Adrenal steroid hormones and metaphyseal bone in children.

PubMed

Remer, Thomas; Boye, Kai R; Hartmann, Michaela F; Neu, Christina; Schoenau, Eckhard; Manz, Friedrich; Wudy, Stefan A

2004-01-01

The responses of metaphyseal bone tissue to physiological variations of endogenous adrenal steroid hormones during childhood are unclear. Therefore, we studied potential hormonal influences in children before the appearance of pubic hair (onset of pubarche). Excretions of major glucocorticoid metabolites (C21), cortisol, sum of adrenarchal dehydroepiandrosterone and its immediate 16-hydroxylated metabolites (DHEA&M), and 5-androstene-3beta,17beta-diol (hermaphrodiol) were analyzed in a cross-sectional study in 24-hour urine samples of 109 healthy boys and girls, aged 6-13 years, using steroid profiling by gas chromatography-mass spectrometry. Total and trabecular volumetric bone mineral densities, bone mineral content (BMC) and bone strength strain index were determined with peripheral quantitative computed tomography at the distal forearm. In multiple regression analyses significant associations with the metaphyseal radius were seen for grip force, age, or BMI depending on gender and bone variable analyzed. DHEA&M did not contribute to the explanation of the variance of any bone variable. However, hermaphrodiol positively explained a significant part of variation of bone mineral densities, and BMC (p < 0.01) in girls. Significantly negative associations with all bone variables were seen in boys for cortisol. The steroid hormones, cortisol and hermaphrodiol, in their physiological ranges, but not the adrenarche marker DHEA&M, appear to associate with metaphyseal bone in a sex-dependent manner during childhood. Copyright (c) 2004 S. Karger AG, Basel.

[The relationship between metabolic disorders and small for gestational age with idiopathic premature adrenarche].

PubMed

Mejorado Molano, Francisco Javier; Andrés Zallo, Laura; Fornos Rodríguez, Marta; Pérez Segura, Pilar; Gavela Pérez, Teresa; Sanz Calvo, María Luisa; Soriano Guillén, Leandro

2017-11-01

There is still controversy on the relationship between idiopathic premature adrenarche (IPA) and a history of small for gestational age, as well as the concomitant presence of obesity and other metabolic disturbances. An attempt is made to study these potential associations in a cohort of girls with IPA from our hospital. A descriptive cross-sectional study was conducted that included girls with a diagnosis of IPA from the Paediatric Department of the Fundación Jiménez Díaz (Madrid, Spain) between January 2007 and May 2015. A record was made of family and personal history with perinatal data, as well as anthropometric data and biochemical values at the time of diagnosis. Out of a total of 76 girls with IPA, 2.7% had a history of small for gestational age. When body mass index was analysed according to modified criteria of WHO 2007/Cole 2000, 11.8% were overweight, and 11.8% were obese at diagnosis. Using the criteria set by the Spanish Ministry of Health, 6.6% were overweight and 18.4% obese, with 21.2% of the girls being insulin resistance, and 13.95% having dyslipidaemia. None of them had hypertension. From a comparative analysis between normal and overweight and obesity IPA girls, the latter had significantly higher levels of triglycerides and insulin, a higher HOMA index, and lower levels of HDL cholesterol. IPA girls included in the study do not have a higher prevalence of small for gestational age compared to the general population. Prevalence of overweight and obesity in girls with IPA is not higher than the prevalence in the normal population. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Steroid profiles in serum by liquid chromatography-tandem mass spectrometry in infants with genital hair.

PubMed

Kaplowitz, Paul; Soldin, Steven J

2007-05-01

In recent years, an increasing number of infants have been seen with fine hair in the genital area and no other signs of androgen excess, but the hormonal basis of this finding is unknown. To compare steroid profiles in infants with genital hair with age-matched control infants, using liquid chromatography-tandem mass spectrometry (LC-TMS) to measure eight steroids (cortisol, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone, testosterone, androstenedione, DHEA, and DHEA-S). Samples were obtained between 1/04 and 12/05 from infants with genital hair, and for comparison, a group of 5-9 year-olds with premature adrenarche, as well as control children of similar ages being seen for thyroid problems or short stature. Steroid profiles in infants with genital hair were similar to those in control infants, except that DHEA-S levels were somewhat higher (17.5 vs. 7.6 microg/dl [476 vs. 207 nmol/l]; p = 0.067), and six of 12 had levels >15 microg/dl (408 nmol/l) vs. one of 12 controls. Testosterone levels were low (<10 ng/dl [<350 pmol/l) in nearly all infants with pubic hair; the main exception was a girl whose father used topical testosterone (31 ng/dl [1076 pmol/l]). Genital hair disappeared in two patients over time but persisted for 6 months to 2 years in most. No pathological increase in steroid levels was found in infants with genital hair vs controls, though a mild elevation of DHEA-S was seen in about half. This suggests that pubic hair in infancy may represent a mild and early onset variant of premature adrenarche, with a benign clinical course.

Determination of 17OHPreg and DHEAS by LC-MS/MS: Impact of Age, Sex, Pubertal Stage, and BMI on the Δ5 Steroid Pathway.

PubMed

Kulle, Alexandra E; Reinehr, Thomas; Simic-Schleicher, Gunter; Hornig, Nadine C; Holterhus, Paul-Martin

2017-01-01

Dehydroepiandrosterone sulfate (DHEAS) and 17-hydroxypregnenolone (17OHPreg) are important for understanding the Δ5 pathway (e.g., in adrenarche and obesity). Although mass spectrometry has become the state-of-the-art method for quantifying steroids, there are few comprehensive age-, sex-, and pubertal stage-specific reference ranges for children. To develop a sensitive and reliable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of DHEAS and 17OHPreg and to establish entire age-, sex- and pubertal stage-specific reference ranges in children. A total of 684 children, 453 (243 female, 210 male) with normal body mass index (BMI; <90th) and 231 (132 female, 99 male) obese subjects (>97th), were categorized into 11 age groups, and age- and Tanner stage (PH)-specific reference ranges were determined. The limit of detection was 0.05 nmol/L for 17OHPreg and 0.5 nmol/L for DHEAS. Levels of both steroids declined after the neonatal period. Comparisons with RIA assays (Siemens, Munich, Germany) (DHEAS) and an in-house kit (17OHPreg) revealed 0.95 and 0.93, respectively, as coefficients of determination. Although DHEAS-generally higher in boys-increased continuously starting at 3 to 6 years, 17OHPreg remained largely constant. In obese patients, both were significantly elevated, also in part after alignment to Tanner stages (PH). UPLC-MS/MS is sensitive and reliable for quantifying DHEAS and 17OHPreg. Our data support differential maturation of CYP17 during adrenarche with successively increasing 17,20-lyase activity but largely constant 17α-hydroxylation activity. Endocrine interpretation of 17OHPreg and DHEAS must consider differential patterns for age, sex, pubertal stage, and BMI. Copyright © 2017 by the Endocrine Society

Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling.

PubMed

Lavery, G G; Idkowiak, J; Sherlock, M; Bujalska, I; Ride, J P; Saqib, K; Hartmann, M F; Hughes, B; Wudy, S A; De Schepper, J; Arlt, W; Krone, N; Shackleton, C H; Walker, E A; Stewart, P M

2013-02-01

Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism. To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases. Clinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics. Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management. Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS).

Juvenile granulosa cell ovarian tumor: a case report and review of literature.

PubMed

Sivasankaran, Sujatha; Itam, Paul; Ayensu-Coker, Leslie; Sanchez, Judith; Egler, Rachel A; Anderson, Matthew L; Brandt, Mary L; Dietrich, Jennifer E

2009-10-01

Juvenile granulosa cell tumors (JGCT) are rare ovarian tumors that frequently present with precocious puberty. Presentation in infants less than a year of age is also rare. We describe a 10-month-old infant who presented with both premature thelarche and adrenarche due to JGCT. Laboratory evaluation revealed classic elevation of estradiol and inhibin B, and less classic elevation of total and free testosterone. Oophorectomy and staging resulted in a diagnosis of Stage IA JGCT. Survival rates are >95% among patients diagnosed under 10 years of age. Tumor recurrence is rare but can occur as late as 48 months. Therefore, tumor surveillance is warranted for patients with even a Stage IA JGCT and involves monitoring serial inhibin B levels along with intermittent imaging.

[Clinical thinking and decision making in practice. A 7-year old boy with rapid growth and pubic hair].

PubMed

Berents-Oosterhof, M Y; Noordam, C; Otten, B J

2000-12-16

A 7-year-old boy was tall, with a developing penis and initial growth of pubic hair. Due to the accelerated growth there was no premature adrenarche and due to the increased testicular volume there must have been a central cause for the production of androgens. Further specific investigations revealed an astrocytoma of the hypothalamus. After radiotherapy, the tumour exhibited no growth. The pubertal development was inhibited and the growth later stimulated by means of medication. In the case of pubertas praecox the growth chart and pubertal stages including testicular volume can help to differentiate between central and peripheral precocious puberty, narrow the diagnostic evaluation and reduce the time of the initial therapy.

Effects of Stress After Hurricanes Katrina and Rita on Pubertal Disorders in Children

PubMed Central

Ponnapakkam, Adharsh; Gensure, Robert

2008-01-01

Hurricanes Katrina and Rita caused widespread damage that resulted in increased stress levels for families living in the New Orleans area. This study examined the relationship between this stress and the onset of puberty in children by conducting a retrospective chart review of patients referred before and after the storm to a pediatric endocrine practice in New Orleans. The total number of new patients referred and the incidence of diagnoses that are unlikely to be affected by stress (ie, thyroid disease and premature adrenarche) were essentially unchanged. On the other hand, the incidence of central precocious puberty decreased by 52% after the storm, while the incidence of pubertal delay increased by 9% in the post storm period. This study thus provides evidence that stress delays the onset of puberty in children. PMID:21603464

Steroid Assays in Paediatric Endocrinology

PubMed Central

2010-01-01

Most steroid disorders of the adrenal cortex come to clinical attention in childhood and in order to investigate these problems, there are many challenges to the laboratory which need to be appreciated to a certain extent by clinicians. The analysis of sex steroids in biological fluids from neonates, over adrenarche and puberty present challenges of specificities and concentrations often in small sample sizes. Different reference ranges are also needed for interpretations. For around 40 years, quantitative assays for the steroids and their regulatory peptide hormones have been possible using immunoassay techniques. Problems are recognised and this review aims to summarise the benefits and failings of immunoassays and introduce where tandem mass spectrometry is anticipated to meet the clinical needs for steroid analysis in paediatric endocrine investigations. It is important to keep a dialogue between clinicians and the laboratory, especially when any laboratory result does not make sense in the clinical investigation. Conflict of interest:None declared. PMID:21274330

Evaluation of puberty by verifying spontaneous and stimulated gonadotropin values in girls.

PubMed

Chin, Vivian L; Cai, Ziyong; Lam, Leslie; Shah, Bina; Zhou, Ping

2015-03-01

Changes in pharmacological agents and advancements in laboratory assays have changed the gonadotropin-releasing hormone analog stimulation test. To determine the best predictive model for detecting puberty in girls. Thirty-five girls, aged 2 years 7 months to 9 years 3 months, with central precocious puberty (CPP) (n=20) or premature thelarche/premature adrenarche (n=15). Diagnoses were based on clinical information, baseline hormones, bone age, and pelvic sonogram. Gonadotropins and E2 were analyzed using immunochemiluminometric assay. Logistic regression for CPP was performed. The best predictor of CPP is the E2-change model based on 3- to 24-h values, providing 80% sensitivity and 87% specificity. Three-hour luteinizing hormone (LH) provided 75% sensitivity and 87% specificity. Basal LH lowered sensitivity to 65% and specificity to 53%. The E2-change model provided the best predictive power; however, 3-h LH was more practical and convenient when evaluating puberty in girls.

Adrenal androgen secretion and dopaminergic activity in anorexia nervosa.

PubMed

Devesa, J; Pérez-Fernández, R; Bokser, L; Gaudiero, G J; Lima, L; Casanueva, F F

1988-01-01

The aim of the present study was to investigate if the postulated deficient adrenal androgen secretion in Anorexia Nervosa (AN), could be associated with a status of sustained dopaminergic hyperactivity. The adrenal responses to ACTH and PRL response to dopaminergic receptor blockade were studied in seven patients with Anorexia Nervosa and seven regularly menstruating women. AN patients showed lower baseline DHEA-sulphate (DHEA-S), androstenedione (Adione) and prolactin (PRL) levels than controls. The response to ACTH revealed evidences of significantly decreased 17-20 desmolase activity in AN, with apparent predominance of glucocorticoid over androgenic pathways relative to controls. Because dopaminergic receptor blockade with Domperidone (DOM) showed intense dopaminergic hyperactivity in AN, we postulate that the adrenal regression seen in the disease is the consequence of a reduced zona reticularis as a consequence of the lack of trophic support by PRL and/or intermediate lobe proopiomelanocortin (IL-POMC). This is consistent with our previous results in pre-adrenarchal dogs and rabbits.

Pubic hair of infancy: endocrinopathy or enigma?

PubMed

Nebesio, Todd D; Eugster, Erica A

2006-03-01

Pubic hair of infancy is a rare condition that has not been well-characterized. A retrospective chart review of infants <12 months of age who presented to our pediatric endocrine clinics with isolated pubic hair over the last 5 years was performed. Eleven patients were identified (6 male and 5 female). The average age at diagnosis was 8.3 +/- 2.0 months. The majority of patients (73%) had pubic hair in an atypical location. Growth pattern, laboratory evaluation, and bone-age radiographs were unremarkable for all the infants. Of the infants that returned for follow-up, pubic hair resolved by the age of 11.0 +/- 1.5 months. From our experience and review of the literature, we suggest that isolated pubic hair of infancy is a benign entity. However, long-term follow-up needs to be done to determine if pubic hair of infancy is an atypical variant of premature adrenarche, which may place these patients at risk for later adult disease.

Nonsalt-losing congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency with normal glomerulosa function.

PubMed

Pang, S; Levine, L S; Stoner, E; Opitz, J M; Pollack, M S; Dupont, B; New, M I

1983-04-01

In studies of a 6-yr-old boy and his non-HLA identical 8-yr-old sister, we demonstrated 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency in the biosynthetic pathways of glucocorticoids and androgens, but not mineralocorticoids. The sister did not manifest abnormal genital development at birth, but developed premature adrenarche at the age of 4 yr, with clitoromegaly and advanced bone age. The brother had perineal hypospadias at birth and developed premature adrenarche at the age of 6 yr. In both siblings, baseline and ACTH-stimulated delta 5 steroids were markedly elevated. The baseline and ACTH-stimulated ratios of delta 5 to delta 4 steroids remained extremely high, and all steroids promptly suppressed with dexamethasone (DEX). Normal baseline PRA and serum and urinary aldosterone (Aldo) levels increased after stimulation with a low Na+ diet. Renal Na+ conservation was normal after dietary Na+ deprivation with and without DEX administration. The PRA to pH 1 Aldo ratio remained normal with normal and low Na+ diets, regardless of DEX administration, indicating normal glomerulosa function with renin stimulation. In both siblings, ACTH increased PRA and Aldo levels, maintaining the PRA to pH 1 Aldo ratio unchanged from the baseline value. In contrast, in control children, PRA was suppressed, while Aldo increased, resulting in a fall of the PRA to pH 1 Aldo ratio. The increase in PRA with exogenous ACTH in these siblings suggests there may be an ACTH-stimulable mineralocorticoid antagonist. During prolonged DEX administration, hCG administration caused a slight increase in 17-hydroxypregnenolone and dehydroepiandrosterone in both the siblings, while testosterone (T) rose poorly in the brother, and estradiol did not rise at all in the sister. These results suggest the possibility of a deficiency of 3 beta-HSD in the gonads as well as the adrenals. After [3H]dehydroepiandrosterone iv infusion, there was normal conversion to [3H]-conjugated testosterone glucuronide, suggesting the presence of normal peripheral 3 beta-HSD activity. We propose that in these siblings, there is a deficiency of 3 beta-HSD in the adrenal zona fasciculata and zona reticularis, whereas 3 beta-HSD activity is intact in the zona glomerulosa. In addition, in these siblings, 3 beta-HSD deficiency was present in the gonads, while peripheral 3 beta-HSD activity appeared to be intact. These cases demonstrate further the heterogeneity of congenital adrenal hyperplasia due to 3 beta-HSD deficiency.

Hair loss in women.

PubMed

Camacho-Martínez, Francisco M

2009-03-01

Female pattern hair loss (FPHL) is a clinical problem that is becoming more common in women. Female alopecia with androgen increase is called female androgenetic alopecia (FAGA) and without androgen increase is called female pattern hair loss. The clinical picture of typical FAGA begins with a specific "diffuse loss of hair from the parietal or frontovertical areas with an intact frontal hairline." Ludwig called this process "rarefaction." In Ludwig's classification of hair loss in women, progressive type of FAGA, 3 patterns were described: grade I or minimal, grade II or moderate, and grade III or severe. Ludwig also described female androgenetic alopecia with male pattern (FAGA.M) that should be subclassified according to Ebling's or Hamilton-Norwood's classification. FAGA.M may be present in 4 conditions: persistent adrenarche syndrome, alopecia caused by an adrenal or an ovarian tumor, posthysterectomy, and as an involutive alopecia. A more recent classification (Olsen's classification of FPHL) proposes 2 types: early- and late-onset with or without excess of androgens in each. The diagnosis of FPHL is made by clinical history, clinical examination, wash test, dermoscopy, trichoscan, trichograms and laboratory test, especially androgenic determinations. Topical treatment of FPHL is with minoxidil, 2-5% twice daily. When FPHL is associated with high levels of androgens, systemic antiandrogenic therapy is needed. Persistent adrenarche syndrome (adrenal SAHA) and alopecia of adrenal hyperandrogenism is treated with adrenal suppression and antiandrogens. Adrenal suppression is achieved with glucocorticosteroids. Antiandrogens therapy includes cyproterone acetate, drospirenone, spironolactone, flutamide, and finasteride. Excess release of ovarian androgens (ovarian SAHA) and alopecia of ovarian hyperandrogenism is treated with ovarian suppression and antiandrogens. Ovarian suppression includes the use of contraceptives containing an estrogen, ethinylestradiol, and a progestogen. Antiandrogens such as cyproterone acetate, always accompanied by tricyclic contraceptives, are the best choice of antiandrogens to use in patients with FPHL. Gonadotropin-releasing hormone agonists such as leuprolide acetate suppress pituitary and gonadal function through a reduction in luteinizing hormone and follicle-stimulating hormone levels. Subsequently, ovarian steroid levels also will be reduced, especially in patients with polycystic ovary syndrome. When polycystic ovary syndrome is associated with insulin resistance, metformin must be considered as treatment. Hyperprolactinemic SAHA and alopecia of pituitary hyperandrogenism should be treated with bromocriptine or cabergoline. Postmenopausal alopecia, with previous high levels of androgens or with prostatic-specific antigen greater than 0.04 ng/mL, improves with finasteride or dutasteride. Although we do not know the reason, postmenopausal alopecia in normoandrogenic women also improves with finasteride or dutasteride at a dose of 2.5 mg per day. Dermatocosmetic concealment with a hairpiece, hair prosthesis as extensions, or partial hairpieces can be useful. Lastly, weight loss undoubtedly improves hair loss in hyperandrogenic women.

Hormones and Human and Nonhuman Primate Growth.

PubMed

Bernstein, Robin Miriam

2017-01-01

The aim of this paper was to review information pertaining to the hormonal regulation of nonhuman primate growth, with specific focus on the growth hormone (GH)-insulin-like growth factor (IGF) axis and adrenal androgens. Hormones of the GH-IGF axis are consistently associated with measures of growth - linear, weight, or both - during the growth period; in adulthood, concentrations of IGF-I, IGF-binding protein-3, and GH-binding protein are not associated with any measures of size. Comparing patterns of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may be especially relevant for understanding whether the childhood stage of growth and development is unique to humans and perhaps other apes. Genetic, hormonal, and morphological data on adrenarche in other nonhuman primate species suggest that this endocrine transition is delayed in humans, chimpanzees, and possibly gorillas, while present very early in postnatal life in macaques. This suggests that although perhaps permitted by an extension of the pre-adolescent growth period, childhood builds upon existing developmental substrates rather than having been inserted de novo into an ancestral growth trajectory. Hormones can provide insight regarding the evolution of the human growth trajectory. © 2017 S. Karger AG, Basel.

Experience with cyproterone acetate in the treatment of precocious puberty.

PubMed

Laron, Z; Kauli, R

2000-07-01

The authors review their experience (1967-present) in the use of cyproterone acetate (CPA) in precocious puberty. CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg b.i.d. (70-100 mg/d). After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial stimulatory effect of the GnRHa as well as an adjunct drug in case of very active adrenarche causing advanced bone age during GnRHa treatment. The final heights of girls treated with CPA and girls treated with D-Trp6-LHRH were found comparable: 157.8+/-5.1 cm vs 159.6+/-6.3 cm, respectively. The main adverse effects were occasional fatigue due to partial adrenal insufficiency with CPA and gynecomastia in a few boys. Liver function tests were normal in all patients with the exception of one boy with severe hypothalamic disease, including precocious puberty, who developed liver cirrhosis 3 years after stopping CPA following 5 years treatment. Other indications for CPA treatment during childhood and adolescence, such as fast puberty, congenital adrenal hyperplasia and acne, are also mentioned.

Cushing disease as possible cause of persistent growth failure despite growth hormone therapy in a small for gestational age male.

PubMed

Heneghan, MaryKathleen; Alemzadeh, Ramin

2011-12-01

Growth hormone (GH) therapy in children with small for gestational age (SGA) has been shown to be of significant therapeutic benefit. We report the case of an 11-year-old Caucasian male who developed early adrenarche, hypertension and insulin resistance on GH therapy for SGA and profound short stature (ht -5 SD). This patient demonstrated a poor response to GH therapy and developed physical and biochemical findings of insulin resistance responsive to metformin therapy. He remained hypertensive, however, and continued to have elevated serum dehydroepiandrosterone sulfate levels. Urinary free cortisol excretion was subsequently found to be elevated. The diagnosis of Cushing's disease was confirmed with inferior petrosal sinus sampling and pituitary MRI. The patient underwent partial adenohypophysectomy with resulting normalization of plasma cortisol levels and associated symptoms. Our patient's diagnosis of Cushing's disease was complicated by his past history of poor growth since birth and history of SGA. The signs of Cushing's disease did not overtly appear until GH therapy was initiated to help treat severe short stature. It is possible that the metabolic effects of GH therapy unmasked the presence of underlying Cushing's disease.

Androgens and innate immunity in rehabilitated semi-captive orangutans (Pongo pygmaeus morio) from Malaysian Borneo.

PubMed

Prall, Sean P; Ambu, Laurentius; Nathan, Senthilvel; Alsisto, Sylvia; Ramirez, Diana; Muehlenbein, Michael P

2015-06-01

Despite the implications for the development of life-history traits, endocrine-immune trade-offs in apes are not well studied. This is due, in part, to difficulty in sampling wild primates, and lack of methods available for immune measures using samples collected noninvasively. Evidence for androgen-mediated immune trade-offs in orangutans is virtually absent, and very little is known regarding their pattern of adrenal development and production of adrenal androgens. To remedy both of these deficiencies, sera were collected from orangutans (Pongo pygmaeus morio) (N = 38) at the Sepilok Orangutan Rehabilitation Centre, Sabah, Malaysia, during routine health screenings. Testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulfate (DHEA-S) were assayed, along with two measures of functional innate immunity. DHEA-S concentrations, but not DHEA, increased with age in this sample of 1-18 year old animals. DHEA concentrations were higher in animals with higher levels of serum bacteria killing ability, while DHEA-S and testosterone concentrations were higher in animals with reduced complement protein activity. Patterns of DHEA-S concentration in this sample are consistent with patterns of adrenarche observed in other apes. Results from this study suggest that in addition to testosterone, DHEA and DHEA-S may have potent effects on immunological activity in this species. © 2015 Wiley Periodicals, Inc.

Evaluation and Referral of Children With Signs of Early Puberty.

PubMed

Kaplowitz, Paul; Bloch, Clifford

2016-01-01

Concerns about possible early pubertal development are a common cause for referral to pediatric medical subspecialists. Several recent studies have suggested that onset of breast and/or pubic hair development may be occurring earlier than in the past. Although there is a chance of finding pathology in girls with signs of puberty before 8 years of age and in boys before 9 years of age, the vast majority of these children with signs of apparent puberty have variations of normal growth and physical development and do not require laboratory testing, bone age radiographs, or intervention. The most common of these signs of early puberty are premature adrenarche (early onset of pubic hair and/or body odor), premature thelarche (nonprogressive breast development, usually occurring before 2 years of age), and lipomastia, in which girls have apparent breast development which, on careful palpation, is determined to be adipose tissue. Indicators that the signs of sexual maturation may represent true, central precocious puberty include progressive breast development over a 4- to 6-month period of observation or progressive penis and testicular enlargement, especially if accompanied by rapid linear growth. Children exhibiting these true indicators of early puberty need prompt evaluation by the appropriate pediatric medical subspecialist. Therapy with a gonadotropin-releasing hormone agonist may be indicated, as discussed in this report. Copyright © 2016 by the American Academy of Pediatrics.

Diagnosis and management of Silver-Russell syndrome: first international consensus statement.

PubMed

Wakeling, Emma L; Brioude, Frédéric; Lokulo-Sodipe, Oluwakemi; O'Connell, Susan M; Salem, Jennifer; Bliek, Jet; Canton, Ana P M; Chrzanowska, Krystyna H; Davies, Justin H; Dias, Renuka P; Dubern, Béatrice; Elbracht, Miriam; Giabicani, Eloise; Grimberg, Adda; Grønskov, Karen; Hokken-Koelega, Anita C S; Jorge, Alexander A; Kagami, Masayo; Linglart, Agnes; Maghnie, Mohamad; Mohnike, Klaus; Monk, David; Moore, Gudrun E; Murray, Philip G; Ogata, Tsutomu; Petit, Isabelle Oliver; Russo, Silvia; Said, Edith; Toumba, Meropi; Tümer, Zeynep; Binder, Gerhard; Eggermann, Thomas; Harbison, Madeleine D; Temple, I Karen; Mackay, Deborah J G; Netchine, Irène

2017-02-01

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

Residual manifestations of hypercortisolemia following surgical treatment in a patient with Cushing syndrome.

PubMed

Bartz, Sara K; Karaviti, Lefkothea P; Brandt, Mary L; Lopez, Monica E; Masand, Prakash; Devaraj, Sridevi; Hicks, John; Anderson, Lauren; Lodish, Maya; Keil, Meg; Stratakis, Constantine A

2015-01-01

Cushing Syndrome is difficult to diagnose, and the comorbidities and persistent late effects of hypercortisolemia after treatment of the primary disease are challenging for the patient and the endocrinologist. To report the case of a girl with obesity and hypertension, ultimately diagnosed with Cushing syndrome due to primary pigmented nodular adrenocortical disease. In this case, the complications of hypercortisolism persisted short term despite surgical intervention. A 4 year old morbidly obese African-American girl with developmental delay presented with hypertensive emergency in the ER and 18-month history of progressive weight gain. Her previous history included premature adrenarche, hypertension, seizures and a random high cortisol with suppressed ACTH. She was subsequently stabilized, and a diagnostic work-up persistently demonstrated elevated cortisol and suppressed ACTH. An abdominal MRI showed bilateral adrenal multinodular disease, consistent with multinodular hyperplasia of the adrenal glands. Based on these findings the patient underwent a bilateral adrenalectomy, which confirmed primary pigmented nodular adrenocortical disease. The patient had a complicated, protracted post-operative course requiring adjustment of therapy for persistent hypertension. Two months after surgery, she was readmitted to the Emergency Department with hyperpyrexia and hypertension and succumbed to the complications of sepsis. This case highlights the significant diagnostic and therapeutic challenges in treating children with Cushing syndrome. Resolution of the source of hypercortisolemia does not imply regression of hypertension or recovery of the immune system. Although the child underwent bilateral adrenalectomy, persistent consequences of prolonged severe hypercortisolism contributed to her death two months later.

The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?

PubMed Central

Bortolato, Marco; Frau, Roberto; Godar, Sean C; Mosher, Laura J; Paba, Silvia; Marrosu, Francesco; Devoto, Paola

2013-01-01

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS. PMID:23795653

Natural history of chronic hepatitis B virus infection from infancy to adult life - the mechanism of inflammation triggering and long-term impacts.

PubMed

Wu, Jia-Feng; Chang, Mei-Hwei

2015-10-20

Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.

Coalitional Physical Competition : Acute Salivary Steroid Hormone Responses among Juvenile Male Soccer Players in Hong Kong.

PubMed

McHale, Timothy S; Chee, Wai-Chi; Chan, Ka-Chun; Zava, David T; Gray, Peter B

2018-06-16

A large body of research links testosterone and cortisol to male-male competition. Yet, little work has explored acute steroid hormone responses to coalitional, physical competition during middle childhood. Here, we investigate testosterone, dehydroepiandrosterone (DHEA), androstenedione, and cortisol release among ethnically Chinese boys in Hong Kong (N = 102), aged 8-11 years, during a soccer match (n = 84) and an intrasquad soccer scrimmage (n = 81), with 63 participants competing in both treatments. The soccer match and intrasquad soccer scrimmage represented out-group and in-group treatments, respectively. Results revealed that testosterone showed no measurable change. DHEA increased during both treatments in the majority of participants and the degree of change had no relation to independent variables (e.g., performance, age, treatment, outcome) or covariate measures (Body Mass Index, Pubertal Development Scale). Most boys experienced androstenedione increases during match play, but no significant differences during the intrasquad soccer scrimmage competitions. The magnitude of change differed significantly between treatments and was positively associated with age. These latter findings suggest boys' androstenedione responses may be sensitive to competitor type (i.e., unknown competitors vs. peers). For most subjects, cortisol significantly increased during match play, decreased during the intrasquad soccer scrimmage, and differed significantly between treatments, suggesting each treatment promoted a different psychological state among competitors. Cortisol/DHEA molar ratio decreased during the intrasquad scrimmage, suggestive of a more relaxed mental state. These data shed new light on potential proximate mechanisms associated with coalitional competition among prepubescent boys, with relevance to adrenarche and life history theory.

[Natural progression of premature pubarche and underlying diseases].

PubMed

Sancho Rodríguez, María Luisa; Bueno Lozano, Gloria; Labarta Aizpún, José Ignacio; de Arriba Muñoz, Antonio

2018-04-25

Premature pubarche (PP) is generally thought to be a benign condition, but it can also be the first sign of underlying disease. To analyse the aetiology and the evolution of the anthropometric, analytical and metabolic risk parameters of a group of patients with PP. A descriptive and analytical retrospective study of 92 patients affected by PP. Anthropometry, analyses, bone age and indicators of lipid metabolism were all evaluated. The sample included 92 patients with PP (67 female and 25 male), with a mean age of 7.1±0.6 for girls and 8.3±0.7 for boys. Small for gestational age was recorded in 7.7%. There was an accelerated bone age (1.20±0.1 years). A total of 21 patients were classified as idiopathic (23%), 60 as idiopathic premature adrenarche (65%), and 11 with non-classic congenital adrenal hyperplasia (12%). Puberty was reached early (11+0.9 years old in boys and 9.9±0.8 in girls), as was menstruation age (11.8+1.1 years old), P<.001. The stature finally reached was close to their genetic stature. There is a positive correlation between body mass index, blood glucose and LDL cholesterol, as well as a tendency towards hyperinsulinaemia. The present study shows that PP is a benign condition in the majority of cases, but non-classic congenital adrenal hyperplasia (12%) is not uncommon. Menstruation and puberty started early and bone age was accelerated. Growth was normal, and more or less in line with genetic size. PP associated with obesity is linked with analytical variations of metabolic risks. Copyright © 2017. Publicado por Elsevier España, S.L.U.

Impact of Early Postnatal Androgen Exposure on Voice Development

PubMed Central

Grisa, Leila; Leonel, Maria L.; Gonçalves, Maria I. R.; Pletsch, Francisco; Sade, Elis R.; Custódio, Gislaine; Zagonel, Ivete P. S.; Longui, Carlos A.; Figueiredo, Bonald C.

2012-01-01

Background The impact of early postnatal androgen exposure on female laryngeal tissue may depend on certain characteristics of this exposure. We assessed the impact of the dose, duration, and timing of early androgen exposure on the vocal development of female subjects who had been treated for adrenocortical tumor (ACT) in childhood. Methods The long-term effects of androgen exposure on the fundamental vocal frequency (F0), vocal pitch, and final height and the presence of virilizing signs were examined in 9 adult (age, 18.4 to 33.5 years) and 10 adolescent (13.6 to 17.8 years) female ACT patients. We also compared the current values with values obtained 0.9 years to 7.4 years after these subjects had undergone ACT surgery, a period during which they had shown normal androgen levels. Results Of the 19 subjects, 17 (89%) had been diagnosed with ACT before 4 years of age, 1 (5%) at 8.16 years, and 1 (5%) at 10.75 years. Androgen exposure (2 to 30 months) was sufficiently strong to cause pubic hair growth in all subjects and clitoromegaly in 74% (14/19) of the subjects, but did not reduce their height from the target value. Although androgen exposure induced a remarkable reduction in F0 (132 Hz) and moderate pitch virilization in 1 subject and partial F0 virilization, resulting in F0 of 165 and 169 Hz, in 2 subjects, the majority had normal F0 ranging from 189 to 245 Hz. Conclusions Female laryngeal tissue is less sensitive to androgen exposure between birth and adrenarche than during other periods. Differential larynx sensitivity to androgen exposure in childhood and F0 irreversibility in adulthood are age-, concentration-, duration-, and timing-dependent events that may also be affected by exposure to inhibitory or stimulatory hormones. Further studies are required to better characterize each of these factors. PMID:23284635

Recommendations for Treatment of Nonclassic Congenital Adrenal Hyperplasia (NCCAH): an Update

PubMed Central

Trapp, Christine M.; Oberfield, Sharon E.

2013-01-01

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders. 21-hydroxylase deficiency, in which there are mutations in CYP21A2 (the gene encoding the adrenal 21-hydroxylase enzyme), is the most common form (90%) of CAH. In classic CAH there is impaired cortisol production with diagnostic increased levels of 17-OH progesterone. Excess androgen production results in virilization and in the newborn female may cause development of ambiguous external genitalia. Three-fourths of patients with classic CAH also have aldosterone insufficiency, which can result in salt-wasting; in infancy this manifests as shock, hyponatremia and hyperkalemia. CAH has a reported incidence of 1:10,000–1:20,000 births although there is an increased prevalence in certain ethnic groups. Nonclassic CAH (NCCAH) is a less severe form of the disorder, in which there is 20–50% of 21-hydroxylase enzyme activity (vs. 0–5% in classic CAH) and no salt wasting. The degree of symptoms related to androgen excess is variable and may be progressive with age, although some individuals are asymptomatic. NCCAH has an incidence of 1:1000–1:2000 births (0.1–0.2% prevalence) in the White population; an even higher prevalence is noted in certain ethnic groups such as Ashkenazi Jews (1–2%). As many as two-thirds of persons with NCCAH are compound heterozygotes and carry a severe and mild mutation on different alleles. This paper discusses the genetics of NCCAH, along with its variable phenotypic expression, and reviews the clinical course in untreated patients, which includes rapid early childhood growth, advanced skeletal age, premature adrenarche, acne, impaired reproductive function in both sexes and hirsutism as well as menstrual disorders in females. Finally, it addresses treatment with glucocorticoids vs. and other alternatives, particularly with respect to long term issues such as adult metabolic disease including insulin resistance, cardiovascular disease, metabolic syndrome, and bone mineral density. PMID:22186144

The transition from pediatric to adult care for youth with epilepsy: Basic biological, sociological, and psychological issues.

PubMed

Camfield, Peter; Camfield, Carol; Busiah, Kanetee; Cohen, David; Pack, Alison; Nabbout, Rima

2017-04-01

Transition from pediatric to adult health care for adolescents with epilepsy is challenging for the patient, family, and health care workers. This paper is the first of three that summarize the main findings from the 2nd Symposium on Transition in Epilepsies, held in Paris from June 14-25, 2016. In this paper we describe five basic themes that have an important effect on transition. First, there are important brain changes in adolescence that leave an imbalance between risk taking and pleasure seeking behaviors and frontal executive function compared with adults. Second, puberty is a major change during the transition age. The three most important but separate neuroendocrine axes involved in puberty are gonadarche (activation of the gonads), adrenarche (activation of adrenal androgen production), and activation of the growth hormone-insulin like growth factor. Third, sexual debut occurs during the transition years, and at an earlier age in adolescents with epilepsy than controls. Adult sexual performance is often unsatisfactory. Although AED-induced alterations in sexual hormones and temporal lobe epilepsy may play a role in hyposexuality, depression, anxiety, and other social factors appear most important. Fourth, psychological development is very important with an evolution from an early stage (ages 10-13years) with concrete thinking, to a middle stage (ages 14-17) with analytic and more abstract introspective thinking, and then to a late stage (ages 18-21) with at least the beginnings of adult reasoning. Epilepsy may derail this relatively orderly progression. Adolescents with autistic spectrum disorder may present with severe behavior problems that are sometimes related to undiagnosed epilepsy. Fifth, bone health in adolescence is critical to establish adequate mineralization for all of adult life. While AED interference with Vitamin D metabolism is important, there is evidence that the effects of AEDs on bone are more complex and involve changes in remodeling. Hence, some non-inducing AEDs may have a significant effect on bone health. All five of these themes lead to recommendations for how to approach adolescents and young adults during transition and some specific interventions to achieve maximum long-term adult independence and quality of life. Copyright © 2016 Elsevier Inc. All rights reserved.

Screening for hypothalamic–pituitary–adrenal axis suppression in asthmatic children remains problematic: a cross-sectional study

PubMed Central

Zöllner, Ekkehard Werner; Lombard, Carl J; Galal, Ushma; Hough, Stephen; Irusen, Elvis M; Weinberg, Eugene

2013-01-01

Objective To determine which parameter is the most useful screening test for hypothalamic–pituitary–adrenal suppression in asthmatic children. Design Cross-sectional study. Setting Paediatric allergy clinics in Cape Town, South Africa. Participants 143 asthmatic children of mostly mixed ancestry, aged 5–12 years. Outcome measures Primary outcome measures included Spearman correlation coefficients (r) calculated between the postmetyrapone (PMTP) serum adrenocorticotropic hormone (ACTH), 11-deoxycortisol (11DOC), 11DOC+ cortisol (C) and height, weight, height velocity, weight velocity, change in systolic blood pressure from supine to standing, early morning urinary free cortisol (UFC), morning C, ACTH and dehydroepiandrosterone sulfate (DHEAS). Secondary outcome measures were the receiver operating characteristics (ROC) curve and the diagnostic statistics for the most promising test. Results All screening variables were weakly correlated with the three PMTP outcomes. Only DHEAS and UFC (nmol/m2) were statistically significant—DHEAS for PMTP ACTH and 11DOC (r=0.20, p=0.025 and r=0.21, p=0.017); UFC (nmol/m2) for PMTP 11DOC and 11DOC+C (r=0.19, p=0.033 and r=0.20, p=0.022). The area under ROC curve for DHEAS in the 5-year to 9-year age group was 0.69 (95% CI 0.47 to 0.92). At DHEAS cut-off of 0.2 µmol/L: sensitivity=0.88 (CI 0.47 to 1.00), specificity=0.61 (CI 0.42 to 0.78), positive predictive value=0.37 (CI 0.16 to 0.62), negative predictive value=0.95 (CI 0.75 to 1.00), accuracy=0.67 (CI 0.50 to 0.81), positive likelihood ratio=2.26 (CI 1.35 to 3.78), negative likelihood ratio=0.20 (CI 0.03 to 1.30). Conclusions No parameter is useful as a universal screening test. DHEAS may be suitable to exclude HPAS before adrenarche. Further research is needed to confirm these findings and identify factors, for example, genetic that may predict or protect against HPAS. PMID:23906954

Use of a potent, long acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty.

PubMed

Boepple, P A; Mansfield, M J; Wierman, M E; Rudlin, C R; Bode, H H; Crigler, J F; Crawford, J D; Crowley, W F

1986-02-01

Studies utilizing the administration of GnRH in various GnRH-deficient models have revealed the critical importance of the dose and mode of delivery of this releasing factor in determining the subsequent pituitary response. Chronic administration of long acting GnRH agonists (GnRHa), like continuous infusion of high doses of the native peptide, results in suppression of pituitary gonadotropin secretion. This selective and reversible suppression of gonadotropin secretion suggested several therapeutic applications for these analogs, particularly in the treatment of central precocious puberty (CPP), a disorder for which the previously available therapies lacked uniform efficacy and were associated with potential side effects. In our series, 74 children with CPP have been treated during the last 5 yr with the potent GnRH agonist, [D-Trp6, Pro9-ethylamide(NEt)]GnRH. Having selected a dose and route of administration that produced uniform suppression of spontaneous and stimulated pituitary gonadotropin secretion, GnRHa therapy resulted in a fall of gonadal sex steroid levels into the prepubertal range, a halting or regression of secondary sexual development, and a complete cessation of menses. Growth velocity slowed during therapy, with this slowing more pronounced during prolonged treatment periods and among those patients with more advanced chronological and skeletal ages. Skeletal maturation was retarded to a greater degree than linear growth, with resultant increases in the predictions for adult stature. Moreover, these benefits have been achieved in the absence of significant side effects. Complete reversal of the suppression of gonadarche has followed discontinuation of therapy; however, patterns of growth and skeletal maturation after discontinuation of GnRHa administration remain to be characterized. Thus, the impact of GnRHa therapy on final height must await further longitudinal study. The selective nature of GnRHa suppression of gonadarche also permits an investigation of the natural history of adrenarche and its discrete influences upon skeletal growth and maturation. In addition, GnRHa therapy of CPP provides a unique opportunity to study the effects of gonadal sex steroids on GH secretion and somatomedin-C (Sm-C) generation during sexual maturation. Finally, the detailed characterization of children with precocious puberty has helped to define more precisely a subset of patients whose precocity occurs in the absence of demonstrable gonadotropin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)