotropin-releasing hormone is prerequisite for the constitutive expression of pituitary annexin A5.

    PubMed

    Yonezawa, Tomohiro; Watanabe, Aiko; Kurusu, Shiro; Kawaminami, Mitsumori

    2015-01-01

    Annexin A5 (ANXA5), a member of the structurally related family of annexin proteins, is expressed in pituitary gonadotropes. We previously reported that ANXA5 expression is stimulated by gonadotropin-releasing hormone (GnRH). In the present study, we investigated ANXA5 expression in the anterior pituitary gland of GnRH-deficient mutant hypogonadal (hpg) mice. RT-PCR demonstrated that luteinizing hormone β subunit (LHβ) and ANXA5 mRNA levels were both lower in the pituitary gland of hpg mice than in wild-type mice. Immunohistochemistry showed that ANXA5 expression throughout the pituitary gland was very low in hpg mice, suggesting that ANXA5 is diminished in gonadotropes and also in other cell types. Subcutaneous administration of a GnRH analogue, des-gly10 (Pro9)-GnRH ethylamide (1 μg/day for 7 days), augmented the expression of LHβ and ANXA5 in the pituitary gland in hpg mice. However, LHβ- and ANXA5-positive cells did not show exactly matched spatial distributions. These findings suggest that GnRH is necessary for constitutive ANXA5 expression in the pituitary gland, not only in gonadotropes but also in other pituitary gland cell types. A close relationship between ANXA5 and LHβ expression was confirmed. It is suggested that a significant role of ANXA5 in the physiologic secretion of LH.

  19. Effect of gonadotropin-releasing hormone on phagocytic leucocytes of rainbow trout.

    PubMed

    Yada, Takashi

    2012-03-01

    To clarify the role of gonadotropin-releasing hormone (GnRH) in the fish immune system, in vitro effect of GnRH was examined in phagocytic leucocytes of rainbow trout (Oncorhynchus mykiss). Gene expression of GnRH-receptor was detected by RT-PCR in leucocytes from head kidney. Administration of sGnRH increased proliferation and mRNA levels of a proinflammatory cytokine, tumor necrosis factor (TNF)-α, in trout leucocytes. Superoxide production in zymosan-stimulated phagocytic leucocytes was also increased by sGnRH in a dose-related manner from 0.01 to 100 nM. There was no significant effect of sGnRH on mRNA levels of growth hormone (GH) expressed in trout phagocytic leucocytes. Immunoneutralization of GH by addition of anti-salmon GH serum into the medium could not block the stimulatory effect of sGnRH on superoxide production. These results indicate that GnRH stimulates phagocytosis in fish leucocytes through a GnRH-receptor-dependent pathway, and that the effect of GnRH is not mediated through paracrine GH in leucocytes.

  20. Male effect pheromone tickles the gonadotrophin-releasing hormone pulse generator.

    PubMed

    Okamura, H; Murata, K; Sakamoto, K; Wakabayashi, Y; Ohkura, S; Takeuchi, Y; Mori, Y

    2010-07-01

    In sheep and goats, the primer pheromone produced by the male induces out-of-seasonal ovulation in anoestrous females, the so-called 'male effect.' Because the initial endocrine event following reception of the pheromone is the stimulation of pulsatile luteinising hormone (LH) secretion, the central target of the pheromone is considered to be the putative gonadotrophin-releasing hormone (GnRH) pulse generator. Using electrophysiological techniques to record multiple-unit activity (MUA) in close proximity to kisspeptin neurones in the arcuate nucleus (ARC) of Shiba goats, we found that bursts (volleys) of MUA occur at regular intervals, and repetitive bursts are invariably associated with discrete pulses of LH, suggesting that the ARC kisspeptin neurones may be the intrinsic source of the GnRH pulse generator. A brief exposure of female goats to the pheromone immediately elicited an instantaneous rise in MUA, which is followed by an MUA volley and an accompanying LH pulse, indicating that the pheromone signal is transmitted to a subset of the ARC kisspeptin neurones to activate them. Because it has been suggested that the neurokinin B and dynorphin coexpressed in those neurones play critical roles in generating rhythmic bursts, they may be involved in the intracellular pheromone actions that are responsible for inducing the GnRH pulse.

  1. Bisphenol A induces corticotropin-releasing hormone expression in the placental cells JEG-3.

    PubMed

    Huang, Hui; Tan, Wenjuan; Wang, C C; Leung, Lai K

    2012-11-01

    Bisphenol A is utilized to make polycarbonate plastics and is an environmental pollutant. Recent research has indicated that it is an endocrine disruptor and may interfere with reproduction. Placental corticotrophin-releasing hormone (CRH) is a peptide hormone which is involved in fetal development. Increased plasma CRH is associated with elevated risk of premature delivery. In the present study, we demonstrated that bisphenol A increased CRH mRNA expression in the placental JEG-3 cells at or above 25μM. Reporter gene assay also demonstrated that bisphenol A could induce CRH gene transactivity. Since cyclic AMP response element (CRE) is a major regulatory element located in CRH promoter, the sequence-specific binding activity was investigated by using electrophoretic mobility shift assay. Our data indicated that bisphenol A increased the CRE binding activity. Western analysis further illustrated that PKA could be the signal triggering the CRE binding and CRH gene transactivation. In summary, the present study demonstrated that bisphenol A could induce CRH expression in placental cells and the underlying signal transduction pathway was also described.

  2. The gonadotropin-releasing hormone system: Perspectives from reproduction to cancer (Review).

    PubMed

    Aguilar-Rojas, Arturo; Pérez-Solis, Marco Allan; Maya-Núñez, Guadalupe

    2016-03-01

    Recently, an increasing amount of evidence indicates that human gonadotropin-releasing hormone (hGnRH) and its receptor (hGnRHR) are important regulatory components not only to the reproduction process but also in the regulation of some cancer cell functions such as cell proliferation, in both hormone-dependent and -independent types of tumors. The hGnRHR is a naturally misfolded protein that is retained mostly in the endoplasmic reticulum; however, this mechanism can be overcome by treatment with several pharmacoperones, therefore, increasing the amount of receptors in the cell membrane. In addition, several reports indicate that the expression level of hGnRHR in tumor cells is even lower than in pituitary or gonadotrope cells. The signal transduction pathways activated by hGnRH in both gonadotrope and different cancer cell types are described in the present review. We also discuss how the rescue of misfolded receptors in tumor cells could be a promising strategy for cancer therapy.

  3. Hormones

    MedlinePlus

    ... affect many different processes, including Growth and development Metabolism - how your body gets energy from the foods you eat Sexual function Reproduction Mood Endocrine glands, which are special groups of cells, make hormones. The major endocrine glands are the ...

  4. Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone.

    PubMed

    Tannenbaum, G S; Gurd, W; Lapointe, M

    1998-09-01

    Pulsatile GH secretion is exquisitely sensitive to perturbations in nutritional status, but the underlying mechanisms are largely unknown. Leptin, a recently discovered adipose cell hormone, is thought to be a sensor of energy stores and to regulate body mass, appetite, and metabolism at the level of the brain. Receptors for leptin are abundantly expressed in hypothalamic nuclei known to be involved in GH regulation, suggesting that leptin may serve as an important hormonal signal to the GH neuroendocrine axis in normal animals. To test this hypothesis, we examined the effects of intracerebroventricular infusion of recombinant murine leptin, at a dose of 1.2 microg/day for 7 days, on both spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in free-moving adult male rats. Concomitant with suppressive effects on food intake, body weight, and basal plasma insulin-like growth factor I, insulin, and glucose concentrations, central infusion of leptin resulted in a 2- to 3-fold augmentation of GH pulse amplitude, 5-fold higher GH nadir levels, and a 2- to 3-fold increase in the integrated area under the 6-h GH response curve compared with those in vehicle-infused controls (P < 0.001). The intracerebroventricular infusion of leptin also produced a 3- to 4-fold increase in GHRH-induced GH release at GH trough times (P < 0.01). These studies demonstrate a potent stimulatory action of leptin on both spontaneous pulsatile GH secretion and the GH response to GHRH. The results suggest that the GH-releasing activity of leptin is mediated, at least in part, by an inhibition of hypothalamic somatostatin release. Thus, leptin may be a critical hormonal signal of nutritional status in the neuroendocrine regulation of pulsatile GH secretion.

  5. Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

    PubMed Central

    Choe, Han Kyoung; Kim, Hee-Dae; Park, Sung Ho; Lee, Han-Woong; Park, Jae-Yong; Seong, Jae Young; Lightman, Stafford L.; Son, Gi Hoon; Kim, Kyungjin

    2013-01-01

    Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) is essential for pituitary gonadotrope function. Although the importance of pulsatile GnRH secretion has been recognized for several decades, the mechanisms underlying GnRH pulse generation in hypothalamic neural networks remain elusive. Here, we demonstrate the ultradian rhythm of GnRH gene transcription in single GnRH neurons using cultured hypothalamic slices prepared from transgenic mice expressing a GnRH promoter-driven destabilized luciferase reporter. Although GnRH promoter activity in each GnRH neuron exhibited an ultradian pattern of oscillations with a period of ∼10 h, GnRH neuronal cultures exhibited partially synchronized bursts of GnRH transcriptional activity at ∼2-h intervals. Surprisingly, pulsatile administration of kisspeptin, a potent GnRH secretagogue, evoked dramatic synchronous activation of GnRH gene transcription with robust stimulation of pulsatile GnRH secretion. We also addressed the issue of hierarchical interaction between the circadian and ultradian rhythms by using Bmal1-deficient mice with defective circadian clocks. The circadian molecular oscillator barely affected basal ultradian oscillation of GnRH transcription but was heavily involved in kisspeptin-evoked responses of GnRH neurons. In conclusion, we have clearly shown synchronous bursts of GnRH gene transcription in the hypothalamic GnRH neuronal population in association with episodic neurohormone secretion, thereby providing insight into GnRH pulse generation. PMID:23509283

  6. Gonadotropin-releasing hormone in mulberry cells of Saccoglossus and Ptychodera (Hemichordata: Enteropneusta).

    PubMed

    Cameron, C B; Mackie, G O; Powell, J F; Lescheid, D W; Sherwood, N M

    1999-04-01

    Mulberry cells are epidermal gland cells bearing a long basal process resembling a neurite and are tentatively regarded as neurosecretory cells. They occur scattered through the ectoderm of the proboscis, collar, and anterior trunk regions of the acorn worms Saccoglossus, usually in association with concentrations of nervous tissue. They contain secretion granules that appear from electron micrographs to be released to the exterior. The granules are immunoreactive with antisera raised against mammalian and salmon gonadotropin-releasing hormone (GnRH). Similar results were obtained with another enteropneust, Ptychodera bahamensis, using antisera raised against tunicate-1 and mammalian GnRH. Mulberry cells were not found in either Cephalodiscus or Rhabdopleura (Hemichordata: Pterobranchia). Extracts of tissues from 4200 Saccoglossus contain an area of immunoreactive GnRH that is detected by an antiserum raised against lamprey GnRH when characterized by high-performance liquid chromatography and radioimmunoassay. This is the first report of the occurrence of GnRH in hemichordates, probably the most primitive group clearly belonging to the chordate lineage. The physiological function of GnRH in enteropneusts is unknown, but an exocrine function appears more likely than an endocrine or neurotransmitter role.

  7. Corticotropin-releasing hormone in the lateral parabrachial nucleus inhibits sodium appetite in rats.

    PubMed

    De Castro e Silva, Emilio; Fregoneze, Josmara B; Johnson, Alan Kim

    2006-04-01

    The present study investigated the role of corticotropin-releasing hormone (CRH) in the lateral parabrachial nucleus (LPBN) in the behavioral control of body fluid homeostasis by determining the effect of bilateral injections of the CRH receptor antagonist, alpha-helical corticotropin-releasing factor (CRF)(9-41), and the CRH receptor agonist, CRH, on sodium chloride (salt appetite) and water (thirst) intake. Groups of adult, male Sprague-Dawley rats had stainless-steel cannulas implanted bilaterally into the LPBN and were sodium depleted or water deprived. Bilateral injections of alpha-helical CRF(9-41) into the LPBN significantly potentiated water and salt intake in the sodium-depleted rats when access to fluids was restored. Bilateral injections of alpha-helical CRF(9-41) into the LPBN (1.0 microg) also increased sodium appetite in water-deprived rats. Conversely, in sodium-depleted animals, bilateral injections of CRH inhibited sodium chloride intake. These results suggest that there is an endogenous CRH inhibitory mechanism operating in the LPBN to modulate the intake of sodium (salt appetite). This mechanism may contribute to the behavioral control of restoration of body fluid homeostasis in sodium-deficient states.

  8. GABA Regulates Corticotropin Releasing Hormone Levels in the Paraventricular Nucleus of the Hypothalamus in Newborn Mice

    PubMed Central

    Stratton, Matthew S.; Searcy, Brian T.; Tobet, Stuart A.

    2011-01-01

    The paraventricular nucleus of the hypothalamus (PVN) is a major regulator of stress responses via release of Corticotropin Releasing Hormone (CRH) to the pituitary gland. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is characteristic of individuals with Major Depressive Disorder (MDD). Postmortem data from individuals diagnosed with MDD show increased levels of CRH mRNA and CRH immunoreactive neurons in the PVN. In the current study, an immunohistochemical (IHC) analysis revealed increased levels of CRH in the PVN of newborn mice lacking functional GABAB receptors. There was no difference in the total number of CRH immunoreactive cells. By contrast, there was a significant increase in the amount of CRH immunoreactivity per cell. Interestingly, this increase in CRH levels in the GABAB receptor R1 subunit knockout was limited to the rostral PVN. While GABAergic regulation of the HPA axis has been previously reported in adult animals, this study provides evidence of region-specific GABA modulation of immunoreactive CRH in newborns. PMID:21236282

  9. Direct effects of catecholamines, thyrotropin-releasing hormone, and somatostatin on growth hormone and prolactin secretion from adenomatous and nonadenomatous human pituitary cells in culture.

    PubMed Central

    Ishibashi, M; Yamaji, T

    1984-01-01

    To determine the mechanism and the site of action of catecholamines as well as hormones including thyrotropin-releasing hormone (TRH)1 and somatostatin on pituitary hormone release in patients with acromegaly and in normal subjects, the effects of these substances on growth hormone (GH) and prolactin (PRL) secretion from adenomatous and nonadenomatous human pituitary cells in culture were examined. When dopamine (0.01-0.1 microM) or bromocriptine (0.01-0.1 microM) was added to the culture media, a significant inhibition of GH and PRL secretion from adenoma cells from acromegalic patients was observed. This inhibition was blocked by D2 receptor blockade with metoclopramide or sulpiride, but not by D1 receptor blockade. Similarly, dopamine suppressed GH and PRL release by nonadenomatous pituitary cells in a dose-dependent manner, which was again blocked by D2 receptor blockade. The minimum effective concentration of dopamine required for a significant inhibition of PRL secretion (0.01 microM) was lower than that for GH release (0.1 microM). Norepinephrine, likewise, caused a suppression of PRL secretion from adenomatous and nonadenomatous pituitary cells. This effect was blocked by sulpiride, phentolamine, however, was ineffective. When TRH was added to the media, both GH and PRL secretion were enhanced in adenoma cells, while only the stimulation of PRL release was observed in nonadenomatous pituitary cells. Coincubation of TRH and dopamine resulted in variable effects on GH and PRL secretion. Somatostatin consistently lowered GH and PRL secretion in both adenomatous and nonadenomatous pituitary cells and completely blocked the TRH-induced stimulation of GH and PRL secretion from adenoma cells. Opioid peptides (1 microM) failed to affect hormone release. These results suggest that no qualitative difference in GH and PRL responses to dopaminergic agonists or to somatostatin exists between adenoma cells of acromegalic patients and normal pituitary cells, and that the

  10. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I.

    PubMed

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-21

    The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I.

  11. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I

    PubMed Central

    Sirotkin, Alexander V.; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-01

    ABSTRACT The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I. PMID:26794607

  12. Effect of gonadotropin-releasing hormone II receptor (GnRHR-II) knockdown on testosterone secretion in the boar

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Unlike the classical gonadotropin-releasing hormone (GnRH-I), the second mammalian GnRH isoform (GnRH-II; His5, Trp7, Tyr8) is a poor stimulator of gonadotropin secretion. In addition, GnRH-II is ubiquitously expressed, with transcript levels highest in tissues outside of the brain. A receptor speci...

  13. Gonadotropin-releasing hormone/human chorionic gonadotropin beta based recombinant antibodies and vaccines.

    PubMed

    Talwar, G P; Vyas, Hemant K; Purswani, Shilpi; Gupta, Jagdish C

    2009-12-01

    Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) are unique targets for the control of fertility. Immunological approaches to neutralizing these hormones have additional utility in cancer treatment. Vaccines have been developed against both GnRH and hCG and these have undergone Phase I/II clinical trials documenting their safety, reversibility and efficacy. The heterospecies dimer hCG vaccine prevented pregnancy in women of proven fertility without impairment of ovulation or derangement of menstrual regularity and bleeding profiles. The protective threshold of antibody titers to achieve efficacy was determined in these first-ever trials. Recently, a recombinant vaccine against the beta subunit of hCG linked to the B subunit of heat labile enterotoxin has been made and expressed as a glycosylated conjugate in Pichia pastoris. Experiments indicate its ability to generate antibodies above the protective threshold in all immunized Balb/c mice. Ectopic expression of hCG/hCGbeta is observed in many advanced stage cancers of various origins. A chimeric high affinity and specific recombinant antibody against hCGbeta linked to curcumin kills hCGbeta expressing T lymphoblastic leukemia cells without any deleterious effect. Several synthetic and recombinant vaccines have been developed against GnRH. These reduce serum testosterone to castration levels causing atrophy of the prostate. Three Phase I/II clinical trials conducted in India and Austria have shown that these vaccines elicit non-surgical reduction of testosterone, a fall in prostate specific antigen and clinical improvement of prostate carcinoma patients. A multimer recombinant vaccine against GnRH has high efficacy for sterilization of pigs and other animals.

  14. Inhibition of maternal behaviour by central infusion of corticotrophin-releasing hormone in marmoset monkeys.

    PubMed

    Saltzman, W; Boettcher, C A; Post, J L; Abbott, D H

    2011-11-01

    Stress can inhibit maternal behaviour and increase rates of child abuse in humans and other animals; however, the neuroendocrine mechanisms are not known. To determine whether corticotrophin-releasing hormone (CRH) plays a role in stress-induced disruption of maternal behaviour in primates, we characterised the effects of acute i.c.v. infusions of CRH on maternal and abusive behaviour in common marmoset monkeys (Callithrix jacchus). Nulliparous females were implanted with indwelling i.c.v. guide cannulae before conception. Between 18 and 58 days after the birth of her first infants, each female underwent a series of i.c.v. infusions of human CRH (0, 2, 8 and 25 μg) in 8 μl of artificial cerebrospinal fluid. In the 70 min after infusion, marmosets were tested with one of their infants, first in their home cage and, subsequently, in an unfamiliar cage in which the infant was confined in a transparent box on the cage floor. In the home cage, the highest dose of CRH significantly reduced the amount of time that mothers spent carrying their infants, as compared to vehicle alone, although it did not reliably affect aggression toward the infant or other behaviours. In the confined-infant test, the highest dose of CRH significantly reduced the amount of time that mothers spent on the cage floor, increased mothers' vocalisation rates, and tended to reduce their activity levels and time spent in proximity to their infant. Twenty-five micrograms of CRH also elicited significant elevations in plasma adrenocorticotrophic hormone and cortisol concentrations compared to vehicle. These results indicate that i.c.v.-administered CRH reduces maternal behaviour in marmoset mothers, in both familiar and unfamiliar environments, but does not increase infant abuse.

  15. Controlled release of the pineal hormone melatonin from hydroxypropylmethylcellulose/sodium alginate matrices in aqueous media containing dioctyl sulfosuccinate.

    PubMed

    Vlachou, Marilena; Tsiakoulia, Athanasia; Eikosipentaki, Aphrodite

    2007-06-01

    An investigation of the controlled release profile of mono-layered formulations of the hormone melatonin in modified aqueous media is described. The tablets used were comprised of hydroxypropylmethylcellulose (HPMC K15M) and sodium alginate with melatonin (fully soluble in the dioctyl sulfosuccinate (DSS) containing simulated intestinal solution). Three different sets of tablets (diameters 7.5, 10.0 and 13.0 mm) were tested with respect to the influence of their sizes on the hormone's release; the general trend observed was that tablets with larger surface area values had lower % release. A decrease in the value of W(o), obtained from the ratio [H(2)O]/[DSS], results to the predominance of DSS conformers in the aqueous media, which are less likely to solubilize melatonin effectively.

  16. A Gonadotropin-Releasing Hormone Agonist Model Demonstrates That Nocturnal Hot Flashes Interrupt Objective Sleep

    PubMed Central

    Joffe, Hadine; Crawford, Sybil; Economou, Nicole; Kim, Semmie; Regan, Susan; Hall, Janet E.; White, David

    2013-01-01

    Objectives: Sleep interruption is often reported by women with hot flashes and night sweats (or vasomotor symptoms, VMS). Although women report that VMS awaken them, polysomnography (PSG) studies have not consistently supported this contention. Design: We mimicked menopause using a gonadotropin-releasing hormone agonist (GnRHa) to investigate whether VMS increase awakenings and wake after sleep onset (WASO). VMS, serum estradiol, and at-home PSGs (two pretreatment, two posttreatment) were measured before and after 4 weeks on GnRHa. Regression models were used to determine the effect of increasing VMS frequency on awakenings and WASO, as measured objectively and subjectively. Participants: Twenty-nine healthy women (mean 27.3 y). Setting: Academic medical center. Interventions: Depot GnRHa (leuprolide 3.75-mg). Results: Serum estradiol was rapidly and uniformly suppressed on GnRHa. Persistent VMS were reported by 69% of women. The number of nighttime VMS correlated directly with the degree of sleep disturbance. Each additional reported nighttime VMS was associated with a 62% increase from baseline in PSG-measured WASO (P = 0.007), a 3% increase in awakenings (P = 0.05), and 6% increase in %N1 sleep (P = 0.02). Nighttime VMS were also associated with increased perceived WASO (312%; P = 0.02), awakenings (16%; P = 0.007), Insomnia Severity Index (P = 0.03), and Pittsburgh Sleep Quality Index (P = 0.03) scores, and decreased perceived sleep efficiency (P = 0.01). Objectively recorded nighttime VMS correlated with PSG-measured WASO (rs = 0.45, P = 0.02). Conclusions: This menopause model demonstrates that nighttime vasomotor symptoms correlate with increased sleep fragmentation. These findings are consistent with a specific contribution of vasomotor symptoms to polysomnography-measured sleep interruption suggesting that nighttime vasomotor symptoms interrupt sleep in the setting of menopause. Citation: Joffe H; Crawford S; Economou N; Kim S; Regan S; Hall JE; White D. A

  17. Effects of Blocking GABA Degradation on Corticotropin-Releasing Hormone Gene Expression in Selected Brain Regions

    PubMed Central

    Tran, Viet; Hatalski, Carolyn G.; Yan, Xiao-Xin; Baram, Tallie Z.

    2011-01-01

    Summary Purpose The γ-aminobutyric acid (GABA) degradation blocker γ-vinyl-GABA (VGB) is used clinically to treat seizures in both adult and immature individuals. The mechanism by which VGB controls developmental seizures is not fully understood. Specifically, whether the anticonvulsant properties of VGB arise only from its elevation of brain GABA levels and the resulting activation of GABA receptors, or also from associated mechanisms, remains unresolved. Corticotropin-releasing hormone (CRH), a neuropeptide present in many brain regions involved in developmental seizures, is a known convulsant in the immature brain and has been implicated in some developmental seizures. In certain brain regions, it has been suggested that CRH synthesis and release may be regulated by GABA. Therefore we tested the hypothesis that VGB decreases CRH gene expression in the immature rat brain, consistent with the notion that VGB may decrease seizures also by reducing the levels of the convulsant molecule, CRH. Methods VGB was administered to immature, 9-day-old rats in clinically relevant doses, whereas littermate controls received vehicle. Results In situ hybridization histochemistry demonstrated a downregulation of CRH mRNA levels in the hypothalamic paraventricular nucleus but not in other limbic regions of VGB-treated pups compared with controls. In addition, VGB-treated pups had increased CRH peptide levels in the anterior hypothalamus, as shown by radioimmunoassay. Conclusions These findings are consistent with a reduction of both CRH gene expression and secretion in the hypothalamus, but do not support an indirect anticonvulsant mechanism of VGB via downregulation of CRH levels in limbic structures. However, the data support a region-specific regulation of CRH gene expression by GABA. PMID:10487181

  18. Mollusc gonadotropin-releasing hormone directly regulates gonadal functions: a primitive endocrine system controlling reproduction.

    PubMed

    Treen, Nicholas; Itoh, Naoki; Miura, Hanae; Kikuchi, Ippei; Ueda, Takenori; Takahashi, Keisuke G; Ubuka, Takayoshi; Yamamoto, Kazutoshi; Sharp, Peter J; Tsutsui, Kazuyoshi; Osada, Makoto

    2012-04-01

    Gonadotropin-releasing hormone (GnRH) is central to the control of vertebrate reproductive cycles and since GnRH orthologs are also present in invertebrates, it is likely that the common ancestor of bilateral animals possessed a GnRH-like peptide. In order to understand the evolutionary and comparative biology of GnRH peptides we cloned the cDNA transcripts of prepro GnRH-like peptides from two species of bivalve molluscs, the Yesso scallop Patinopecten yessoensis and the Pacific oyster Crassostrea gigas. We compared their deduced uncleaved and mature amino acid sequences with those from other invertebrates and vertebrates, and determined their sites of expression and biological activity. The two molluscan GnRH sequences increased the number of known protostome GnRHs to six different forms, indicating the current classification of protostome GnRHs requires further revision. In both molluscs, RT-PCR analysis showed that the genes were highly expressed in nervous tissue with lower levels present in peripheral tissues including the gonads, while immunocytochemistry, using anti-octopus GnRH-like peptide, demonstrated the presence of GnRH-like peptide in neural tissue. Putative scallop GnRH-like peptide stimulated spermatogonial cell division in cultured scallop testis, but the scallop GnRH-like peptide did not stimulate LH release from cultured quail pituitary cells. This is the first report of the cloning of bivalve GnRH-like peptide genes and of molluscan GnRH-like peptides that are biologically active in molluscs, but not in a vertebrate.

  19. Identification of the growth-hormone-releasing peptide-2 (GHRP-2) in a nutritional supplement.

    PubMed

    Thomas, Andreas; Kohler, Maxie; Mester, Joachim; Geyer, Hans; Schänzer, Wilhelm; Petrou, Michael; Thevis, Mario

    2010-03-01

    Black market products of a pharmaceutical nature and nutritional supplements have received substantial and increasing attention because of potential performance enhancement in elite and non-professional sports. In addition, improved general health is claimed for non-competing individuals. The risks and foreseeable dangers of the uncontrolled use of highly potent and non-approved pharmaceutical compounds in healthy individuals are of considerable concern. In the present case report, the emerging drug candidate GHRP-2 with verified growth-hormone-releasing properties was identified and quantified in tablets offered as an over-the-counter nutritional supplement. The impact of this orally active peptide on the hGH/IGF-axis has been established for several years and its illicit use in elite sports has been assumed. As a releasing factor for hGH, GHRP-2 belongs to the list of substances prohibited by the World Anti-Doping Agency (WADA). Unfortunately, to date there is no routinely performed assay for the determination of these peptides potentially occurring in biological fluids of competing athletes, but the present data will facilitate the implementation by providing principle analytical information on liquid chromatographic and mass spectrometric behaviour. Qualitative identification of the target analyte after extraction from the tablet matrix was performed by high resolution/high accuracy mass spectrometry after liquid chromatographic separation under consideration of the accurate masses and the ratios of the protonated molecules and their fragment ions derived from their collisionally induced dissociation. Quantitative results were obtained by means of liquid chromatography coupled to a triple quadrupole mass spectrometer and linear regression using an external calibration curve (with GHRP-2 reference compound) adjusted via internal standard (Hexarelin). Hereby, the content of GHRP-2 was determined with approximately 50 µg per tablet.

  20. Sulfated gastrin stimulates ghrelin and growth hormone release but inhibits insulin secretion in cattle.

    PubMed

    Zhao, Hongqiong; Yannaing, Swe; Thanthan, Sint; Kuwayama, Hideto

    2011-11-01

    This study was designed to determine the effects of gastrin on the circulating levels of ghrelin, growth hormone (GH), insulin, glucagon and glucose in ruminants. Two experiments were done in eight Holstein steers. Animals were randomly assigned to receive intravenous bolus injections: (1) 0.1% bovine serum albumin in saline as vehicle, 0.8, 4.0 and 20.0 μg/kg body weight (BW) of bovine sulfated gastrin-34; (2) vehicle, 0.53 μg/kg BW of bovine sulfated gastrin-17 alone or combined with 20.0 μg/kg BW of [D-Lys(3)]-GHRP-6, the selective antagonist of GHS-R1a. Blood samples were collected from -10 to 150 min relative to injection time. Concentrations of acyl and total ghrelin in response to gastrin-34 injection were significantly increased in a dose-dependent manner. Concentrations of GH were also markedly elevated by gastrin-34 injection; however, the effect of 20.0 μg/kg was weaker than that of 4.0 μg/kg. The three doses of gastrin-34 equally decreased insulin levels within 15 min and maintained the level until the time of last sampling. Gastrin-34 had no effect (P > 0.05) on the levels of glucagon and glucose. Levels of acyl ghrelin increased after administration of gastrin-17 alone or combined with [D-Lys(3)]-GHRP-6; however, [D-Lys(3)]-GHRP-6 did not block the elevation of GH by gastrin-17. The present results indicate that sulfated gastrin stimulates both ghrelin and GH release, but the GHS-R1a may not contribute to the release of GH by gastrin. Moreover, sulfated gastrin seems to indirectly maintain the homeostasis of blood glucose through the down-regulation of insulin in ruminants.

  1. Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

    PubMed Central

    Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A

    2016-01-01

    A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593

  2. Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons.

    PubMed

    Campbell, Rebecca E; Gaidamaka, Galina; Han, Seong-Kyu; Herbison, Allan E

    2009-06-30

    The pulsatile release of gonadotropin-releasing hormone (GnRH) is critical for mammalian fertility, but the mechanisms underlying the synchronization of GnRH neurons are unknown. In the present study, the full extent of the GnRH neuron dendritic tree was visualized by patching and filling individual GnRH neurons with biocytin in acute brain slices from adult GnRH-green fluorescent protein (GFP) transgenic mice. Confocal analysis of 42 filled GnRH neurons from male and female adult mice revealed that the dendrites of the great majority of GnRH neurons (86%) formed multiple close appositions with dendrites of other GnRH neurons. Two types of interactions were encountered; the predominant interaction was one of vertical dendritic bundling where dendrites were found to wrap around each other in the same axis. The other interaction was one in which a GnRH neuron dendrite intercepted other GnRH neuron dendrites in a perpendicular fashion. Electron microscopy using pre-embedded, silver-enhanced immunogold labeling for both GnRH and GFP peptides in GnRH-GFP transgenic mice, confirmed that GnRH neuron dendrites were often immediately juxtaposed. Membrane specializations, including punctae and zonula adherens, were found connecting adjacent dendritic elements of GnRH neurons. Remarkably, individual afferent axon terminals were found to synapse with multiple GnRH neuron dendrites at sites of bundling. Together, these data demonstrate that GnRH neurons are not isolated from one another but, rather, interconnected via their long dendritic extensions. The observation of shared synaptic input to bundled GnRH neuron dendrites suggests a mechanism of GnRH neuron synchronization.

  3. Control of thyrotropin glycosylation in normal rat pituitary cells in culture: effect of thyrotropin-releasing hormone

    SciTech Connect

    Ponsin, G.; Mornex, R.

    1983-08-01

    Regulation of glycosylation of TSH was studied in primary cultures of normal rat pituitary cells. (3H)Glucosamine or (3H)proline incorporation into immunoprecipitable TSH and trichloroacetic acid-precipitable proteins was measured after incubation periods ranging from 4-72 h. TSH release was assessed by RIA of TSH in the medium. TRH (30 nM) specifically increased the glycosylation of TSH despite the fact that it did not stimulate (3H)proline incorporation into the hormone even after 72 h of continuous labeling. The TRH-stimulated (3H)glucosamine-labeled TSH was completely recovered in the incubation medium. Effective concentrations of TRH were in the same range as those necessary for stimulation of TSH release (10(-10) - 10(-6) M). Somatostatin (50 nM) and T3 (10 microM) antagonized TRH effects on both TSH release and glycosylation. Stages of TSH glycosylation were discriminated by the addition to the culture medium of tunicamycin (10 micrograms/ml) or monensin (25 microM), which are known to inhibit core and terminal glycosylation of proteins, respectively. Medium (3H)glucosamine-labeled TSH was fully glycosylated, whereas a large part of the intracellular hormone was only core glycosylated. This suggests that terminal glycosylation of TSH could be related to hormone secretion. TRH stimulated essentially only terminal glycosylation of TSH. No alteration of core glycosylation of the hormone was observed after TRH treatment. The stimulating effect of TRH on terminal glycosylation of TSH is probably related to its ability to stimulate hormone release.

  4. Growth hormone releasing factor (GRF) increases free arachidonate levels in the pituitary: a role for lipoxygenase products

    SciTech Connect

    Canonico, P.L.; Speciale, C.; Sortino, M.A.; Cronin, M.J.; MacLeod, R.M.; Scapagnini, U.

    1986-01-20

    GRF, a specific stimulator of GH release, increased in a concentration- and time-dependent manner pituitary (/sup 3/H)-arachidonate levels in vitro. This effect was antagonized by 100 nM somatostatin. Exogenous arachidonate also stimulated GH release in vitro. Quinacrine, a phospholipase A2 inhibitor, reduced both basal and GRF-stimulated free arachidonate levels as well as GH release. The cyclooxygenase inhibitor indomethacin was ineffective, while BW755c, which also inhibits the lipoxygenase pathway, produced a further increase in the levels of the fatty acid stimulated by GRF and potently reduced GH release. These results provide additional evidence for the involvement of arachidonate metabolism in the hormone-releasing effect of GRF at the somatotroph. 14 references, 1 figure, 2 tables.

  5. Lead (Pb) alters the norepinephrine-induced secretion of luteinizing hormone releasing hormone from the median eminence of adult male rats in vitro

    SciTech Connect

    Bratton, G.R.; Hiney, J.K.; Dees, W.L. )

    1994-01-01

    In the present study, the authors evaluated the in vitro effects of lead (Pb) on basal and stimulated luteinizing hormone releasing hormone (LHRH) and Prostaglandin E[sub 2] (PGE[sub 2]) secretion. Median eminences (ME) were removed from brains of adult male rats and preincubated for 15 minutes in Krebs-Ringer bicarbonate glucose buffer in an atmosphere of 95% O[sub 2]-5% CO[sub 2]. These media were discarded and all MEs were subjected to one of the following experiments. In Experiment 1, all MEs were incubated for 30 minutes in medium only. These media were collected and replaced with medium only (controls) or with medium containing Pb doses ranging from 5 to 20 [mu]M. After this 60-minute incubation, media were collected, then replaced with new medium containing 60 [mu]M norepinephrine (NE), or NE plus each dose of Pb, then incubated for a final 30-minute period. Experiment 2 was conducted as above, except PGE[sub 2] (2.8 [mu]M) replaced the NE. In both experiments, the amounts of LHRH released was measured by RIA. In experiment 3, NE was again used for the challenge; however, this time, the amount of PGE[sub 2] released was measured by RIA. Results indicate that Pb did not alter basal LHRH release, but compared with controls, significantly blocked NE-induced LHRH release in a dose-related manner. Conversely, Pb had no effect on the PGE[sub 2]-induced release of LHRH. Additionally, Pb did not alter basal PGE[sub 2] release; however, it significantly blocked the NE-induced release of PGE[sub 2]. Since NE-induced LHRH release is mediated by PGE[sub 2], these results support the hypothesis that Pb is capable of altering the hypothalamus and suggest that this effect is due, at least in part, to the diminished PGE[sub 2] synthesis/release within the ME, resulting in diminished LHRH secretion.

  6. Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice.

    PubMed

    Xie, T Y; Ngo, S T; Veldhuis, J D; Jeffery, P L; Chopin, L K; Tschöp, M; Waters, M J; Tolle, V; Epelbaum, J; Chen, C; Steyn, F J

    2015-12-01

    Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of

  7. Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons

    PubMed Central

    Koemeter-Cox, Andrew I.; Sherwood, Thomas W.; Green, Jill A.; Steiner, Robert A.; Berbari, Nicolas F.; Yoder, Bradley K.; Kauffman, Alexander S.; Monsma, Paula C.; Brown, Anthony; Askwith, Candice C.; Mykytyn, Kirk

    2014-01-01

    Most central neurons in the mammalian brain possess an appendage called a primary cilium that projects from the soma into the extracellular space. The importance of these organelles is highlighted by the fact that primary cilia dysfunction is associated with numerous neuropathologies, including hyperphagia-induced obesity, hypogonadism, and learning and memory deficits. Neuronal cilia are enriched for signaling molecules, including certain G protein-coupled receptors (GPCRs), suggesting that neuronal cilia sense and respond to neuromodulators in the extracellular space. However, the impact of cilia on signaling to central neurons has never been demonstrated. Here, we show that the kisspeptin receptor (Kiss1r), a GPCR that is activated by kisspeptin to regulate the onset of puberty and adult reproductive function, is enriched in cilia projecting from mouse gonadotropin-releasing hormone (GnRH) neurons. Interestingly, GnRH neurons in adult animals are multiciliated and the percentage of GnRH neurons possessing multiple Kiss1r-positive cilia increases during postnatal development in a progression that correlates with sexual maturation. Remarkably, disruption of cilia selectively on GnRH neurons leads to a significant reduction in kisspeptin-mediated GnRH neuronal activity. To our knowledge, this result is the first demonstration of cilia disruption affecting central neuronal activity and highlights the importance of cilia for proper GPCR signaling. PMID:24982149

  8. Heat produces uteroplacental circulatory disturbance in pregnant rats through action of corticotropin releasing hormone (CRH).

    PubMed

    Nakamura, H; Nagase, H; Ogino, K; Hatta, K; Matsuzaki, I

    2000-01-01

    There is some evidence showing an existence of corticotropin releasing hormone (CRH) and opioid peptides, including beta-endorphin (betaEP), in human placenta, whereas physiological roles of the placental peptides in response to stress remain to be elucidated. To clarify the involvement of CRH and opioid system in the uteroplacental circulation in the pregnant rats exposed to heat, we examined the effects of heat and intravenous administration of CRH receptor antagonist alpha-helical CRH (9-41) on the uteroplacental blood flow, as well as blood CRH, and blood and placental betaEP in pregnant rats. Heat did not change uterine blood flow in virgin rats, but reduced uteroplacental blood flow in pregnant rats. The reduced uteroplacental blood flow induced by heat in pregnant rats was reversed by the administration of alpha-helical CRH. Independent of the status of pregnancy, heat increased blood CRH, which was not reversed by alpha-helical CRH. Although heat did not change placental betaEP, alpha-helical CRH reduced blood and placenta betaEP in pregnant rats. These results suggest that the uteroplacental circulatory disturbance caused by heat is mediated by CRH, possibly through the involvement of CRH receptor in rat placenta. The placental opioid system seems unlikely to be involved in the mediation of uteroplacental circulation.

  9. Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells.

    PubMed

    Rosati, Fabiana; Sturli, Niccolò; Cungi, Maria Chiara; Morello, Matteo; Villanelli, Fabio; Bartolucci, Gianluca; Finocchi, Claudia; Peri, Alessandro; Serio, Mario; Danza, Giovanna

    2011-04-01

    Neurosteroids are involved in Central Nervous System development, brain functionality and neuroprotection but little is known about regulators of their biosynthesis. Recently gonadotropins, Gonadotropin-releasing Hormone (GnRH) and their receptors have been localized in different brain regions, such as hippocampus and cortex. Using human neuronal-like cells we found that GnRH up-regulates the expression of key genes of cholesterol and steroid synthesis when used in a narrow range around 1.0 nM. The expression of Hydroxysterol D24-reductase (seladin-1/DHCR24), that catalyzes the last step of cholesterol biosynthesis, is increased by 50% after 90 min of incubation with GnRH. StAR protein and P450 side chain cleavage (P450scc) are up-regulated by 3.3 times after 90 min and by 3.5 times after 3 h, respectively. GnRH action is mediated by LH and 1.0 nM GnRH enhances the expression of LHβ as well. A two fold increase of cell cholesterol is induced after 90 min of GnRH incubation and 17β-estradiol (E2) production is increased after 24, 48 and 72 h. These data indicate for the first time that GnRH regulates both cholesterol and steroid biosynthesis in human neuronal-like cells and suggest a new physiological role for GnRH in the brain.

  10. Thyrotropin-Releasing Hormone (TRH) Promotes Wound Re-Epithelialisation in Frog and Human Skin

    PubMed Central

    Zhang, Guo-You; Emelianov, Vladimir; Paredes, Roberto; Debus, Sebastian; Augustin, Matthias; Funk, Wolfgang; Amaya, Enrique; Kloepper, Jennifer E.; Hardman, Matthew J.; Paus, Ralf

    2013-01-01

    There remains a critical need for new therapeutics that promote wound healing in patients suffering from chronic skin wounds. This is, in part, due to a shortage of simple, physiologically and clinically relevant test systems for investigating candidate agents. The skin of amphibians possesses a remarkable regenerative capacity, which remains insufficiently explored for clinical purposes. Combining comparative biology with a translational medicine approach, we report the development and application of a simple ex vivo frog (Xenopus tropicalis) skin organ culture system that permits exploration of the effects of amphibian skin-derived agents on re-epithelialisation in both frog and human skin. Using this amphibian model, we identify thyrotropin-releasing hormone (TRH) as a novel stimulant of epidermal regeneration. Moving to a complementary human ex vivo wounded skin assay, we demonstrate that the effects of TRH are conserved across the amphibian-mammalian divide: TRH stimulates wound closure and formation of neo-epidermis in organ-cultured human skin, accompanied by increased keratinocyte proliferation and wound healing-associated differentiation (cytokeratin 6 expression). Thus, TRH represents a novel, clinically relevant neuroendocrine wound repair promoter that deserves further exploration. These complementary frog and human skin ex vivo assays encourage a comparative biology approach in future wound healing research so as to facilitate the rapid identification and preclinical testing of novel, evolutionarily conserved, and clinically relevant wound healing promoters. PMID:24023889

  11. The role of limited proteolysis of thyrotropin-releasing hormone in thermoregulation. Final report

    SciTech Connect

    Prasad, C.

    1982-01-01

    Cyclo (His-Pro) is a biologiclly active cyclic dipeptide derived from thyrotropin-releasing hormone by its limited proteolysis. We have developed a specific radioimmunoassay for this cyclic peptide and shown its presence throughout rat and monkey brains. The normal rat brain concentration of cyclo (His-Pro) ranged from 35-61 pmols/brain. The elution profiles of rat brain cyclo (His-Pro)-like immunoreactivity and synthetic radioactive cyclo (His-Pro) following gel filtration, ion-exchange chromatography and high pressure liquid chromatography were similar. An analysis of the regional distribution of cyclo (His-Pro) and TRH in rat and monkey brains exhibited no apparent precursor-product relationship. Studies on the neuroanatomic sites for the thermoregulatory effects of cyclo (His-Pro) suggested that the neural loci responsible for cyclo (His-Pro)-induced hypothermia resides within POA/AHA. The endogenous levels of brain cyclo (His-Pro) were elevated when rats were made either hypothyroid by surgical thyroidectomy or forced to drink alcohol for six weeks. These studies demonstrate that cyclo (His-Pro) is present throughout the central nervous system in physiologically relevant concentrations which can be modified by appropriate physiological and pharamacological manipulations. These data in conjunction with earlier reports of multiple biological activities of exogenous cyclo (His-Pro), suggest that endogenous cyclo (His-Pro) is a biological active peptide and it may play a neurotransmitter or neuromodulator role in the central nervous system.

  12. Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation

    PubMed Central

    Qin, Yong Jie; Chan, Sun On; Chong, Kelvin Kam Lung; Li, Benjamin Fuk Loi; Ng, Tsz Kin; Yip, Yolanda Wong Ying; Chen, Haoyu; Zhang, Mingzhi; Block, Norman L.; Cheung, Herman S.; Schally, Andrew V.; Pang, Chi Pui

    2014-01-01

    Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone–growth hormone–insulin-like growth factor-1 (GHRH–GH–IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific transcription factor-1, GHRH-R splice variant 1, GHRH, and GH following LPS insult. Elevation of GHRH-R and GH receptor was localized on the epithelium of the iris and ciliary body, and GHRH-R was confined to the infiltrating macrophages and leukocytes in aqueous humor but not to those in stroma. Treatment with GHRH-R antagonist decreased LPS-stimulated surges of GH and IGF1 in aqueous humor and alleviated inflammation by reducing the infiltration of macrophages and leukocytes and the production of TNF-α, IL-1β, and monocyte chemotactic protein-1. Our results indicate that inflammation in the iris and ciliary body involves the activation of GHRH signaling, which affects the recruitment of immune cells and the production of proinflammatory mediators that contribute to EIU pathogenesis. Moreover, the results suggest that GHRH-R antagonists are potential therapeutic agents for the treatment of acute ocular inflammation. PMID:25489106

  13. Immunoneutralization of gonadotropin-releasing hormone type-III suppresses male reproductive behavior of cichlids.

    PubMed

    Ogawa, Satoshi; Akiyama, Go; Kato, Shumei; Soga, Tomoko; Sakuma, Yasuo; Parhar, Ishwar S

    2006-08-07

    To investigate the roles of gonadotropin-releasing hormone (GnRH) types in reproductive behaviors, antisera against GnRH1, GnRH2 and GnRH3 were stereotaxically administered into the intracerebroventricular region to neutralize the three native GnRH types in the brain of male tilapia Oreochromis niloticus. Reproductive behaviors (nest-building and aggressive behaviors), and morphological changes of the three GnRH systems were investigated by immunocytochemistry. GnRH1, GnRH2 and GnRH3 immunoreactive fibers were significantly decreased following injections of GnRH antisera indicating successful neutralization of their respective endogenous GnRH peptides. GnRH1- and GnRH2-immunoneutralization did not inhibit reproductive behaviors but GnRH3-immunoneutralization significantly decreased nest-building ability (Saline: 26.5 +/- 3.7%/day versus GnRH3: 6.1 +/- 2.9%/day, P < 0.001), nest size (Saline: 0.67 +/- 0.09 points versus GnRH3: 0.10 +/- 0.05 points, P < 0.0002) and aggressive behavior (Saline: 2.34 +/- 0.19 points versus GnRH3 1.06 +/- 0.12 points, P < 0.0001). These observations provide evidence that GnRH3 is a potent neuromodulator of reproductive behaviors in male tilapia.

  14. Autoradiographic localization of thyrotropin releasing hormone (TRH) receptors in the central nervous system

    SciTech Connect

    Manaker, S.

    1985-01-01

    Quantitative autoradiography was used to examine the distribution of thyrotropin-releasing hormone (TRH) receptors in the rat and human central nervous system (CNS). The binding of (/sup 3/H)-3-methyl-histidine/sup 2/-TRH ((/sup 3/H)-MeTRH) to TRH receptors was saturable, of a high affinity (K/sub d/ = 5 nM), and specific for TRH analogs. Studies with neurotoxins ibotenic acid and 6-hydroxydopamine (6-OHDA) suggest that TRH receptors within the amygdala are predominantly located on cell bodies, and not nerve terminals. Finally, an examination was made of the concentrations of TRH receptors in spinal cords of patients with amyotrophic lateral sclerosis (ALS), a degenerative disease of the motor neurons located in Lamina IX. Large decreases in TRH receptors were noted in ALS spinal cords, when compared to non-neurological controls, probably reflecting the loss of motor neurons. In addition, decreases in the TRH receptor concentration of Lamina II were observed. This finding may reflect the sensitivity of neurons throughout the CNS to the pathophysiologic mechanisms of neuronal degeneration which cause ALS.

  15. Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells.

    PubMed

    Lund, Carina; Pulli, Kristiina; Yellapragada, Venkatram; Giacobini, Paolo; Lundin, Karolina; Vuoristo, Sanna; Tuuri, Timo; Noisa, Parinya; Raivio, Taneli

    2016-08-09

    Gonadotropin-releasing hormone (GnRH) neurons regulate human puberty and reproduction. Modeling their development and function in vitro would be of interest for both basic research and clinical translation. Here, we report a three-step protocol to differentiate human pluripotent stem cells (hPSCs) into GnRH-secreting neurons. Firstly, hPSCs were differentiated to FOXG1, EMX2, and PAX6 expressing anterior neural progenitor cells (NPCs) by dual SMAD inhibition. Secondly, NPCs were treated for 10 days with FGF8, which is a key ligand implicated in GnRH neuron ontogeny, and finally, the cells were matured with Notch inhibitor to bipolar TUJ1-positive neurons that robustly expressed GNRH1 and secreted GnRH decapeptide into the culture medium. The protocol was reproducible both in human embryonic stem cells and induced pluripotent stem cells, and thus provides a translational tool for investigating the mechanisms of human puberty and its disorders.

  16. Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy

    PubMed Central

    Giannogonas, Panagiotis; Apostolou, Athanasia; Manousopoulou, Antigoni; Theocharis, Stamatis; Macari, Sofia A.; Psarras, Stelios; Garbis, Spiros D.; Pothoulakis, Charalabos; Karalis, Katia P.

    2016-01-01

    In inflammatory bowel disease (IBD), compromised restitution of the epithelial barrier contributes to disease severity. Owing to the complexity in the pathogenesis of IBD, a variety of factors have been implicated in its progress. In this study, we report a functional interaction between macroautophagy and Corticotropin Releasing Hormone (Crh) in the gut. For this purpose we used DSS colitis model on Crh −/− or wild-type (wt) with pharmacological inhibition of autophagy. We uncovered sustained basal autophagy in the gut of Crh −/− mice, which persisted over the course of DSS administration. Autophagy inhibition resulted in partial rescue of Crh −/− mice, while it increased the expression of Crh in the wt gut. Similarly, Crh deficiency was associated with sustained activation of base line autophagy. In vitro models of amino acid deprivation- and LPS-induced autophagy confirmed the in vivo findings. Our results indicate a novel role for Crh in the intestinal epithelium that involves regulation of autophagy, while suggesting the complementary action of the two pathways. These data suggest the intriguing possibility that targeting Crh stimulation in the intestine may provide a novel therapeutic approach to support the integrity of the epithelial barrier and to protect from chronic colitis. PMID:26987580

  17. Puberty, statural growth, and growth hormone release in children with cerebral palsy

    PubMed Central

    Kuperminc, Michelle N.; Gurka, Matthew J.; Houlihan, Christine M.; Henderson, Richard C.; Roemmich, James N.; Rogol, Alan D.

    2010-01-01

    Objective Children with cerebral palsy (CP) are smaller than normally growing children.. The association between the growth hormone (GH) axis and growth in children with CP during puberty is unknown. We compared growth and markers of the GH axis in pre-pubertal and pubertal children with moderate to severe CP and without CP over a three-year period. Study design Twenty children with CP, ages 6–18, Gross Motor Function Classification System levels III–V, were compared to a group of sixty-three normally growing children of similar age. Anthropometry, Tanner stage, bone age, and laboratory analyses were performed every six months for three years. Laboratory values included spontaneous overnight GH release, fasting IGF-1 and IGFBP-3. Repeated measures models were used to evaluate interactions among Tanner stage and group (children with CP vs. reference children), taking into account gender, age, and nutritional status. Results Children with CP grew more slowly than those without CP at all Tanner stages (p<0.01). Patterns of IGF-1 and GH secretion in children with CP were similar to those of the reference group; however, the concentrations of IGF-1 (p<0.01) and GH (p<0.01) were lower in girls with CP, with a similar trend for boys (p=0.10 and 0.14, respectively). Conclusions Diminished circulating IGF-1 and GH concentrations may explain the differences in growth between the two groups. PMID:20216931

  18. Gonadotropin-releasing hormone in protostomes: insights from functional studies on Aplysia californica.

    PubMed

    Sun, Biao; Kavanaugh, Scott I; Tsai, Pei-San

    2012-05-01

    Several protostomian molecules that structurally resemble chordate gonadotropin-releasing hormone (GnRH) have been identified through cloning, biochemical purification or data mining. These molecules share considerable sequence and structural similarities with chordate GnRH, leading to the current belief that protostomian and chordate forms of GnRH share a common ancestor. However, the physiological significance of these protostomian GnRH-like molecules remains poorly understood. This knowledge gap hampers our understanding of how GnRH has evolved functionally over time. This review provides a summary of our recent functional characterization of a GnRH-like molecule (ap-GnRH) in a gastropod mollusk, Aplysia californica, and presents preliminary proof for a cognate ap-GnRH receptor (ap-GnRHR). Our data reveal that ap-GnRH is a general neural regulator capable of exerting diverse central and motor effects, but plays little or no role in reproductive activation. This notion is supported by the abundance of a putative ap-GnRHR transcript in the central nervous system and the foot. Comparing these results to the available functional data from a cephalopod mollusk, Octopus vulgaris, we surmise that protostomian GnRH-like molecules are likely to assume a wide range of physiological roles, and reproductive activation is not an evolutionarily conserved role of these molecules. Future functional studies using suitable protostomian models are required to identify functional changes in protostomian GnRH-like molecules that accompany major taxa-level transitions.

  19. Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

    SciTech Connect

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. )

    1990-07-01

    The effect of chronic administration of morphine and its withdrawal on the binding of 3H-(3-MeHis2)thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.

  20. Gonadotropin-releasing hormone receptor in spinal cord neurons of embryos and adult rats.

    PubMed

    Quintanar, J Luis; Salinas, Eva; González, Rodolfo

    2009-09-11

    Mammalian gonadotropin-releasing hormone (GnRH) and its receptor have been found in the neuroendocrine reproductive axis. However, they can be localized in other extra-pituitary tissues as well including the central nervous system. The present study reports the expression of GnRH receptor and its mRNA in spinal cord neurons of rat embryos and adult rats, using immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). Immunohistochemistry showed that the spinal cord neurons of rat embryos and adult rats expressed the GnRH receptor. The study of GnRH receptor mRNAs revealed that both cultured spinal cord neurons of rat embryos and adult rats expressed the GnRH receptor mRNA. Additional in vitro experiments showed that the expression of GnRH receptor mRNA was less in the spinal cord neurons exposed to GnRH compared to unexposed ones. These results raise the possibility that GnRH may play other roles independently from its participation in reproductive function.

  1. Morphological changes of gonadotropin-releasing hormone neurons in the rat preoptic area across puberty

    PubMed Central

    Xue, Haogang; Gai, Xiaodong; Sun, Weiqi; Li, Chun; Liu, Quan

    2014-01-01

    Gonadotropin-releasing hormone (GnRH) neurons in the preoptic area may undergo morphological changes during the pubertal period when their activities are upregulated. To clarify the regulatory mechanism of puberty onset, this study aimed to investigate the morphological changes of GnRH neurons in the preoptic area of GnRH-enhanced green fluorescent protein transgenic rats. Under confocal laser microscopy, pubertal GnRH neurons exhibited an inverted Y distribution pattern. Prepubertal GnRH neurons were generally unipolar and bipolar, and were distinguished as smooth type cells with few small processes or irregular type cells with many spine-like processes in the proximal dendrites. The number of GnRH neurons in the preoptic area and spine-like processes were increased during the course of reproductive maturation. There was no significant difference between male and female rats. Immunofluorescence staining revealed synaptophysin punctae close to the distal end of GnRH neurons, indicating that some presynaptic terminals may form a synaptic linkage with these neurons. PMID:25221583

  2. Suppression of boar taint in cryptorchid pigs using a vaccine against the gonadotropin-releasing hormone.

    PubMed

    Gutzwiller, A; Ampuero Kragten, S

    2013-12-01

    Thirteen unilaterally cryptorchid Large White pigs, which had been immunized at 4 and 8 weeks of age and a third time at 64 ± 4 kg body weight against the gonadotropin releasing hormone with the vaccine Improvac®, were slaughtered at the age of 170 ± 9 days at a body weight of 102 ± 12 kg. Twelve pigs tested negative in the olfactory test of the salivary gland; their descended testicles were small and their fat androstenone concentration was low compared to normally developed boars of a previous experiment which had been vaccinated twice with Improvac® according the manufacturer's recommendation. One cryptorchid boar, which tested positive in the olfactory test and whose testicular weight and fat androstenone concentration corresponded to values of unvaccinated boars of the same age, obviously had not responded to the vaccination. It is an open question if the vaccination protocol for normal boars is sufficient to prevent boar taint in the majority of cryptorchid pigs, too.

  3. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.

    PubMed

    Howard, Sasha R; Guasti, Leonardo; Ruiz-Babot, Gerard; Mancini, Alessandra; David, Alessia; Storr, Helen L; Metherell, Lousie A; Sternberg, Michael Je; Cabrera, Claudia P; Warren, Helen R; Barnes, Michael R; Quinton, Richard; de Roux, Nicolas; Young, Jacques; Guiochon-Mantel, Anne; Wehkalampi, Karoliina; André, Valentina; Gothilf, Yoav; Cariboni, Anna; Dunkel, Leo

    2016-06-01

    Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP‡.

  4. Structural study of human growth hormone-releasing factor fragment (1?29) by vibrational spectroscopy

    NASA Astrophysics Data System (ADS)

    Carmona, P.; Molina, M.; Lasagabaster, A.

    1995-05-01

    The conformational structure of fragment 1-29 of human growth hormone releasing factor, hGHRF (1-29), in aqueous solution and in the solid state is investigated by infrared and Raman spectroscopy. The polypeptide backbone is found to be unordered in the solid state. However, the spectra of the peptide prepared as 5% (w/w) aqueous solutions show that approximately 28% of the peptide is involved in intermolecular β-sheet aggregation. The remainder of the peptide exists largely as disordered and β-sheet conformations with a small portion of α-helices. Tyrosine residues are found to be exposed to the solvent. The secondary structures are quantitatively examined through infrared spectroscopy, the conformational percentages being near those obtained by HONDAet al. [ Biopolymers31, 869 (1991)] using circular dichroism. The fast hydrogen/deuterium exchange in peptide groups and the absence of any NMR sign indicative of ordered structure [ G. M. CLOREet al., J. Molec. Biol.191, 553 (1986)] support that the solution conformations of the non-aggregated peptide interconvert in dynamic equilibrium. Some physiological advantages that may derive from this conformational flexibility are also discussed

  5. Synthesis of Mono-PEGylated Growth Hormone Releasing Peptide-2 and Investigation of its Biological Activity.

    PubMed

    Hu, Xiaoyu; Xu, Beihua; Zhou, Ziniu

    2015-10-01

    The purpose of this study was to investigate an efficient synthetic route to the mono-PEGylated growth hormone releasing peptide-2 (GHRP-2) and its biological activity in vivo. The commercially available key PEGylating reagent, mPEG-NHS ester, was successfully utilized to the synthesis of mono-PEGylated GHRP-2, during which the PEGylation profiles of GHRP-2 were monitored by high-performance liquid chromatography (HPLC). The product was purified by cation exchange chromatography, and its biological activity was conducted in rats. The desired mono-PEGylated GHRP-2 as the major product was readily obtained in anhydrous aprotic solvent, such as dimethyl formamide (DMF) and dimethylsulfoxide (DMSO), when the molar ratio of mPEG-NHS ester to GHRP-2 was fixed to be 0.8:1. The products were characterized by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. The evaluation of the biological activity for the products showed that the mono-PEGylated GHRP-2 gave a more stable activity than GHRP-2, suggesting that PEGylation led to the increase in the half-life of GHRP-2 in plasma without greatly impairing the biological activity. PEGylation of the GHRP-2 is a good choice for the development of the GHRP-2 applications.

  6. [Effect of bacterial endotoxin on migration of gonadotropin-releasing, hormone producing neurons in rat embryogenesis].

    PubMed

    Sharova, V S; Izvol'skaia, M S; Voronova, S N; Zakharova, L A

    2011-01-01

    The effect of bacterial lipopolysaccharide endotoxin (LPS), immune system activator, on differentiation and migration of gonadotropin-releasing, hormone producing neurons in rat embryogenesis has been studied. Intraperitoneal introduction of LPS (18 jg/kg) to pregnant rats on the 12th day of pregnancy led to 50% decrease in total number of GRH-neurons in the forebrain of 17-day-old embryos and 17% decrease in 19-day-old embryos. At the same time, the number of GRH-neurons in the nasal area of the head of 17- and 19-day-old embryos increased by 40 and 50%, respectively, whereas it increased by 20% in olfactory bulbs of 17-day-old embryos and did not changed in olfactory bulbs of 19-day-old embryos. Neither the total number of neurons nor their distribution patterns were affected by the introduction of LPS into pregnant rats on the 15th day of pregnancy. Singular localization of GRH-neurons in embryo forebrain was observed after LPS administration, whereas the neurons were located by groups of 3-4 cells in rostral areas. Therefore, at the early stages of pregnancy, LPS was shown to suppress initial stages of differentiation and migration of GRH producing neurons. The effects observed in our study may be mediated by LPS-induced, proinflammatory cytokines.

  7. Alpha-adrenergic control of growth hormone release during surgical stress in man.

    PubMed

    Vigas, M; Malatinský, J; Németh, S; Jurcovicová, J

    1977-04-01

    The mechanisms involved in the initial release of growth hormone (GH) during cholecystectomy have been studied after the administration of phentolamine in saline and in isotonic glucose, and after the administration of 10% glucose. Infusion of these substances was started 10 min before and terminated 30 min after skin incision. The serum GH levels 30 min after skin incision in a nontreated control group were raised to 14.4 +/- 1.0 ng/ml. The alpha-adrenergic blockade by phentolamine (20 mg during 40 min) regardless of whether administered in saline or in isotonic glucose inhibited GH response to surgery (4.3 +/- 2.1 ng/ml, or 2.2 +/- 0.4 ng/ml). The administration of 10% glucose (40 g during 40 min) led to a diminished response in some, but not in all the patients (6.2 +/- 1.2 ng/ml). It is concluded that the alpha-adrenergic mechanism participates in GH response to surgery.

  8. Reduction of thyrotropin-releasing hormone concentrations in central nervous system of African lungfish during estivation.

    PubMed

    Kreider, M S; Winokur, A; Pack, A I; Fishman, A P

    1990-03-01

    Thyrotropin-releasing hormone (TRH) has been implicated as an important modulator of arousal state in mammals. Changes in the content of TRH in several brain regions accompany hibernation in the ground squirrel. In the present study, the involvement of TRH in the regulation of arousal was further investigated in the African lungfish, Protopterus annectens, which contain high concentrations of TRH throughout its central nervous system and enter a hibernation-like state, estivation. Lungfish were divided into three groups. Group 1 was fed normally, group 2 was starved while aquatic, and group 3 was allowed to enter into a state of estivation. After 3 months, the lungfish were sacrificed and the concentrations of TRH, norepinephrine, dopamine, and serotonin were determined in the telencephalon, diencephalon, medulla, and spinal cord. In estivation, there was a significant decline in the concentration of TRH in the diencephalon, with no alteration in other regions. Starvation had no effect on regional TRH concentrations. The concentration of norepinephrine, dopamine, and serotonin did not change in estivation; however, a significant elevation of norepinephrine in the diencephalon and dopamine in the telencephalon was observed in starvation. Starvation and estivation were associated with significant declines in the protein content of the diencephalon and medulla. The estivation-linked decline in TRH in the diencephalon of the lungfish is similar to the decrease in TRH content in the hypothalamus in hibernating ground squirrels. These findings lend further support to the importance of TRH in the regulation of arousal state.

  9. Spectroscopic studies on the conformational transitions of a bovine growth hormone releasing factor analog

    NASA Astrophysics Data System (ADS)

    Sarver, Ronald W.; Friedman, Alan R.; Thamann, Thomas J.

    1997-10-01

    The secondary structure of the bovine growth hormone releasing factor analog, [Ile 2, Ser 8,28, Ala 15, Leu 27, Hse 30] bGRF(1-30)-NH-Ethyl, acetate salt (U-90699F) was studied in solution by Fourier transform infrared and Raman spectroscopies. Spectroscopic studies revealed that concentrated aqueous solutions of U-90699F (100 mg ml -1) undergo a secondary structure transition from disordered coil/α-helix to intermolecular β-sheet. Disordered coil and α-helical structure were grouped together in the infrared and Raman studies since the amide I vibrations are close in frequency and overlap in assignments was possible. Before the conformational transition, the facile exchange of the peptide's amide hydrogens for deuterium indicated that the majority of amide hydrogens were readily accessible to solvent. The kinetics of the conformational transition coincided with an increase in solution viscosity and turbidity. An initiation phase preceded the conformational transition during which only minor spectral changes were observed by infrared spectroscopy. The initiation phase and reaction kinetics were consistent with a highly cooperative nucleation ultimately leading to a network of intermolecular β-sheet structure and gel formation. Increased temperature accelerated the conformational transition. The conformational transition was thermally irreversible but the β-sheet structure of aggregated or gelled peptide could be disrupted by dilution and agitation.

  10. Epigenetic Upregulation of Corticotrophin-Releasing Hormone Mediates Postnatal Maternal Separation-Induced Memory Deficiency

    PubMed Central

    Wang, Aiyun; Nie, Wenying; Li, Haixia; Hou, Yuhua; Yu, Zhen; Fan, Qing; Sun, Ruopeng

    2014-01-01

    Accumulating evidences demonstrated that early postnatal maternal separation induced remarkable social and memory defects in the adult rodents. Early-life stress induced long-lasting functional adaptation of neuroendocrine hypothalamic-pituitary-adrenal axis, including neuropeptide corticotrophin-releasing hormone (CRH) in the brain. In the present study, a significantly increased hippocampal CRH was observed in the adult rats with postnatal maternal separation, and blockade of CRHR1 signaling significantly attenuated the hippocampal synaptic dysfunction and memory defects in the modeled rats. Postnatal maternal separation enduringly increased histone H3 acetylation and decreased cytosine methylation in Crh promoter region, resulting from the functional adaptation of several transcriptional factors, in the hippocampal CA1 of the modeled rats. Enriched environment reversed the epigenetic upregulation of CRH, and ameliorated the hippocampal synaptic dysfunction and memory defects in the adult rats with postnatal maternal separation. This study provided novel insights into the epigenetic mechanism underlying postnatal maternal separation-induced memory deficiency, and suggested environment enrichment as a potential approach for the treatment of this disorder. PMID:24718660

  11. The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis.

    PubMed

    Chwalisz, Kristof; Surrey, Eric; Stanczyk, Frank Z

    2012-06-01

    Gonadotropin-releasing hormone agonists (GnRHa) are an effective treatment of endometriosis-associated pelvic pain. The use of hormonal add-back therapy can alleviate the hypoestrogenic symptoms associated with GnRHa therapy, while preserving therapeutic efficacy. Norethindrone acetate (NETA) is a unique progestin that has both estrogenic and androgenic properties and is effective as an add-back regimen without estrogen supplementation. Through its estrogenic activity, NETA exerts beneficial effects on bone mineral density and vasomotor symptoms in women treated with GnRHa. In addition, NETA exhibits strong endometrial antiproliferative effects, which may result in further benefits for the endometriosis patient population. However, NETA add-back may be associated with progestogenic side effects and may lower high-density lipoprotein due to androgenic activity. These effects must be balanced with the overall benefits of NETA add-back therapy.

  12. QSAR models for predicting the activity of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists derived from erythromycin A using quantum chemical properties.

    PubMed

    Fernández, Michael; Caballero, Julio

    2007-04-01

    Multiple linear regression (MLR) combined with genetic algorithm (GA) and Bayesian-regularized Genetic Neural Networks (BRGNNs) were used to model the binding affinity (pK(I)) of 38 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A for the Human Luteinizing Hormone-Releasing Hormone (LHRH) receptor using quantum chemical descriptors. A multiparametric MLR equation with good statistical quality was obtained that describes the features relevant for antagonistic activity when the substituent at the position 3 of the erythronolide core was varied. In addition, four-descriptor linear and nonlinear models were established for the whole dataset. Such models showed high statistical quality. However, the BRGNN model was better than the linear model according to the external validation process. In general, our linear and nonlinear models reveal that the binding affinity of the compounds studied for the LHRH receptor is modulated by electron-related terms.

  13. Atrazine inhibits pulsatile gonadotropin-releasing hormone (GnRH) release without altering GnRH messenger RNA or protein levels in the female rat.

    PubMed

    Foradori, Chad D; Zimmerman, Arthur D; Hinds, Laura R; Zuloaga, Kristen L; Breckenridge, Charles B; Handa, Robert J

    2013-01-01

    Atrazine (ATR) is a commonly used pre-emergence/early postemergence herbicide. Previous work has shown that exposure to high doses of ATR in rats results in blunting of the hormone-induced luteinizing hormone (LH) surge and inhibition of pulsatile LH release without significantly reducing pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) agonist. Accompanying the reduction in the LH surge was an attenuation of GnRH neuronal activation. These findings suggest that ATR exposure may be acting to inhibit GnRH release. In this study, we examined GnRH directly to determine the effect of high doses of ATR on GnRH pulsatile release, gene expression, and peptide levels in the female rat. Ovariectomized adult female Wistar rats were treated with ATR (200 mg/kg) or vehicle for 4 days via gavage. Following the final treatment, GnRH release was measured from ex vivo hypothalamic explants for 3 h. In another experiment, animals were administered either vehicle or ATR (50, 100, or 200 mg/kg) daily for 4 days. Following treatment, in situ hybridization was performed to examine total GnRH mRNA and the primary GnRH heterogeneous nuclear RNA transcript. Finally, GnRH immunoreactivity and total peptide levels were measured in hypothalamic tissue of treated animals. ATR treatment resulted in no changes to GnRH gene expression, peptide levels, or immunoreactivity but a reduction in GnRH pulse frequency and an increased pulse amplitude. These findings suggest that ATR acts to inhibit the secretory dynamics of GnRH pulses without interfering with GnRH mRNA and protein synthesis.

  14. A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol

    PubMed Central

    Langley, Ruth E.; Kynaston, Howard G.; Alhasso, Abdulla A.; Duong, Trinh; Paez, Edgar M.; Jovic, Gordana; Scrase, Christopher D.; Robertson, Andrew; Cafferty, Fay; Welland, Andrew; Carpenter, Robin; Honeyfield, Lesley; Abel, Richard L.; Stone, Michael; Parmar, Mahesh K.B.; Abel, Paul D.

    2016-01-01

    Background Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. Objective To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). Design, setting, and participants Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. Interventions LHRHa as per local practice, OP (FemSeven 100 μg/24 h patches). Outcome measurements and statistical analysis The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. Results and limitations A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001). Conclusions Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. Patient summary This study found that prostate cancer patients treated with transdermal oestradiol

  15. Effects of inorganic and organic manganese supplementation on gonadotropin-releasing hormone-I and follicle-stimulating hormone expression and reproductive performance of broiler breeder hens.

    PubMed

    Xie, Jingjing; Tian, Chuanhuan; Zhu, Yongwen; Zhang, Liyang; Lu, Lin; Luo, Xugang

    2014-04-01

    Manganese is an essential microelement. Manganese deficiency affects reproduction performance and reproductive hormones in layers. However, little is known about its effects and the possible mechanism in regulating reproduction in broiler breeder hens. In the current study, broiler breeder hens at peak production were fed with diets supplemented with 0, 120, or 240 mg of Mn/kg as MnSO4 or Mn proteinate for 13 wk. Manganese supplementation did not alter egg laying rate, egg weight, fertility, hatchability, or hatchling weight over a 13-wk trial period. However, 240 mg of Mn/kg supplementation significantly increased serum Mn (P < 0.05). Manganese supplements increased the eggshell breaking strength (P < 0.05) without affecting the eggshell thickness. There was no difference in serum cholesterol and estradiol. Expression of follicle-stimulating hormone) and gonadotropin-releasing hormone-I (GnRH-I) genes was significantly elevated by 240 mg of Mn/kg (P < 0.05). Furthermore, inorganic Mn supplementation doubled GnRH-I expression compared with supplementation with the organic form (P < 0.05), although serum Mn was comparable between these 2 supplements. No obvious difference was shown in gene expression of luteinizing hormone, prolactin, GnRH-I receptor, inducible NO synthase, and dopamine receptor D1 in the pituitary as well as tyrosine hydroxylase and inducible NO synthase in the hypothalamus. This suggests that dietary Mn supplementation could improve eggshell quality in the long term. The central mechanism of nontoxic high doses of Mn suggested the transcriptional activation of GnRH-I and follicle-stimulating hormone genes. The central effect of inorganic Mn activating GnRH-I genes compared with the reduced effect by organic Mn could possibly be due to a decreased capacity of the latter passing through the blood-brain barrier.

  16. Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans

    PubMed Central

    Vadakkadath Meethal, Sivan; Gallego, Miguel J; Haasl, Ryan J; Petras, Stephen J; Sgro, Jean-Yves; Atwood, Craig S

    2006-01-01

    Background The Caenorhabditis elegans genome is known to code for at least 1149 G protein-coupled receptors (GPCRs), but the GPCR(s) critical to the regulation of reproduction in this nematode are not yet known. This study examined whether GPCRs orthologous to human gonadotropin-releasing hormone receptor (GnRHR) exist in C. elegans. Results Our sequence analyses indicated the presence of two proteins in C. elegans, one of 401 amino acids [GenBank: NP_491453; WormBase: F54D7.3] and another of 379 amino acids [GenBank: NP_506566; WormBase: C15H11.2] with 46.9% and 44.7% nucleotide similarity to human GnRHR1 and GnRHR2, respectively. Like human GnRHR1, structural analysis of the C. elegans GnRHR1 orthologue (Ce-GnRHR) predicted a rhodopsin family member with 7 transmembrane domains, G protein coupling sites and phosphorylation sites for protein kinase C. Of the functionally important amino acids in human GnRHR1, 56% were conserved in the C. elegans orthologue. Ce-GnRHR was actively transcribed in adult worms and immunoanalyses using antibodies generated against both human and C. elegans GnRHR indicated the presence of a 46-kDa protein, the calculated molecular mass of the immature Ce-GnRHR. Ce-GnRHR staining was specifically localized to the germline, intestine and pharynx. In the germline and intestine, Ce-GnRHR was localized specifically to nuclei as revealed by colocalization with a DNA nuclear stain. However in the pharynx, Ce-GnRHR was localized to the myofilament lattice of the pharyngeal musculature, suggesting a functional role for Ce-GnRHR signaling in the coupling of food intake with reproduction. Phylogenetic analyses support an early evolutionary origin of GnRH-like receptors, as evidenced by the hypothesized grouping of Ce-GnRHR, vertebrate GnRHRs, a molluscan GnRHR, and the adipokinetic hormone receptors (AKHRs) and corazonin receptors of arthropods. Conclusion This is the first report of a GnRHR orthologue in C. elegans, which shares significant

  17. Bed rest suppresses bioassayable growth hormone release in response to muscle activity

    NASA Technical Reports Server (NTRS)

    McCall, G. E.; Goulet, C.; Grindeland, R. E.; Hodgson, J. A.; Bigbee, A. J.; Edgerton, V. R.

    1997-01-01

    Hormonal responses to muscle activity were studied in eight men before (-13 or -12 and -8 or -7 days), during (2 or 3, 8 or 9, and 13 or 14 days) and after (+2 or +3 and +10 or +11 days) 17 days of bed rest. Muscle activity consisted of a series of unilateral isometric plantar flexions, including 4 maximal voluntary contractions (MVCs), 48 contractions at 30% MVC, and 12 contractions at 80% MVC, all performed at a 4:1-s work-to-rest ratio. Blood was collected before and immediately after muscle activity to measure plasma growth hormone by radioimmunoassay (IGH) and by bioassay (BGH) of tibia epiphyseal cartilage growth in hypophysectomized rats. Plasma IGH was unchanged by muscle activity before, during, or after bed rest. Before bed rest, muscle activity increased (P < 0.05) BGH by 66% at -13 or -12 days (2,146 +/- 192 to 3,565 +/- 197 microg/l) and by 92% at -8 or -7 days (2,162 +/- 159 to 4,161 +/- 204 microg/l). After 2 or 3 days of bed rest, there was no response of BGH to the muscle activity, a pattern that persisted through 8 or 9 days of bed rest. However, after 13 or 14 days of bed rest, plasma concentration of BGH was significantly lower after than before muscle activity (2,594 +/- 211 to 2,085 +/- 109 microg/l). After completion of bed rest, muscle activity increased BGH by 31% at 2 or 3 days (1,807 +/- 117 to 2,379 +/- 473 microg/l; P < 0.05), and by 10 or 11 days the BGH response was similar to that before bed rest (1,881 +/- 75 to 4,160 +/- 315 microg/l; P < 0.05). These data demonstrate that the ambulatory state of an individual can have a major impact on the release of BGH, but not IGH, in response to a single bout of muscle activity.

  18. A screen for modulators reveals that orexin-A rapidly stimulates thyrotropin releasing hormone expression and release in hypothalamic cell culture.

    PubMed

    Cote-Vélez, Antonieta; Martínez Báez, Anabel; Lezama, Leticia; Uribe, Rosa María; Joseph-Bravo, Patricia; Charli, Jean-Louis

    2017-02-02

    In the paraventricular nucleus of the mammalian hypothalamus, hypophysiotropic thyrotropin releasing hormone (TRH) neurons integrate metabolic information and control the activity of the thyroid axis. Additional populations of TRH neurons reside in various hypothalamic areas, with poorly defined connections and functions, albeit there is evidence that some may be related to energy balance. To establish extracellular modulators of TRH hypothalamic neurons activity, we performed a screen of neurotransmitters effects in hypothalamic cultures. Cell culture conditions were chosen to facilitate the full differentiation of the TRH neurons; these conditions had permitted the characterization of the effects of known modulators of hypophysiotropic TRH neurons. The major end-point of the screen was Trh mRNA levels, since they are generally rapidly (0.5-3h) modified by synaptic inputs onto TRH neurons; in some experiments, TRH cell content or release was also analyzed. Various modulators, including histamine, serotonin, β-endorphin, met-enkephalin, and melanin concentrating hormone, had no effect. Glutamate, as well as ionotropic agonists (kainate and N-Methyl-d-aspartic acid), increased Trh mRNA levels. Baclofen, a GABAB receptor agonist, and dopamine enhanced Trh mRNA levels. An endocannabinoid receptor 1 inverse agonist promoted TRH release. Somatostatin increased Trh mRNA levels and TRH cell content. Orexin-A rapidly increased Trh mRNA levels, TRH cell content and release, while orexin-B decreased Trh mRNA levels. These data reveal unaccounted regulators, which exert potent effects on hypothalamic TRH neurons in vitro.

  19. Effect of aging on GHRF-induced growth hormone release from anterior pituitary cells in primary culture

    SciTech Connect

    Spik, K.W.; Boyd, R.L.; Sonntag, W.E.

    1991-03-01

    Five criteria were developed to validate the primary cell culture model for comparison of GRF-induced release of growth hormone in pituitary tissue from aging animals. Pituitaries from young (5-mo), middle-aged (14-mo), and old (24-mo) male Fischer 344 rats were dispersed using either trypsin/trypsin inhibitor or dispase and compared with respect to the number of pituitary cells recovered, cell viability, 3H-leucine incorporation into total protein, time course for recovery of optimal response to GRF, and the dose-relationship for GRF-induced release of growth hormone 2, 4, and 6 days after dispersal. Results indicated that direct comparison of cellular responses between tissues from young, middle-aged, and old rats in primary cell culture is confounded by variations in time for recovery of optimal responses, the effects of the enzymes used for dispersal, and the methods used to express the data.

  20. Molecular Coevolution of Neuropeptides Gonadotropin-Releasing Hormone and Kisspeptin with their Cognate G Protein-Coupled Receptors

    PubMed Central

    Kim, Dong-Kyu; Cho, Eun Bee; Moon, Mi Jin; Park, Sumi; Hwang, Jong-Ik; Do Rego, Jean-Luc; Vaudry, Hubert; Seong, Jae Young

    2012-01-01

    The neuropeptides gonadotropin-releasing hormone (GnRH) and kisspeptin (KiSS), and their receptors gonadotropin-releasing hormone receptor (GnRHR) and kisspeptin receptor (KiSSR) play key roles in vertebrate reproduction. Multiple paralogous isoforms of these genes have been identified in various vertebrate species. Two rounds of genome duplication in early vertebrates likely contributed to the generation of these paralogous genes. Genome synteny and phylogenetic analyses in a variety of vertebrate species have provided insights into the evolutionary origin of and relationship between paralogous genes. The paralogous forms of these neuropeptides and their receptors have coevolved to retain high selectivity of the ligand–receptor interaction. These paralogous forms have become subfunctionalized, neofunctionalized, or dysfunctionalized during evolution. This article reviews the evolutionary mechanism of GnRH/GnRHR and KiSS/KiSSR, and the fate of the duplicated paralogs in vertebrates. PMID:22291614

  1. Familial idiopathic gonadotropin deficiency not linked to gene for gonadotropin-releasing hormone (GnRH) in Brazilian kindred

    SciTech Connect

    Faraco, J.; Francke, U.; Toledo, S.

    1994-09-01

    Familial idiopathic gonadotropin deficiency (FIGD) is an autosomal recessive disorder which results in failure to develop secondary sexual characteristics. The origin is a hypothalamic defect resulting in insufficient secretion of gonadotropin-releasing hormone GnRH (also called LHRH, luteinizing hormone releasing hormone) and follicle-stimuating hormone (FSH). FIGD has been determined to be a separate entity from Kallmann syndrome which presents with hypogonadism as well as anosmia. The FIGD phenotype appears to be analogous to the phenotype of the hpg (hypogonadal) mouse. Because the hpg phenotype is the result of a structurally abnormal GnRH gene, we have studied the GnRH gene in individuals from a previously reported Brazilian FIGD family. An informative dimorphic marker in the signal peptide sequence of the GnRH gene allowed assessment of linkage between the disease gene and the GnRH locus in this pedigree. We have concluded that the GnRH locus is not linked to the disease-causing mutation in these hypogonadal individuals. Recent evidence suggests that neuropeptide Y (NPY) may play a role in the initiation of puberty. We hypothesize that mutations in NPY may result in failure to secrete GnRH. We have characterized three diallelic frequent-cutter restriction fragment length polymorphisms within the human NPY locus, and are currently using these markers to determine if the NPY gene is linked to, and possibly the site of the disease mutation in this kindred.

  2. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene.

    PubMed

    Mantovani, Giovanna; Maghnie, Mohamad; Weber, Giovanna; De Menis, Ernesto; Brunelli, Valeria; Cappa, Marco; Loli, Paola; Beck-Peccoz, Paolo; Spada, Anna

    2003-09-01

    Heterozygous inactivating mutations in the Gs alpha gene cause Albright's hereditary osteodystrophy. Consistent with the observation that only maternally inherited mutations lead to resistance to hormone action [pseudohypoparathyroidism type Ia (PHP Ia)], recent studies provided evidence for a predominant maternal origin of Gs alpha transcripts in endocrine organs, such as thyroid, gonad, and pituitary. The aim of this study was to investigate the presence of pituitary resistance to hypothalamic hormones acting via Gs alpha-coupled receptors in patients with PHP Ia. Six of nine patients showed an impaired GH responsiveness to GHRH plus arginine, consistent with a complete GH deficiency (GH peak from 2.6-8.6 microg/liter, normal > 16.5), and partial (GH peak 13.9 and 13.6 microg/liter) and normal responses were found in two and one patient, respectively. Accordingly, IGF-I levels were below and in the low-normal range in seven and two patients. All patients had a normal cortisol response to 1 microg ACTH test, suggesting a normal corticotroph function that was confirmed by a normal ACTH and cortisol response to CRH test in three patients. In conclusion, we report that in addition to PTH and TSH resistance, patients with PHP Ia display variable degrees of GHRH resistance, consistent with Gs alpha imprinting in human pituitary.

  3. Inhibition of L-dopa induced growth hormone release in normal and diabetic subjects by glucose administration.

    PubMed

    Vigas, M; Klimes, I; Jurcovicova, J; Kolesar, P; Repcekova-Jezova, D

    1977-12-01

    Administration of L-dopa 1 g induced an increase of plasma growth hormone (GH) levels in seven of ten healthy volunteers and in six of ten hyperglycemic insulin-dependent diabetic subjects; the maximal GH response was higher in normal subjects. Addition of 100 g glucose orally to the L-dopa completely abolished the GH response of both groups. The difference between the effect of endogenous hyperglycemia and the effect of a sudden increase of blood sugar after glucose administration on L-dopa induced GH release in diabetic subjects may be explain by the resetting of the hypothalamic control for pituitary GH release to higher levels of blood glucose.

  4. Fertility Rates in Young Korean Breast Cancer Patients Treated with Gonadotropin-Releasing Hormone and Chemotherapy

    PubMed Central

    Kim, Isaac; Ryu, Jai Min; Paik, Hyun-June; Park, Sungmin; Bae, Soo Youn; Lee, Se Kyung; Yu, Jonghan; Kim, Seok Won; Nam, Seok Jin

    2017-01-01

    Purpose Gonadotropin-releasing hormone (GnRH) agonists have been used with adjuvant chemotherapy to protect ovarian function. However, there are no data on the actual pregnancy rates among young breast cancer patients receiving GnRH agonists and concurrent chemotherapy in Korea. Methods Among patients who underwent surgery from January 2002 to April 2012, premenopausal patients aged between 20 and 40 years were included in the analysis. We retrospectively reviewed clinicopathologic features (e.g., age, obstetric and menstruation history), recurrence, and survival status. The rate of resumption of menstruation was calculated in all patients. In the married group, pregnancy and delivery rates were also recorded. Results Among 101 patients, 19 were lost to follow-up and 82 were eligible for the analysis. Among them, 31 were married, 10 of 51 got married, and 41 remained unmarried through the follow-up period. Among the married patients, 15 became pregnant and gave birth to 19 babies, whereas 26 did not become pregnant. The pregnancy rate in the married group was 50.0% (15/30). Three of 15 pregnancies (20.0%) were multiparous. Most of the delivered babies were healthy and 80.0% of patients had no problems breastfeeding (12/15). More than half the patients in all groups recovered menstrual status within 12 months. Conclusion Fifty percent of young breast cancer patients who attempted pregnancy succeeded in pregnancy after adjuvant chemotherapy and GnRH agonists. Further studies that include control groups are required to confirm whether the use of GnRH agonists improves pregnancy. PMID:28382099

  5. Inhibition of Maternal Behaviour by Central Infusion of Corticotrophin-releasing Hormone in Marmoset Monkeys

    PubMed Central

    Saltzman, Wendy; Boettcher, Carissa A.; Post, Jennifer L.; Abbott, David H.

    2011-01-01

    Stress can inhibit maternal behaviour and increase rates of child abuse in humans and other animals; however, the neuroendocrine mechanisms are not known. To determine whether corticotrophin-releasing hormone (CRH) plays a role in stress-induced disruption of maternal behaviour in primates, we characterised the effects of acute intracerebroventricular (ICV) infusions of CRH on maternal and abusive behaviour in common marmoset monkeys (Callithrix jacchus). Nulliparous females were implanted with indwelling ICV guide cannulae prior to conception. Between 18 and 58 days after the birth of her first infants, each female underwent a series of ICV infusions of human CRH (0, 2, 8, and 25 μg) in 8 μl artificial cerebrospinal fluid. In the 70 minutes following infusion, marmosets were tested with one of their infants, first in their home cage and subsequently in an unfamiliar cage in which the infant was confined in a transparent box on the cage floor. In the home cage, the highest dose of CRH significantly reduced the amount of time that mothers spent carrying their infants, as compared to vehicle alone, but did not reliably affect aggression toward the infant or other behaviours. In the confined-infant test, the highest dose of CRH significantly reduced the amount of time that mothers spent on the cage floor, increased mothers’ vocalization rates, and tended to reduce their activity levels and time spent in proximity to their infant. 25 μg CRH also elicited significant elevations in plasma ACTH and cortisol concentrations, as compared to vehicle. These results indicate that ICV-administered CRH reduces maternal behaviour in marmoset mothers, in both familiar and unfamiliar environments, but does not increase infant abuse. PMID:21554432

  6. Long-term effects of gonadotropin-releasing hormone analogs in girls with central precocious puberty.

    PubMed

    Kim, Eun Young

    2015-01-01

    Gonadotropin-releasing hormone analogs (GnRHa) are widely used to treat central precocious puberty (CPP). The efficacy and safety of GnRHa treatment are known, but concerns regarding long-term complications are increasing. Follow-up observation results after GnRHa treatment cessation in female CPP patients up to adulthood showed that treatment (especially <6 years) was beneficial for final adult height relative to that of pretreated or untreated patients. Puberty was recovered within 1 year after GnRHa treatment discontinuation, and there were no abnormalities in reproductive function. CPP patients had a relatively high body mass index (BMI) at the time of CPP diagnosis, but BMI standard deviation score maintenance during GnRHa treatment seemed to prevent the aggravation of obesity in many cases. Bone mineral density decreases during GnRHa treatment but recovers to normal afterwards, and peak bone mass formation through bone mineral accretion during puberty is not affected. Recent studies reported a high prevalence of polycystic ovarian syndrome in CPP patients after GnRHa treatment, but it remains unclear whether the cause is the reproductive mechanism of CPP or GnRHa treatment itself. Studies of the psychosocial effects on CPP patients after GnRHa treatment are very limited. Some studies have reported decreases in psychosocial problems after GnRHa treatment. Overall, GnRHa seems effective and safe for CPP patients, based on long-term follow-up studies. There have been only a few long-term studies on GnRHa treatment in CPP patients in Korea; therefore, additional long-term follow-up investigations are needed to establish the efficacy and safety of GnRHa in the Korean population.

  7. Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population.

    PubMed

    Grabe, Hans Jörgen; Schwahn, Christian; Appel, Katja; Mahler, Jessie; Schulz, Andrea; Spitzer, Carsten; Fenske, Kristin; Barnow, Sven; Lucht, Michael; Freyberger, Harald Jürgen; John, Ulrich; Teumer, Alexander; Wallaschofski, Henri; Nauck, Matthias; Völzke, Henry

    2010-12-05

    Dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis have been implicated in the pathogenesis of depressive disorders and the corticotropin-releasing hormone (CRH) was found to modulate emotional memory consolidation. Recently, two studies have reported an interaction between childhood abuse and the TAT-haplotype of the CRH-Receptor Gene (CRHR1) connecting childhood adversities and genetic susceptibility to adult depression. We tested the hypothesis of an interaction of childhood maltreatment with single nucleotide polymorphisms (SNPs) and haplotypes of the CRHR1 gene not previously investigated. Caucasian subjects (n = 1,638) from the German general population (Study of Health in Pomerania, SHIP) were analyzed. As in the previous studies, childhood abuse and neglect were assessed with the Childhood Trauma Questionnaire (CTQ) and depression with the Beck Depression Inventory (BDI-2). The CRHR1-SNPs were genotyped on the Affymetrix Genome-Wide Human SNP Array 6.0 platform. We identified an interaction between the TAT-haplotype and childhood physical neglect. The interaction with physical neglect showed significant (P < 0.05) results in 23 of the 28 SNPs, with rs17689882 (P = 0.0013) reaching "gene-wide" significance. Although we did not replicate the specific interaction of abuse and the TAT-haplotype of the CRHR1 gene we confirmed the relevance of an interplay between variants within the CRHR1 gene and childhood adversities in the modulation of depression in adults. The largest effect was found for rs17689882, a SNP previously not analyzed. Relevant sample differences between this and prior studies like lower BDI-2 scores, less childhood maltreatment and higher psychosocial functioning may account for the differences in gene-environment interaction findings. © 2010 Wiley-Liss, Inc.

  8. Flufenamic acid modulates multiple currents in gonadotropin-releasing hormone neurons

    PubMed Central

    Wang, Yong; Kuehl-Kovarik, M. Cathleen

    2010-01-01

    Reproduction in mammals is dependent upon the appropriate neurosecretion of gonadotropin-releasing hormone (GnRH), yet the endogenous generation of activity underlying GnRH secretion remains poorly understood. We have demonstrated that the depolarizing afterpotential (DAP), which modulates bursting activity, is reduced in isolated GnRH neurons from aged animals. Calcium-activated non-specific cation (CAN) channels contribute to the DAP in other vertebrate neurosecretory cells. We used the CAN channel blocker flufenamic acid (FFA) to examine the contribution of CAN channels to the DAP in GnRH neurons during aging. Recordings were performed on isolated fluorescent GnRH neurons from young, middle-aged and aged female mice. Flufenamic acid inhibited spontaneous activity, but significantly increased the DAP in neurons from young and middle-aged animals. Apamin did not significantly potentiate the DAP, but did reduce the effects of FFA, suggesting that the increased DAP is partially due to blockade of apamin-sensitive SK channels. Flufenamic acid increased the current underlying the DAP (IADP) and decreased the preceding fast outward current (IOUT) at all ages. These current responses were not affected by apamin, but TEA evoked similar changes. Thus, a potassium current, likely mediated through BK channels, contributes to the fast AHP and appears to offset the DAP; this current is sensitive to FFA, but insensitive to age. The effect of FFA on the DAP, but not IADP, is diminished in aged animals, possibly reflecting an age-related modulation of the apamin-sensitive SK channel. Future studies will examine the expression of SK channels during the aging process in GnRH neurons. PMID:20655884

  9. Inhibition of thyrotropin response to TSH-releasing hormone by thyroxine in hypothyroid rats

    SciTech Connect

    Boado, R.J.; Zaninovich, A.A.; Ulloa, E.R.; Fernandez Pol, J.A.

    1985-05-01

    Pharmacological amounts of throxine (T4) can inhibit the thyrotropin (TSH) response to TSH-releasing hormone (TRH) before its conversion to triiodothyronine (T3) in the hypophysis of euthyroid rate. The present work tested physiological doses of T4 in hypothyroid rats. Rats were treated with iopanoic acid (IOP) 5 mg/100 g BW 24, 12 and 1.5 hours preceding the study, to prevent intrapituitary conversion of T4 to T3. Nonradioactive T4 was injected iv at time 0. At 20 min a 1 ..mu..g/100 g BW dose of TRH was injected iv. Blood samples were drawn at times 0, 20, and 30 min for determination by radioimmunoassay of plasma T4, T3, and TSH. In untreated rats basal TSH was 1450 +- 200 (SEM) ..mu..U/ml. At 20 min it was 105 +- 12% the basal value and at 30 min (10 min post-TRH) plasma TSH rose to 165 +- 14%. In T4-treated rats, those injected with IOP or with the vehicle alone both had the TSH response suppressed. IOP reduced intrapitutiary T3 from 4.6 +- 2.4 to 0.5 +- 0.2 fmol/min/gland. Thirty min. following the iv injection of 150 ..mu..Ci of double-labeled /sup 125/I-T4, the in vitro cytoplasmic radioactivity in control rats was 1.3 +- 0.13 x 10-/sup 2/% of the injected dose (75% T4, 17% T3), while in nuclei it was 4.2 +- 3.6 x 10-/sup 3/% (5l% T4, 28% T3). The injection of 25 ..mu..g of nonradioactive T4 decreased /sup 125/I-T4 in cytoplasm with no changes in nuclei. These findings suggest an intrinsic capacity of T4 to control TRH stimulation of TSH through binding to cytoplasmic receptors.

  10. Gonadotropin‑releasing hormone inhibits the proliferation and motility of nasopharyngeal carcinoma cells.

    PubMed

    Teng, Loong Hung; Ahmad, Munirah; Ng, Wayne Tiong Weng; Sabaratnam, Subathra; Rasan, Maria Ithaya; Parhar, Ishwar; Khoo, Alan Soo Beng

    2015-10-01

    Gonadotropin‑releasing hormone (GnRH), or its analogues have been demonstrated to exhibit anti‑proliferative effects on tumour cells in ovarian, endometrial and breast cancer through GnRH‑receptors (GnRH‑R). However, the role of GnRH in nasopharyngeal carcinoma (NPC) remains to be elucidated. In order to investigate the effects of GnRH in NPC, the present study examined the expression of the GnRH‑R transcript in NPC and investigated the phenotypic changes in HK1 cells, a recurrent NPC‑derived cell line, upon receiving GnRH treatment. Firstly, the GnRH‑R transcript was demonstrated in the NPC cell lines and four snap frozen biopsies using reverse transcription‑quantitative polymerase chain reaction. In addition, immunohistochemistry revealed the expression of GnRH‑R in two of the eight (25%) NPC specimens. Treatment with GnRH induced a rapid increase in intracellular ionised calcium concentration in the NPC cells. GnRH and its agonists, triptorelin and leuprolide, exerted anti‑proliferative effects on the NPC cells, as determined using an MTS assay. GnRH did not induce any cell cycle arrest in the HK1 cells under the conditions assessed in the present study. Time‑lapse imaging demonstrated a reduction in cell motility in the GnRH‑treated cells. In conclusion, GnRH, or its analogues may have antitumour effects on NPC cells. The consequences of alterations in the levels of GnRH on the progression of NPC require further examination.

  11. Gonadotropin-releasing hormone inhibits the proliferation and motility of nasopharyngeal carcinoma cells

    PubMed Central

    TENG, LOONG HUNG; AHMAD, MUNIRAH; NG, WAYNE TIONG WENG; SABARATNAM, SUBATHRA; RASAN, MARIA ITHAYA; PARHAR, ISHWAR; KHOO, ALAN SOO BENG

    2015-01-01

    Gonadotropin-releasing hormone (GnRH), or its analogues have been demonstrated to exhibit anti-proliferative effects on tumour cells in ovarian, endometrial and breast cancer through GnRH-receptors (GnRH-R). However, the role of GnRH in nasopharyngeal carcinoma (NPC) remains to be elucidated. In order to investigate the effects of GnRH in NPC, the present study examined the expression of the GnRH-R transcript in NPC and investigated the phenotypic changes in HK1 cells, a recurrent NPC-derived cell line, upon receiving GnRH treatment. Firstly, the GnRH-R transcript was demonstrated in the NPC cell lines and four snap frozen biopsies using reverse transcription-quantitative polymerase chain reaction. In addition, immunohistochemistry revealed the expression of GnRH-R in two of the eight (25%) NPC specimens. Treatment with GnRH induced a rapid increase in intracellular ionised calcium concentration in the NPC cells. GnRH and its agonists, triptorelin and leuprolide, exerted anti-proliferative effects on the NPC cells, as determined using an MTS assay. GnRH did not induce any cell cycle arrest in the HK1 cells under the conditions assessed in the present study. Time-lapse imaging demonstrated a reduction in cell motility in the GnRH-treated cells. In conclusion, GnRH, or its analogues may have antitumour effects on NPC cells. The consequences of alterations in the levels of GnRH on the progression of NPC require further examination. PMID:26151677

  12. Gonadotropin-releasing hormone (GnRH) modulates auditory processing in the fish brain.

    PubMed

    Maruska, Karen P; Tricas, Timothy C

    2011-04-01

    Gonadotropin-releasing hormone 1 (GnRH1) neurons control reproductive activity, but GnRH2 and GnRH3 neurons have widespread projections and function as neuromodulators in the vertebrate brain. While these extra-hypothalamic GnRH forms function as olfactory and visual neuromodulators, their potential effect on processing of auditory information is unknown. To test the hypothesis that GnRH modulates the processing of auditory information in the brain, we used immunohistochemistry to determine seasonal variations in these neuropeptide systems, and in vivo single-neuron recordings to identify neuromodulation in the midbrain torus semicircularis of the soniferous damselfish Abudefduf abdominalis. Our results show abundant GnRH-immunoreactive (-ir) axons in auditory processing regions of the midbrain and hindbrain. The number of extra-hypothalamic GnRH somata and the density of GnRH-ir axons within the auditory torus semicircularis also varied across the year, suggesting seasonal changes in GnRH influence of auditory processing. Exogenous application of GnRH (sGnRH and cGnRHII) caused a primarily inhibitory effect on auditory-evoked single neuron responses in the torus semicircularis. In the majority of neurons, GnRH caused a long-lasting decrease in spike rate in response to both tone bursts and playbacks of complex natural sounds. GnRH also decreased response latency and increased auditory thresholds in a frequency and stimulus type-dependent manner. To our knowledge, these results show for the first time in any vertebrate that GnRH can influence context-specific auditory processing in vivo in the brain, and may function to modulate seasonal auditory-mediated social behaviors.

  13. Characterization and validation of bovine gonadotripin releasing hormone receptor (GNRHR) polymorphisms.

    PubMed

    Lirón, J P; Prando, A; Ripoli, M V; Rogberg-Muñoz, A; Posik, D M; Baldo, A; Peral-García, P; Giovambattista, G

    2011-12-01

    Gonadotropin releasing hormone and its receptor (GNRHR) play a critical role in sexual differentiation and reproduction. Available evidence shows a strong genetic component in the timing of puberty. In bovines, there are significant differences within and among beef breeds in the time when bulls reach puberty. Despite its economic importance, there are not many SNPs or genetic markers associated with this characteristic. The aims of the study were to identify DNA polymorphism in the bovine GNRHR by re-sequencing analysis, determine haplotype phases, and perform a population study in a selected tag SNP in six breeds. Eight SNPs were detected, including: one in the Upstream Regulatory Region (URR), five in the coding regions, and two in non-coding regions. This polymorphism level corresponds to one variant every 249.4bp and a global nucleotide diversity of 0.385. Two haplogroups comprising nine haplotypes and two linkage blocks were detected. Despite 5 tag SNPs were required to capture all variability, just one SNP allowed to define both haplogroups, and only two SNPs were needed to differentiate the most common haplotypes. An additional taq SNP was necessary to identify both URR variants. Allele-frequency analysis of a selected taq SNP among breeds showed a geographical cline. European Bos taurus breeds had lower frequencies of the C allele than B. indicus type cattle, while Creole cattle and Wagyu breeds had intermediate frequency. There was a significant correlation between frequency profile and timing of puberty among the studied breeds, which seems to suggest that genetic variation within bovine GNRHR gene could explain at least part of the reported variability.

  14. Effects of corticotropin-releasing hormone on respiratory parameters during sleep in normal men.

    PubMed

    Mann, K; Röschke, J; Benkert, O; Aldenhoff, J; Nink, M; Beyer, J; Lehnert, H

    1995-01-01

    Corticotropin-releasing hormone (CRH) is well-known to be a centrally acting respiratory stimulant after systemic application both in healthy subjects and in patients suffering from respiratory failure. In order to study the effects of CRH on sleep EEG and respiratory parameters during sleep, 14 healthy male volunteers were investigated in a single-blind placebo controlled design. After an adaptation night, polysomnography was performed during two successive nights between 23.00 hrs. and 7.00 hrs. During one night placebo was applied, on the other 50 micrograms ovine CRH was administered intravenously as a bolus every hour from 0.00 hrs. to 6.00 hrs. For the assessment of respiration, blood oxygen saturation and thoracic wall movements were measured, as well as nasal and oral airflow using the thermistor method. Sleep efficiency parameters and subjective perception of sleep quality were not affected following CRH. The following alterations were found regarding sleep architecture: REM sleep as well as slow wave sleep showed a tendency to decrease under CRH, whereas light sleep tended to increase. After an injection of CRH a stimulation of respiration could be observed, with an increase of tidal volume over a time interval of a few minutes. Blood oxygen saturation was only slightly increased. Cortisol and ACTH concentrations were found to be constantly elevated. These results indicate that respiration during sleep is clearly affected by CRH with only slight alterations of global sleep parameters. No association was found between stimulation of ventilation and the occurrence of arousals; the respiratory analeptic effect of CRH thus appears to be specific.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Divergent evolution of two corticotropin-releasing hormone (CRH) genes in teleost fishes

    PubMed Central

    Grone, Brian P.; Maruska, Karen P.

    2015-01-01

    Genome duplication, thought to have happened twice early in vertebrate evolution and a third time in teleost fishes, gives rise to gene paralogs that can evolve subfunctions or neofunctions via sequence and regulatory changes. To explore the evolution and functions of corticotropin-releasing hormone (CRH), we searched sequenced teleost genomes for CRH paralogs. Our phylogenetic and synteny analyses indicate that two CRH genes, crha and crhb, evolved via duplication of crh1 early in the teleost lineage. We examined the expression of crha and crhb in two teleost species from different orders: an African cichlid, Burton's mouthbrooder, (Astatotilapia burtoni; Order Perciformes) and zebrafish (Danio rerio; Order Cypriniformes). Furthermore, we compared expression of the teleost crha and crhb genes with the crh1 gene of an outgroup to the teleost clade: the spotted gar (Lepisosteus oculatus). In situ hybridization for crha and crhb mRNA in brains and eyes revealed distinct expression patterns for crha in different teleost species. In the cichlid, crha mRNA was found in the retina but not in the brain. In zebrafish, however, crha mRNA was not found in the retina, but was detected in the brain, restricted to the ventral hypothalamus. Spotted gar crh1 was found in the retina as well as the brain, suggesting that the ancestor of teleost fishes likely had a crh1 gene expressed in both retina and brain. Thus, genome duplication may have freed crha from constraints, allowing it to evolve distinct sequences, expression patterns, and likely unique functions in different lineages. PMID:26528116

  16. Gonadotropin releasing hormone in the primitive vertebrate family Myxinidae: reproductive neuroanatomy and evolutionary aspects.

    PubMed

    Sills, Eric Scott; Palermo, Gianpiero D

    2013-01-01

    The family Myxinidae embraces all hagfish species, and occupies an evolutionary niche intermediate between ancestral vertebrates and the gnathostomes (jawed vertebrates). Gonadotropin releasing hormone (GnRH) modulates neuroendocrine activity in vertebrates and works in the context of the hypothalamic-pituitary (H-P) axis. The appearance of this neuroendocrine axis marks one of the most crucial developmental achievements in vertebrate evolution, because it enabled further diversification in general growth, metabolism, osmoregulation and reproduction as jawed vertebrates evolved. GnRH studies in hagfish draw attention because such work may be considered as providing proxy data for similar investigations conducted upon long extinct species. Indeed, the fossil record reveals little anatomical difference between those hagfish living 300 million years ago and their modern descendants. Accordingly, the hagfish can offer important evolutionary lessons as they have some highly unusual characteristics not seen in any other vertebrate; they retain many representative features of an ancestral state from which all vertebrates originated. Indeed, because central control of reproduction is perhaps the most basic function of the vertebrate H-P axis, and given the importance of GnRH in this network, research on GnRH in hagfish can help elucidate the early evolution of the H-P system itself. Like all vertebrates, hagfish have a functional hypothalamic area and a pituitary gland, constituting a basic H-P axis. But what role does GnRH play in the reproductive system of this "living fossil"? How can understanding GnRH in hagfish help advance the knowledge of vertebrate neuroendocrinology? Here, information on neuroendocrine function and the role of GnRH specifically in this very basal vertebrate is reviewed.

  17. Long-term effects of gonadotropin-releasing hormone analogs in girls with central precocious puberty

    PubMed Central

    2015-01-01

    Gonadotropin-releasing hormone analogs (GnRHa) are widely used to treat central precocious puberty (CPP). The efficacy and safety of GnRHa treatment are known, but concerns regarding long-term complications are increasing. Follow-up observation results after GnRHa treatment cessation in female CPP patients up to adulthood showed that treatment (especially <6 years) was beneficial for final adult height relative to that of pretreated or untreated patients. Puberty was recovered within 1 year after GnRHa treatment discontinuation, and there were no abnormalities in reproductive function. CPP patients had a relatively high body mass index (BMI) at the time of CPP diagnosis, but BMI standard deviation score maintenance during GnRHa treatment seemed to prevent the aggravation of obesity in many cases. Bone mineral density decreases during GnRHa treatment but recovers to normal afterwards, and peak bone mass formation through bone mineral accretion during puberty is not affected. Recent studies reported a high prevalence of polycystic ovarian syndrome in CPP patients after GnRHa treatment, but it remains unclear whether the cause is the reproductive mechanism of CPP or GnRHa treatment itself. Studies of the psychosocial effects on CPP patients after GnRHa treatment are very limited. Some studies have reported decreases in psychosocial problems after GnRHa treatment. Overall, GnRHa seems effective and safe for CPP patients, based on long-term follow-up studies. There have been only a few long-term studies on GnRHa treatment in CPP patients in Korea; therefore, additional long-term follow-up investigations are needed to establish the efficacy and safety of GnRHa in the Korean population. PMID:25729392

  18. Chronic exposure to hypergravity affects thyrotropin-releasing hormone levels in rat brainstem and cerebellum

    NASA Technical Reports Server (NTRS)

    Daunton, N. G.; Tang, F.; Corcoran, M. L.; Fox, R. A.; Man, S. Y.

    1998-01-01

    In studies to determine the neurochemical mechanisms underlying adaptation to altered gravity we have investigated changes in neuropeptide levels in brainstem, cerebellum, hypothalamus, striatum, hippocampus, and cerebral cortex by radioimmunoassay. Fourteen days of hypergravity (hyperG) exposure resulted in significant increases in thyrotropin-releasing hormone (TRH) content of brainstem and cerebellum, but no changes in levels of other neuropeptides (beta-endorphin, cholecystokinin, met-enkephalin, somatostatin, and substance P) examined in these areas were found, nor were TRH levels significantly changed in any other brain regions investigated. The increase in TRH in brainstem and cerebellum was not seen in animals exposed only to the rotational component of centrifugation, suggesting that this increase was elicited by the alteration in the gravitational environment. The only other neuropeptide affected by chronic hyperG exposure was met-enkephalin, which was significantly decreased in the cerebral cortex. However, this alteration in met-enkephalin was found in both hyperG and rotation control animals and thus may be due to the rotational rather than the hyperG component of centrifugation. Thus it does not appear as if there is a generalized neuropeptide response to chronic hyperG following 2 weeks of exposure. Rather, there is an increase only of TRH and that occurs only in areas of the brain known to be heavily involved with vestibular inputs and motor control (both voluntary and autonomic). These results suggest that TRH may play a role in adaptation to altered gravity as it does in adaptation to altered vestibular input following labyrinthectomy, and in cerebellar and vestibular control of locomotion, as seen in studies of ataxia.

  19. Corticotropin-Releasing Hormone Drives Anandamide Hydrolysis in the Amygdala to Promote Anxiety

    PubMed Central

    Gray, J. Megan; Vecchiarelli, Haley A.; Morena, Maria; Lee, Tiffany T.Y.; Hermanson, Daniel J.; Kim, Alexander B.; McLaughlin, Ryan J.; Hassan, Kowther I.; Kühne, Claudia; Wotjak, Carsten T.; Deussing, Jan M.; Patel, Sachin

    2015-01-01

    Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid–CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert “tonic” regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety. PMID:25740517

  20. Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2.

    PubMed

    Deussing, Jan M; Breu, Johannes; Kühne, Claudia; Kallnik, Magdalena; Bunck, Mirjam; Glasl, Lisa; Yen, Yi-Chun; Schmidt, Mathias V; Zurmühlen, Regine; Vogl, Annette M; Gailus-Durner, Valérie; Fuchs, Helmut; Hölter, Sabine M; Wotjak, Carsten T; Landgraf, Rainer; de Angelis, Martin Hrabé; Holsboer, Florian; Wurst, Wolfgang

    2010-07-07

    Urocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands of corticotropin-releasing hormone receptor type 2 (CRH-R2). To determine the physiological role of UCN3, we generated UCN3-deficient mice, in which the UCN3 open reading frame was replaced by a tau-lacZ reporter gene. By means of this reporter gene, the nucleus parabrachialis and the premammillary nucleus were identified as previously unknown sites of UCN3 expression. Additionally, the introduced reporter gene enabled the visualization of axonal projections of UCN3-expressing neurons from the superior paraolivary nucleus to the inferior colliculus and from the posterodorsal part of the medial amygdala to the principal nucleus of the bed nucleus of the stria terminalis, respectively. The examination of tau-lacZ reporter gene activity throughout the brain underscored a predominant expression of UCN3 in nuclei functionally connected to the accessory olfactory system. Male and female mice were comprehensively phenotyped but none of the applied tests provided indications for a role of UCN3 in the context of hypothalamic-pituitary-adrenocortical axis regulation, anxiety- or depression-related behavior. However, inspired by the prevalent expression throughout the accessory olfactory system, we identified alterations in social discrimination abilities of male and female UCN3 knock-out mice that were also present in male CRH-R2 knock-out mice. In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories.

  1. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    SciTech Connect

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  2. Conformational origin of a difficult coupling in a human growth hormone releasing factor analog.

    PubMed

    Deber, C M; Lutek, M K; Heimer, E P; Felix, A M

    1989-01-01

    During the solid-phase synthesis of the human growth hormone releasing factor (GRF) analog [Ala15, Leu27, Asn28] -GRF(1-32)-OH, incorporation of Boc-Gln16 was determined to be incomplete. While aggregation of growing resin-bound peptide chains with concomitant beta-sheet formation and "precipitation" has been proposed to account in general for such "difficult coupling," no feature of sequence in the Gln16 region of this GRF analog provided an immediate rationale for this result. We now report 500 MHz 1H NMR spectra of a series of resin-bound GRF segments surrounding the Gln16 position (19-32 through 14-32), swelled in dimethylsulfoxide-d6 solutions [GRF(14-32) = Leu14-Ala-Gln-Leu-Ser(Bzl)-Ala-Arg(Tos)-Lys(CIZ)-Leu- Leu-Gln-Asp(OcHex)-Ile-Leu-Asn-Arg(Tos)-Gln-Gln-Gly32-PAM resin]. While relatively sharp spectra are observed for GRF(19-32), components with resonances broadened by an order-of-magnitude appear in spectra of the 18-32 and 17-32 peptide-resin, and the entire spectrum of 16-32 is ill-resolved and highly broadened. Subsequent spectra sharpen again (15-32, 14-32). These combined synthesis/spectroscopic experimental results, in conjunction with predictive analyses using standard Chou-Fasman 2 degrees structure parameters, suggest that the completeness of the Gln16 coupling is hindered by formation of a specific, folded beta-sheet/beta-turn structure in GRF(16-32) (with the turn located at 18-21, "upstream" of the difficult coupling site), and accompanying aggregation of peptide chains. This analysis suggests that awareness of such potential beta-sheet/beta-turn sequences can guide analog choices, and/or facilitate pre-programming of synthesis steps in anticipation of problem couplings.

  3. Activity-dependent modulation of gonadotrophin-releasing hormone neurone activity by acute oestradiol.

    PubMed

    Romanò, Nicola; Herbison, Allan E

    2012-10-01

    Oestradiol (E₂) exerts potent feedback actions upon gonadotrophin-releasing hormone (GnRH) neurones and part of this feedback action may occur through the rapid action of E₂. Using a transgenic GnRH-Pericam mouse line that allows real-time intracellular calcium concentrations ([Ca²⁺](i)) to be monitored in adult GnRH neurones in a brain slice preparation, we examined the acute effects of 100 pM-100 nM E₂ on [Ca²⁺](i) transients in spontaneously active GnRH neurones. Approximately 30% of GnRH neurones exhibit spontaneous [Ca²⁺](i) transients at a frequency greater than two transients/15 min in adult female mice. In these cells, treatment with an incremental 1, 10, 100 nM E₂ protocol or 100 pM E₂ alone resulted in the suppression or complete cessation of [Ca²⁺](i) transients in 15 of 18 (83%) GnRH neurones. This effect was mimicked by E₂ bound to albumin, suggesting a membrane site of action, and was maintained in oestrogen receptor β knockout mice, indicating that this receptor is not essential for the rapid suppression of [Ca²⁺](i) transients. These findings contrast with those GnRH neurones exhibiting very few or no [Ca²⁺](i) transients (< 2 transients/15 min) that exhibit the opposite response of being activated by acute E₂. A series of dual calcium-cell-attached electrical recordings showed that [Ca²⁺](i) transients were associated with GnRH neurone burst firing and that E₂ suppression or activation of [Ca²⁺](i) transients was mirrored by a depression or initiation of burst firing. Taken together, these studies demonstrate that the acute actions of E₂ on GnRH neurones are critically dependent upon their pattern of burst firing.

  4. Growth hormone-releasing hormone-producing pancreatic neuroendocrine tumor in a multiple endocrine neoplasia type 1 family with an uncommon phenotype.

    PubMed

    Sala, Elisa; Ferrante, Emanuele; Verrua, Elisa; Malchiodi, Elena; Mantovani, Giovanna; Filopanti, Marcello; Ferrero, Stefano; Pietrabissa, Andrea; Vanoli, Alessandro; La Rosa, Stefano; Zatelli, Maria C; Beck-Peccoz, Paolo; Verga, Uberta

    2013-07-01

    The objective of this study was to describe a multiple endocrine neoplasia type 1 (MEN1) family characterized by primary hyperparathyroidism, in association with acromegaly because of ectopic growth hormone-releasing hormone (GHRH) secretion by a pancreatic neuroendocrine tumor in a young man and with a bronchial carcinoid in his mother. We investigate the clinical, radiological imaging, histopathologic findings, and therapy. An 18-year-old man successfully underwent subtotal parathyroidectomy for primary hyperparathyroidism. A subsequent genetic analysis showed a MEN1 gene mutation. Three years later, acromegaly because of ectopic GHRH secretion was diagnosed (pituitary MRI negative and elevated GHRH levels). A search for an ectopic tumor was unsuccessful and somatostatin analog therapy was started. Successively, scintigraphy with somatostatin analogs (68-Ga-DOTATOC-PET) showed three focal areas in the pancreatic tail. Distal pancreatectomy showed multiple pancreatic neuroendocrine tumors and hormonal status was normalized. Afterwards, the evaluation of the patient's mother, carrying the same mutation, indicated a primary hyperparathyroidism and a 4 cm lung mass. The patient underwent subtotal pneumonectomy and the histological analysis was consistent with the diagnosis of a typical bronchial carcinoid. In conclusion, an atypical phenotype may be recorded in MEN1 families, thus emphasizing the importance of the new imaging and surgical techniques in the diagnosis and treatment of such a rare disease.

  5. Aromatase inhibitors with or without luteinizing hormone-releasing hormone agonist for metastatic male breast cancer: report of four cases and review of the literature.

    PubMed

    Kuba, Sayaka; Ishida, Mayumi; Oikawa, Masahiro; Nakamura, Yoshiaki; Yamanouchi, Kosho; Tokunaga, Eriko; Taguchi, Kenichi; Esaki, Taito; Eguchi, Susumu; Ohno, Shinji

    2016-11-01

    The roles of aromatase inhibitors (AIs) and luteinizing hormone-releasing hormone (LH-RH) agonists in the management of male breast cancer remain uncertain, with no reports in Japanese men. We report four Japanese male patients with metastatic breast cancer treated with AIs with or without an LH-RH agonist, and consider the relationship between treatment effect and estradiol (E2) concentration. Three patients were initially treated with AI alone after selective estrogen receptor modulators (SERMs), and one received AIs plus an LH-RH agonist after a SERM. Two patients treated with an AI alone responded, one patient with E2 levels below the lower assay limit and the other with levels above the limit. The other treated with an AI alone experienced progression regardless of the E2 levels below the lower assay limit, however, responded after the addition of an LH-RH agonist. E2 concentrations were related to the efficacy of treatment in one patient. The patient initially treated with an AI plus an LH-RH agonist also responded. No grade 3 or 4 adverse events were observed in any of the patients treated with AIs with or without an LH-RH agonist. AIs with or without an LH-RH agonist offer an effective treatment option for hormone receptor-positive metastatic male breast cancer.

  6. Hormone therapy in acne.

    PubMed

    Lakshmi, Chembolli

    2013-01-01

    Underlying hormone imbalances may render acne unresponsive to conventional therapy. Relevant investigations followed by initiation of hormonal therapy in combination with regular anti-acne therapy may be necessary if signs of hyperandrogenism are present. In addition to other factors, androgen-stimulated sebum production plays an important role in the pathophysiology of acne in women. Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. Hormonal therapy may also be beneficial in female acne patients with normal serum androgen levels. An understanding of the sebaceous gland and the hormonal influences in the pathogenesis of acne would be essential for optimizing hormonal therapy. Sebocytes form the sebaceous gland. Human sebocytes express a multitude of receptors, including receptors for peptide hormones, neurotransmitters and the receptors for steroid and thyroid hormones. Various hormones and mediators acting through the sebocyte receptors play a role in the orchestration of pathogenetic lesions of acne. Thus, the goal of hormonal treatment is a reduction in sebum production. This review shall focus on hormonal influences in the elicitation of acne via the sebocyte receptors, pathways of cutaneous androgen metabolism, various clinical scenarios and syndromes associated with acne, and the available therapeutic armamentarium of hormones and drugs having hormone-like actions in the treatment of acne.

  7. Gonadotropin-inhibitory hormone (GnIH) in the amphibian brain and its relationship with the gonadotropin releasing hormone (GnRH) system: An overview.

    PubMed

    Jadhao, Arun G; Pinelli, Claudia; D'Aniello, Biagio; Tsutsui, Kazuyoshi

    2017-01-01

    It is well known that the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) plays an important role as a primary factor regulating gonadotropin secretion in reproductive processes in vertebrates. The discovery of the presence of a gonadotropin-inhibitory hormone (GnIH) in the brains of birds has further contributed to our understanding of the reproduction control by the brain. GnIH plays a key role in inhibition of reproduction and acts on the pituitary gland and GnRH neurons via a novel G protein-coupled receptor (GPR147). GnIH decreases gonadotropin synthesis and release, thus inhibiting gonadal development and maintenance. The GnRH and GnIH neuronal peptidergic systems are well reported in mammals and birds, but limited information is available regarding their presence and localization in the brains of other vertebrate species, such as reptiles, amphibians and fishes. The aim of this review is to compile and update information on the localization of GnRH and GnIH neuronal systems, with a particular focus on amphibians, summarizing the neuroanatomical distribution of GnIH and GnRH and emphasizing the discovery of GnIH based on RFamide peptides and GnIH orthologous peptides found in other vertebrates and their functional significance.

  8. Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75.

    PubMed Central

    Yano, T; Pinski, J; Halmos, G; Szepeshazi, K; Groot, K; Schally, A V

    1994-01-01

    Female athymic nude mice bearing xenografts of OV-1063 human epithelial ovarian cancer cell line were treated with potent luteinizing hormone (LH)-releasing hormone (LH-RH) antagonist SB-75 (Cetrorelix; [Ac-D-Nal(2)1, D-Phe(4 CI)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH in which Ac-D-Nal(2) = N-acetyl-3-(2-naphthyl)-D-alanine, D-Phe(4CI) = 4-chloro-D-phenylalanine, D-Pal(3) = 3-(3-pyridyl)-D-alanine, and D-Cit = D-Citrulline) or with the agonist [D-Trp6]LH-RH. In the first experiment, SB-75 and [D-Trp6]LH-RH were administered in the form of microcapsules releasing 60 and 25 micrograms/day, respectively. In the second study, the analogs were given by daily s.c. injections in doses of 100 micrograms/day. In both experiments, tumor growth, as measured by reduction in tumor volume, percentage change in tumor volume, tumor burden, and increase in tumor doubling time, was significantly inhibited by treatment with SB-75 but not with [D-Trp6]LH-RH. Uterine and ovarian weights were reduced and serum LH levels decreased by administration of either analog. Chronic treatment with SB-75 greatly reduced the concentration of receptors for epidermal growth factor and insulin-like growth factor I in tumor cell membranes, a phenomenon that might be related to tumor growth inhibition. It is possible that the antitumoral effects of SB-75 on OV-1063 ovarian cancers are exerted not only through the suppression of the pituitary-gonadal axis, but also directly. In view of its strong inhibitory effect on the growth of OV-1063 ovarian cancers in vivo, the potent LH-RH antagonist SB-75 might be considered for possible hormonal therapy of advanced epithelial ovarian carcinoma. PMID:7518926

  9. A comparison of human chorionic gonadotropin and luteinizing hormone releasing hormone on the induction of spermiation and amplexus in the American toad (Anaxyrus americanus)

    PubMed Central

    2012-01-01

    Background Captive breeding programs for endangered amphibian species often utilize exogenous hormones for species that are difficult to breed. The purpose of our study was to compare the efficacy of two different hormones at various concentrations on sperm production, quantity and quality over time in order to optimize assisted breeding. Methods Male American toads (Anaxyrus americanus) were divided into three separate treatment groups, with animals in each group rotated through different concentrations of luteinizing hormone releasing hormone analog (LHRH; 0.1, 1.0, 4.0 and 32 micrograms/toad), human chorionic gonadotropin (hCG; 50, 100, 200, and 300 IU), or the control over 24 hours. We evaluated the number of males that respond by producing spermic urine, the sperm concentration, percent motility, and quality of forward progression. We also evaluated the effects of hCG and LHRH on reproductive behavior as assessed by amplexus. Data were analyzed using the Generalized Estimating Equations incorporating repeated measures over time and including the main effects of treatment and time, and the treatment by time interaction. Results The hormone hCG was significantly more effective at stimulating spermiation in male Anaxyrus americanus than LHRH and showed a dose-dependent response in the number of animals producing sperm. At the most effective hCG dose (300 IU), 100% of the male toads produced sperm, compared to only 35% for the best LHRH dose tested (4.0 micrograms). In addition to having a greater number of responders (P < 0.05), the 300 IU hCG treatment group had a much higher average sperm concentration (P < 0.05) than the treatment group receiving 4.0 micrograms LHRH. In contrast, these two treatments did not result in significant differences in sperm motility or quality of forward progressive motility. However, more males went into amplexus when treated with LHRH vs. hCG (90% vs. 75%) by nine hours post-administration. Conclusion There is a clear

  10. Dihydropyridine-sensitive calcium channel activity related to prolactin, growth hormone, and luteinizing hormone release from anterior pituitary cells in culture: interactions with somatostatin, dopamine, and estrogens

    SciTech Connect

    Drouva, S.V.; Rerat, E.; Bihoreau, C.; Laplante, E.; Rasolonjanahary, R.; Clauser, H.; Kordon, C.

    1988-12-01

    In the present work, we determined the activity of voltage-dependent dihydropyridine (DHP)-sensitive Ca2+ channels related to PRL, GH, and LH secretion in primary cultures of pituitary cells from male or female rats. We investigated their modulation by 17 beta-estradiol (E2) and their involvement in dopamine (DA) and somatostatin (SRIF) inhibition of PRL and GH release. BAY-K-8644 (BAYK), a DHP agonist which increases the opening time of already activated channels, stimulated PRL and GH secre