Fraietta, Renato; Zylberstejn, Daniel Suslik; Esteves, Sandro C
Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Hypogonadotropic hypogonadism can be congenital or acquired. Congenital hypogonadotropic hypogonadism is divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and congenital normosmic isolated hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism). The incidence of congenital hypogonadotropic hypogonadism is approximately 1-10:100,000 live births, and approximately 2/3 and 1/3 of cases are caused by Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism, respectively. Acquired hypogonadotropic hypogonadism can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X. The clinical characteristics of hypogonadotropic hypogonadism are androgen deficiency and a lack/delay/stop of pubertal sexual maturation. Low blood testosterone levels and low pituitary hormone levels confirm the hypogonadotropic hypogonadism diagnosis. A prolonged stimulated intravenous GnRH test can be useful. In Kallmann syndrome, cerebral MRI can show an anomalous morphology or even absence of the olfactory bulb. Therapy for hypogonadotropic hypogonadism depends on the patient's desire for future fertility. Hormone replacement with testosterone is the classic treatment for hypogonadism. Androgen replacement is indicated for men who already have children or have no desire to induce pregnancy, and testosterone therapy is used to reverse the symptoms and signs of hypogonadism. Conversely, GnRH or gonadotropin therapies are the best options for men wishing to have children. Hypogonadotropic hypogonadism is one of the rare conditions in which specific
Lamm, Steven; Chidakel, Aaron; Bansal, Rohan
The relationship between obesity and hypogonadism is complicated. The relationship is bidirectional and there are numerous causative and correlative factors on both sides of the equation. Obesity is increasing in prevalence in epidemic proportions. Likewise, we are beginning to see the rapid increase in the incidence of male hypogonadism. It is only recently that we are learning the ways in which these 2 conditions exacerbate each other, and we are only beginning to understand how by treating one of these conditions, we can help to treat the other as well. Copyright © 2016 Elsevier Inc. All rights reserved.
Edelstein, Daniel; Dobs, Adrian; Basaria, Shehzad
Male hypogonadism is a common endocrine problem that affects men of all ages. Recently, there has been a surge in testosterone use among middle-aged and older men who in the past may have been considered to have borderline or even normal testosterone levels. This increasing use of testosterone therapy among men has paralleled the increasing improvements in the development of treatments for male hypogonadism that have been made over the past few decades. Current therapies using transdermal formulations and long-acting injectables such as testosterone undecanoate are quickly replacing the old injectable testosterone esters. In recent years, pharmaceutical sales and prescription data have readily shown a shift in the testosterone marketplace towards greater use of slightly more expensive treatments such as transdermal therapies, which are easier to administer and yield more physiological levels of testosterone. On the horizon are several new compounds in development, such as selective androgen receptor modulators (SARMS), 7alpha-methyl-19-nortestosterone, aromatase inhibitors, clomifene, dihydrotestosterone and human chorionic gonadotropin. Compounds such as SARMs are designed to selectively target androgen receptors in specific tissues (such as bone and muscles), in the hope of dispersing some of the side effects experienced on the prostate, which are presently associated with therapy of exogenous testosterone.
Slti, I S; Salem, Z
In one family several male and female members had hypogonadism and frontoparietal alopecia, whereas other members with normal sexual development had normal scalp hair. Clinical and laboratory evaluation of three affected young men (two brothers and their cousin) revealed that the hypogonadism was the result of decreased serum concentrations of follicle stimulating and luteinizing hormones. There was no evidence of a deficiency of any other pituitary hormone. Long-term treatment of the three patients with human chorionic gonadotropin resulted in an increase in the serum testosterone concentration, the appearance of male secondary sex characteristics and an increase in the size of the external genitalia. Images FIG. 2 FIG. 4 PMID:466617
Beattie, M C; Adekola, L; Papadopoulos, V; Chen, H; Zirkin, B R
Leydig cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of cellular changes have been identified in the steroidogenic pathway of aged Leydig cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum. Many of the changes in steroid formation that characterize aged Leydig cells can be elicited by the experimental alteration of the redox environment of young cells, suggesting that changes in the intracellular redox balance may cause reduced T production. Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children. There are promising new approaches to increase serum T by directly stimulating Leydig cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences.
Thirumalai, Arthi; Berkseth, Kathryn E.; Amory, John K.
The treatment of hypogonadism in men is of great interest to both patients and providers. There are a number of testosterone formulations currently available and several additional formulations under development. In addition, there are some lesser-used alternative therapies for the management of male hypogonadism, which may have advantages for certain patient groups. The future of hypogonadism therapy may lie in the development of selective androgen receptor modulators that allow the benefits of androgens whilst minimizing unwanted side effects. PMID:28149506
Thirumavalavan, Nannan; Wilken, Nathan A; Ramasamy, Ranjith
The prevalence of both hypogonadism and renal failure is increasing. Hypogonadism in men with renal failure carries with it significant morbidity, including anemia and premature cardiovascular disease. It remains unclear whether testosterone therapy can affect the morbidity and mortality associated with renal failure. As such, in this review, we sought to evaluate the current literature addressing hypogonadism and testosterone replacement, specifically in men with renal failure. The articles chosen for this review were selected by performing a broad search using Pubmed, Embase and Scopus including the terms hypogonadism and renal failure from 1990 to the present. This review is based on both primary sources as well as review articles. Hypogonadism in renal failure has a multifactorial etiology, including co-morbid conditions such as diabetes, hypertension, old age and obesity. Renal failure can lead to decreased luteinizing hormone production and decreased prolactin clearance that could impair testosterone production. Given the increasing prevalence of hypogonadism and the potential morbidity associated with hypogonadism in men with renal failure, careful evaluation of serum testosterone would be valuable. Testosterone replacement therapy should be considered in men with symptomatic hypogonadism and renal failure, and may ameliorate some of the morbidity associated with renal failure. Patients with all stages of renal disease are at an increased risk of hypogonadism that could be associated with significant morbidity. Testosterone replacement therapy may reduce some of the morbidity of renal failure, although it carries risk.
Lawrence, Kristi L.; Stewart, Felicia; Larson, Brandi M.
Abstract: Evidence suggests that providers are not adhering to current testosterone replacement therapy guidelines when treating male hypogonadism. Understanding the diagnosis and management of this condition is further complicated by conflicting recommendations among available guidelines. NPs must select and follow the best guideline recommendations available to optimally treat male hypogonadism. PMID:28085783
Coward, Robert M; Rajanahally, Saneal; Kovac, Jason R; Smith, Ryan P; Pastuszak, Alexander W; Lipshultz, Larry I
The use of anabolic androgenic steroids has not been traditionally discussed in mainstream medicine. With the increased diagnosis of hypogonadism a heterogeneous population of men is now being evaluated. In this larger patient population the existence of anabolic steroid induced hypogonadism, whether transient or permanent, should now be considered. We performed an initial retrospective database analysis of all 6,033 patients who sought treatment for hypogonadism from 2005 to 2010. An anonymous survey was subsequently distributed in 2012 to established patients undergoing testosterone replacement therapy. Profound hypogonadism, defined as testosterone 50 ng/dl or less, was identified in 97 men (1.6%) in the large retrospective cohort initially reviewed. The most common etiology was prior anabolic androgenic steroid exposure, which was identified in 42 men (43%). Because of this surprising data, we performed an anonymous followup survey of our current hypogonadal population of 382 men with a mean±SD age of 49.2±13.0 years. This identified 80 patients (20.9%) with a mean age of 40.4±8.4 years who had prior anabolic androgenic steroid exposure. Hypogonadal men younger than 50 years were greater than 10 times more likely to have prior anabolic androgenic steroid exposure than men older than 50 years (OR 10.16, 95% CI 4.90-21.08). Prior anabolic androgenic steroid use significantly correlated negatively with education level (ρ=-0.160, p=0.002) and number of children (ρ=-0.281, p<0.0001). Prior anabolic androgenic steroid use is common in young men who seek treatment for symptomatic hypogonadism and anabolic steroid induced hypogonadism is the most common etiology of profound hypogonadism. These findings suggest that it is necessary to refocus the approach to evaluation and treatment paradigms in young hypogonadal men. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
... in loss of sex drive and may cause: Impotence Infertility Osteoporosis Weakness Men normally have lower testosterone ... Breast discharge Breast enlargement (men) Hot flashes (women) Impotence Loss of body hair Loss of menstrual period ...
Watson, Sara; Fuqua, John S; Lee, Peter A
The treatment of adolescent males with hypogonadism using testosterone is dependent on the underlying diagnosis as well as the patient's and family's preferences. Those with testicular failure, always a pathologic condition, begin lifelong therapy, while short-term therapy is often begun for those who have a delayed puberty. There is a wide variety of testosterone formulations available, with differences in adverse events sometimes associated with the method of administration. The goals of treatment involve stimulating physical puberty, including achievement of virilization, a normal muscle mass and bone mineral density for age, and improvement in psychosocial wellbeing. While androgen therapy results in physical changes of puberty, the potential for fertility must be considered for those with permanent gonadotropin deficiency. in this population, therapy with gonadotropins or gonadotropin releasing hormone may be effective. For those with testicular failure, fertility may be possible but requires assisted reproductive procedures.
Surampudi, Prasanth; Swerdloff, Ronald S; Wang, Christina
Introduction Men who have symptoms associated with persistently low serum total testosterone level should be assessed for testosterone replacement therapy. Areas covered Acute and chronic illnesses are associated with low serum testosterone and these should be recognized and treated. Once the diagnosis of male hypogonadism is made, the benefits of testosterone treatment usually outweigh the risks. Without contraindications, the patient should be offered testosterone replacement therapy. The options of testosterone delivery systems (injections, transdermal patches/gels, buccal tablets, capsules and implants) have increased in the last decade. Testosterone improves symptoms and signs of hypogonadism such as sexual function and energy, increases bone density and lean mass and decreases visceral adiposity. In men who desire fertility and who have secondary hypogonadism, testosterone can be withdrawn and the patients can be placed on gonadotropins. New modified designer androgens and selective androgen receptor modulators have been in preclinical and clinical trials for some time. None of these have been assessed for the treatment of male hypogonadism. Expert opinion Despite the lack of prospective long-term data from randomized, controlled clinical trials of testosterone treatment on prostate health and cardiovascular disease risk, the available evidence suggests that testosterone therapy should be offered to symptomatic hypogonadal men. PMID:24758365
Masukawa, H; Ozaki, T; Nogimori, T
A 17-year-old male diagnosed as having Cat Eye Syndrome (CES) with hypogonadotropic hypogonadism showed short stature and no development of secondary sex characteristics. Exogeneous gonadotropin replacement therapy combining human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) was started. As a result, the short stature and androgen deficiency were relieved. The critical region of CES was tetrasomy of 22 pter-->q11. Abnormalities of other chromosomes which cause hypogonadotropic hypogonadism may exist, thus further investigation is needed.
In one study, Natesto nasal gel administered intranasally 3 times daily was effective in raising low serum testosterone levels into the normal range in patients with hypogonadism. Whether patients will find this method of administration more acceptable than an intramuscular injection every 2-4 weeks or once-daily application to the skin remains to be determined. Based on the lack of convincing evidence of benefit in older men and concerns about its safety, the FDA has warned against using testosterone to treat hypogonadism due solely to aging.
Høst, Christian; Skakkebæk, Anne; Groth, Kristian A; Bojesen, Anders
Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of both hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome. PMID:24407186
Høst, Christian; Skakkebæk, Anne; Groth, Kristian A; Bojesen, Anders
Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be diffi cult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of both hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.
van de Meerendonk, Hendrik W P C; Mijnhout, G S Sophie; Groeneveld, Paul H P
Unexplained anaemia is not uncommon. We present two male patients suffering from longstanding mild anaemia, for which no cause could be found. We performed an extensive analysis, but there were no signs of malignant disease, chronic inflammation, renal failure, hypothyroidism, myelodysplastic syndrome, haemolysis or nutritional deficiencies. However, both patients had symptoms of hypogonadism, confirmed by biochemical testing. The 56-year-old man known with metabolic syndrome turned out to have secondary hypogonadism without a pituitary tumour and the 75-year-old man had primary hypogonadism. After exclusion of prostate carcinoma, testosterone substitution therapy was started in both patients, which improved their haematocrits and sexual and general well-being substantially. Testosterone exerts anabolic effects in multiple organ systems; in bone marrow it potentiates the stimulatory effect of erythropoietin on erythropoiesis. Primary hypogonadism frequently occurs in elderly patients, while secondary hypogonadism is frequently seen in middle-aged men with type 2 diabetes mellitus and obesity.
Finkelstein, J.S.; Klibanski, A.; Neer, R.M.; Greenspan, S.L.; Rosenthal, D.I.; Crowley, W.F. Jr.
To assess the effect of testosterone deficiency on skeletal integrity in men, we determined bone density in 23 hypogonadal men with isolated gonadotropin-releasing hormone deficiency and compared those values with ones from controls. Cortical bone density, as assessed by single-photon absorptiometry of the nondominant radius, ranged from 0.57 to 0.86 g/cm2 (mean +/- SE, 0.71 +/- 0.02) in patients with fused epiphyses and from 0.57 to 0.67 g/cm2 (mean, 0.61 +/- 0.01) in patients with open epiphyses, both of which were significantly (p less than 0.001) lower than normal. Spinal trabecular bone density, as assessed by computed tomography, was similarly decreased (p less than 0.0001) and ranged from 42 to 177 mg K2HPO4/cm3 (mean, 112 +/- 7). Cortical bone density was at least 2 SD below normal in 16 of 23 men, and 8 men had spinal bone densities below the fracture threshold of 80 to 100 mg K2HPO4/cm3. Osteopenia was equally severe in men with immature and mature bone ages, suggesting that abnormal bone development plays an important role in the osteopenia of men with idiopathic hypogonadotropic hypogonadism.
Üçer, Oktay; Gümüş, Bilal
Late-onset hypogonadism (LOH) in aging men is a clinical and biochemical syndrome caused by an age-related decline in testosterone. Despite published in guidelines and recommendations, uncertainty surrounds the profile of clinical symptoms as well as the biochemical threshold of diagnosis. The only evidence-based treatment of late-onset hypogonadism is testosterone replacement therapy. The actual available evidence of the long-term risks and outcomes of testosterone-replacement therapy remains very limited, and carefully designed placebo-controlled trials of testosterone administration to assess the risks and benefits of such a therapy are required. Until such evidence is available, testosterone treatment should be restricted to elderly men with very low testosterone levels in the presence of clinical symptoms, and the advantages and disadvantages need to be accurately assessed. Careful monitoring of potential side effects is necessary. The purpose of this review is to discuss what is known and what remains unclear with respect to the benefits and risks of testosterone replacement treatment. PMID:26328172
Bhattacharya, Rajib K; Bhattacharya, Shelley B
Late-onset hypogonadism is an underdiagnosed and easily treated condition defined by low serum testosterone levels in men older than 65 years. When treated, a significant improvement in quality of life may be reached in this rapidly rising sector of the population. During the evaluation, laboratory tests and a full medication review should be performed to exclude other illnesses or adverse effects from medications. The major goal of treatment in this population is treating the symptoms related to hypogonadism. There has not been clear evidence supporting universally giving older men with low serum testosterone levels and hypogonadal symptoms testosterone replacement therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
Hengge, Ulrich R
Hypogonadism is highly prevalent in HIV-infected patients and has been associated with the late stages of AIDS and AIDS wasting. There are a number of studies exploring treatment options. Testosterone replacement, with the exception of the transscrotal delivery patch, has been observed to have a beneficial effect on lean body mass and body weight in hypogonadal and eugonadal men with the AIDS wasting syndrome. Resistance exercise training also has had favorable effects on body weight and muscle cell mass. In hypogonadal men with AIDS treated with testosterone replacement therapy, researchers noted a positive effect on depression scores.
Sharma, Vishwamitra; Perros, Petros
This article focuses on the evaluation and management of hypogonadism in aging male patients in the light of recent guidelines. The benefits of treating severe hypogonadism resulting from identifiable pituitary or primary gonadal disease are well established. Milder forms of hypogonadism in the aging male, known as andropause, are common, and constitute an expanding area of clinical interest and research. Several studies indicate that testosterone replacement therapy may produce a wide range of benefits for men with hypogonadism, including improvement in libido, bone density, muscle mass, body composition, mood, and cognition. Currently available data are insufficient to permit a definitive verdict on the balance between risks and benefits of testosterone replacement therapy in aging males.
Narayanan, R P; Bujawansa, S; Qureshi, Z; Rimmer, M; Heald, A
It is accepted that care must be taken in initiating testosterone replacement in hypogonadal individuals with historically low androgen levels. However less is reported about the influence of restoration of normal endogenous testosterone production on behaviour.Here we report how the adverse sequelae of successful treatment of hypogonadism secondary to hyperprolactinaemia, manifesting as irritability and low threshold to aggression, were managed through a joint approach between psychiatrist and physician.
Zitzmann, M; Nieschlag, E
The definition of late-onset-hypogonadism as a hybrid form of primary and secondary hypogonadism corresponds to pathophysiological facts of the age-related decline in gonadal as well as hypothalamic-pituitary functions, eventually manifesting in clinically relevant hypogonadism. To what extent advancing age modulates incidence and nature of hypogonadal symptoms has not been completely investigated. The benefits of testosterone substitution therapy in older men await demonstration in long-term studies and to date, it should be restricted to specialized centers. Currently, serum testosterone levels <12 nmol/l, accompanied by symptoms of androgen deficiency, are regarded as an indication for substitution, provided a prostate carcinoma has been excluded. While late-onset hypogonadism decreases libido, it does not play a direct role in the increasing incidence of erectile dysfunction with advancing age; this symptom is rather associated with vessel-endothelial impairment and may serve as a sentinel symptom for cardiovascular disease. Treatment with phosphodiesterase-5-inhibitors can be regarded as standard; in case of concomitant late-onset hypogonadism, testosterone will have a positive synergistic effect on erectile function.
Garcia, Jose M; Li, Huiling; Mann, Douglas; Epner, Daniel; Hayes, Teresa G; Marcelli, Marco; Cunningham, Glenn R
Patients with cancer often develop anorexia, fatigue, and decreased muscle mass. These signs and symptoms are nonspecific, and they frequently occur in other conditions, including hypogonadism. The objectives of this study were 1) to measure testosterone levels in patients with cancer and 2) to examine the correlations between testosterone, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), ghrelin levels, and appetite in patients with cancer patients and in a noncancer control group. This was designed as a cross-sectional study in the setting of a university-affiliated Veterans Affairs Medical Center. The study population included 31 male patients with cancer and 25 gender-matched noncancer controls of similar age. The variables total testosterone (TT), calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), TNF-alpha, IL-6, IGF-1, and active ghrelin were measured in fasting morning plasma samples. Appetite was measured according to a visual analog scale. The main outcome measures were cFT and cBT. Cancer patients had mean TT levels similar to levels in the noncancer control group but significantly lower levels of cFT, cBT, IGF-1, and appetite. SHBG, LH, TNF-alpha, IL-6, and ghrelin levels were increased in patients with cancer compared with the control group. cFT and cBT levels were correlated inversely with IL-6 and ghrelin levels and were correlated directly with IGF-1 levels and appetite. Patients with cancer had lower levels of biologically active testosterone. TT was not adequate for the evaluation of hypogonadism, because SHBG levels were increased. A reliable measurement of FT and/or BT should be used. LH was elevated in the patients with cancer, indicating that low FT levels were caused by primary testicular dysfunction. The authors postulated that high IL-6 or ghrelin levels inhibit testosterone synthesis, although a
Peric, Stojan; Nisic, Tanja; Milicev, Milena; Basta, Ivana; Marjanovic, Ivan; Peric, Marina; Lavrnic, Dragana; Rakocevic Stojanovic, Vidosava
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It affects many organs and systems besides muscle. Aim of this study was to assess frequency of erectile dysfunction (ED) and hypogonadism, the correlation between them and the impact of ED on quality of life (QoL) in patients with DM1. A series of 25 men (aged from 22 to 58 years) with a diagnosis of DM1 was analyzed. Muscular Impairment Rating Scale (MIRS) was used to assess severity of muscular involvement. Erectile function was assessed using the short form of the International Index of Erectile Function test (IIEF-5). Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were assessed. All patients completed the Serbian version of the SF-36 questionnaire as a measure of health-related QoL. ED was present in 18 (72%) of patients. Seven (28%) patients were euogonadic, 16 (64%) had compensated hypogonadism and 2 (8%) had primary hypogonadism. ED was somewhat more common in patients with hypogonadism (78% vs. 57%). Mental composite score of SF-36 was lower in patients with ED (p<0.05). Our results showed that 72% of men with DM1 had ED and hypogonadism. Studies with larger number of subjects are needed to resolve cascade of events that lays behind ED in DM1. Development of therapeutic strategies may have positive impact on QoL. Substitutive therapy with androgens may be benefitial.
Pitteloud, Nelly; Durrani, Sadia; Raivio, Taneli; Sykiotis, Gerasimos P
Idiopathic hypogonadotropic hypogonadism (IHH) is an important human disease model. Investigations of the genetics of IHH have facilitated insights into critical pathways regulating sexual maturation and fertility. IHH has been traditionally considered a monogenic disorder. This model holds that a single gene defect is responsible for the disease in each patient. In the case of IHH, 30% of cases are explained by mutations in one of eleven genes. In recent years, several lines of evidence have challenged the monogenic paradigm in IHH. First, disease-associated mutations display striking incomplete penetrance and variable expressivity within and across IHH families. Second, each locus is responsible for only a small percentage of cases. Third, more than one disease-associated mutation seems to be segregating in some families with IHH, and their combined or separate presence in individuals accounts for the variability in disease severity. Finally, IHH is not strictly a congenital and life-long disorder; occasionally it manifests itself during adulthood (adult-onset IHH); in other cases, the disease is not permanent, as evidenced by normal activity of the hypothalamic-pituitary-gonadal axis after discontinuation of treatment in adulthood (IHH reversal). Together, these observations suggest that IHH is not strictly a monogenic mendelian disease, as previously thought. Rather, it is emerging as a digenic, and potentially oligogenic disease, in which hormonal and/or environmental factors may critically influence genetic predisposition and clinical course. Future investigations of IHH should characterize the extent of the involvement of multiple genes in disease pathogenesis, and elucidate the contributions of epigenetic factors. Copyright 2010 S. Karger AG, Basel.
Garrido Oyarzún, María Fernanda; Castelo-Branco, Camil
Turner syndrome and idiopathic congenital hypogonadism including Kallmann syndrome are conditions associated to a large number of widely known comorbidities that need a medical support forever. One of the characteristics shared by both conditions is the lack of sexual development that influencing the sexuality functioning and quality of life of the affected women. Few studies have been conducted to assess these topics, but they need to be considered in the treatment to all women with hypogonadism. This review on the major medical issues and psychological aspects, also focus in the present knowledge about sexual function and quality of life of women with Turner syndrome and idiopathic congenital hypogonadism, which aims to help in the comprehensive management of these patients.
Baillargeon, Jacques; Al Snih, Soham; Raji, Mukaila A; Urban, Randall J; Sharma, Gulshan; Sheffield-Moore, Melinda; Lopez, David S; Baillargeon, Gwen; Kuo, Yong-Fang
Testosterone deficiency has been linked with autoimmune disease and an increase in inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor, and interleukin-6 (IL-6). However, no large-scale longitudinal studies have examined this association. We examined whether untreated hypogonadism was associated with an increased risk of rheumatic autoimmune disease in a large nationally representative cohort. Using one of the nation's largest commercial insurance databases, we conducted a retrospective cohort study in which we identified 123,460 men diagnosed with hypogonadism between January 1, 2002 and December 31, 2014 and with no prior history of rheumatic autoimmune disease. We matched this cohort to 370,380 men without hypogonadism, at a 1 to 3 ratio, on age and index/diagnosis date. All patients were followed until December 31, 2014 or until they lost insurance coverage or were diagnosed with a rheumatic autoimmune disease. Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHRs). Untreated hypogonadism was associated with an increased risk of developing any rheumatic autoimmune disease (HR = 1.33, 95 % CI = 1.28, 1.38), rheumatoid arthritis (HR = 1.31, 95 % CI = 1.22, 1.44), and lupus (HR = 1.58, 95 % CI = 1.28, 1.94). These findings persisted using latency periods of 1 and 2 years. Hypogonadism was not associated with the control outcome, epilepsy (HR = 1.04, 95 % CI = 0.96, 1.15). Patients diagnosed with hypogonadism who were not treated with testosterone had an increased risk of developing any rheumatic autoimmune disease, rheumatoid arthritis, and lupus. Future research should further examine this association, with particular attention to underlying mechanisms.
Antonini, Giovanni; Clemenzi, Alessandro; Bucci, Elisabetta; De Marco, Emanuela; Morino, Stefania; Di Pasquale, Antonella; Latino, Pamela; Ruga, Gilda; Lenzi, Andrea; Vanacore, Nicola; Radicioni, Antonio F
Myotonic dystrophy type 1 (DM1) is characterized by both a premature appearance of age-related phenotypes and multiple organ involvement, which affects skeletal and smooth muscle as well as the eye, heart, central nervous system, and endocrine system. Although erectile dysfunction (ED) is a frequent complaint in patients with DM1, it has not been investigated in great depth. Hypogonadism, which is reported to be one of the physical causes of ED in the general population, frequently occurs in DM1. We planned this case-control study to evaluate the relationship between hypogonadism, as defined by the sexual hormone profile (FSH, LH, testosterone (T) and prolactin) and ED, as assessed by means of an internationally validated self-administered questionnaire (IIEF). DM1 patients had significantly increased mean levels of both gonadotropins (FSH and LH) (p < 0.0001) and a reduced mean level of T (p < 0.0001) when compared to controls. Twelve patients were eugonadic (normal LH, T, and FSH), while 18 displayed hormonal evidence of hypogonadism, characterized by tubular failure (increased FSH) in all the subjects and associated with interstitial failure in 14 subjects: seven with primary hypogonadism (increased LH and reduced T) and seven with compensated hypogonadism (increased LH and normal T). Patients with hormonal evidence of interstitial failure had a larger CTG expansion (p = 0.008), longer disease duration (p = 0.013), higher grade of disease (p = 0.004) and lower erectile function score (p = 0.02) than eugonadic patients. Impotence occurred in 13/14 hypogonadic patients with interstitial failure and in 5/12 eugonadic patients (p = 0.017, OR = 18.2).
The aim of this work was to review the pharmacokinetic and clinical profile of Testim (Auxilium Pharmaceuticals, Norristown, Pennsylvania) 1% gel formulation of testosterone for the treatment of male hypogonadism. An English-language search of the medical literature was conducted using PubMed (1998-December 2004) and EMBASE (1998-December 2004). Search terms included ag(e)ing male, male hypogonadism, late-onset hypogonadism, testosterone, testosterone deficiency, testosterone therapy, testosterone replacement therapy, androgen therapy, testosterone gel, and Testim. Bibliographies of retrieved articles were also reviewed. Five published clinical studies were reviewed. Testim 50 mg showed clear pharmacokinetic differences from AndroGel (known as Testogel in Europe; Unimed Pharmaceuticals, Inc., and Solvay Pharmaceuticals, Inc., Marietta, Georgia) 1% testosterone gel 50 mg, with increases of 30% (90% CI, 8%-57%) and 47% (90% CI, 20%-79%) versus AndroGel, respectively, in AUC(0-24h) for total serum testosterone and free testosterone. In a 30-day study of 638 men with hypogonadism, sexual desire scores and sexual motivation scores increased after Testim treatment at weeks 1, 2, 3, and 4 (each, P < 0.001). During 12 months of treatment with Testim 50 or 100 mg in 371 men with hypogonadism, total serum testosterone levels were raised to and maintained within the normal adult range, lean body mass increased by 2.2 kg (P < 0.001), fat mass fell by 2.1% (P < 0.001), and bone mineral density increased by 2.58% (P < 0.001). Mean scores for sexual desire, performance, motivation, and spontaneous erections were all significantly higher (all, P < 0.001) than at baseline for all time points during 12-month studies of Testim. In 2 studies comparing Testim with different testosterone patches, treatment with the gel resulted in 10-fold fewer application-site reactions than either patch. In men with hypogonadism, Testim gel raised and maintained serum testosterone levels to within the
Kumanov, Philip; Tomova, Analia; Isidori, Aldo; Nordio, Maurizio
The pineal gland, through the rhythmic production of melatonin, seems to play an important role in the control of the reproductive function of many vertebrate species. In contrast, the effects of the pineal gland in humans and the relationship between gonadotropins and melatonin secretion are not yet clarified. On the basis of these considerations, the aim of the present study was to clarify whether melatonin serum concentrations were altered in males with different hypothalamo-pituitary-gonadal disturbances, in comparison to normal individuals. We have studied 36 individuals divided into three groups according to their gonadotropin status: normals, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. They were submitted to blood sample withdrawal at 03.00, 11.00 and 19.00 h for melatonin determination according to a radioimmunological method, without extraction of the sample. The results obtained in the present study suggest the existence of an interaction between the pituitary and the pineal gland. In fact, in the case of hypersecretion of gonadotropins, nocturnal melatonin release is reduced, while night melatonin secretion is increased in the opposite situation (hypogonadotropic hypogonadism). Both these endocrine pathologies are characterized by a reduced sexual steroid secretion; for that reason, this reduction cannot be regarded as responsible for the two opposite dysfunctions of melatonin release. In conclusion, our study shows that darkness-dependent release of melatonin in males with hypogonadotropic hypogonadism is significantly higher in comparison with the healthy men, while it is significantly reduced in patients with hypergonadotropic hypogonadism. A strong significant negative correlation is also found between gonadotropins and melatonin release.
Rambhatla, Amarnath; Mills, Jesse N.; Rajfer, Jacob
Estradiol, normally considered a female hormone, appears to play a significant role in men in a variety of physiologic functions, such as bone metabolism, cardiovascular health, and testicular function. As such, estradiol has been targeted by male reproductive and sexual medicine specialists to help treat conditions such as infertility and hypogonadism. The compounds that modulate estradiol levels in these clinical conditions are referred to as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). In a certain subset of infertile men, particularly those with hypogonadism, or those who have a low serum testosterone to estradiol ratio, there is some evidence suggesting that SERMs and AIs can reverse the low serum testosterone levels or the testosterone to estradiol imbalance and occasionally improve any associated infertile or subfertile state. This review focuses on the role these SERMs and AIs play in the aforementioned reproductive conditions. PMID:27601965
Primary disorders of the gonad or those secondary to abnormalities of the hypothalamic pituitary axis result in hypogonadism. The range of health problems of childhood and adolescence that affect this axis has increased, as most children now survive chronic illness, but many have persisting deficits in gonadal function as a result of their underlying condition or its treatment. An integrated approach to hormone replacement is needed to optimize adult hormonal and bone health, and to offer opportunities for fertility induction and preservation that were not considered possible in the past. Timing of presentation ranges from birth, with disorders of sexual development, through adolescent pubertal failure, to adult fertility problems. This review addresses diagnosis and management of hypogonadism and focuses on new management strategies to address current concerns with fertility preservation. These include Turner syndrome, and fertility presevation prior to childhood cancer treatment. New strategies for male hormone replacement therapy that may impinge upon future fertility are emphasized.
Wong, Evelyn M; Lehman, Anna; Acott, Philip; Gillis, Jane; Metzger, Daniel L; Sirrs, Sandra
Glycogen storage disease type 1 is an autosomal recessive disorder with an incidence of 1 in 100,000. Long-term complications include chronic blood glucose lability, lactic academia, short stature, osteoporosis, delayed puberty, gout, progressive renal insufficiency, systemic or pulmonary hypertension, hepatic adenomas at risk for malignant transformation, anemia, vitamin D deficiency, hyperuricemic nephrocalcinosis, inflammatory bowel syndrome (type 1b), hypertriglyceridemia, and irregular menstrual cycles. We describe hypogonadotropic hypogonadism as a novel complication in glycogen storage disease (GSD) type 1. Case Studies and Methods: Four unrelated patients with GSD 1a (N = 1) and 1b (N = 3) were found to have hypogonadotropic hypogonadism diagnosed at different ages. Institutional Research Ethics Board approval was obtained as appropriate. Participant consent was obtained. A retrospective chart review was performed and clinical symptoms and results of investigations summarized as a case series. All patients were confirmed biochemically to have low luteinizing hormone (LH) and follicular stimulating hormone (FSH), and correspondingly low total testosterone. Clinical symptoms of hypogonadism varied widely. Investigations for other causes of hypogonadotropic hypogonadism were unremarkable. In addition, all patients were found to have disproportionately low bone mineral density at the lumbar spine compared to the hip. Common to all patients was erratic metabolic control, including recurrent hypoglycemia and elevated lactate levels. Recurrent elevations in cortisol in response to hypoglycemia may be the underlying pathology leading to suppression of gonadotropin-releasing hormone (GnRH) release. Incorporating clinical and/or biochemical screening of the hypothalamic-pituitary-gonadal axis may be important in the management of this disease. Testosterone therapy however needs to be carefully considered because of the risk of hepatic adenomas.
Chang, Simon; Skakkebæk, Anne; Gravholt, Claus Højbjerg
Klinefelter syndrome (KS), though described more than 70 years ago, still imposes significant diagnostic challenges. Based on data from epidemiological studies, KS is associated with increased morbidity and mortality. Although the pathophysiology and etiology behind these observations are as yet not well understood, a significant contribution of hypogonadism, central to the syndrome, is traditionally suspected. However, other unknown effects inherent to the syndrome also seem to modify the disease pattern. Herein we show that KS is under-diagnosed since only roughly 25% of patients are diagnosed and the mean age of diagnosis is during adult life. KS is associated with increased morbidity resulting in loss of 2-5 years in lifespan with increased mortality from different diseases and a poor socioeconomic profile. Small testes, hypergonadothrophic hypogonadism and cognitive impairment are usually found. The accompanying hypogonadism can lead to altered body composition and a risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Cancer risk is generally not different from that observed in the background population, although specific cancers like breast cancer and extragonadal germ cell tumors are seen more frequently in KS. The mainstay of medical treatment is testosterone replacement therapy to both attenuate acute and long-term consequences of hypogonadism and possibly prevent the frequent comorbidity. We believe that the diagnostic challenges should be tackled more efficiently, while there is also a pressing need to generate better evidence for timing and the proper dose of testosterone replacement. We advocate for a multidisciplinary setup with the inclusion of pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists and endocrinologists.
Macchi, Chiara; Steffani, Liliana; Oleari, Roberto; Lettieri, Antonella; Valenti, Luca; Dongiovanni, Paola; Romero-Ruiz, Antonio; Tena-Sempere, Manuel; Cariboni, Anna; Magni, Paolo; Ruscica, Massimiliano
Iron overload leads to multiple organ damage including endocrine organ dysfunctions. Hypogonadism is the most common non-diabetic endocrinopathy in primary and secondary iron overload syndromes. To explore the molecular determinants of iron overload-induced hypogonadism with specific focus on hypothalamic derangements. A dysmetabolic male murine model fed iron-enriched diet (IED) and cell-based models of gonadotropin-releasing hormone (GnRH) neurons were used. Mice fed IED showed severe hypogonadism with a significant reduction of serum levels of testosterone (-83%) and of luteinizing hormone (-86%), as well as reduced body weight gain, body fat and plasma leptin. IED mice had a significant increment in iron concentration in testes and in the pituitary. Even if iron challenge of in vitro neuronal models (GN-11 and GT1-7 GnRH cells) resulted in 10- and 5-fold iron content increments, respectively, no iron content changes were found in vivo in hypothalamus of IED mice. Conversely, mice placed on IED showed a significant increment in hypothalamic GnRH gene expression (+34%) and in the intensity of GnRH-neuron innervation of the median eminence (+1.5-fold); similar changes were found in the murine model HFE(-/-), resembling human hemochromatosis. IED-fed adult male mice show severe impairment of hypothalamus-pituitary-gonadal axis without a relevant contribution of the hypothalamic compartment, which thus appears sufficiently protected from systemic iron overload. Copyright © 2017 Elsevier B.V. All rights reserved.
MULLIGAN, T; FRICK, MF; ZURAW, QC; STEMHAGEN, A; MCWHIRTER, C
The Hypogonadism in Males study estimated the prevalence of hypogonadism [total testosterone (TT) <300 ng/dl] in men aged ≥45 years visiting primary care practices in the United States. A blood sample was obtained between 8 am and noon and assayed for TT, free testosterone (FT) and bioavailable testosterone (BAT). Common symptoms of hypogonadism, comorbid conditions, demographics and reason for visit were recorded. Of 2162 patients, 836 were hypogonadal, with 80 receiving testosterone. Crude prevalence rate of hypogonadism was 38.7%. Similar trends were observed for FT and BAT. Among men not receiving testosterone, 756 (36.3%) were hypogonadal; odds ratios for having hypogonadism were significantly higher in men with hypertension (1.84), hyperlipidaemia (1.47), diabetes (2.09), obesity (2.38), prostate disease (1.29) and asthma or chronic obstructive pulmonary disease (1.40) than in men without these conditions. The prevalence of hypogonadism was 38.7% in men aged ≥45 years presenting to primary care offices. PMID:16846397
Rushton, A R; Genel, M
Two teenaged children born of normal parents in a consanguineous family had evidence of abnormal neurological, endocrine, and ectodermal development. They had mental retardation, hearing loss, ocular dysmetria, hyperreflexia, and ataxia consistent with olivopontocerebellar degeneration. They had hypogonadotrophic hypogonadism and extremely short stature despite normal serum growth hormone and somatomedin-C. There was also hypodontia with peg shaped teeth and mid-face hypoplasia. This syndrome of hypoplasia of mid-lind structures appeared to be inherited as an autosomal recessive trait. Images PMID:7328612
Matsumoto, Ryusuke; Shimizu, Chikara; Nagai, So; Taniguchi, Satoshi; Umetsu, Masaaki; Kimura, Yasunori; Atsumi, Toshiya; Yoshioka, Narihito; Kubo, Mitsumasa; Koike, Takao
A 34-year-old Japanese man diagnosed as having cat-eye syndrome (CES) with isolated idiopathic hypogonadotropic hypogonadism (IHH) was treated at our university. He showed preauricular pits/tags, downward slanting palpebral fissures, ocular hypertelorism, and strabismus. However, ocular coloboma and anal atresia, major characteristic features of CES, were negative. Chromosomal analysis revealed malformation in chromosome 22 and eunuchoid features and a low grade development of secondary sexual characteristics were also evident. Endocrinological examinations revealed that this patient was in a state of isolated IHH. Although CES with IHH is extremely rare, endocrine disorders should be given due attention.
Leung, Kevin Matthew Yen Bing; Alrabeeah, Khalid; Carrier, Serge
Late-onset male hypogonadism has long been recognized as a treatable medical condition; however, misconceptions about the use of testosterone replacement therapy (TRT) have often led urologists away from its more mainstream use. This paper aims to bring the reader up-to-date on the current understanding of TRT, starting with when and who to treat. Various formulations of TRT, each with its own risks and benefits, are also detailed. Finally, a comprehensive analysis of the current literature's views into the various controversies of TRT including its impact on prostate health, sexual health, cardiovascular health, frailty, and mood is discussed.
Rosano, Giuseppe M C; Vitale, Cristiana; Fini, Massimo
Although numerous randomized studies have shown that testosterone replacement therapy (TRT) improves intermediate outcomes in patients at risk and in those with proven cardiovascular disease (CVD), results derived mainly from registries and observational studies have suggested an increased cardiovascular risk in elderly men receiving often supra-therapeutic doses of testosterone. Recent meta-analyses have shown that when testosterone has been used in patients with pre-existing cardiovascular conditions, the effect on the disease has been either beneficial or neutral. Similar results have been reported in hypo- and eugonadal men. Contrasting results have been reported by two trials of testosterone treatment in frail elderly men. Reports from poorly analyzed databases have reported an increased risk of cardiovascular events with testosterone use. More recently, a population-based study showed no increased cardiovascular risk of testosterone replacement in hypogonadal men. Available data from controlled clinical trials suggest that the use of testosterone in elderly men does not increase cardiovascular risk nor the risk of events. Studies in men with CVD, angina, or heart failure report a benefit from testosterone replacement in men with or without hypogonadism. Therefore, at present, the cardiovascular benefits of TRT in elderly men outweigh the risks. This is particularly evident in those men with pre-existing CVD.
Vogl, T.J.; Stemmler, J.; Bergman, C.; Balzer, J.O.; Felix, R.; Heye, B.; Schopohl, J.; Danek, A.
To identify morphologic differences between Kallman syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) and establish a role for magnetic resonance (MR) imaging in these disorders. Twenty-eight patients were compared with 10 eugonal male volunteers. Eighteen patients had KS (hypogonadotropic hypogonadism with anosmia) and 10 had IHH. All participants underwent hormone analysis, a sniff-bottle smell test, and gadolinium-enhanced MR imaging. Changes in the hypothalamic-hypophyseal region and the rhinencephalon were evaluated. MR imaging revealed intracranial morphologic changes in all patients on plain T1-weighted sections. Seventeen patients with KS demonstrated aplasia of an olfactory bulb; one olfactory sulcus was absent in six, rudimentary in four, and normal in eight. Olfactory bulbs were present in all 10 IHH patients and three showed one slightly hypoplastic bulb. Ten patients with KS and three with IHH showed an enlarged paranasal sinus system. Further MR findings were similar. MR imaging demonstrates abnormalities of the rhinencephalon present in KS patients and occasionally absent in IHH patients. 18 refs., 10 figs., 1 tab.
Becerra Fernández, Antonio; Enríquez Acosta, Luis
One of the most important elements in men's live is the ability to engage in normal sexual activity; loss of this activity has always been considered especially important. The relationship between sexual activity, as well as other masculine characteristics, and the testicles has been well known since ancient times and has been related to the slow decrease in testosterone secretion with advanced age. Male hypogonadism is one of the most frequent and under-diagnosed endocrine diseases. Several terms have been proposed to refer to clinical situations caused by the age-related decline in male gonadal function; currently, the most widely accepted term is late-onset hypogonadism (LOH). LOH consists of a clinical and biochemical syndrome associated with advanced age (in men), characterized by typical symptoms and reduced serum testosterone concentrations, which can affect multiple organs and systems and reduce quality of life. This syndrome can be treated and the alterations produced can be reversed. To achieve this, a diagnostic protocol that approaches the multiple factors related to the risks and benefits of treatment is required. Copyright © 2008 Sociedad Española de Endocrinología y Nutrición. Published by Elsevier Espana. All rights reserved.
Tanriverdi, F; Unluhizarci, K; Selcuklu, A; Casanueva, F F; Kelestimur, F
Traumatic brain injury (TBI) is a frequent health problem and increased prevalence of neurendocrine dysfunction in patients with TBI has been reported. Sports injuries and particularly boxing may result in pituitary dysfunction. However, transient hypogonadotropic hypogonadism after an acute head trauma due to boxing and/or kickboxing has not been defined yet. We describe the case of a 20-yr-old male amateur kickboxer who was admitted to hospital complaining of decreased libido and impotence 2 weeks after an intensive bout. Basal hormone levels were compatible with mild hyperprolactinemia and hypogonadotpopic hypogonadism. GH axis was evaluated by GHRH+GHRP-6 test and peak GH level was within normal reference range. Three months later his complaints improved and abnormalities in basal hormone levels normalized. He was also re-evaluated 9 months after the first evaluation; basal hormone levels were within normal ranges and he had no complaints. In conclusion acute head trauma due to kickboxing may cause transient gonadotropin deficiency. Therefore, screening the pituitary functions of sportsmen dealing with combative sports is crucial.
Liu, Joceline S; Jones, Madeline; Casey, Jessica T; Fuchs, Amanda B; Cashy, John; Lin, William W
To determine the temporal relationship between vasectomy, varicocele, and hypogonadism diagnosis. Many young men undergo their first thorough genitourinary examination in their adult lives at the time of vasectomy consultation, providing a unique opportunity for diagnosis of asymptomatic varicoceles. Varicoceles have recently been implicated as a possible reversible contributor to hypogonadism. Hypogonadism may be associated with significant adverse effect, including decreased libido, impaired cognitive function, and increased cardiovascular events. Early diagnosis and treatment of hypogonadism may prevent these adverse sequelae. Data were collected from the Truven Health Analytics MarketScan database, a large outpatient claims database. We reviewed records between 2003 and 2010 for male patients between the ages of 25 and 50 years with International Classification of Diseases, Ninth Revision codes for hypogonadism, vasectomy, and varicocele, and queried dates of first claim. A total of 15,679 men undergoing vasectomies were matched with 156,790 men with nonvasectomy claims in the same year. Vasectomy patients were diagnosed with varicocele at an earlier age (40.9 vs 42.5 years; P=.009). We identified 224,817 men between the ages of 25 and 50 years with a claim of hypogonadism, of which 5883 (2.6%) also had a claim of varicocele. Men with hypogonadism alone were older at presentation compared with men with an accompanying varicocele (41.3 [standard deviation±6.5] vs 34.9 [standard deviation±6.1]; P<.001). Men undergoing vasectomies are diagnosed with varicoceles at a younger age than age-matched controls. Men with varicoceles present with hypogonadism earlier than men without varicoceles. Earlier diagnosis of varicocele at the time of vasectomy allows for earlier detection of hypogonadism. Copyright © 2014 Elsevier Inc. All rights reserved.
Ross, I L; Levitt, N S; Blom, D J; Haarburger, D
Hypogonadism may complicate Addison's disease (primary hypoadrenalism), but prevalence and metabolic sequelae of hypogonadism in Addison's disease are poorly described. We recruited patients from the South African Addison's disease national registry who received stable replacement doses of hydrocortisone and had no acute illness. Male biochemical testosterone deficiency was defined as an early morning basal testosterone<9.9 nmol/l and premature ovarian failure (POF) when menopause occurred before 40 years of age. Cardiometabolic risk variables were measured in males only. Male hypogonadism prevalence was 33% (14/42), and 10 patients had newly diagnosed hypogonadism. Two untreated patients had elevated FSH or LH (>10 or 12 IU/l). Testosterone deficiency did not correlate with age, disease duration or hydrocortisone dose. Untreated male hypogonadal subjects had a higher (mean ± standard deviation) BMI compared to eugonadal subjects 29.2 ± 4.9 kg/m(2) vs. 24.7 ± 3.4 kg/m(2) (p=0.01) and a higher median (interquartile range) high-sensitive-CRP 6.4 (2.5-14.0) mg/l vs. 1.45 (0.6-2.8) mg/l (p=0.002). There were no differences between the 2 groups in lipids, lipoproteins and fasting glucose. The median (interquartile range) DHEAS was lower in the hypogonadal 0.31 (0.27-0.37) μmol/l, compared with the eugonadal group 0.75 (0.50-1.51) μmol/l (p=0.005). POF was documented in 11% of female patients. Male testosterone deficiency was highly prevalent in this cohort and was primarily due to secondary hypogonadism. Only BMI and hs-CRP were increased in untreated male hypogonadal subjects. Male and female hypogonadism appears to be a common complication of Addison's disease and may contribute to its morbidity. © Georg Thieme Verlag KG Stuttgart · New York.
Lunenfeld, Bruno; Zitzmann, Michael; Arver, Stefan; Kalinchenko, Svetlana; Tishova, Yuliya; Morgentaler, Abraham
Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men. PMID:25657080
George, Mskhalaya; Yulia, Tishova; Svetlana, Kalinchenko
The prevalence of androgen deficiency in reproductive-aged men is increasing and needs new approach to long-term hypogonadism treatment that can preserve fertility. An open non-controlled pilot study included 18 men with eugonadotropic hypogonadism, who received transdermal testosterone gel treatment for 3 months. Sperm analysis was made before treatment and after 3 month of testosterone therapy. Testosterone level was normalized in all patients, but no negative effect was observed on spermatogenesis. Testosterone gel therapy may be a therapy of choice in hypogonadal men of reproductive age but further studies are needed.
Guerrieri, Gioia M.; Wakim, Paul G.; Keenan, P.A.; Schenkel, Linda A; Berlin, Kate; Gibson, Carolyn J.; Rubinow, David R.; Schmidt, Peter J.
Background Despite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates. Objective To evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism. Methods Men (n = 16) and women (n = 15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 68 weeks of GnRH agonist-induced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models. Results During both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects). Conclusion The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in
Abreu, Ana Paula; Kaiser, Ursula B.; Latronico, Ana Claudia
The prokineticin system comprises two multifunctional secreted proteins, prokineticin-1 (PROK1) and prokineticin-2 (PROK2), and their cognate G protein-coupled receptors. The prokineticins were originally identified as endogenous regulators of gastrointestinal motility. Currently, these bioactive peptides are involved in a wide spectrum of biological functions, including angiogenesis, neurogenesis, circadian rhythms, nociception, hematopoiesis and immune response. Mice homozygous for null mutations in Prokr2 or Prok2 recapitulate the human phenotype of Kallmann syndrome, exhibiting severe atrophy of the reproductive system and hypoplastic olfactory bulbs. Indeed, the evidence from several naturally inactivating mutations in the PROK2 and PROKR2 genes in patients with Kallmann syndrome and normosmic hypogonadotropic hypogonadism also indicate the essential role of PROK2 in olfactory bulb morphogenesis and GnRH secretion in humans. PMID:20502053
Chiles, Kelly A
Prescription sales of Testosterone and erectile aids such as phosphodiesterase-5 inhibitors are at an all-time high, underscoring the importance of hypogonadism (HG) and erectile dysfunction (ED) to men's health. The effect of these debilitating conditions has a major impact on the quality of men's lives. Some risk factors for HG or ED including aging, obesity, smoking, and a sedentary lifestyle. Notably, these are the same risk factors for several other medical co-morbidities that contribute to significant morbidity and mortality in men. HG and ED often co-exist with cardiovascular disease, diabetes, and osteoporosis. This review will explore these three co-morbidities that overlap with HG and ED, and will provide a review of their relationship with each other.
Prescription sales of Testosterone and erectile aids such as phosphodiesterase-5 inhibitors are at an all-time high, underscoring the importance of hypogonadism (HG) and erectile dysfunction (ED) to men’s health. The effect of these debilitating conditions has a major impact on the quality of men’s lives. Some risk factors for HG or ED including aging, obesity, smoking, and a sedentary lifestyle. Notably, these are the same risk factors for several other medical co-morbidities that contribute to significant morbidity and mortality in men. HG and ED often co-exist with cardiovascular disease, diabetes, and osteoporosis. This review will explore these three co-morbidities that overlap with HG and ED, and will provide a review of their relationship with each other. PMID:27141446
Harada, Naoki; Hanaoka, Ryo; Hanada, Kazuki; Izawa, Takeshi; Inui, Hiroshi; Yamaji, Ryoichi
ABSTRACT Low testosterone levels increase the risk for cardiovascular disease in men and lead to shorter life spans. Our recent study showed that androgen deprivation via castration altered fecal microbiota and exacerbated risk factors for cardiovascular disease, including obesity, impaired fasting glucose, excess hepatic triglyceride accumulation, and thigh muscle weight loss only in high-fat diet (HFD)-fed male mice. However, when mice were administered antibiotics that disrupted the gut microbiota, castration did not increase cardiovascular risks or decrease the ratio of dried feces to food intake. Here, we show that changes in cecal microbiota (e.g., an increased Firmicutes/Bacteroidetes ratio and number of Lactobacillus species) were consistent with changes in feces and that there was a decreased cecal content secondary to castration in HFD mice. Castration increased rectal body temperature and plasma adiponectin, irrespective of diet. Changes in the gut microbiome may provide novel insight into hypogonadism-induced cardiovascular diseases. PMID:27656762
Central hypogonadotropic hypogonadism (CHH) is an emerging pathological condition frequently associated with overweight, metabolic syndrome, diabetes, and midline defects. The genetic mechanisms involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying CHH, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. Indeed, all detected gene variants may explain a small proportion of the affected patients (43%), indicating that other genes or epigenetic mechanisms are involved in the onset of CHH. The aim of this review is to summarize the current knowledge on genetic background of CHH, organizing the large amount of data present in the literature in a clear and concise manner, to produce a useful guide available for researchers and clinicians. PMID:25254043
Harada, Naoki; Hanaoka, Ryo; Hanada, Kazuki; Izawa, Takeshi; Inui, Hiroshi; Yamaji, Ryoichi
Low testosterone levels increase the risk for cardiovascular disease in men and lead to shorter life spans. Our recent study showed that androgen deprivation via castration altered fecal microbiota and exacerbated risk factors for cardiovascular disease, including obesity, impaired fasting glucose, excess hepatic triglyceride accumulation, and thigh muscle weight loss only in high-fat diet (HFD)-fed male mice. However, when mice were administered antibiotics that disrupted the gut microbiota, castration did not increase cardiovascular risks or decrease the ratio of dried feces to food intake. Here, we show that changes in cecal microbiota (e.g., an increased Firmicutes/Bacteroidetes ratio and number of Lactobacillus species) were consistent with changes in feces and that there was a decreased cecal content secondary to castration in HFD mice. Castration increased rectal body temperature and plasma adiponectin, irrespective of diet. Changes in the gut microbiome may provide novel insight into hypogonadism-induced cardiovascular diseases.
Vezzoli, Valeria; Duminuco, Paolo; Bassi, Ivan; Guizzardi, Fabiana; Persani, Luca; Bonomi, Marco
Congenital hypogonadotropic hypogonadism (CHH) is a rare disease characterized by delayed/absent puberty and infertility due to an inadequate secretion or action of gonadotrophin-releasing hormone (GnRH), with an otherwise structurally and functionally normal hypothalamic-pituitary-gonadal (HPG) axis. CHH is genetically heterogeneous but, due to the infertility of affected individuals, most frequently emerges in a sporadic form, though numerous familial cases have also been registered. In around 50-60% of cases, CHH is associated with a variety of non-reproductive abnormalities, most commonly anosmia/hyposmia, which defines Kallmann Syndrome (KS) by its presence. Broadly-speaking, genetic defects that directly impact on hypothalamic secretion, regulation, or action of GnRH result in a pure neuroendocrine phenotype, normosmic CHH (nCHH), whereas genetic defects that impact of embryonic migration of GnRH neurons to the hypothalamus most commonly result in KS, though nCHH can also arise. Hence, the description of several pedigrees, comprising subjects exhibiting KS and others with nCHH. Although more than 24 genes have been described to be involved in CHH, molecular variants of these do not presently explain more than 35-45% of reported cases. Therefore, numerous other unidentified genes (or conceivably, epigenetic mechanisms) remain to be described to fully understand the pathogenesis of CHH, explaining the emergent idea that CHH is a complex genetic disease characterized by variable expressivity and penetrance. This review summarizes the current state of knowledge on the complex genetic basis of congenital hypogonadotropic hypogonadism and aims to be accessible to both researchers and clinicians.
Dwyer, Andrew A; Tiemensma, Jitske; Quinton, Richard; Pitteloud, Nelly; Morin, Diane
Men with congenital hypogonadotrophic hypogonadism (CHH) typically require lifelong hormonal therapy, and discontinuing treatment can have negative health consequences. Little is known about adherence to treatment or the psychosocial impact of CHH. A sequential, multiple methods approach was used. A quantitative online survey assessed adherence to treatment, depressive symptoms and illness perceptions. Subsequently, qualitative focus groups explored patient-reported factors for adherence. Adult men with CHH on at least 1 year of treatment were recruited internationally. Adherence (Morisky medication adherence scale), depressive symptoms (Zung self-rating depression scale) and patient perception of CHH (revised illness perception questionnaire) were assessed in an online survey, and comparisons were made to reference groups. Patient focus group discussions were conducted and thematic analysis was employed to identify patient-reported factors for adherence. In total, 101 men on long-term treatment were included (mean age 37 ± 11 years). Forty three percent (43/101) exhibited low medication adherence and a significantly elevated prevalence of mild, moderate or severe depressive symptoms (27%, 17%, 20%, respectively, all P < 0·001 vs reference population). Patients reported negative illness perceptions and significant psychosocial consequences. Focus group discussions (n = 3, 26 total patients) identified patient-, health professional- and healthcare system-related barriers as targets for improving adherence. Congenital hypogonadotrophic hypogonadism men are challenged to adhere to long-term treatment. Poor adherence may contribute to adverse effects on bone, sexual and psychological health. The psychosocial morbidity of CHH is significant and appears to be underappreciated by healthcare providers. © 2016 John Wiley & Sons Ltd.
Amor, D J; Delatycki, M B; Gardner, R J; Storey, E
Cerebellar ataxia and hypergonadotropic hypogonadism comprise a rare and presumably heterogeneous association. Inheritance in most cases appears to be autosomal recessive, and associated features include deafness, intellectual impairment, and neuropathy. Typically, onset of ataxia is in the first decade and hypogonadism results in primary amenorrhoea in females. We describe two sisters with a previously undescribed pattern of adult onset progressive cerebellar ataxia and secondary amenorrhoea due to hypergonadotropic hypogonadism. Sensorineural deafness with vestibular hypofunction and peripheral sensory impairment were also present, and intellect was normal. Onset of neurological symptoms was in the third decade, with secondary amenorrhoea occurring at the ages of 16 and 32 years, respectively. The association of ataxia and hypergonadotropic hypergonadism has been classified both as a variant of Holmes type ataxia and as a variant of Perrault syndrome, but we suggest the use of a separate category of ataxia with hypergonadotropic hypogonadism. Copyright Wiley-Liss. Inc.
Sylvester, P. E.
Post mortem examinations were done on two adult siblings (one female and one male) who had been clinically described as suffering from mental handicap, deaf mutism, ataxia, hypogonadism, and hormonal disorders. (DB)
Haider, Ahmad; Haider, Karim S; Saad, Farid
In daily practice, clinicians are often confronted with obese type 2 diabetes mellitus (T2DM) patients for whom the treatment plan fails and who show an inadequate glycemic control and/or no sustainable weight loss. Untreated hypogonadism can be the reason for such treatment failure. This case describes the profound impact testosterone therapy can have on a male hypogonadal patient with metabolic syndrome, resulting in a substantial and sustained loss of body weight, pronounced improvement of all critical laboratory values and finally complete remission of diabetes. Hypogonadism occurs frequently in men with T2DM.In case of pronounced abdominal fat deposition and T2DM, the male patient should be evaluated for testosterone deficiency.Untreated hypogonadism can complicate the successful treatment of patients with T2DM.Under testosterone therapy, critical laboratory values are facilitated to return back to normal ranges and even complete remission of diabetes can be achieved.
Corona, Giovanni; Bianchini, Silvia; Sforza, Alessandra; Vignozzi, Linda; Maggi, Mario
There is evidence demonstrating that sexual complaints represent the most specific symptoms associated with late onset hypogonadism, while central obesity is the most specific sign. In obese men, hypogonadism can further worsen the metabolic profile and increase abdominal fat. In addition, although hypogonadism can exacerbate obesity-associated erectile dysfunction (ED), recent data suggest that a direct contribution of fat-derived factors could be hypothesized. In particular, an animal model recently documented that fat accumulation induces several hepatic pro-inflammatory genes closely linked to corpora cavernosa endothelial dysfunction. Lifestyle modifications and weight loss are the first steps in the treatment of ED patients with obesity or metabolic diseases. In symptomatic hypogonadal men with metabolic impairment and obesity, combining the effect of testosterone substitution with lifestyle modifications could result in better outcomes.
Coss, Christopher C; Jones, Amanda; Hancock, Michael L; Steiner, Mitchell S; Dalton, James T
Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defined clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism. PMID:24407183
Coss, Christopher C; Jones, Amanda; Hancock, Michael L; Steiner, Mitchell S; Dalton, James T
Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defi ned clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.
Sylvester, P. E.
Post mortem examinations were done on two adult siblings (one female and one male) who had been clinically described as suffering from mental handicap, deaf mutism, ataxia, hypogonadism, and hormonal disorders. (DB)
Muthusamy, Karthik; Sudhakar, Sniya V; Yoganathan, Sangeetha; Thomas, Maya Mary; Alexander, Mathew
Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H) syndrome is a rare hypomyelination disorder with around 40 cases reported worldwide. Children with hypomyelination, hypodontia, hypogonadotropic hypogonadism syndrome present with varying degrees of developmental delay with a spastic ataxic syndrome with delayed eruption of teeth along with disruption in the eruption sequence, hypogonadotropic hypogonadism, and a fluctuating clinical course with intercurrent infections and varying periods of stability. The disorder is caused by mutations in POL3A and POL3B genes and is collectively termed as pol III-related leukodystrophies. Here we describe 2 children with hypomyelination, hypodontia, hypogonadotropic, hypogonadism syndrome and the association of multiple vertebral fusion anomalies in one of them, which has not been previously described in the literature. We conclude that the spectrum of the disorder is not limited to brain parenchyma alone and involves all the structures arising from neural ectoderm, and this needs further research. © The Author(s) 2014.
Milardi, Domenico; Grande, Giuseppe; Giampietro, Antonella; Vendittelli, Francesca; Palumbo, Sara; Tartaglione, Linda; Marana, Riccardo; Pontecorvi, Alfredo; de Marinis, Laura; Zuppi, Cecilia; Capoluongo, Ettore
Testosterone deficiency has become a frequently diagnosed condition in today's society affected by epidemic obesity, and is associated with cardiovascular risk. Recent studies have established the importance of altered vascular endothelium function in cardiovascular disease. The damage to the endothelium might also cause endothelial cell detachment, resulting in increased numbers of circulating endothelial cells (CEC) within the bloodstream. To evaluate whether hypogonadism could modify CEC count in peripheral bloodstream, we investigated peripheral blood CEC count using the CellSearch System, a semiautomatic method to accurately and reliably enumerate CECs, which are sorted based on a CD146(+), CD105(+), DAPI(+), CD45(-) phenotype, in a population of 20 patients with hypogonadism. The control group comprised 10 age- and sex-matched healthy participants. CEC count per milliliter was significantly increased in patients with hypogonadism vs the control group. In the group with hypogonadism, an inverse exponential correlation was present between testosterone levels and CEC count per milliliter. A direct linear correlation was present between waist circumference and CECs and between body mass index and CECs. The regression analysis showed that testosterone was the significant independent determinant of CECs. Our results underline that male hypogonadism is associated with endothelial dysfunction. The correlation between CEC and waist circumference underlines that visceral obesity may be synergically implicated in this regulation. Future studies are required to unveil the mechanisms involved in the pathogenesis of testosterone-induced endothelial disfunction, which may provide novel therapeutic targets to be incorporated in the management of hypogonadism.
Surampudi, Prasanth N.; Wang, Christina; Swerdloff, Ronald
Hypogonadism in older men is a syndrome characterized by low serum testosterone levels and clinical symptoms often seen in hypogonadal men of younger age. These symptoms include decreased libido, erectile dysfunction, decreased vitality, decreased muscle mass, increased adiposity, depressed mood, osteopenia, and osteoporosis. Hypogonadism is a common disorder in aging men with a significant percentage of men over 60 years of age having serum testosterone levels below the lower limits of young male adults. There are a variety of testosterone formulations available for treatment of hypogonadism. Data from many small studies indicate that testosterone therapy offers several potential benefits to older hypogonadal men. A large multicenter NIH supported double blind, placebo controlled study is ongoing, and this study should greatly enhance the information available on efficacy and side effects of treatment. While safety data is available across many age groups, there are still unresolved concerns associated with testosterone therapy. We have reviewed the diagnostic methods as well as benefits and risks of testosterone replacement therapy for hypogonadism in aging men. PMID:22505891
Kim, Hyo Jeong; Lee, Dong-Yun; Yoon, Byung-Koo; Choi, DooSeok
To evaluate uterine development with estrogen replacement therapy in patients with primary amenorrhea due to hypogonadism. Retrospective study. Thirty-five women. Women who were younger than 20 years of age and who had primary amenorrhea and an immaturely shaped uterus were included. Changes in uterine cross-sectional area (UXA) and uterine maturity in pelvic ultrasound after 2 year of estrogen replacement therapy were assessed on the basis of the etiology of primary hypogonadism. Patients were classified into three groups according to the etiology of primary hypogonadism: Turner syndrome (n = 19), hypogonadotropic hypogonadism after brain surgery (n = 10), and premature ovarian insufficiency after cancer treatment (n = 6). Overall, the mean UXA significantly increased (from 3.1 ± 1.8 to 11.6 ± 4.9 cm(2)) after estrogen replacement therapy (P < .001), but the final UXA was significantly smaller in patients with premature ovarian insufficiency compared with other etiologies. In logistic regression analysis, etiology and the cumulative dose of estrogen were associated with uterine maturation (P = .011 and .004, respectively). Estrogen replacement therapy induced growth of the uterus in patients with primary hypogonadism. However, the response to estrogen replacement therapy varied on the basis of the total cumulative dose of estrogen and etiology of primary hypogonadism. Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.
It is well recognized that bone loss accelerates in hypogonadal states, with female menopause being the classic example of sex hormones affecting the regulation of bone metabolism. Underrepresented is our knowledge of the clinical and metabolic consequences of overt male hypogonadism, as well as the more subtle age-related decline in testosterone on bone quality. While menopause and estrogen deficiency are well-known risk factors for osteoporosis in women, the effects of age-related testosterone decline in men on bone health are less well known. Much of our knowledge comes from observational studies and retrospective analysis on small groups of men with variable causes of primary or secondary hypogonadism and mild to overt testosterone deficiencies. This review aims to present the current knowledge of the consequences of adult male hypogonadism on bone metabolism. The direct and indirect effects of testosterone on bone cells will be explored as well as the important differences in male osteoporosis and assessment as compared to that in females. The clinical consequence of both primary and secondary hypogonadism, as well as testosterone decline in older males, on bone density and fracture risk in men will be summarized. Finally, the therapeutic options and their efficacy in male osteoporosis and hypogonadism will be discussed. PMID:28408926
Rey, R A; Grinspon, R P; Gottlieb, S; Pasqualini, T; Knoblovits, P; Aszpis, S; Pacenza, N; Stewart Usher, J; Bergadá, I; Campo, S M
Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving
Agarwal, Pankaj Kumar; Singh, Parminder; Chowdhury, Subhankar; Sharma, S. K.; Majumdar, Anirban; Shah, Parag; Sahay, Rakesh; Ayyar, S. Vageesh; Phatale, Hemant; Batra, Chandar M.; Syed, Raeesuddin; Shetty, Pradeep
Background: A high prevalence of hypogonadism in men with Type-2 diabetes mellitus (T2DM) has been reported worldwide. Objectives: To evaluate the prevalence of hypogonadism in Indian males with T2DM and assess the primary and secondary hypogonadism along with androgen deficiency. Materials and Methods: In this cross-sectional study, 900 men with T2DM were evaluated using androgen deficiency in aging male questionnaire. They were screened for demographic characteristics, gonadal hormone levels, lipid profile, and glycosylated hemoglobin. Results: The prevalence of hypogonadism in T2DM patients was found to be 20.7% (186 out of 900). Hypogonadism was of testicular origin (primary) in 48/186 (25.8%) patients, of pituitary or hypothalamic origin (secondary) in 14/186 (7.53%), and remaining 124/186 (66.67%) patients were found to have low testosterone with the inappropriate normal level of luteinizing hormone and Follicle-stimulating hormone. 451/900 (50.1%) patients were only symptomatic but had normal testosterone levels. Further 263 patients out 900 were asymptomatic, of which 51/900 (5.7%) patients had low levels of testosterone and 212/900 (23.5%) patients had normal testosterone level without symptoms. There were no deaths or other serious adverse events except mild pyrexia which was not related to the study. Conclusion: Hypogonadism diagnosis, at times, might not be validated with the help of androgen deficiency questionnaire or symptoms only. Given the large number of patients of T2DM in India, the incidence of hypogonadism is more in diabetic patients as compared to the general population. Hence, implementation of screening programs in diabetic patients is necessary to understand and detect individuals with low serum total testosterone at any early stage and to supplement testosterone accordingly. PMID:28217500
The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime. PMID:26790381
Kotan, Leman Damla; Cooper, Charlton; Darcan, Şükran; Carr, Ian M.; Özen, Samim; Yan, Yi; Hamedani, Mohammad K.; Gürbüz, Fatih; Mengen, Eda; Turan, İhsan; Ulubay, Ayça; Akkuş, Gamze; Yüksel, Bilgin; Topaloğlu, A. Kemal; Leygue, Etienne
Objective: What initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH). Methods: A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing. Results: Our studies revealed three independent families in which IHH/delayed puberty is associated with inactivating SRA1 variants. SRA1 was the first gene to be identified to function through its protein as well as noncoding functional ribonucleic acid products. These products act as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand-dependent activity of the estrogen receptor alpha, as assessed by luciferase reporter assay in HeLa cells. Conclusion: Our findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans. Furthermore, SRA1 with its alternative products and functionality may provide a potential explanation for the versatility and complexity of the pubertal process. PMID:27086651
Kim, Soo Hyun
The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime.
Dwyer, Andrew A; Jayasena, Channa N; Quinton, Richard
The phenomenon known as "mini-puberty" refers to activation of the neonatal hypothalamo-pituitary axis causing serum concentrations of gonadotrophins and testosterone (T) to approach adult male levels. This early neonatal period is a key proliferative window for testicular germ cells and immature Sertoli cells. Although failure to spontaneously initiate (adolescent) puberty is the most evident consequence of a defective gonadotropin-releasing hormone (GnRH) neurosecretory network, absent mini-puberty is also likely to have a major impact on the reproductive phenotype of men with congenital hypogonadotrophic hypogonadism (CHH). Furthermore, the phase of male mini-puberty represents a key window-of-opportunity to identify congenital GnRH deficiency (either isolated CHH, or as part of combined pituitary hormone deficiency) in childhood. Among male neonates exhibiting "red flag" indicators for CHH (i.e. maldescended testes with or without cryptorchidism) a single serum sample (between 4-8 weeks of life) can pinpoint congenital GnRH deficiency far more rapidly and with much greater accuracy than dynamic tests performed in later childhood or adolescence. Potential consequences for missing absent mini-puberty in a male neonate include the lack of monitoring of pubertal progression/lack of progression, and the missed opportunity for early therapeutic intervention. This article will review our current understanding of the mechanisms and clinical consequences of mini-puberty. Furthermore, evidence for the optimal clinical management of patients with absent mini-puberty will be discussed.
Weiss, Jeffrey; Hurley, Lisa A; Harris, Rebecca M; Finlayson, Courtney; Tong, Minghan; Fisher, Lisa A; Moran, Jennifer L; Beier, David R; Mason, Christopher; Jameson, J Larry
Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low-density genome-wide SNP arrays. Ten of the 15 lines were pursued further using higher-resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism, candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility.
Gooren, L J; Behre, H M
Testosterone has a steeply dose-dependent effect on muscle mass and strength irrespective of gonadal status. So, for reasons of fairness, people who engage in competitive sports should not administer exogenous testosterone raising their blood testosterone levels beyond the range of normal. There is a ban on exogenous androgens for men and women in sports, but an exception has been made for men with androgen deficiency due to pituitary or testicular disease. Men who receive testosterone administration for the indication hypogonadism have an interest in the use of testosterone preparations generating blood testosterone levels within the normal range of healthy, eugonadal men. On the grounds of a positive correlation between blood testosterone concentrations muscle and volume/strength, they are best served with a parenteral testosterone preparation, rather than transdermal testosterone, but they should not run the risk of being excluded from competition because of supraphysiological testosterone levels. The latter is a realistic risk with the traditional parenteral testosterone esters. The new parenteral testosterone undecanoate preparation offers much better perspectives. Its pharmacokinetics have been investigated in detail and there is a fair degree of predictability of resulting blood testosterone levels with use of this preparation.
Maione, Luigi; Albarel, Frederique; Bouchard, Philippe; Gallant, Megan; Flanagan, Colleen A.; Bobe, Regis; Cohen-Tannoudji, Joelle; Pivonello, Rosario; Colao, Annamaria; Brue, Thierry; Millar, Robert P.; Lombes, Marc; Young, Jacques; Guiochon-Mantel, Anne; Bouligand, Jerome
Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative “hot spot”. Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH. PMID:23936060
Marconi, Marcelo; Souper, Renato; Hartmann, Jonathan; Alvarez, Matías; Fuentes, Ignacio; Guarda, Francisco J
Previous series have demonstrated that Clomiphene Citrate (CC) is an effective treatment to increase Total Testosterone (TT) in Late Onset Hypogonadism (LOH) patients. However, what happens to TT levels after ending CC treatment is still debatable. The objective of this study is to evaluate TT levels 3 months after the discontinuation of CC in patients with LOH who were previously successfully treated with the same drug. Twenty-seven patients with LOH that were successfully treated (achieved TT levels >11nmol/l) with CC 50mgs daily for 50 days were prospectively recruited in our Andrological outpatient clinic. CC was then stopped for 3 months and TT levels were measured at the end of this period. Mean TT level before discontinuation of CC was 22.7±8.1nmol/L (mean±SD). Three months after discontinuation, mean TT level significantly decreased in all pa¬tients, 10.2±3.9nmol/l (p < 0.01). Twenty-one patients (78%) decreased TT levels under 11nmol/L. Six patients (22%) had TT levels that remained within the normal recommended range (≥11nmol/l). No statistical significant differences were observed between both groups. In the short term LOH does not seem to be a reversible condition in most patients after CC treatment. More studies with longer follow-up are needed to evaluate the kinetics of TT in LOH. Copyright® by the International Brazilian Journal of Urology.
Marconi, Marcelo; Souper, Renato; Hartmann, Jonathan; Alvarez, Matías; Fuentes, Ignacio; Guarda, Francisco J.
ABSTRACT Objective: Previous series have demonstrated that Clomiphene Citrate (CC) is an effective treatment to increase Total Testosterone (TT) in Late Onset Hypogonadism (LOH) patients. However, what happens to TT levels after ending CC treatment is still debatable. The objective of this study is to evaluate TT levels 3 months after the discontinuation of CC in patients with LOH who were previously successfully treated with the same drug. Materials and Methods: Twenty-seven patients with LOH that were successfully treated (achieved TT levels >11nmol/l) with CC 50mgs daily for 50 days were prospectively recruited in our Andrological outpatient clinic. CC was then stopped for 3 months and TT levels were measured at the end of this period. Results: Mean TT level before discontinuation of CC was 22.7±8.1nmol/L (mean±SD). Three months after discontinuation, mean TT level significantly decreased in all patients, 10.2±3.9nmol/l (p<0.01). Twenty-one patients (78%) decreased TT levels under 11nmol/L. Six patients (22%) had TT levels that remained within the normal recommended range (≥11nmol/l). No statistical significant differences were observed between both groups. Conclusion: In the short term LOH does not seem to be a reversible condition in most patients after CC treatment. More studies with longer follow-up are needed to evaluate the kinetics of TT in LOH. PMID:27622282
Jadhav, Unmesh; Harris, Rebecca M.; Jameson, J. Larry
DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; also known as NROB1, nuclear receptor subfamily 0, group B, member 1) encodes a nuclear receptor that is expressed in embryonic stem (ES) cells, steroidogenic tissues (gonads, adrenals), the ventromedial hypothalamus (VMH), and pituitary gonadotropes. Humans with DAX1 mutations develop an X-linked syndrome referred to as adrenal hypoplasia congenita (AHC). These boys typically present in infancy with adrenal failure but later fail to undergo puberty because of hypogonadotropic hypogonadism (HHG). The adrenal failure reflects a developmental abnormality in the transition of the fetal to adult zone, resulting in glucocorticoid and mineralocorticoid deficiency. The etiology of HHG involves a combined and variable deficiency of hypothalamic GnRH secretion and/or pituitary responsiveness to GnRH resulting in low LH, FSH and testosterone. Treatment with exogenous gonadotropins generally does not induce spermatogenesis. Animal models indicate that DAX1 also plays a critical role in testis development and function. As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as steroidogenic factor 1 (SF1). In addition to reproductive tissues, DAX1 is also expressed at high levels in ES cells and plays a role in the maintenance of pluripotentiality. Here we review the clinical manifestations associated with DAX1 mutations as well as the evolving information about its function based on animal models and in vitro studies. PMID:21672607
Dandona, Paresh; Dhindsa, Sandeep
Studies over the last few years have clearly established that at least 25% of men with type 2 diabetes have subnormal free testosterone concentrations in association with inappropriately low LH and FSH concentrations. Another 4% have subnormal testosterone concentrations with elevated LH and FSH concentrations. The Endocrine Society, therefore, now recommends the measurement of testosterone in patients with type 2 diabetes on a routine basis. The subnormal testosterone concentrations are not related to glycosylated hemoglobin or duration of diabetes, but are associated with obesity, very high C-reactive protein concentrations, and mild anemia. In addition, subnormal testosterone concentrations in these men are associated with a two to three times elevated risk of cardiovascular events and death in two early studies. Short-term studies of testosterone therapy in hypogonadal men with type 2 diabetes have demonstrated an increase in insulin sensitivity and a decrease in waist circumference. However, the data on the effect of testosterone replacement on glycemic control and cardiovascular risk factors such as cholesterol and C-reactive protein concentrations are inconsistent. As far as sexual function is concerned, testosterone treatment increases libido but does not improve erectile dysfunction and thus, phosphodiesterase inhibitors may be required. Trials of a longer duration are clearly required to definitively establish the benefits and risks of testosterone replacement in patients with type 2 diabetes and low testosterone.
Dabaja, Ali A; Goldstein, Marc
In the past, the indications for varicocelectomy are primarily for infertility with abnormal semen parameters, testicular hypotrophy/atrophy in adolescents, and/or pain. The surgical treatment of varicocele for hypogonadism is controversial and debated. Recently, multiple reports in the literature have suggested that varicocele is associated with hypogonadism and varicocele repair can increase testosterone levels. Men with hypogonadal symptoms should have at least two serum testosterone levels. Microsurgical varicocelectomy may be beneficial for men with clinically palpable varicoceles with documented hypogonadism. In this review, we summarize the most recent literature linking varicocele to hypogonadism and sexual dysfunction and the impact of repair on serum testosterone levels. We performed a search of the published English literature. The key words used were “varicocele and hypogonadism” and “varicocele surgery and testosterone.” We included published studies after 1998. We, also, evaluated the effect of surgery on the changes in the serum testosterone level regardless of the indication for the varicocele repair. PMID:26696437
Dandona, P; Rosenberg, M T
There is a high prevalence of hypogonadism in the older adult male population and the proportion of older men in the population is projected to rise in the future. As hypogonadism increases with age and is significantly associated with various comorbidities such as obesity, type 2 diabetes, hypertension, osteoporosis and metabolic syndrome, the physician is increasingly likely to have to treat hypogonadism in the clinic. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood and fatigue. Diagnosis of the condition requires the presence of low serum testosterone levels and the presence of hypogonadal symptoms. There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets. These are efficacious in establishing eugonadal testosterone levels in the blood and relieving symptoms. Restoration of testosterone levels to the normal range improves libido, sexual function, and mood; reduces fat body mass; increases lean body mass; and improves bone mineral density. Testosterone treatment is contraindicated in subjects with prostate cancer or benign prostate hyperplasia and risks of treatment are perceived to be high by many physicians. These risks, however, are often exaggerated and should not outweigh the benefits of testosterone treatment. PMID:20518947
Ayanian, S; Irwig, M S
The global obesity epidemic is having a profound impact on the health of populations. From a reproductive standpoint, obesity has been associated with infertility and hypogonadism. We present the case of a 29-year-old male-to-female transsexual with super obesity (body mass index >50) who was found to have profound hypogonadism with total and free testosterone levels in the normal female reference range. There is virtually no literature on the hormonal sequelae of obesity in transsexual people. The patient was prescribed an aromatase inhibitor, letrozole 2.5 mg twice daily for 2 weeks, to determine the role of oestrogen in the hypogonadism. The aromatase inhibitor reduced the serum oestradiol concentration from 125 to 6.9 pm. There were dramatic corresponding rises in total testosterone (2.8 to 10.7 nm), luteinising hormone (4.1 to 20.5 mIU ml(-1) ) and follicle stimulating hormone (1.8 to 15.3 mIU ml(-1) ). This diagnostic test demonstrated the important role of oestrogen in mediating the hypogonadism. After the testing, the patient was started on oestrogen therapy after a careful discussion of the benefits versus risks of oestrogen therapy. We anticipate that similar cases of hypogonadism in male-to-female transsexuals will likely become more common in an era of increased obesity rates.
Pye, S R; Huhtaniemi, I T; Finn, J D; Lee, D M; O'Neill, T W; Tajar, A; Bartfai, G; Boonen, S; Casanueva, F F; Forti, G; Giwercman, A; Han, T S; Kula, K; Lean, M E; Pendleton, N; Punab, M; Rutter, M K; Vanderschueren, D; Wu, F C W
Late-onset hypogonadism (LOH) has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of low T. The natural history of LOH, especially its relationship to mortality, is currently unknown. The aim of this study was to clarify the associations between LOH, low T, and sexual symptoms with mortality in men. Prospective data from the European Male Aging Study (EMAS) on 2599 community-dwelling men aged 40-79 years in eight European countries was used for this study. All-cause, cardiovascular, and cancer-related mortality was measured. One hundred forty-seven men died during a median follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After adjusting for age, center, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH had a 5-fold [hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.7, 11.4] higher risk of all-cause mortality. Compared with eugonadal men, the multivariable-adjusted risk of mortality was 2-fold higher in those with T less than 8 nmol/L (irrespective of symptoms; HR 2.3; 95% CI 1.2, 4.2) and 3-fold higher in those with three sexual symptoms (irrespective of serum T; compared with asymptomatic men; HR 3.2; 95% CI 1.8, 5.8). Similar risks were observed for cardiovascular mortality. Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of T and the presence of sexual symptoms contribute independently. Detecting low T in men presenting with sexual symptoms offers an opportunity to identify a small subgroup of aging men at particularly high risk of dying.
Hirsch, Dania; Benbassat, Carlos; Toledano, Yoel; S'chigol, Irena; Tsvetov, Gloria; Shraga-Slutzky, Ilana; Eizenberg, Yoav; Shimon, Ilan
Data on pituitary imaging in adult male patients presenting with hypogonadotrophic hypogonadism (HH) and no known pituitary disease are scarce. To assess the usefulness of pituitary imaging in the evaluation of men presenting with HH after excluding known pituitary disorders and hyperprolactinemia. A historical prospective cohort of males with HH. Men who presented for endocrine evaluation from 2011 to 2014 with testosterone levels <10.4 nmol/L (300 ng/mL), normal LH and FSH levels and no known pituitary disease. Seventy-five men were included in the analysis. Their mean age and BMI were 53.4 ± 14.8 years and 30.7 ± 5.2 kg/m2, respectively. Mean total testosterone, LH, and FSH were 6.2 ± 1.7 nmol/L, 3.4 ± 2 and 4.7 ± 3.1 mIU/L, respectively. Prolactin level within the normal range was obtained in all men (mean 161 ± 61, range 41-347 mIU/L). Sixty-two men had pituitary MRI and 13 performed CT. In 61 (81.3%) men pituitary imaging was normal. Microadenoma was found in 8 (10.7%), empty sella and thickened pituitary stalk in one patient (1.3%) each. In other four patients (5.3%) a small or mildly asymmetric pituitary gland was noted. No correlation was found between testosterone level and the presence of pituitary anomalies. This study suggests that the use of routine hypothalamic-pituitary imaging in the evaluation of IHH, in the absence of clinical characteristics of other hormonal loss or sellar compression symptoms, will not increase the diagnostic yield of sellar structural abnormalities over that reported in the general population.
Hypogonadism is a common problem in the end-stage renal disease (ESRD) and renal transplant population. It has widespread systemic effects and has been linked with mortality in dialysis patients and at the time of renal transplant. The etiology is likely multifactorial and most patients are afflicted by various comorbidities that can contribute to hypogonadism. Clinical manifestations are mostly nonspecific. We review the approach to the diagnosis of hypogonadism, focusing on both laboratory values and clinical signs and symptoms. We review treatment with testosterone replacement in this population and highlight various studies that tend to have small sample sizes. Though these studies provide insight into testosterone replacement, the need for larger studies is emphasized to better understand the effects and safety of therapy. PMID:28078220
Özbek, Mehmet Nuri; Demirbilek, Hüseyin; Baran, Rıza Taner; Baran, Ahmet
Objective: Deficiency of sex steroids has a negative impact on bone mineral content. In studies conducted on postmenopausal women and animal studies, elevated follicle-stimulating hormone (FSH) levels were found to be correlated with a decrease in bone mineralization and osteoporosis. The aim of the present study was to evaluate bone mineral density (BMD) in adolescent girls with hypogonadotropic and hypergonadotropic hypogonadism and also to investigate the correlation between FSH level and BMD. Methods: The study group included 33 adolescent girls with hypogonadism (14 with hypogonadotropic hypogonadism and 19 with hypergonadotropic hypogonadism). FSH, luteinizing hormone, estradiol levels, and BMD (using dual energy x-ray absorptiometry) were measured. Results: There were no statistically significant differences between the chronological age and bone age of the two patient groups, namely, with hypogonadotropic and hypergonadotropic hypogonadism. There was also no significant difference between BMD z-score values obtained from measurements from the spine and the femur neck of patients in the two groups (p-values were 0.841 and 0.281, respectively). In the hypergonadotropic group, a moderately negative correlation was detected between FSH level and BMD z-score measured from the femur neck (ρ=-0.69, p=0.001), whilst no correlation was observed between FSH levels and height adjusted BMD-z scores measured from the spine (ρ=0.17, p=0.493). FSH level was not found to be an independent variable affecting BMD z-score. Conclusion: BMD z-scores were detected to be similar in adolescent girls with hypogonadotropic and hypergonadotropic hypogonadism, and FSH levels were not found to have a clinically relevant impact on BMD. PMID:27087454
Cobo, Gabriela; Gallar, Paloma; Di Gioia, Cristina; García Lacalle, Concepción; Camacho, Rosa; Rodriguez, Isabel; Ortega, Olimpia; Mon, Carmen; Vigil, Ana; Lindholm, Bengt; Carrero, Juan Jesús
Testosterone deficiency (hypogonadism) is common among men undergoing haemodialysis, but its clinical implications are not well characterized. Testosterone is an anabolic hormone that induces erythrocytosis and muscle synthesis. We hypothesized that testosterone deficiency would be associated with low muscle mass, physical inactivity and higher dosages of erythropoietin-stimulating agents (ESA). Single-center cross-sectional study of 57 male haemodialysis patients. None of the patients was undergoing testosterone replacement therapy. Total testosterone was measured in serum. Body composition (by bioelectrical impedance analysis) and physical activity (by the use of pedometers) were assessed. Patients with testosterone levels below the normal range were considered hypogonadal. Mean testosterone level was 321±146ng/dL; 20 patients (35%) were hypogonadal. Hypogonadal patients were older and had lower mean arterial blood pressure, higher interleukin-6 levels, lower lean body mass and higher fat body mass. A negative association between testosterone and normalized ESA dose was found in uni- and multivariate regression analyses. Testosterone levels directly correlated with lean body mass regardless of confounders. Hypogonadal patients had lower physical activity than their counterparts [2753±1784 vs. 4291±3225steps/day (p=0.04)]. The relationship between testosterone and physical activity was independent of age, comorbidities and inflammatory markers, but dependent on the proportion of muscle mass. Hypogonadism is common in our male haemodialysis population and is associated with higher ESA doses, reduced muscle mass and lower physical activity. The link between low testosterone levels and physical inactivity may conceivably relate to reduced muscle mass due to inadequate muscle protein synthesis. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.
Ashby, Helen L; Gama, Rouvick M; Sur, Hariom; Inglis, John; Ford, Clare; Gama, Rousseau
Primary testicular failure is characterized by low serum testosterone with appropriately high serum gonadotrophins, that is hypergonadotrophic hypogonadism. We report on a 27-year-old man with congenital adrenal hyperplasia (CAH) and infertility due to testicular adrenal rest rumours (TART) resulting in primary testicular failure but presenting with azoospermia, elevated serum testosterone and very low serum gonadotrophins. Hypergonadotrophic hypogonadism was unmasked by increasing glucocorticoid dosage. It is important to recognise the limitations of follicle-stimulating hormone, luteinising hormone and testosterone in assessing testicular function in men with CAH. Abnormal semen analysis may be the best indicator of testicular dysfunction in men with CAH.
Katulanda, Prasad; Rajapakse, J Rasika D K; Kariyawasam, Jayani; Jayasekara, Rohan; Dissanayake, Vajira H W
48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder, and renal malformatons. Klinefelter syndrome was clinically suspected. The karyotype confirmed the diagnosis of 48,XXYY syndrome. This is the first reported case of 48,XXYY syndrome from Sri Lanka.
D'Amore, M; Minenna, G; D'Amore, S; Scagliusi, P; Caprio, S
Acromegaly is a rare disease that, in the majority of cases, is due to the presence of a benign growth hormone (GH)-producing tumor of the pituitary. Growth hormone has profound effects on linear bone growth, bone metabolism, and bone mass. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. The Autors describe a case of patient affected by acromegaly without hypogonadism with serious osteoporosis and biological signs of osteomalacia.
Davidiuk, Andrew J.
Testosterone deficiency (TD) has become a growing concern in the field of men’s sexual health, with an increasing number of men presenting for evaluation of this condition. Given the increasing demand for testosterone replacement therapy (TRT), a panel of experts met in August of 2015 to discuss the treatment of men who present for evaluation in the setting of low or normal gonadotropin levels and the associated signs and symptoms of hypogonadism. This constellation of factors can be associated with elements of both primary and secondary hypogonadism. Because this syndrome commonly occurs in men who are middle-aged and older, it was termed adult-onset hypogonadism (AOH). AOH can be defined by the following elements: low levels of testosterone, associated signs and symptoms of hypogonadism, and low or normal gonadotropin levels. Although there are significant benefits of TRT for patients with AOH, candidates also need to understand the potential risks. Patients undergoing TRT will need to be monitored regularly because there are potential complications that can develop with long-term use. This review is aimed at providing a deeper understanding of AOH, discussing the benefits and risks of TRT, and outlining each modality of TRT in use for AOH. PMID:28078213
Di Sante, Gabriele; Wang, Liping; Wang, Chenguang; Jiao, Xuanmiao; Casimiro, Mathew C.; Chen, Ke; Pestell, Timothy G.; Yaman, Ismail; Di Rocco, Agnese; Sun, Xin; Horio, Yoshiyuki; Powell, Michael J.; He, Xiaohong; McBurney, Michael W.
Hypogonadatropic hypogonadism (HH) can be acquired through energy restriction or may be inherited as congenital hypogonadotropic hypogonadism and its anosmia-associated form, Kallmann's syndrome. Congenital hypogonadotropic hypogonadism is associated with mutations in a group of genes that impact fibroblast growth factor 8 (FGF8) function. The Sirt1 gene encodes a nicotinamide adenine dinucleotide-dependent histone deacetylase that links intracellular metabolic stress to gene expression. Herein Sirt1−/− mice are shown to have HH due to failed GnRH neuronal migration. Sirtuin-1 (Sirt1) catalytic function induces GnRH neuronal migration via binding and deacetylating cortactin. Sirt1 colocalized with cortactin in GnRH neurons in vitro. Sirt1 colocalization with cortactin was regulated in an FGF8/fibroblast growth factor receptor-1 dependent manner. The profound effect of Sirt1 on the hormonal status of Sirt1−/− mice, mediated via defective GnRH neuronal migration, links energy metabolism directly to the hypogonadal state. Sirt1-cortactin may serve as the distal transducer of neuronal migration mediated by the FGF8 synexpression group of genes that govern HH. PMID:25545407
Rubio-Cabezas, Oscar; Gómez, José Luis; Gleisner, Andrea; Hattersley, Andrew T.
Context: Biallelic mutations in NEUROG3 are known to cause early-onset malabsorptive diarrhea due to congenital anendocrinosis and diabetes mellitus at a variable age. No other endocrine disorders have been described so far. We report four patients with homozygous NEUROG3 mutations who presented with short stature and failed to show any signs of pubertal development. Case Description: Four patients (two males, two females) were diagnosed with homozygous mutations in NEUROG3 on the basis of congenital malabsorptive diarrhea and diabetes. All four had severe short stature and failed to develop secondary sexual characteristics at an appropriate age, despite some having normal body mass index. The absence of gonadal function persisted into the third decade in one patient. Upon testing, both basal and stimulated LH and FSH levels were low, with the remaining pituitary hormones within the normal range. Magnetic resonance imaging scans of the hypothalamic-pituitary axis did not reveal structural abnormalities. A diagnosis of hypogonadotropic hypogonadism was made, and replacement therapy with sex hormones was started. Conclusions: The high reproducibility of this novel phenotype suggests that central hypogonadism and short stature are common findings in patients with mutations in NEUROG3. Growth rate needs to be carefully monitored in these patients, who also should be routinely screened for hypogonadism when they reach the appropriate age. NEUROG3 mutations expand on the growing number of genetic causes of acquired hypogonadotropic hypogonadism. PMID:27533310
Schubert, M; Jockenhövel, F
Late-onset hypogonadism (LOH) is defined by reduced serum testosterone levels (either total testosterone or free testosterone) and the careful exclusion of any form of classical hypogonadism. When the androgen decline associated with advancing age causes detrimental physiological and mental effects, the syndrome is known as symptomatic LOH (SLOH). A detailed medical history and physical examination are the bases of the diagnosis, and should always precede any biochemical investigations. A general screening of men above a certain age for testosterone deficiency is not feasible. Questionnaires may assist in identifying men who suffer from LOH. Common clinical symptoms of SLOH are lethargy, fatigue, decreased sense of well-being, reduced physical and mental activity, diminished libido, increased sweating, depressive mood, reduced muscle and bone mass or even osteoporosis, erectile dysfunction, and mild anemia. When clinical symptoms are present, the laboratory work-up should focus on total testosterone serum levels. Total testosterone levels <200 ng/dl indicate hypogonadism. In cases of testosterone levels between 200 and 400 ng/dl, measurement should be repeated and supplemented by determination of free testosterone, either by appropriate laboratory methods or the calculation of free testosterone index. In case of very low testosterone levels, classical secondary hypogonadism needs to be considered and excluded. For the safety reasons to exclude contraindications of therapy with androgens, and for follow-up investigations during therapy prostate-specific antigen (PSA), hemoglobin and hematocrit are of interest.
Liao, C-H; Wu, Y-N; Lin, F-Y; Tsai, W-K; Liu, S-P; Chiang, H-S
Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells required for endothelial repair. A low EPC number can be considered as an independent predictor of endothelial dysfunction and future cardiovascular events. Recent evidence shows that patients with hypogonadal symptoms without other confounding risk factors have a low number of circulating progenitor cells (PCs) and EPCs, thus highlighting the role of testosterone in the proliferation and differentiation of EPCs. Here, we investigate if testosterone replacement therapy (TRT) can increase circulating EPC number in men with late onset hypogonadism. Forty-six men (age range, 40-73 years; mean age, 58.3 years) with hypogonadal symptoms were recruited, and 29 men with serum total testosterone (TT) levels less than 350 ng/dL received TRT using transdermal testosterone gel (Androgel; 1% testosterone at 5 g/day) for 12 months. Circulating EPC numbers (per 100 000 monocytes) were calculated using flow cytometry. There was no significant association between serum TT levels and the number of circulating EPCs before TRT. Compared with the number of mean circulating EPCs at baseline (9.5 ± 6.2), the number was significantly higher after 3 months (16.6 ± 11.1, p = 0.027), 6 months (20.3 ± 15.3, p = 0.006) and 12 months (27.2 ± 15.5, p = 0.017) of TRT. Thus, we conclude that serum TT levels before TRT are not significantly associated with the number of circulating EPCs in men with late onset hypogonadism. However, TRT can increase the number of circulating EPCs, which implies the benefit of TRT on endothelial function in hypogonadal men.
Cobo, Gabriela; Cordeiro, Antonio C; Amparo, Fernanda Cassulo; Amodeo, Celso; Lindholm, Bengt; Carrero, Juan Jesús
Hypogonadism is a common endocrine disorder in men with chronic kidney disease (CKD), but its pathophysiology is poorly understood. We here explore the plausible contribution of abdominal adiposity and leptin hyperproduction to testosterone deficiency in this patient population. Cross-sectional analysis with all men included the Malnutrition, Inflammation and Vascular Calcification cohort, which enrolled consecutive nondialyzed patients with CKD stages 3-5. A total of 172 men with CKD stages 3-5 nondialysis (median age 61 [45-75] years, median glomerular filtration rate 24 [9-45] mL/min/1.73 m(2)). In them, serum levels of total testosterone, estrogen, sex hormone binding globulin, and leptin were quantified, together with visceral adipose tissue (VAT) by thoracic and abdominal CT scan. None, observational study. Total testosterone, hypogonadism. The median level of total testosterone was 11.7 (7.3-18.4) nmol/L, with hypogonadism (<10 nmol/L) present in 52 (30%) patients. Testosterone-deficient patients presented with significantly higher body mass index, waist circumference, and VAT. An inverse correlation between testosterone and VAT (rho = -0.25, P = .001) or waist circumference (rho = -0.20, P = .008) was found, also after multivariate adjustment including sex hormone binding globulin and estrogen. Total testosterone was inversely correlated with serum leptin (rho = -0.22, P = .003), and the ratio of leptin/VAT, an index of leptin hyperproduction, was strongly and independently associated with the prevalence of hypogonadism in multivariable regression analyses. Visceral adiposity independently associated with lower testosterone levels among men with CKD stage 3-5 nondialysis. The observed link between hyperleptinemia and hypogonadism is in line with previous evidence on direct effects of leptin on testosterone production. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Hajjar, R R; Kaiser, F E; Morley, J E
To determine the complications, toxicities, and compliance of long term testosterone replacement in hypogonadal males, we retrospectively assessed 45 elderly hypogonadal men receiving testosterone replacement therapy and 27 hypogonadal men taking testosterone. Hypogonadism was defined as a bioavailable testosterone serum concentration of 72 ng/dL or less. Both groups received baseline physical examinations and blood tests. The testosterone-treated group received 200 mg testosterone enanthate or cypionate im every 2 weeks, and follow-up examinations and blood samplings were performed every 3 months. The control group had a single follow-up blood test and physical examination. There was no significant difference in the initial blood tests in the two groups. At 2 yr follow-up, only the hematocrit showed a statistically significant increase in the testosterone-treated group compared to the control group (P < 0.001). A decrease in the urea nitrogen to creatinine ratio and an increase in the prostate-specific antigen concentration was not statistically significant. Eleven (24%) of the testosterone-treated subjects developed polycythemia sufficient to require phlebotomy or the temporary withholding of testosterone, one third of which occurred less than 1 yr after starting testosterone treatment. There was no significant difference in the incidence of new illness in the two groups during the 2-yr follow-up. Although self-assessment of libido was dramatically improved in the testosterone-treated group (P < 0.0001), approximately one third of the subjects discontinued therapy. In conclusion, testosterone replacement therapy appears to be well tolerated by over 84% of the subjects. Long term testosterone replacement to date appears to be a safe and effective means of treating hypogonadal elderly males, provided that frequent follow-up blood tests and examinations are performed.
Maggi, Mario; Heiselman, Darell; Knorr, Jack; Iyengar, Smriti; Paduch, Darius A; Donatucci, Craig F
Hypogonadism is defined as decreased testosterone levels in men. Hypogonadism can be accompanied by erectile, orgasmic, and ejaculatory dysfunction. To evaluate whether treatment with testosterone solution 2% (testosterone) could improve ejaculatory function in a cohort of hypogonadal men. Sexually active, hypogonadal men at least 18 years old (total testosterone < 300 ng/dL) were randomized to receive testosterone or placebo for 12 weeks. Effects of testosterone on primary outcomes were evaluated using the International Index of Erectile Function (IIEF) and the Men's Sexual Health Questionnaire, Ejaculatory Dysfunction, Short Form (MSHQ-EjD-SF) questionnaires. Treatment differences were calculated using analysis of covariance. In total, 715 men (mean age = 55 years) were randomized to placebo (n = 357) or testosterone (n = 358). Most sexually active men who reported IIEF scores had some degree of erectile dysfunction (IIEF erectile function score < 26). Although ejaculatory function score (MSHQ-EjD-SF) improved in the testosterone group compared with placebo (P < .001), improvement on the "bother" item did not reach statistical significance. Treatment-related adverse events in the testosterone group affecting at least 1% of patients were increased hematocrit, upper respiratory tract infection, arthralgia, burning sensation, fatigue, increased prostate-specific antigen, erythema, and cough. Few patients in either treatment group developed at least one adverse event leading to discontinuation (testosterone = 1.98% vs placebo = 3.09%; P = .475). Hypogonadal men receiving testosterone solution 2% therapy experience significantly greater improvement in ejaculatory function, compared with placebo, as assessed by the MSHQ-EjD-SF. However, improvement in "bother" was not statistically different between the two groups. Testosterone therapy was generally well tolerated. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights
Peak, Taylor C; Haney, Nora M; Wang, William; DeLay, Kenneth J; Hellstrom, Wayne J
The production of testosterone occurs within the Leydig cells of the testes. When production fails at this level from either congenital, acquired, or systemic disorders, the result is primary hypogonadism. While numerous testosterone formulations have been developed, none are yet fully capable of replicating the physiological patterns of testosterone secretion. Multiple stem cell therapies to restore androgenic function of the testes are under investigation. Leydig cells derived from bone marrow, adipose tissue, umbilical cord, and the testes have shown promise for future therapy for primary hypogonadism. In particular, the discovery and utilization of a group of progenitor stem cells within the testes, known as stem Leydig cells (SLCs), has led not only to a better understanding of testicular development, but of treatment as well. When combining this with an understanding of the mechanisms that lead to Leydig cell dysfunction, researchers and physicians will be able to develop stem cell therapies that target the specific step in the steroidogenic process that is deficient. The current preclinical studies highlight the complex nature of regenerating this steroidogenic process and the problems remain unresolved. In summary, there appears to be two current directions for stem cell therapy in male primary hypogonadism. The first method involves differentiating adult Leydig cells from stem cells of various origins from bone marrow, adipose, or embryonic sources. The second method involves isolating, identifying, and transplanting stem Leydig cells into testicular tissue. Theoretically, in-vivo re-activation of SLCs in men with primary hypogonadism due to age would be another alternative method to treat hypogonadism while eliminating the need for transplantation. PMID:27822338
Tirabassi, G; Corona, G; Lamonica, G R; Lenzi, A; Maggi, M; Balercia, G
Functional hypercortisolism is generated by conditions able to chronically activate hypothalamic-pituitary-adrenal axis and has been proven to have a negative role in several complications. However, no study has evaluated the possible influence of diabetes mellitus-associated functional hypercortisolism on male hypogonadism and sexual function. We aimed to identify any association of hypothalamic-pituitary-adrenal axis dysregulation measures with testosterone and sexual function in men simultaneously affected by diabetes mellitus and late-onset hypogonadism. Fifteen diabetes mellitus and late-onset hypogonadism subjects suffering from functional hypercortisolism and fifteen diabetes mellitus and late-onset hypogonadism subjects who were free of functional hypercortisolism were retrospectively reviewed. Clinical, hormonal, and sexual parameters were considered. Hypercortisolemic subjects showed higher values of body mass index, waist, and glycated hemoglobin and lower ones of testosterone compared to normocortisolemic ones. All sexual parameters, except for orgasmic function, were significantly worse in hypercortisolemic than in normocortisolemic subjects. Hypercortisolemic patients showed higher values of cortisol after dexamethasone and urinary free cortisol as well as a lesser ACTH response after corticotropin releasing hormone test (ACTH area under curve) compared to normocortisolemic ones. No significant association was found at Poisson regression analysis between hormonal and sexual variables in normocortisolemic patients. In hypercortisolemic subjects, negative and significant associations of cortisol response after corticotropin releasing hormone (cortisol area under curve) with erectile function (β: -0.0008; p: 0.015) and total international index of erectile function score (β: -0.0006; p: 0.001) were evident. This study suggests for the first time the impairing influence of the dysregulated hypothalamic-pituitary-adrenal axis on sexual function in
Lodh, Moushumi; Mukhopadhyay, Rajarshi
Background: McCune Albright syndrome is rare with an estimated prevalence of 1 in 100,000 to 1 in 1,000,000 persons. The classical clinical triad consists of fibrous dysplasia of the bone, café-au-lait skin spots and precocious puberty. However, in rare cases, there may be primary hypogonadism and amenorrhea. Case Presentation: An eighteen-year-old female presented with amenorrhea. She had a short stature, round face, thick neck, and short fourth metacarpals and metatarsals. The secondary sexual characters were absent. Serum calcium, phosphorus and parathyroid concentrations were normal, but gonadotropin hormones were very low. X-ray examination revealed short fourth and fifth metacarpals, short left metatarsal, and short fibula. Conclusion: These local bony abnormalities along with the biochemical findings helped us to diagnose this case as an unusual presentation of primary hypogonadism with features of McCune Albright’s syndrome where there was amenorrhea rather than preocious puberty. PMID:27478774
Santosa, Sylvia; Jensen, Michael D.
Testosterone has long been known to affect body fat distribution, although the underlying mechanisms remain elusive. We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. Twelve men with chronic hypogonadism and 13 control men matched for age and body composition: 1) underwent measures of body composition with dual energy x-ray absorptiometry and an abdominal CT scan; 2) consumed an experimental meal containing [3H]triolein to determine the fate of meal FA (biopsy-measured adipose storage vs. oxidation); 3) received infusions of [U-13C]palmitate and [1-14C]palmitate to measure rates of direct free (F)FA storage (adipose biopsies). Adipose tissue lipoprotein lipase, acyl-CoA synthetase (ACS), and diacylglycerol acetyl-transferase (DGAT) activities, as well as, CD36 content were measured to understand the mechanism by which alterations in fat storage occur in response to testosterone deficiency. Results of the study showed that hypogonadal men stored a greater proportion of both dietary FA and FFA in lower body subcutaneous fat than did eugonadal men (both p<0.05). Femoral adipose tissue ACS activity was significantly greater in hypogonadal than eugonadal men, whereas CD36 and DGAT were not different between the two groups. The relationships between these proteins and FA storage varied somewhat between the two groups. We conclude that chronic effects of testosterone deficiency has effects on leg adipose tissue ACS activity which may relate to greater lower body FA storage. These results provide further insight into the role of androgens in body fat distribution and adipose tissue metabolism in humans. PMID:22363653
Şilfeler, Dilek Benk; Karateke, Atilla; Keskin Kurt, Raziye; Aldemir, Özgür; Buğra Nacar, Alper; Baloğlu, Ali
Malouf syndrome is a very rarely encountered syndrome which was first diagnosed in 1985 upon the examination of two sisters, with findings of hypergonadotropic hypogonadism, dilated cardiomyopathy, blepharoptosis, and broad nasal base. Later on, Narahara diagnosed another sporadic case with the same findings. A survey of relevant literature leads us to three women cases in total. Here we present two cases of Malouf syndrome and literature review. PMID:25544917
Rigotti, N.A.; Neer, R.M.; Jameson, L.
Women with anorexia nervosa have reduced skeletal mass. Both anorexia and osteopenia are less common in men. We describe a 22-year-old man with anorexia nervosa and severe osteopenia involving both cortical and trabecular bone who developed a pelvic fracture and multiple vertebral compression fractures. He was found to have secondary hypogonadotropic hypogonadism that was reversible with weight gain. This case illustrates the need to consider osteopenia as a potential complication of anorexia nervosa in males as well as females.
Rump, R; Hamel, B C; Pinckers, A J; van Dop, P A
We describe two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia, Boucher-Neuhäuser syndrome, a rare but distinct pleiotropic single gene disorder with an autosomal recessive pattern of inheritance. The cases presented illustrate that this syndrome is still poorly recognised. We provide a review and analysis of previously reported cases and the differential diagnosis, which might aid in the identification of additional cases. Images PMID:9321767
Entrala-Bernal, Carmen; Montes-Castillo, Cristina; Alvarez-Cubero, Maria Jesus; Gutiérrez-Alcántara, Carmen; Fernandez-Rosado, Francisco; Martinez-Espίn, Esther; Sánchez-Malo, Carolina; Santiago-Fernández, Piedad
Kallmann Syndrome (KS) is a genetic disease of embryonic development which is characterized by the association of hypogonadotropic hypogonadism (HH) due to a deficit of the gonadotropin-releasing hormone (GnRH) and a hypo/anosmia (including a hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs). Even though it is a genotypically and phenotypically heterogeneous clinical disease, there are some key genes related to KS (KAL1, FGFR1 (KAL2), GNRHR, KISSR1 (GPR54), GNRH1, NELF and PROK2). The aim of this study was to present a case report of a genetic diagnosis of KS linked to the presence of mutations in the FGFR1 (fibroblast growth factor receptor 1, also known as KAL2) gene. This diagnosis was made in a 44-year old female affected by a hypogonadism for which she had received intermittent treatment until she was 30 years old based on the patient's own decision. The molecular analysis of FGFR1 identified the mutation c. 246_247delAG (p.T82Xfs110) in heterozygosis on exon 3 of the KAL2 gene. This is the first report of this mutation related to idiopathic hypogonadotrophic hypogonadism (IHH).
Ruvolo, Giovanni; Roccheri, Maria Carmela; Brucculeri, Anna Maria; Longobardi, Salvatore; Cittadini, Ettore; Bosco, Liana
An observational clinical and molecular study was designed to evaluate the effects of the administration of recombinant human FSH on sperm DNA fragmentation in men with a non-classical form of hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia. In the study were included 53 men with a non-classical form of hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia. In all patients, sperm DNA fragmentation index (DFI), assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) in situ DNA nick end-labelling (TUNEL) assay, was evaluated before starting the treatment with 150 IU of recombinant human FSH, given three times a week for at least 3 months. Patients' semen analysis and DNA fragmentation index were re-evaluated after the 3-month treatment period. After recombinant human FSH therapy, we did not find any differences in terms of sperm count, motility and morphology. The average DNA fragmentation index was significantly reduced (21.15 vs 15.2, p<0.05), but we found a significant reduction in patients with high basal DFI values (>15 %), while no significant variation occurred in the patients with DFI values ≤ 15 %. Recombinant human FSH administration improves sperm DNA integrity in hypogonadotropic hypogonadism and idiopathic oligoasthenoteratozoospermia men with DNA fragmentation index value >15 % .
Stenvinkel, Peter; Bárány, Peter
Anemia, inflammation, resistance to erythropoiesis-stimulating agents (ESA) and hypogonadism (testosterone deficiency) are highly prevalent conditions, which heralds poor prognosis, in chronic kidney disease (CKD). It has been speculated that testosterone stimulates erythropoiesis via production of hematopoietic growth factors and possibly improvement of iron bioavailability. Where as inflammation stimulates synthesis of the liver-derived iron regulatory protein hepcidin, a recent study suggests that testosterone inhibits hepcidin synthesis, thus offering a possible novel mechanism for testosterone-induced erythropoiesis. As any agent that lowers hepcidin may be an effective strategy to normalize iron homeostasis and overcome renal anemia, testosterone deficiency should be considered in this patient group. Indeed, a recent study in males with CKD showed that hypogonadism may be an additional cause of anemia and reduced ESA responsiveness. Thus, a randomized controlled trial is needed to test the possibility that restoration of testosterone levels in hypogonadal CKD males may translate into lower prevalence of anemia, better ESA responsiveness and better quality of life.
Background In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available. Methods To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route), we tested the administration of testosterone via a gel formulation for one year. Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol), pain (VAS and other pain questionnaires), andrological (Ageing Males' Symptoms Scale - AMS) and psychological (POMS, CES-D and SF-36) parameters were evaluated at baseline (T0) and after 3, 6 and 12 months (T3, T6, T12 respectively). Results The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters (VAS, Area%) remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time. Conclusions In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management. PMID:21332999
George, Jyothis T; Millar, Robert P; Anderson, Richard A
Hypogonadism occurs commonly in men with type 2 diabetes (T2DM) and severe obesity. Current evidence points to a decreased secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus and thereby decreased secretion of gonadotropins from the pituitary gland as a central feature of the pathophysiology in these men. Hyperglycaemia, inflammation, leptin and oestrogen-related feedback have been proposed to make aetiological contributions to the hypogonadotropic hypogonadism of T2DM. However, the neuroendocrine signals that link these factors with modulation of GnRH neurons have yet to be identified. Kisspeptins play a central role in the modulation of GnRH secretion and, thus, downstream regulation of gonadotropins and testosterone secretion in men. Inactivating mutations of the kisspeptin receptor have been shown to cause hypogonadotropic hypogonadism in man, whilst an activating mutation is associated with precocious puberty. Data from studies in experimental animals link kisspeptin expression with individual factors known to regulate GnRH secretion, including hyperglycaemia, inflammation, leptin and oestrogen. We therefore hypothesise that decreased endogenous kisspeptin secretion is the common central pathway that links metabolic and endocrine factors in the pathology of testosterone deficiency seen in men with obesity and T2DM. We propose that the kisspeptin system plays a central role in integrating a range of metabolic inputs, thus constituting the link between energy status with the hypothalamic-pituitary-gonadal axis, and put forward potential clinical studies to test the hypothesis.
Jimenez-Balderas, F Javier; Tapia-Serrano, Rosario; Fonseca, M Eugenia; Arellano, Jorge; Beltran, Arturo; Yañez, Patricia; Camargo-Coronel, Adolfo; Fraga, Antonio
Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter's syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann's syndrome and two had idiopathic cryptorchidism. Eight (61%) of the 13 patients studied had RADs unrelated to the etiology of their hypogonadism. Of these, four had ankylosing spondylitis and histocompatibility B27 antigen, two had systemic lupus erythematosus (in one case associated with antiphospholipids), one had juvenile rheumatoid arthritis, and one had juvenile dermatomyositis. In comparison with the low frequencies of RADs in the general population (about 0.83%, including systemic lupus erythematosus, 0.03%; dermatomyositis, 0.04%; juvenile rheumatoid arthritis, 0.03%; ankylosing spondylitis, 0.01%; rheumatoid arthritis, 0.62%; and other RAD, 0.1%), there were surprisingly high frequencies of such disorders in this small group of patients with untreated hypogonadism (P < 0.001) and very low serum testosterone levels (P = 0.0005). The presence of RADs in these patients was independent of the etiology of their hypogonadism and was associated with marked gonadal failure with very low testosterone levels. PMID:11714390
Yeap, Bu B; Grossmann, Mathis; McLachlan, Robert I; Handelsman, David J; Wittert, Gary A; Conway, Ann J; Stuckey, Bronwyn Ga; Lording, Douglas W; Allan, Carolyn A; Zajac, Jeffrey D; Burger, Henry G
This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should
Saboor Aftab, S A; Kumar, S; Barber, T M
Obesity, secondary (hypogonadotrophic) hypogonadism (SH), sleep disorders [such as obstructive sleep apnoea (OSA)] and type 2 diabetes mellitus (T2DM) in men have complex interlinks both with respect to mutual aetiopathogenesis as well as therapeutics. Correction of the attendant hypogonadism in obese men may serve to break this link and have beneficial effects beyond restoration of normal sexual function. Male obesity-associated secondary hypogonadism (MOSH) should be regarded as a distinct clinical entity and subtype of SH. A high index of suspicion for the presence of MOSH must be maintained by clinicians when assessing obese men. The pathogenesis of MOSH remains incompletely understood. Furthermore, the optimal management of MOSH and its associated sequelae will require long-term prospective studies that in turn will inform the development of future clinical guidelines for this important and prevalent condition. © 2012 Blackwell Publishing Ltd.
Lee, Hang; Webb, Matthew L.; Joffe, Hadine; Finkelstein, Joel S.
Context: The hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood. Objective: To determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men. Design: Two randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately. Setting: A single-site academic medical center. Participants: Healthy men ages 20–50, with normal serum testosterone levels. Intervention: Cohort 1 (n = 198, 81% completion) received goserelin acetate every 4 weeks to suppress gonadal steroids and were randomized to placebo or 1.25, 2.5, 5, or 10 g of testosterone gel daily for 16 weeks. Cohort 2 (n = 202, 78% completion) received the same regimen as cohort 1 plus anastrozole to block aromatization of testosterone. Controls (n = 37, 89% completion) received placebos for goserelin acetate and testosterone. Main Outcome Measures: Incidence of visits with VMS. This was a preplanned secondary analysis. Results: VMS were reported at 26% of visits in cohort 1, and 35% of visits in cohort 2 (P = .02), demonstrating an effect of estradiol deficiency. When adjacent estradiol level groups in cohort 1 were compared, the largest difference in VMS incidence was observed between the 5–9.9 and 10–14.9 pg/mL groups (38% vs 16%, P < .001). In cohort 2, the 10-g testosterone group differed significantly from placebo (16% vs 43%, P = .048) after adjustment for small differences in estradiol levels, indicating that high testosterone levels may suppress VMS. Conclusions: Estradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect. PMID:27300575
Bonomi, Marco; Vladimiro Libri, Domenico; Guizzardi, Fabiana; Guarducci, Elena; Maiolo, Elisabetta; Pignatti, Elisa; Asci, Roberta; Persani, Luca
Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary–gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network. PMID:22138902
Rabijewski, Michał; Papierska, Lucyna; Piątkiewicz, Paweł
Around 40% of diabetic men have lowered testosterone and symptoms of hypogonadism but the prevalence of hypogonadism among prediabetic men is unknown. The aim of this study was to investigate the prevalence of late-onset hypogonadism (LOH) in population of Polish men with prediabetes. This study was performed in 196 prediabetic men and in 184 normoglycemic, control group. Prediabetes was defined as impaired fasting glucose, impaired glucose tolerance and/or HbA1c 5.7-6.4%. LOH was defined as low libido, diminished frequency of morning erections and erectile dysfunctions in men with total testosterone <12 nmol/l. Total testosterone (TT) level in prediabetes group was 11.78 ± 1.76 and 16.37 ± 1.6 nmol/l in control group (p < 0.001). LOH was diagnosed in 30% prediabetic men and in 13.6% control men. There were negative relationships between calculated free testosterone (cFT) and HbA1c (r = -0.3856; p < 0.005). In prediabetic group, TT and cFT levels were lower in patients with impaired glucose tolerance than impaired fasting glucose (p < 0.05 and p < 0.02, respectively). We showed inverse relationships between IIEF-5 score and cFT (r = -0.414, p < 0.005) and between IIEF-5 and HbA1c (r = -0.395, p < 0.002). In population of Polish men with prediabetes we observed high prevalence of LOH. Routine testosterone screening should be performed in all prediabetic men.
Shoskes, Daniel A; Barazani, Yagil; Fareed, Khaled; Sabanegh, Edmund
The relationship between Testosterone Replacement Therapy (TRT) and prostate cancer remains controversial. Most TRT studies show no change in prostate specific antigen (PSA) but some men do have PSA rise or develop an abnormal digital rectal exam (aDRE). Our objective was to examine the biopsy results of men with symptomatic hypogonadism before or during therapy. Data was extracted from our medical record on men with hypogonadism who had a prostate biopsy within the past 4 years done by 3 Urologists with guideline driven practice patterns. 96 men were identified. Mean age at biopsy was 63 (range 40-85) and median PSA was 3.78ng/dL (0.5-662). Of the 61 men not on TRT, median PSA was 4.34 (0.5 to 662) and mean total testosterone 254 (191-341). There were 29 (47.5%) prostate cancers found (6 Gleason score 6, 13 Gleason score 7, 10 Gleason score 8 or 9). Of the 35 men on TRT, median PSA was 3.27 (0.5 to 13.7). The %PSA increase ranged from 2 to 251% (mean 93.5%). Mean total testosterone was 383 (146-792). Of the 14 men treated < 2 years, none had cancer. Of the 21 men treated 2 or more years 5 had cancer (2 Gleason score 6, 3 Gleason score 7). Men with hypogonadism and a clinical indication for biopsy often have prostate cancer, many high grade. No men with an initial PSA rise on TRT had cancer. Men on long term TRT should be monitored with PSA and DRE per guidelines.
Berg, G; Schreier, L; Geloso, G; Otero, P; Nagelberg, A; Levalle, O
Testosterone serum levels may influence the lipoprotein metabolism and possibly atherogenic risk. Our aim was to investigate the effects of long-term testosterone supplementation in hypogonadal men on multiple lipoprotein markers. 18 Hypogonadal men were studied before and after 3, 6, and 18 (n = 7) months of treatment with testosterone enanthate. During treatment, serum testosterone and estradiol increased, reaching normal levels (p < 0.0001 and 0.003, respectively). This was associated with a decrease in HDL cholesterol (from 1.40 +/- 0.10 mmol/l to 1.22 +/- 0.08 mmol/l, p < 0.001) after six months at the expense of HDL2 cholesterol (p < 0.01), as well as apoprotein A1 (from 139 +/- 3.4 mg/dl to 126 +/- 3.0 mg/dl, p < 0.005). Hepatic lipase activity increased (p < 0.05) and correlated positively with testosterone (r = 0.56, p < 0.02) and negatively with HDL cholesterol (r = - 0.58, p < 0.02). Total and LDL cholesterol, triglycerides, and apoprotein B did not increase. Among the seven patients who completed 18 months of treatment, triglycerides, total cholesterol, LDL and HDL cholesterol, as well as total cholesterol/HDL cholesterol ratio values did not differ from baseline while apoprotein A1 (p < 0.03) and HDL cholesterol (p < 0.015) remained decreased and hepatic lipase unchanged. Restoration of testosterone levels in hypogonadal men in this study did not reveal unfavorable changes based on total cholesterol/HDL cholesterol and LDL cholesterol/apoprotein B ratios, which are both atherogenic risk markers. Whether the changes in light of lipoprotein metabolism will adversely influence cardiovascular risk over time remains to be determined.
Bonomi, Marco; Libri, Domenico Vladimiro; Guizzardi, Fabiana; Guarducci, Elena; Maiolo, Elisabetta; Pignatti, Elisa; Asci, Roberta; Persani, Luca
Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network.
González-Sales, Mario; Barrière, Olivier; Tremblay, Pierre-Olivier; Nekka, Fahima; Desrochers, Julie; Tanguay, Mario
The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysis. The circadian rhythm of the testosterone was described by a stretched cosine function. Model parameters were estimated using NONMEM(®) 7.3. The effect of different covariates on the testosterone levels was investigated. Model evaluation was performed using non-parametric bootstrap and predictive checks. A stretched cosine function deeply improved the data goodness of fit compared to the standard trigonometric function (p < 0.001; ΔOFV = -204). The effect of the age and the semester, defined as winter and spring versus summer and fall, were significantly associated with the baseline levels of testosterone (p < 0.001, ΔOFV = -15.6, and p < 0.001, ΔOFV = -47.0). Model evaluation procedures such as diagnostic plots, visual predictive check, and non-parametric bootstrap evidenced that the proposed stretched cosine function was able to model the time course of the diurnal testosterone levels in hypogonadal males with accuracy and precision. The circadian rhythm of the testosterone levels was better predicted by the proposed stretched cosine function than a standard cosine function. Testosterone levels decreased by 5.74 ng/dL (2.4%) every 10 years and were 19.3 ng/dL (8.1%) higher during winter and spring compared to summer and fall.
Tanna, Monique S; Schwartzbard, Arthur; Berger, Jeffery S; Underberg, James; Gianos, Eugenia; Weintraub, Howard S
Testosterone replacement therapy is recommended for men with clinical androgen deficiency with decades of evidence supporting its use for treatment of sexual, physical, and psychological consequences of male hypogonadism. In this updated review, the authors discuss the implications of testosterone deficiency and conflicting evidence regarding testosterone replacement therapy and its effects on the cardiovascular system. Based on mounting evidence, the authors conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and concurrent cardiovascular risk factors and even manifest cardiovascular disease after a thorough discussion of potential risks and with guideline-recommended safety monitoring.
Madhu, S. V.; Aslam, M.; Aiman, A. J.; Siddiqui, A.; Dwivedi, S.
Aim: The present study is carried out to investigate hypogonadism using serum testosterone levels in male Type 2 diabetes mellitus (T2DM) subjects with and without coronary artery disease (CAD). Subjects and Methods: A total of 150 age and body mass index-matched male subjects in the age group of 30–70 years were recruited in three groups; Group A - subjects with normal glucose tolerance, Group B - T2DM subjects without CAD, and Group C - T2DM subjects with CAD (n = 50 each group). Subjects with CAD were diagnosed on the basis of electrocardiogram, treadmill testing, stress echocardiography, or coronary angiography. Total testosterone (TT), free testosterone (FT), bioavailable testosterone, calculated FT and glycemic parameters were measured and compared between all the three study groups. One-way ANOVA followed by post hoc Tukey's test and Pearson's coefficient of correlation tests were used for analysis. Results: Hypogonadism (TT <3 ng/ml) was observed in 40% (20/50) of subjects in Group C and 32% (16/50) of subjects in Group B as compared to only 14% (7/50) of subjects in Group A (Groups A vs. B; P = 0.055, Groups A vs. C; P = 0.006 and Groups B vs. C; P = 0.53). Group C subjects had significantly lower levels of TT (3.55 ± 1.46 ng/ml vs. 4.73 ± 2.17 ng/ml, P = 0.005), calculated FT (0.062 ± 0.0255 pg/ml vs. 0.0951 ± 0.0508 pg/ml, P ≤ 0.001), and bioavailable testosterone (1.48 ± 0.65 ng/ml vs. 2.18 ± 1.20 ng/ml, P ≤ 0.001) compared to control Group A subjects. There was no significant difference in any of the testosterone parameters between Groups A and B. Furthermore, an overall positive correlation was found between hypogonadism and CAD (r = 0.177, P = 0.030, n = 150). Conclusion: We observed hypogonadism as indicated by low testosterone levels in a significant proportion of male T2DM subjects with CAD. PMID:28217495
Gawlik, Aneta; Hankus, Magdalena; Such, Kamila; Drosdzol-Cop, Agnieszka; Madej, Paweł; Borkowska, Marzena; Zachurzok, Agnieszka; Malecka-Tendera, Ewa
Turner syndrome is the most common example of hypergonadotropic hypogonadism resulting from gonadal dysgenesis. Most patients present delayed, or even absent, puberty. Premature ovarian failure can be expected even if spontaneous menarche occurs. Laboratory markers of gonadal dysgenesis are well known. The choice of optimal hormone replacement therapy in children and adolescents remains controversial, particularly regarding the age at which therapy should be initiated, and the dose and route of estrogen administration. On the basis of a review of the literature, we present the most acceptable schedule of sex steroid replacement therapy in younger patients with Turner syndrome.
Bogefors, C; Isaksson, S; Bobjer, J; Kitlinski, M; Leijonhufvud, I; Link, K; Giwercman, A
More than 95% of testicular cancer are cured but they are at increased long-term risk of cardiovascular disease. The risk of cardiovascular disease and treatment intensity was reported, but it is unknown whether this effect of cancer therapy is direct or indirect, mediated through androgen deficiency. Our aim was, therefore, to evaluate whether testicular cancer patients have increased the prevalence of risk factors of cardiovascular disease and if these risk factors are associated with hypogonadism and/or the cancer treatment given. In 92 testicular cancer patients (mean 9.2 years follow-up) and age-matched controls, blood samples were analysed for lipids, total testosterone, luteinizing hormone (LH), glucose and insulin. An estimate of insulin resistance, HOMAir was calculated. Hypogonadism was defined as total testosterone < 10 nmol/L and/or LH > 10 IU/L and/or androgen replacement. In testicular cancer men with hypogonadism, compared with eugonadal patients, higher insulin (mean difference: 3.10 mIU/L; p = 0.002) and HOMAir (mean difference: 0.792; p = 0.007) were detected. Hypogonadism group presented with increased risk (OR = 4.4; p = 0.01) of metabolic syndrome. Most associations between the treatment given and the metabolic parameters became statistically non-significant after adjustment for hypogonadism. In conclusion, testicular cancer patients with signs of hypogonadism presented with significantly increased risk of metabolic syndrome and investigation of endocrine and metabolic parameters is warranted in these patients. © 2017 American Society of Andrology and European Academy of Andrology.
Öztin, Hasan; Çağıltay, Eylem; Çağlayan, Sinan; Kaplan, Mustafa; Akpak, Yaşam Kemal; Karaca, Nilay; Tığlıoğlu, Mesut
Male hypogonadism is defined as the deficiency of testosterone or sperm production synthesized by testicles or the deficiency of both. The reasons for hypogonadism may be primary, meaning testicular or secondary, meaning hypothalamohypophyseal. In hypogonadotropic hypogonadism (HH), there is indeficiency in gonadotropic hormones due to hypothalamic or hypophyseal reasons. Gonadotropin-releasing hormone (GnRH) is an important stimulant in releasing follicular stimulant hormone (FSH), mainly luteinizing hormone (LH). GnRH omitted is under the effect of many hormonal or stimulating factors. Kisspeptin is present in many places of the body, mostly in hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Kisspeptin has a suppressor effect on the metastasis of many tumors such as breast cancer and malign melanoma metastases, and is called "metastin" for this reason. Kisspeptin is a strong stimulant of GnRH. In idiopathic hypogonadotropic hypogonadism (IHH) etiology, there is gonadotropic hormone release indeficiency which cannot be clearly described. A total of 30 male hypogonatropic hypogonadism diagnosed patients over 30 years of age who have applied to Haydarpasa Education Hospital Endocrinology and Metabolic Diseases Service were included in the study. Compared to the control group, the effect of kisspeptin on male patients with hypogonatropic hypogonadism and on insulin resistance developing in hypogonadism patients was investigated in our study. A statistically significant difference was detected between average kisspeptin measurements of the groups (p < 0.01). Kisspeptin measurement of the cases in the patient group were detected significantly high. No statistically significant relation was detected among kisspeptin and LH/FSH levels. Although a positive low relation was detected between kisspeptin measurements of patient group cases and homeostasis model assessment of insulin resistance (HOMA-IR) measurements, this relation was statistically
De Sousa, Sunita M C; Chapman, Ian M; Falhammar, Henrik; Torpy, David J
Dopamine agonists are the first line of therapy for prolactinomas, with high rates of biochemical control and tumour shrinkage. Toxicity is considered to be low and manageable by switching of agents and dose reduction. Dopamine agonist-induced impulse control disorders are well described in the neurology setting, but further data are required regarding this toxicity in prolactinoma patients. We performed a multicenter retrospective cohort study of eight men with prolactinomas and associated central hypogonadism. The eight men had no prior history of psychiatric disease, but each developed disruptive hypersexuality whilst on dopamine agonist therapy at various doses. Cabergoline, bromocriptine and quinagolide were all implicated. Hypersexuality had manifold consequences, including relationship discord, financial loss, reduced work performance, and illicit activity. We hypothesise that this phenomenon is due to synergy between reward pathway stimulation by dopamine agonists, together with rapid restoration of the eugonadal state after prolonged hypogonadism. We refer here to this distinct drug toxicity as 'dopa-testotoxicosis'. Given the profound impact in these patients and their families, cessation of dopamine agonists should be considered in men who develop hypersexuality, and pituitary surgery may be required to facilitate this. Awareness of this distinct impulse control disorder should enable further research into the prevalence, natural history and management of dopa-testotoxicosis. The condition is likely under-reported due to the highly personal nature of the symptoms and we suggest a simple written questionnaire to screen for hypersexuality and other behavioural symptoms within the first six months of dopamine agonist treatment.
Barton, David J.; Kumar, Raj G.; McCullough, Emily H.; Galang, Gary; Arenth, Patricia M.; Berga, Sarah L.; Wagner, Amy K.
Objective (1) Examine relationships between persistent hypogonadotropic hypogonadism (PHH) and long-term outcomes after severe traumatic brain injury (TBI); (2) determine if sub-acute testosterone levels can predict PHH. Setting Level 1 trauma center at a university hospital. Participants Consecutive sample of men with severe TBI between 2004 and 2009. Design Prospective cohort study. Main Measures Post-TBI blood samples were collected during week 1, every 2 weeks until 26 weeks, and at 52 weeks. Serum hormone levels were measured, and individuals were designated as having PHH if ≥50% of samples met criteria for hypogonadotropic hypogonadism. At 6 and 12 months post-injury, we assessed global outcome, disability, functional cognition, depression, and quality-of-life. Results We recruited 78 men; median (IQR) age was 28.5 (22–42) years. 34 patients (44%) had PHH during the first year post-injury. Multivariable regression, controlling for age, demonstrated PHH status predicted worse global outcome scores, more disability, and reduced functional cognition at 6 and 12 months post-TBI. Two-step testosterone screening for PHH at 12–16 weeks post-injury yielded a sensitivity of 79% and specificity of 100%. Conclusion PHH status in men predicts poor outcome after severe TBI, and PHH can accurately be predicted at 12–16 weeks. PMID:26360007
Tan, R S; Scally, M C
Anabolic steroid-induced hypogonadism (ASIH) is the functional incompetence of the testes with subnormal or impaired production of testosterone and/or spermatozoa due to administration of androgens or anabolic steroids. Anabolic-androgenic steroid (AAS), both prescription and nonprescription, use is a cause of ASIH. Current AAS use includes prescribing for wasting associated conditions. Nonprescription AAS use is also believed to lead to AAS dependency or addiction. Together these two uses account for more than four million males taking AAS in one form or another for a limited duration. While both of these uses deal with the effects of AAS administration they do not account for the period after AAS cessation. The signs and symptoms of ASIH directly impact the observation of an increase in muscle mass and muscle strength from AAS administration and also reflect what is believed to demonstrate AAS dependency. More significantly, AAS prescribing after cessation adds the comorbid condition of hypogonadism to their already existing chronic illness. ASIH is critical towards any future planned use of AAS or similar compound to effect positive changes in muscle mass and muscle strength as well as an understanding for what has been termed anabolic steroid dependency. The further understanding and treatments that mitigate or prevent ASIH could contribute to androgen therapies for wasting associated diseases and stopping nonprescription AAS use. This paper proposes a unified hypothesis that the net effects for anabolic steroid administration must necessarily include the period after their cessation or ASIH.
Karapanou, Olga; Vlassopoulou, Barbara; Tzanela, Marinella; Papadopoulos, Dimitrios; Angelidakis, Panagiotis; Michelakakis, Helen; Ioannidis, George; Mihalatos, Markos; Kamakari, Smaragda; Tsagarakis, Stylianos
We present the clinical and hormonal findings of a young male with X-linked adrenoleukodystrophy (X-ALD), with special emphasis on the biochemical and clinical pattern of hypogonadism. A patient, with primary adrenal insufficiency since the age of 5 years, developed progressive neurological symptoms at the age of 29. Diagnosis of X-ALD was established by elevated serum very long chain fatty acids (VLCFAs) and genetic testing. His sexual body hair was sparse. Hormonal investigations revealed normal testosterone and inappropriately elevated LH levels. Androgen receptor gene analysis was negative for mutations or polymorphic variants associated with decreased receptor activity. Signs of hypogonadism in patients with confirmed X-ALD are not exclusively due to primary testicular failure. Tissue specific androgen resistance represents an alternative possibility. Since no loss-of-function mutations were detected in the androgen receptor, it is speculated that the patient's androgen resistance could be part of a functional defect mediated through VLCFA accumulation at the testosterone receptor and/or post-receptor levels.
Wagner, G J; Rabkin, J G
We conducted a small exploratory study to assess whether testosterone therapy is an effective treatment for clinical symptoms characteristic of hypogonadism in eugonadal men with AIDS. Treatment consisted of 12 weeks of bi-weekly intramuscular injections of testosterone cypionate. Twenty-three men enrolled in the study; mean age was 37 and 44% were ethnic minorities. All had an AIDS diagnosis and the mean CD4 cell count was 150 cells/mm3. All baseline serum testosterone levels were within the laboratory reference range and above 500 ng/dl. Diminished libido was an inclusion criterion, plus each patient had at least one additional symptom (low mood, low energy, loss of appetite and/or weight). Nineteen men completed the trial and a majority of patients responded with regard to libido (89%), mood (67%), energy (71%), and appetite (67%) as rated by the Clinical Global Impressions Scale. With the exception of appetite, self and clinician rated measures showed significant improvement in all symptom domains. Among the 14 study completers with significant weight loss, the average weight gain was 2.3 kg, with a 1.8 kg increase in body cell mass and no change in body fat. These results suggest that testosterone is as effective in treating these symptoms in eugonadal men with AIDS as we have found in our research with hypogonadal HIV+men.
Nord, Christoffer; Ahlgren, Ulf; Eriksson, Maria; Vernersson-Lindahl, Emma; Helland, Åslaug; Alexeyev, Oleg A.; Hallberg, Bengt; Palmer, Ruth H.
Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis. PMID:25955180
Alterations of bone metabolism have been observed in numerous studies of HIV-infected patients. Sex steroids are known to profoundly influence bone mass and bone turnover. Hypogonadism is common in HIV-infection. Therefore, we performed a cross sectional study of 80 male HIV-infected patients without wasting syndrome, and 20 healthy male controls, in whom we analyzed urine and serum samples for both calciotropic hormones and markers of bone metabolism and of endocrine testicular function. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry both in the lumbar spine and Ward's triangle of the left hip. None of the patients received highly-active-antiretroviral-therapy (HAART). Compared to eugonadal HIV-infected patients, subjects with hypogonadism (n = 32; 40%) showed statistically significant decrease of serum osteocalcin (p < 0.05) and elevated urinary excretion of crosslinks (p < 0.05). However, we found 13 and 15, respectively, patients with osteopenia (t-score -1.0 to -2.5 SD below normal) of the lumbar spine. The dissociation between bone formation and resorption and the reduction of of BMD (p < 0.05) is stronger expressed in patients with hypogonadism. Habitual hypogonadism appears to be of additional relevance for bone metabolism of male HIV-positive patients prior to HAART. PMID:19258214
Verdú Solans, J; Roig Grau, I; Almirall Banqué, C
A 84 year-old patient, in therapy with androgen deprivation during the last 5 years due a prostate cancer, is presented with a osteoporotic fracture of the first lumbar vertebra. The pivotal role of the primary care physician, in the prevention of the osteoporosis secondary to the hypogonadism in these patients, is highlighted.
Shao, Wei-min; Bai, Wen-jun; Chen, Yi-min; Liu, Lei; Wang, Yu-jie
Two cases of hypogonadotropic hypogonadism caused by pituitary stalk interruption syndrome treated by pulse infusion of gonadorelin via micropump were reported, and their clinical features and the treatment process of pulse infusion of gonadorelin via micropump summarized. Both of the 2 patients were presented primarily with hypogonadotropic hypogonadism. After the treatment with pulse infusion of gonadorelin via micropump, their syndrome of androgen deficiency improved and the gonadotropin levels promoted at the end of 12 weeks' follow-up. Pulse infusion of gonadorelin via micropump is an alternative to treat hypogonadotropic hypogonadism caused by pituitary stalk interruption syndrome.
Arver, Stefan; Luong, Ba; Fraschke, Anina; Ghatnekar, Ola; Stanisic, Sanja; Gultyev, Dmitry; Müller, Elvira
Testosterone replacement therapy (TRT) has been recommended for the treatment of primary and secondary hypogonadism. However, long-term implications of TRT have not been investigated extensively. The aim of this analysis was to evaluate health outcomes and costs associated with life-long TRT in patients suffering from Klinefelter syndrome and late-onset hypogonadism (LOH). A Markov model was developed to assess cost-effectiveness of testosterone undecanoate (TU) depot injection treatment compared with no treatment. Health outcomes and associated costs were modeled in monthly cycles per patient individually along a lifetime horizon. Modeled health outcomes included development of type 2 diabetes, depression, cardiovascular and cerebrovascular complications, and fractures. Analysis was performed for the Swedish health-care setting from health-care payer's and societal perspective. One-way sensitivity analyses evaluated the robustness of results. The main outcome measures were quality-adjusted life-years (QALYs) and total cost in TU depot injection treatment and no treatment cohorts. In addition, outcomes were also expressed as incremental cost per QALY gained for TU depot injection therapy compared with no treatment (incremental cost-effectiveness ratio [ICER]). TU depot injection compared to no-treatment yielded a gain of 1.67 QALYs at an incremental cost of 28,176 EUR (37,192 USD) in the Klinefelter population. The ICER was 16,884 EUR (22,287 USD) per QALY gained. Outcomes in LOH population estimated benefits of TRT at 19,719 EUR (26,029 USD) per QALY gained. Results showed to be considerably robust when tested in sensitivity analyses. Variation of relative risk to develop type 2 diabetes had the highest impact on long-term outcomes in both patient groups. This analysis suggests that lifelong TU depot injection therapy of patients with hypogonadism is a cost-effective treatment in Sweden. Hence, it can support clinicians in decision making when considering
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Komiya, Akira; Watanabe, Akihiko; Fuse, Hideki
"Male menopause" or "andropause" has been used as a popular term in public derived from the term "menopause" in females. However, there is no clear definition for this disorder. Recently, academic societies officially recommended to use "late-onset hypogonadism in males" (LOH) as an academic word. State of andropause and LOH is not the same but partially overlapped. In 2007, Japan's own guideline for LOH was published. Unlike Western countries, LOH is diagnosed by measuring serum free testosterone level because total testosterone did not show age-related decrease in a large Japanese male study. Patients with lower FT level undergo androgen replacement therapy. For those with normal FT, other treatments are recommended. Approval of more agents (i.e. androgen gel or oral medicine) for androgen replacement is awaited.
Gelhorn, Heather L; Roberts, Laurie J; Khandelwal, Nikhil; Revicki, Dennis A; DeRogatis, Leonard R; Dobs, Adrian; Hepp, Zsolt; Miller, Michael G
The Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF) is a patient-reported outcome measurement designed to evaluate the symptoms of hypogonadism. The HIS-Q-SF is an abbreviated version including17 items from the original 28-item HIS-Q. To conduct item analyses and reduction, evaluate the psychometric properties of the HIS-Q-SF, and provide guidance on score interpretation. A 12-week observational longitudinal study of hypogonadal men was conducted as part of the original HIS-Q psychometric evaluation. Participants completed the original HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12, and the PROMIS Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change scales and a clinical form. Item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed. One hundred seventy-seven men participated (mean age = 54.1 years, range = 23-83). Similar to the full HIS-Q, the final abbreviated HIS-Q-SF instrument includes five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For key domains, test-retest reliability was very good, and construct validity was good for all domains. Known-groups validity was demonstrated for all domain scores, subdomain scores, and total score based on the Clinical Global Impression-Severity. All domains and subdomains were responsive to change based on patient-rated anchor questions. The HIS-Q-SF could be a useful tool in clinical practice, epidemiologic studies, and other academic research settings. Careful consideration was given to the
Eldar-Geva, Talia; Hirsch, Harry J; Pollak, Yehuda; Benarroch, Fortu; Gross-Tsur, Varda
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3 ± 7.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting-center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20 ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual-specific treatment; contraceptive pills, intra-uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26-year-old woman with inhibin B and FSH levels 53 ng/ml and 6.4 IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult.
Steidle, Christopher; Witt, Michael A; Matrisciano, Justin; Block, Jon E
There is a slow but continuous decline in testosterone (T) levels with age, with a substantial percentage of males exhibiting T levels in the hypogonadal range. This age-dependent decline in circulating androgens is associated, in large part, with reduced sexual functioning and libido. The effectiveness of TestimR 1% (Auxilium Pharmaceuticals, Inc., Norristown, Pennsylvania) topical T gel was evaluated in older hypogonadal males who failed to experience satisfactory symptom relief after treatment with AndroGelR 1% (Solvay Pharmaceuticals, Inc., Marietta, Georgia). In this open-label study, consecutive subjects were assigned randomly to experimental treatment with Testim 1% (5 g) or to maintenance therapy (control group) with AndroGel 1% (5 g). Seventy-six experimental subjects and 75 control subjects were followed for 4 weeks to evaluate improvements in sexual functioning and satisfaction. Changes from baseline in the 5 domains of the Brief Male Sexual Function Inventory were compared between groups. The mean percentage improvement favored the experimental treatment in sexual drive (23% vs 16%, P < 0.3), erectile function (32% vs 8%, P < 0.03), ejaculatory function (11% vs 9%, P < 0.4), problem assessment (47% vs 12%, P < 0.01), and sexual satisfaction (62% vs 23%, P < 0.02). A greater percentage of subjects also reported satisfaction with the experimental treatment (55% vs 33%, P < 0.02), and these subjects were less likely to require upward dose titration at the final follow-up visit (53% vs 72%, P < 0.03). Consideration of Testim 1% gel in patients who have an inadequate response to prior T therapy is encouraged, although it is difficult to estimate the contribution of nonspecific study effects (eg, placebo) in this trial.
Kanayama, Gen; Hudson, James I.; DeLuca, James; Isaacs, Stephanie; Baggish, Aaron; Weiner, Rory; Bhasin, Shalender; Pope, Harrison G.
Aims To assess the frequency and severity of hypogonadal symptoms in male long-term anabolic-androgenic steroid (AAS) misusers who have discontinued AAS use. Design Cross-sectional, naturalistic. Setting Outpatient facility. Participants Twenty-four male former long-term AAS users and 36 non-AAS-using weightlifters, recruited by advertisement in Massachusetts, USA. Five of the former users were currently receiving treatment with physiologic testosterone replacement, leaving 19 untreated users for the numerical comparisons below. Measurements The Structured Clinical Interview for DSM-IV, questions regarding history of AAS use, physical examination, serum hormone determinations, and the International Index of Erectile Function (IIEF). Findings Compared with the 36 non-AAS-using weightlifters, the 19 untreated former AAS users displayed significantly smaller testicular volumes (estimated difference [95% confidence interval (CI)]: 2.3 [0.1, 4.5] ml; p = 0.042) and lower serum testosterone levels (estimated difference: 131 [25, 227] dL; p = 0.009), with five users showing testosterone levels below 200 ng/dL despite abstinence from AAS for 3–26 months. Untreated former users also displayed significantly lower scores on the IIEF Sexual Desire subscale (estimated difference: 2.4 [1.3, 3.5] points on a 10-point scale; p < 0.001). In the overall group of 24 treated plus untreated former users, 7 (29%) had experienced major depressive episodes during AAS withdrawal; 4 of these had not experienced major depressive episodes at any other time. Two men (8%) had failed to regain normal libidinal or erectile function despite adequate replacement testosterone treatment. Conclusions Among long-term anabolic-androgenic steroid misusers, anabolic-androgenic steroid-withdrawal hypogonadism appears to be common, frequently prolonged, and associated with substantial morbidity. PMID:25598171
Valdes-Socin, Hernan; Rubio Almanza, Matilde; Tomé Fernández-Ladreda, Mariana; Debray, François Guillaume; Bours, Vincent; Beckers, Albert
The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology. PMID:25071724
You, Tongjian; Disanzo, Beth L; Arsenis, Nicole C
Hypogonadism is associated with obesity and other features of metabolic syndrome in males. The purpose of this study was to compare lean and obese male Zucker rats on their reproductive endocrine function in response to aerobic exercise training. Lean (Fa/Fa) and obese (fa/fa) male Zucker rats at 2 months of age were randomly assigned to a sedentary and an aerobic exercise training group (lean sedentary, n = 7; lean exercise, n = 8; obese sedentary, n = 7; obese exercise, n = 7). The exercise group walked on a rat treadmill, starting at 10 m · min(-1) for 20 min and building up to 20 m · min(-1) for 60 min, five times per week for 8 wk. Serum levels of total and free testosterone and testicular levels of testosterone, as well as epididymal and inguinal adipose tissue monocyte chemotactic protein 1 release levels, were measured. There were significant obesity-by-exercise interactions on serum levels of total and free testosterone and testicular levels of testosterone (all P < 0.05). Compared to lean sedentary rats, obese sedentary rats had lower serum and testicular testosterone levels (0.72- to 0.74-fold, all P < 0.001). There were no group differences between lean sedentary and lean exercise rats on serum and testicular testosterone levels. However, compared to the obese sedentary group, the obese exercise group had higher serum and testicular testosterone levels (1.37- to 1.47-fold, all P < 0.05). In the whole cohort, serum and testicular testosterone levels were inversely related to epididymal adipose tissue monocyte chemotactic protein 1 secretion (r = -0.40 to r = -0.45, all P < 0.05). Our results support that aerobic exercise training could improve severe obesity-related hypogonadism in male Zucker rats. The underlying mechanism needs to be further clarified.
Treatment of schizophrenic illness usually involves the long-term administration of antipsychotic drugs. Most antipsychotic agents antagonise the actions of endogenous dopamine (DA) at DA-2 receptors in the brain. The relative affinity for, and binding time to, DA-2 receptors was considered to be one of the key determinants of the antipsychotic potency of classical antipsychotic drugs. Some newer atypical antipsychotics, of which clozapine is the prototype, have a relatively poor affinity for DA-2 receptors; whereas other atypical antipsychotics are potent DA-2 antagonists. The propensity of antipsychotic agents to cause hyperprolactinaemia is related to their potency in antagonising DA-2 receptors on the anterior pituitary. In our studies, bone loss was consistently related to DA-2 antagonist potency of antipsychotic drugs, rather than their classification using conventional 'typical' versus 'atypical' systems. It is established that hyperprolactinaemia causes suppression of the reproductive endocrine axis and consequent bone mineral density (BMD) loss. Results from our group and others have demonstrated that a similar pathophysiological process is occurring in individuals with antipsychotic-induced hyperprolactinaemia. We found high rates of osteoporosis and osteopenia in those taking long-term antipsychotic drugs, and this was related to the dose and duration of treatment. Bone loss was associated with hypogonadism in male and female groups. Young Caucasian women appear to be particularly vulnerable to developing hyperprolactinaemia and the associated hypogonadism and bone loss. The occurrence of menstrual dysfunction should alert clinical suspicions of hyperprolactinaemia and bone de-mineralisation. Lastly, there are no published trials examining the effects of hormone replacement on BMD in those taking long-term antipsychotic drugs, but preliminary findings from our studies suggest that active management of bone loss in those with antipsychotic-associated bone
Yang, Luo; Zhang, Si Xiao; Dong, Qiang; Xiong, Zi Bing; Li, Xiang
To demonstrate the efficacy of hormone treatment on the patients with hypogonadotropic hypogonadism (HH), we summarized our more than 10 years experience. A total of 242 male patients (age range 15-52 years old) with HH including two Kallmann syndrome treated at the andrology outpatient clinics of university hospital in the past 10 years were reviewed retrospectively. The patients were divided into three groups based on the different treatment strategy. There were 84 patients treated with human chorionic gonadotropin (hCG) (group 1, hCG treatment group), 74 patients treated with hCG plus human menopause gonadotropin (hMG) (group 2, hCG + hMG treatment group), and 84 patients treated with testosterone (group 3, T treatment group). Sex characteristics, testicular volume, and sperm production were determined before and after the treatments. The therapeutic effects in the three groups were analyzed statistically. In total, 42 patients of group 1 (50.0%) and 56 of group 2 (75.7%) had their testicular volumes increased after 6-18 months treatment, from 2.0 ± 1.1 to 6.8 ± 3.2 mL and 2.1 ± 1.1 to 8.8 ± 3.9 mL, respectively. Only six patients of group 3 had their testicular volumes increased but no statistically significant. Among the patients with testes growth, 34 patients of group 1 and 48 patients of group 2 achieved spermatogenesis, and three of them made their wives pregnant naturally. During the follow-up after treatment, there were 36 patients finally defined as delayed puberty, and 204 patients defined as idiopathic hypogonadotropic hypogonadism. For the hormonal treatment of HH, testosterone therapy could not stimulate testes growth and spermatogenesis, but HCG therapy and hCG/hMG combination therapy both are effective, while hCG/hMG combination therapy could achieve better therapeutic effects.
Wainwright, Steven R; Lieblich, Stephanie E; Galea, Liisa A M
The incidence of depression is 2-3× higher in women particularly during the reproductive years, an occurrence that has been associated with levels of sex hormones. The age-related decline of testosterone levels in men corresponds with the increased acquisition of depressive symptoms, and hormone replacement therapy can be efficacious in treating depression in hypogonadal men. Although it is not possible to model depression in rodents, it is possible to model some of the symptoms of depression including a dysregulated stress response and altered neuroplasticity. Among animal models of depression, chronic mild unpredictable stress (CMS) is a common paradigm used to induce depressive-like behaviours in rodents, disrupt the hypothalamic-pituitary adrenal axis and decrease hippocampal neuroplasticity. The purpose of this study was to assess the effect of hypogonadism, produced by gonadectomy, on the acquisition of depressive-like behaviours and changes in hippocampal neuroplasticity in adult male Sprague-Dawley rats. A 21-day unpredictable CMS protocol was used on gonadectomised (GDX) and sham-operated males which produced an attenuation of weight gain in the GDX males receiving CMS treatment (GDX-CMS). Behavioural analysis was carried out to assess anxiety- and depressive-like behaviours. The combination of GDX and CMS produced greater passive behaviours within the forced swim test than CMS exposure alone. Similarly, hippocampal cell proliferation, neurogenesis and the expression of the neuroplastic protein polysialated neural cell adhesion molecule (PSA-NCAM) were all significantly reduced in the GDX-CMS group compared to all other treatment groups. These findings indicate that testicular hormones confer resiliency to chronic stress in males therefore reducing the likelihood of developing putative physiological, behavioural or neurological depressive-like phenotypes.
Xu, Ming; Hu, Chen; Khan, Hussein-hamed; Shi, Fang-hong; Cong, Xiao-dong; Li, Qing; Dai, Yin; Dai, De-zai
Aim: Argirein (rhein-arginine) is a derivative of rhein isolated from Chinese rhubarb (Rheum Officinale Baill.) that exhibits antioxidant and anti-inflammatory activities. In the present study we investigated the effects of argirein on stress-induced (hypergonadotrophic) and diabetic (hypogonadotrophic) hypogonadism in male rats. Methods: Stress-induced and diabetic hypogonadism was induced in male rats via injection of isoproterenol (ISO) or streptozotocin (STZ). ISO-injected rats were treated with argirein (30 mg·kg−1·d−1, po) or testosterone replacement (0.5 mg·kg−1·d−1, sc) for 5 days, and STZ-injected rats were treated with argirein (40–120 mg·kg−1·d−1, po) or aminoguanidine (100 mg·kg−1·d−1, po) for 4 weeks. After the rats were euthanized, blood samples and testes were collected. Serum hormone levels were measured, and the expression of endothelin receptor A (ETA), connexin 43 (Cx43) and other proteins in testes was detected. For in vitro experiments, testis homogenate was prepared from normal male rats, and incubated with ISO (1 μmol/L) or high glucose (27 mmol/L). Results: ISO injection induced hyper-gonadotrophic hypogonadism characterized by low testosterone and high FSH and LH levels in the serum, whereas STZ injection induced hypogonadotrophic hypogonadism as evidenced by low testosterone and low FSH and LH levels in the serum. In the testes of ISO- and STZ-injected rats, the expression of ETA, MMP-9, NADPH oxidase and pPKCε was significantly increased, and the expression of Cx43 was decreased. Administration of argirein attenuated both the abnormal serum hormone levels and the testis changes in ISO- and STZ-injected rats, and aminoguanidine produced similar actions in STZ-injected rats; testosterone replacement reversed the abnormal serum hormone levels, but did not affect the testis changes in ISO-injected rats. Argirein (0.3–3 μmol/L) exerted similar effects in testis homogenate incubated with ISO or high glucose in
Shimon, Ilan; Lubina, Alexandra; Gorfine, Malka; Ilany, Jacob
Men with hypogonadotropic hypogonadism (HH) due to hypothalamic-pituitary disease present with low serum testosterone levels combined with undetectable, low, or normal gonadotropin levels. Treatment consists of testosterone replacement to reverse the symptoms of androgen deficiency. The aim of this study was to examine the dynamics and feedback inhibition of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in relation to testosterone in 38 men with HH treated with testosterone. Findings were compared with 11 men with primary hypergonadism (PH). Testosterone replacement led to a suppression of FSH levels from 2.8 IU/L at baseline to 1.1 IU/L and to a suppression of LH levels from 2.3 to 0.8 IU/L. There was a linear correlation between levels of FSH and LH (after natural log transformation for both) and testosterone levels in both the HH and PH groups. However, the differences in intercepts and slopes between the groups were significant. To determine whether nonsuppressed FSH or LH during testosterone replacement reduces the probability of eugonadism, as reflected by normal testosterone levels, gonadotropin levels were measured and categorized as low (<0.5 IU/L), medium (0.5-2 IU/L), and high levels (>2 IU/L). The higher FSH or LH levels were found to significantly decrease the chance for achieving eugonadism. In conclusion, in men with HH due to hypothalamic-pituitary disease or injury, the pituitary-testicular hormonal axis maintains its physiological negative feedback between testosterone and gonadotropins. Thus, gonadotropin levels in men with HH might be useful, together with testosterone concentrations, for assessing the adequacy of androgen replacement.
Shi, Chang-He; Schisler, Jonathan C.; Rubel, Carrie E.; Tan, Song; Song, Bo; McDonough, Holly; Xu, Lei; Portbury, Andrea L.; Mao, Cheng-Yuan; True, Cadence; Wang, Rui-Hao; Wang, Qing-Zhi; Sun, Shi-Lei; Seminara, Stephanie B.; Patterson, Cam; Xu, Yu-Ming
Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms. PMID:24113144
SWERDLOFF, RONALD S.; DIAZ-ARJONILLA, MARUJA; DUDLEY, ROBERT E.; FAULKNER, SANDRA; BROSS, RACHELLE; LEUNG, ANDREW; BARAVARIAN, SIMA; HULL, LAURA; LONGSTRETH, JAMES A.; KULBACK, STEVEN; FLIPPO, GREGORY; WANG, CHRISTINA
Many hypogonadal men prefer oral testosterone (T) treatment. Oral T undecanoate (TU) is available in many countries, but not in the United States. We aimed to assess the pharmacokinetics of oral TU in a new self-emulsifying drug delivery system formulation. Pharmacokinetics studies were conducted in 3 parts: 12 hypogonadal men were enrolled in 2 centers for a 1-day dosing study; 29 participants were enrolled from 3 centers for a 7-day dosing study; and 15 participants were enrolled from 1 center for a 28-day dosing study. Serial blood samples for serum sex hormone measurements by liquid chromatography–tandem mass spectrometry were drawn for up to 36 hours after oral TU administration. Mean serum T levels (Cavg) after oral dosing of T 200 mg as TU twice daily with food were within the adult male range in most participants in the 1-, 7-, and 28-day dosing studies but were much lower in the fasting state. The dose-proportional increase in Cavg of serum T after oral T 300 mg twice daily resulted in more participants with supraphysiologic serum T levels. In the 28-day study, trough serum T reached a steady state at day 7. Serum dihydrotestosterone and estradiol levels tracked serum T concentration. Dihydrotestosterone-testosterone ratios increased 3-fold after oral TU administration. Oral T 200 mg twice daily as TU in a new SEDDS formulation may be a viable therapy for hypogonadal men. PMID:21474786
Constantinou, Caterina; Mpatsoulis, Diogenis; Natsos, Anastasios; Petropoulou, Peristera-Ioanna; Zvintzou, Evangelia; Traish, Abdulmaged M.; Voshol, Peter J.; Karagiannides, Iordanes; Kypreos, Kyriakos E.
Here, we investigated how LDL receptor deficiency (Ldlr−/−) modulates the effects of testosterone on obesity and related metabolic dysfunctions. Though sham-operated Ldlr−/− mice fed Western-type diet for 12 weeks became obese and showed disturbed plasma glucose metabolism and plasma cholesterol and TG profiles, castrated mice were resistant to diet-induced obesity and had improved glucose metabolism and reduced plasma TG levels, despite a further deterioration in their plasma cholesterol profile. The effect of hypogonadism on diet-induced weight gain of Ldlr−/− mice was independent of ApoE and Lrp1. Indirect calorimetry analysis indicated that hypogonadism in Ldlr−/− mice was associated with increased metabolic rate. Indeed, mitochondrial cytochrome c and uncoupling protein 1 expression were elevated, primarily in white adipose tissue, confirming increased mitochondrial metabolic activity due to thermogenesis. Testosterone replacement in castrated Ldlr−/− mice for a period of 8 weeks promoted diet-induced obesity, indicating a direct role of testosterone in the observed phenotype. Treatment of sham-operated Ldlr−/− mice with the aromatase inhibitor exemestane for 8 weeks showed that the obesity of castrated Ldlr−/− mice is independent of estrogens. Overall, our data reveal a novel role of Ldlr as functional modulator of metabolic alterations associated with hypogonadism. PMID:24837748
Yoshida, Takeshi; Awaya, Tomonari; Shibata, Minoru; Kato, Takeo; Numabe, Hironao; Kobayashi, Junya; Komatsu, Kenshi; Heike, Toshio
Ataxia-telangiectasia-like disorder (ATLD) is a rare autosomal recessive disorder, and has symptoms similar to ataxia-telangiectasia (AT). ATLD is caused by mutations in the MRE11 gene, involved in DNA double-strand break repair (DSBR). In contrast to AT, ATLD patients lack key clinical features, such as telangiectasia or immunodeficiency, and are therefore difficult to be diagnosed. We report a female ATLD patient presenting with hypergonadotropic hypogonadism and hypersegmented neutrophils, previously undescribed features in this disorder, and potential diagnostic clues to differentiate ATLD from other conditions. The patient showed slowly progressive cerebellar ataxia from 2 years of age, and MRI revealed atrophy of the cerebellum, oculomotor apraxia, mild cognitive impairment, writing dystonia, hypergonadotropic hypogonadism with primary amenorrhea, and hypersegmented neutrophils. Western blot assay demonstrated total loss of MRE11 and reduction of ATM-dependent phosphorylation; thus, we diagnosed ATLD. Genetically, a novel missense mutation (c.140C>T) was detected in the MRE11 gene, but no other mutation was found in the patient. Our presenting patient suggests that impaired DSBR may be associated with hypergonadotropic hypogonadism and neutrophil hypersegmentation. In conclusion, when assessing patients with ataxia of unknown cause, ATLD should be considered, and the gonadal state and peripheral blood smear samples evaluated. © 2014 Wiley Periodicals, Inc.
Wiehle, Ronald; Cunningham, Glenn R; Pitteloud, Nelly; Wike, Jenny; Hsu, Kuang; Fontenot, Gregory K; Rosner, Michele; Dwyer, Andrew; Podolski, Joseph
Objectives To determine the pharmacodynamic profile of serum total testosterone and luteinizing hormone (LH) levels in men with secondary hypogonadism after initial and chronic daily oral doses of enclomiphene citrate vs transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate in comparison with transdermal testosterone on other hormones and markers in men with secondary hypogonadism. Patients and Methods This was a randomized, single-blind, two-centre, phase II study to evaluate the effects of three different doses of enclomiphene citrate (6.25, 12.5 and 25 mg) vs transdermal testosterone on 24-h LH and total testosterone in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (the intent-to-treat population), but four men had testosterone levels >350 ng/dL at baseline. Forty-four men completed the study per protocol. All subjects enrolled in this trial had serum total testosterone in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions. Total testosterone and LH levels were assessed each hour for 24 h to examine the effects at each of three treatment doses of enclomiphene citrate vs a standard dose (5 g) of transdermal testosterone. In the initial profile, total testosterone and LH were determined in a naïve population after a single initial oral or transdermal treatment (day 1). This was contrasted to that seen after 6 weeks of continuous daily oral or transdermal treatment (day 42). The pharmacokinetics of enclomiphene citrate were assessed in a select subpopulation. Serum samples were obtained over the course of the study to determine the levels of various hormones and lipids. Results After 6 weeks of continuous use, the mean (sd) concentration of total testosterone at day 42 was 604 (160) ng/dL for men taking the highest dose of enclomiphene citrate (enclomiphene citrate, 25 mg daily) and 500 (278) ng in those men treated with transdermal
While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Some authors blame advertising and the availability of more convenient formulations whilst other have pointed out that the routine testing of men with erectile dysfunction (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous underdiagnosis and undertreatment by adherence to evidence-based guidelines. Urologists and primary care physicians are the most frequent initiators of TRT, usually for erectile dysfunction. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing clearly that therapy associated with clear rise in testosterone levels are associated with reduced mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively they have compared nontreated patients with undertreated or on-compliant subjects involving a range of different therapy regimens. Recent evidence suggests long acting injections may be associated with decreased cardiovascular risk but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5α reductase in skin. The multiple effects of TRT
Smith, Ryan P; Khanna, Abhinav; Coward, Robert M; Rajanahally, Saneal; Kovac, Jason R; Gonzales, Marshall A; Lipshultz, Larry I
A variety of modalities for testosterone replacement therapy (TRT) are available, including topical gels, injections, and Testopel subcutaneous testosterone pellets (STP). STP are becoming more commonly utilized in the United States; however, patient preferences, expectations, and usage patterns regarding this therapy remain poorly characterized. To identify factors influencing patients' decisions to initiate or discontinue STP. A total of 175 men from an academic urology clinic who were currently using or who had previously used STP for hypogonadism received a 32-item electronic survey. Assessment of the impact of convenience, efficacy, side effects, cost, and symptom relief on initiation and discontinuation of STP. One hundred and thirteen men (64.6% response rate) of mean age 51.4 years who previously underwent a mean of 2.8 STP implant procedures completed the survey. Fifty-nine (52.2%) and 40 (35.4%) men had switched to STP from topical gel and injection therapy, respectively, whereas 14 (12.4%) men initially started TRT with STP. Convenience (68.8%) was the most important factor in patients' decision to start STP, while cost of the previous form of TRT (14.7%) was least important. At the time of the survey, 32 men (28.3%) had discontinued STP therapy. Cost of therapy (50%) was the primary factor in discontinuing STP. There was no difference in serum testosterone levels between men who continued STP and those who discontinued therapy (642.8 vs. 629.0 ng/dL, P = 0.83). Overall, 68.1% of patients continued STP therapy at the time of survey completion. Convenience is the most important factor in a patient's decision to initiate STP; however, physician recommendation also plays a substantial role. Cost was the primary reason for discontinuation. Upon survey completion, greater than two-thirds of respondents elected to continue STP therapy. STP are a viable treatment option for hypogonadal men seeking a convenient and efficacious alternative modality of TRT
Although suppressed serum testosterone (T) is common in ageing men, only a small proportion of them develop the genuine syndrome of low T associated with diffuse sexual (e.g., erectile dysfunction), physical (e.g. loss of vigor and frailty) and psychological (e.g., depression) symptoms. This syndrome carries many names, including male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late-onset hypogonadism (LOH) describes it best and is therefore generally preferred. The decrease of T in LOH is often marginal, and hypogonadism can be either due to primary testicular failure (low T, high luteinizing hormone (LH)) or secondary to a hypothalamic-pituitary failure (low T, low or inappropriately normal LH). The latter form is more common and it is usually associated with overweight/obesity or chronic diseases (e.g., type 2 diabetes mellitus, the metabolic syndrome, cardiovascular and chronic obstructive pulmonary disease, and frailty). A problem with the diagnosis of LOH is that often the symptoms (in 20%-40% of unselected men) and low circulating T (in 20% of men >70 years of age) do not coincide in the same individual. The European Male Ageing Study (EMAS) has recently defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum T (total T <11 nmol l-1 and free T <220 pmol l-1 ) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections). By these criteria, only 2% of 40- to 80-year-old men have LOH. In particular obesity, but also impaired general health, are more common causes of low T than chronological age per se. Evidence-based information whether, and how, LOH should be treated is sparse. The most logical approach is lifestyle modification, weight reduction and good treatment of comorbid diseases. T replacement is widely used for the treatment, but evidence-based information about its real benefi ts and short- and
Morelli, Annamaria; Vignozzi, Linda; Maggi, Mario
The etiology of metabolic syndrome (MetS) is complex and involves the interplay between environmental, lifestyle and genetic determinants. MetS in men can be associated with a biochemical pattern of partial hypogonadotropic hypogonadism (HH). A similar pattern has been noted in both men and women with a variety of acute illnesses and chronic diseases, and there is ongoing debate regarding whether this phenomenon might adaptive (e.g. diverting resources from reproduction into survival), or maladaptive (e.g. anemia, sarcopenia, osteopenia and fatigue of androgen-deficiency amplify and widen the adverse consequences of the original disease-trigger). In women with hypothalamic amenorrhea (HA-HH secondary to chronic bioenergetic deficit from dietary restriction and/or intensive exercise), a genetic link to congenital HH (CHH) was recently established; women carrying monoallelic CHH gene mutations will typically not develop CHH, but are significantly more susceptible to HA. However, the male reproductive axis seems to be more resistant to similar environmental insults. In contrast, MetS-associated HH (mHH) is specifically a male phenomenon; the reproductive phenotype of females with MetS tending instead towards hyperandrogenism, rather than hypogonadism. The underlying pathogenic mechanisms responsible for mHH have not been clearly identified and, as yet, there has been no investigation of a potential role for CHH mutation carriage in its etiology. Over the decades, the use of either genetic- or diet-induced obesity and/or MetS animal models has greatly helped to illuminate the complex etiology of metabolic dysregulation, but the strong relationship between obesity/MetS and mHH in males has been largely neglected, with little or no information about the regulation of reproductive function by metabolic factors under conditions of bioenergetic excess. However, the pathogenic link between MetS and HH in males has been recently investigated in an animal model of high fat
Rogol, A D; Tkachenko, N; Bryson, N
Advantages of testosterone nasal gel include ease of administration, low dose, and no risk of secondary transference. The efficacy and safety of testosterone nasal gel was evaluated in hypogonadal males. The ninety-day, randomized, open-label, dose-ranging study, included potential dose titration and sequential safety extensions to 1 year. At 39 US outpatient sites, 306 men (mean age 54.4 years) with two fasting morning total serum testosterone levels <300 ng/dL were randomized (n = 228, b.i.d. dosing; n = 78, t.i.d. dosing). Natesto(™) Testosterone Nasal Gel was self-administered, using a multiple-dose dispenser, as two or three daily doses (5.5 mg per nostril, 11.0 mg single dose). Total daily doses were 22 mg or 33 mg. The primary endpoint was the Percentage of patients with Day-90 serum total testosterone average concentration (C(avg)) value within the eugonadal range (≥300 ng/dL, ≤1050 ng/dL). At Day 90, 200/273 subjects (73%; 95% CI 68, 79) in the intent-to-treat (ITT) population and 180/237 subjects (76%; 71, 81) in the per-protocol (PP) population were in the normal range. Also, in the normal range were 68% (61, 74) of ITT subjects and 70% (63, 77) of PP subjects in the titration arm, as well as, 90% (83, 97) of ITT subjects and 91% (84, 98) of PP subjects in the fixed-dose arm. Natesto(™) 11 mg b.i.d. or 11 mg t.i.d. restores normal serum total testosterone levels in most hypogonadal men. Erectile function, mood, body composition, and bone mineral density improved from baseline. Treatment was well tolerated; adverse event rates were low. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.). This study lacked a placebo or an active comparator control which limited the ability to adequately assess some measures.
Morrison, B F; Reid, M; Madden, W; Burnett, A L
Hypogonadism, which is highly prevalent in men with sickle cell disease (SCD), affects quality of life and causes great morbidity. The safety of testosterone replacement therapy (TRT) in SCD in relation to priapism episodes is relatively unknown. Our aim was to monitor the safety of TRT in a cohort of seven hypogonadal men with SCD. Testosterone undecanoate (Nebido) 1 g was administered intramuscularly to adult men with homozygous SCD (Hb SS) having hypogonadism [serum total testosterone ≤12.0 nmol/L (346 ng/dL), reference range 12.5-38.1 nmol/L (360-1098 ng/dL)] for 12 months. Serum total testosterone, haemoglobin, haematocrit, renal and liver function tests, glucose and PSA measurements were done at baseline and 12-month follow-up. Trough serum total testosterone, haemoglobin and haematocrit were measured three monthly. Priapism events and adverse drug events were assessed every 3 months. International Index of Erectile Function (IIEF), Androgen Deficiency in the Ageing Male (ADAM) and World Health Organization Quality of Life (WHOQOL) questionnaires were administered at baseline, 6 and 12 months. Seven men with a mean age of 34.4 years were treated. Median total testosterone increased from 10.6 to 11.2 nmol/L (p = 0.46). Median serum lactate dehydrogenase levels decreased from 1445 to 1143.5 IU/L (p < 0.05), while all other laboratory indices remained stable. Injection site pain was the most frequently reported adverse event, with no increases in painful crises, hypersensitivity or oedema. After TRT, there was no significant increase in priapism frequency. Median questionnaire scores were increased for the IIEF (46-68, p = 0.018), reduced for ADAM (5.0-2.0, p = 0.016) and unchanged for WHOQOL (98-103, p = 0.086). TRT using testosterone undecanoate with eugonadal intent for hypogonadism appears to be safe in men with SCD. This treatment does not appear to promote priapism occurrences and rather it possibly improves sexual function. Future prospective
Giagulli, V A; Carbone, M D; Ramunni, M I; Licchelli, B; De Pergola, G; Sabbà, C; Guastamacchia, E; Triggiani, V
The aim of this retrospective observational study was to evaluate whether adding liraglutide to lifestyle changes, metformin (Met) and testosterone replacement therapy (TRT), by means of improving weight and glycaemic control, could boost erectile function in type 2 diabetic obese men with overt hypogonadism and erectile dysfunction (ED) in a 'real-life setting'. Forty-three obese, diabetic and hypogonadal men (aged 45-59 years) were evaluated because of complaining about the recent onset of ED. They were subdivided into two groups according to whether hypogonadism occurred after puberty (G1; n = 30: 25 with dysfunctional hypogonadism and 5 with acquired hypogonadotropic hypogonadism) or before puberty (G2; n = 13: 10 with Klinefelter's syndrome and 3 with idiopathic hypogonadotropic hypogonadism). Both G1 and G2 patients were given a combination of testosterone (T) [testosterone undecanoate (TU) 1000 mg/every 12 weeks] and Met (2000-3000 mg/day) for 1 year. In the poor responders (N) to this therapy in terms of glycaemic target (G1N: n = 16; G2N: n = 10), liraglutide (L) (1.2 μg/day) was added for a second year, while the good responders (Y) to T + Met (G1Y: 14/30 and G2Y: 3/13) continued this two drugs regimen therapy for another year. All patients were asked to fill in the International Index of Erectile Function (IIEF 15) questionnaire before starting TU plus Met (T1) and after 12 months (T2) and 24 months (T3) of treatment. Patients underwent a clinical examination and a determination of serum sex hormone binding globulin (SHBG), total testosterone (T) and glycosylated haemoglobin (HbA1c) at T1, T2 and T3. At T2, each patient obtained an improvement of ED (p < 0.01) and of the metabolic parameters without reaching, however, the glycaemic goals [HbA1c = >7.5% (>58 mmol/mol)], while T turned out to be within the range of young men. L added to TU and Met regimen in G1N and G2N allowed these patients to reach not only the glycaemic target [HbA1c = <7.5% (<58 nmol
Aoki, Akira; Fujitani, Kohei; Takagi, Kohei; Kimura, Tomoki; Nagase, Hisamitsu; Nakanishi, Tsuyoshi
The steroid hormones synthesized by the male gonads play diverse roles in biological processes. Androgens, the primary hormones produced by the male gonads, are key regulators of fat homeostasis, hence androgen-deprivation therapies often induce obesity. However, the molecular mechanism by which male gonadal dysfunction leads to obesity remains unclear, because results from animal studies regarding fat accumulation in the context of gonadal defects do not reflect clinical findings. Here, we investigated the mechanism underlying the development of obesity in animals with male gonadal dysfunction by analyzing the long-term physiological changes in adult male mice with surgical castration. Nine weeks after surgery, white adipose tissue (WAT) mass was higher in the castrated (Cas) mice than in sham-operated (Sham) mice. In addition, castration induced hyperlipidemia and hyperglycemia. However, genes involved in lipid metabolism, including hormone-sensitive lipase, were unchanged in the adipose tissue of the Cas mice, despite the increase in WAT. In contrast, a hepatic gluconeogenesis gene, glucose-6-phosphatase, was significantly upregulated in the Cas mice than in Sham mice. Our findings suggest that long-term hypogonadism in mice mimics the effects in humans, and a potential molecular basis for the induction of obesity in this model is impairment of hepatic gluconeogenesis.
Borst, Stephen E; Yarrow, Joshua F; Fernandez, Carmen; Conover, Christine F; Ye, Fan; Meuleman, John R; Morrow, Matthew; Zou, Baiming; Shuster, Jonathan J
Serum concentrations of neuroactive androgens decline in older men and, in some studies, low testosterone is associated with decreased cognitive function and incidence of depression. Existing studies evaluating the effect of testosterone administration on cognition in older men have been largely inconclusive, with some studies reporting minor to moderate cognitive benefit, while others indicate no cognitive effect. Our objective was to assess the cognitive effects of treating older hypogonadal men for 1 year with a supraphysiological dose of testosterone, either alone or in combination with finasteride (a type II 5α-reductase inhibitor), in order to determine whether testosterone produces cognitive benefit and whether suppressed dihydrotestosterone influences cognition. Sixty men aged ≥ 60 years with a serum testosterone concentration of ≤ 300 ng/dL or bioavailable testosterone ≤ 70 ng/dL and no evidence of cognitive impairment received testosterone-enanthate (125 mg/week) versus vehicle, paired with finasteride (5 mg/day) versus placebo using a 2×2 factorial design. Testosterone caused a small decrease in depressive symptoms as assessed by the Geriatric Depression Scale and a moderate increase in visuospatial memory as assessed by performance on a recall trial of the Rey-Osterrieth Complex Figure Test. Finasteride caused a small increase in performance on the Benton Judgment of Line Orientation test. In total, major improvements in cognition were not observed either with testosterone or finasteride. Further studies are warranted to determine if testosterone replacement may improve cognition in other domains.
Fukami, Kei; Yamagishi, Sho-ichi; Sakai, Kazuko; Kaida, Yusuke; Minami, Aki; Nakayama, Yosuke; Ando, Ryotaro; Obara, Nana; Ueda, Seiji; Wada, Yoshifumi; Okuda, Seiya
Late-onset hypogonadism (LOH) and depression contribute to cardiovascular disease (CVD) in male hemodialysis (HD) patients. Carnitine deficiency is frequently observed in HD patients, playing a role in CVD. We examined whether carnitine deficiency was independently associated with LOH and depression in these patients. Twenty-six male HD patients underwent determinations of serum levels of free carnitine and testosterone. Status of LOH and depression were evaluated by questionnaires using aging male symptoms' (AMS) scale and self-rating depression scale (SDS), respectively. Free carnitine and testosterone levels in male HD patients were significantly lower than those in age-matched healthy male subjects. Linear regression analysis showed that AMS scale was positively associated with SDS. Univariate regression analysis revealed that total carnitine (inversely), free carnitine (inversely) and HD duration were correlated with AMS scale. Multiple stepwise regression analysis revealed that free carnitine was an independent determinant of AMS scale. Furthermore, free carnitine was also independently correlated with SDS in male HD patients. This study demonstrated that decreased free carnitine levels were independently associated with AMS scale and SDS in male HD patients. The observations suggest that decreased free carnitine levels could be a marker and therapeutic target of LOH and depression in uremic men with HD.
Borst, Stephen E; Yarrow, Joshua F; Fernandez, Carmen; Conover, Christine F; Ye, Fan; Meuleman, John R; Morrow, Matthew; Zou, Baiming; Shuster, Jonathan J
Serum concentrations of neuroactive androgens decline in older men and, in some studies, low testosterone is associated with decreased cognitive function and incidence of depression. Existing studies evaluating the effect of testosterone administration on cognition in older men have been largely inconclusive, with some studies reporting minor to moderate cognitive benefit, while others indicate no cognitive effect. Our objective was to assess the cognitive effects of treating older hypogonadal men for 1 year with a supraphysiological dose of testosterone, either alone or in combination with finasteride (a type II 5α-reductase inhibitor), in order to determine whether testosterone produces cognitive benefit and whether suppressed dihydrotestosterone influences cognition. Sixty men aged ≥60 years with a serum testosterone concentration of ≤300 ng/dL or bioavailable testosterone ≤70 ng/dL and no evidence of cognitive impairment received testosterone-enanthate (125 mg/week) versus vehicle, paired with finasteride (5 mg/day) versus placebo using a 2×2 factorial design. Testosterone caused a small decrease in depressive symptoms as assessed by the Geriatric Depression Scale and a moderate increase in visuospatial memory as assessed by performance on a recall trial of the Rey-Osterrieth Complex Figure Test. Finasteride caused a small increase in performance on the Benton Judgment of Line Orientation test. In total, major improvements in cognition were not observed either with testosterone or finasteride. Further studies are warranted to determine if testosterone replacement may improve cognition in other domains. PMID:25143719
Angelova, Petya; Momchilova, Albena; Petkova, Diana; Staneva, Galya; Pankov, Roumen; Kamenov, Zdravko
The aim of this study was to investigate the effects of testosterone replacement therapy (TRT) on erythrocyte membrane (EM) lipid composition and physico-chemical properties in hypogonadal men. EM isolated from three patients before and after TRT with injectable testosterone undecanoate or testosterone gel were used for analysis of the phospholipid and fatty acid composition, cholesterol/phospholipid ratio, membrane fluidity, ceramide level and enzyme activities responsible for sphingomyelin metabolism. TRT induced increase of phosphatidylethanolamine (PE) in the EMs and sphingomyelin. Reduction of the relative content of the saturated palmitic and stearic fatty acids and a slight increase of different unsaturated fatty acids was observed in phosphatidylcholine (PC). TRT also induced decrease of the cholesterol/total phospholipids ratio and fluidization of the EM. The TRT induced increase of PE content and the reduction of saturation in the PC acyl chains induced alterations in the structure of EM could result in higher flexibility of the erythrocytes. The increase of the SM-metabolizing enzyme neutral sphingomyelinase, which regulates the content of ceramide in membranes has a possible impact on the SM signaling pathway. We presume that the observed effect of TRT on the composition and fluidity of the EM contributes for improvement of blood rheology and may diminish the thrombosis risk. Larger studies are needed to confirm the findings of this pilot study.
Boulanger, Gaella; Cibois, Marie; Viet, Justine; Fostier, Alexis; Deschamps, Stéphane; Pastezeur, Sylvain; Massart, Catherine; Gschloessl, Bernhard; Gautier-Courteille, Carole; Paillard, Luc
CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1 was upregulated. Cyp19a1 encodes aromatase, which transforms testosterone into estradiol. Administration of testosterone or the aromatase inhibitor letrozole partly rescued the spermiogenesis defects, indicating that a lack of testosterone associated with excessive aromatase contributes to the testicular phenotype. In vivo and in vitro interaction assays demonstrated that CELF1 binds to Cyp19a1 mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1 translation. We conclude that CELF1 downregulates Cyp19a1 (Aromatase) posttranscriptionally to achieve high concentrations of testosterone compatible with spermiogenesis completion. We discuss the implications of these findings with respect to reproductive defects in men, including patients suffering from isolated hypogonadotropic hypogonadism and myotonic dystrophy type I.
Gonçalves, Catarina I; Aragüés, José M; Bastos, Margarida; Barros, Luísa; Vicente, Nuno; Carvalho, Davide
Objective Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and, unlike Kallmann syndrome, is associated with a normal sense of smell. Mutations in the GNRHR gene cause autosomal recessive nCHH. The aim of this study was to determine the prevalence of GNRHR mutations in a group of 40 patients with nCHH. Design Cross-sectional study of 40 unrelated patients with nCHH. Methods Patients were screened for mutations in the GNRHR gene by DNA sequencing. Results GNRHR mutations were identified in five of 40 patients studied. Four patients had biallelic mutations (including a novel frameshift deletion p.Phe313Metfs*3, in two families) in agreement with autosomal recessive inheritance. One patient had a heterozygous GNRHR mutation associated with a heterozygous PROKR2 mutation, thus suggesting a possible role of synergistic heterozygosity in the pathogenesis of the disorder. Conclusions This study further expands the spectrum of known genetic defects associated with nCHH. Although GNRHR mutations are usually biallelic and inherited in an autosomal recessive manner, the presence of a monoallelic mutation in a patient should raise the possibility of a digenic/oligogenic cause of nCHH. PMID:28611058
Lou, X Y; Nishi, Y; Haji, M; Antoku, Y; Tanaka, S; Ikuyama, S; Yanase, T; Takayanagi, R; Nawata, H
To clarify the Sertoli cell and Leydig cell function in hypogonadic male patients with myotonic dystrophy (DM), serum concentrations of inhibin, total testosterone (TT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay in 6 male DM patients (41 to 56 years old, 47.7 +/- 5.05 years old) and compared with those in normal adult men. In 116 healthy men aged from 24 to 92 years, serum inhibin and TT levels decreased and serum FSH and LH concentrations increased with advancing age. There was an inverse correlation between serum inhibin and FSH. These results support the concept of negative feedback regulation system of FSH secretion by inhibin. Male DM patients showed significantly lower serum TT and higher concentrations of FSH and LH, compared with the age-matched 39 normal adult men (49-59 years old, 48.2 +/- 6.14 years old). However, there was no significant difference in serum inhibin levels between the patients and normal counterparts. These results indicate that the Sertoli cell function is reserved in male DM patient, although the Leydig cell function is impaired. It is also suggested that in these patients a negative feedback control system between inhibin and FSH may be disordered to some extent.
Linnér, Carl; Svartberg, Johan; Giwercman, Aleksander; Giwercman, Yvonne Lundberg
Estradiol (E2) is, apart from its role as a reproductive hormone, also important for cardiac function and bone maturation in both genders. It has also been shown to play a role in insulin production, energy expenditure and in inducing lipolysis. The aim of the study was to investigate if low circulating testosterone or E2 levels in combination with variants in the estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) genes were of importance for the risk of type-2 diabetes. The single nucleotide polymorphisms rs2207396 and rs1256049, in ESR1 and ESR2, respectively, were analysed by allele specific PCR in 172 elderly men from the population-based Tromsø study. The results were adjusted for age. In individuals with low total (≤11 nmol/L) or free testosterone (≤0.18 nmol/L) being carriers of the variant A-allele in ESR1 was associated with 7.3 and 15.9 times, respectively, increased odds ratio of being diagnosed with diabetes mellitus type 2 (p = 0.025 and p = 0.018, respectively). Lower concentrations of E2 did not seem to increase the risk of being diagnosed with diabetes. In conclusion, in hypogonadal men, the rs2207396 variant in ESR1 predicts the risk of type 2 diabetes.
Kim, Jin Wook
Testosterone is the principal androgen in the human male. The decline of testosterone with aging was recognized to be associated with a number of symptoms and signs that reduce the quality of life and that may even have severe, debilitating consequences. Clinically, late-onset hypogonadism (LOH) is diagnosed by use of biochemical and clinical measures. Despite published guidelines and recommendations, however, uncertainty surrounds the profile of clinical symptoms as well as the biochemical threshold of diagnosis. Clinicians should be aware of these shortcomings while adhering to the guidelines. Current treatment methods are centered on restoring testosterone to mid to lower levels of young men with natural testosterone replacements. Although recent studies have highlighted possible additional benefits involving improvement of systemic disorders, the goal of treatment is to improve sexual function, while observing for adverse effects in the prostate. Overall, the problem of LOH in debilitating the quality of life and well-being is real, and by following proper guidelines with attentiveness to the results of treatment trials, testosterone replacement therapy presents a safe and effective treatment option. PMID:22195260
Yi, Hyon-Seung; Kim, Ji Min; Ju, Sang Hyeon; Lee, Younghak; Kim, Hyun Jin
Isolated hypogonadotropic hypogonadism (IHH) is known to decrease bone mineral density due to deficiency of sex steroid hormone. Graves' disease is also an important cause of secondary osteoporosis. However, IHH does not preclude the development of primary hyperthyroidism caused by Graves' disease, leading to more severe osteoporosis rapidly. Here, we describe the first case of 35-year-old Asian female patient with IHH accompanied by Graves' disease and osteoporosis-induced multiple fractures. Endocrine laboratory findings revealed preserved anterior pituitary functions except for secretion of gonadotropins and showed primary hyperthyroidism with positive autoantibodies. Sella magnetic resonance imaging showed slightly small sized pituitary gland without mass lesion. Dual energy X-ray absorptiometry revealed severe osteoporosis in lumbar spine and femur neck of the patient. Plain film radiography of the pelvis and shoulder revealed a displaced and nondisplaced fracture, respectively. After surgical fixation with screws for the femoral fracture, the patient was treated with antithyroid medication, calcium, and vitamin D until now and has been recovering fairly well. We report a patient of IHH with Graves' disease and multiple fractures that is a first case in Korea. PMID:26981520
Screening of autosomal gene deletions in patients with hypogonadotropic hypogonadism using multiplex ligation-dependent probe amplification: detection of a hemizygosis for the fibroblast growth factor receptor 1.
Trarbach, Ericka Barbosa; Teles, Milena Gurgel; Costa, Elaine Maria Frade; Abreu, Ana Paula; Garmes, Heraldo Mendes; Guerra, Gil; Baptista, Maria Tereza Matias; de Castro, Margaret; Mendonca, Berenice Bilharinho; Latronico, Ana Claudia
Congenital hypogonadotropic hypogonadism with anosmia (Kallmann syndrome) or with normal sense of smell is a heterogeneous genetic disorder caused by defects in the synthesis, secretion and action of gonadotrophin-releasing hormone (GnRH). Mutations involving autosomal genes have been identified in approximately 30% of all cases of hypogonadotropic hypogonadism. However, most studies that screened patients with hypogonadotropic hypogonadism for gene mutations did not include gene dosage methodologies. Therefore, it remains to be determined whether patients without detected point mutation carried a heterozygous deletion of one or more exons. We used the multiplex ligation-dependent probe amplification (MLPA) assay to evaluate the potential contribution of heterozygous deletions of FGFR1, GnRH1, GnRHR, GPR54 and NELF genes in the aetiology of GnRH deficiency. We studied a mutation-negative cohort of 135 patients, 80 with Kallmann syndrome and 55 with normosmic hypogonadotropic hypogonadism. One large heterozygous deletion involving all FGFR1 exons was identified in a female patient with sporadic normosmic hypogonadotropic hypogonadism and mild dimorphisms as ogival palate and cavus foot. FGFR1 hemizygosity was confirmed by gene dosage with comparative multiplex and real-time PCRs. FGFR1 or other autosomal gene deletion is a possible but very rare event and does not account for a significant number of sporadic or inherited cases of isolated GnRH deficiency.
Anderson, R A; Martin, C W; Kung, A W; Everington, D; Pun, T C; Tan, K C; Bancroft, J; Sundaram, K; Moo-Young, A J; Baird, D T
The synthetic steroid 7alpha-methyl-19-nortestosterone (MENT) is a potent androgen that is resistant to 5alpha-reductase. It thus has decreased activity at the prostate and may have advantages over testosterone-based regimens in long term treatment or as part of a male contraceptive. Administration to eugonadal men results in suppression of gonadotropins, but its ability to support androgen-dependent behavior has not been investigated. For sustained release administration, MENT acetate was used, because its diffusion characteristics were more suitable for use in implants. However, upon release the acetate is rapidly hydrolyzed, and MENT is the biologically active moiety in circulation. We studied the effects of MENT on sexual interest and activity, spontaneous erection, and mood states in comparison with testosterone enanthate (TE) in 20 Caucasian and Chinese hypogonadal men recruited in Edinburgh and Hong Kong (n = 10 in each center). Outcomes were measured using a combination of daily diaries, semistructured interviews, and questionnaires. Nocturnal penile tumescence (NPT) was also recorded in the Edinburgh group. After withdrawal of androgen replacement treatment (wash-out phase) for a minimum of 6 weeks, subjects were randomized to two groups in a cross-over design. Drug treatment regimens were of 6-week duration and consisted of two implants, each containing 115 mg MENT acetate, inserted s.c. into the upper arm and removed after 6 weeks and two injections of TE (200 mg, i.m.) 3 weeks apart. MENT treatment resulted in stable plasma MENT concentrations of 1.4 +/- 0.1 nmol/L after 3 weeks and 1.3 +/- 0.1 nmol/L after 6 weeks (mean +/- SEM; all men). Nadir testosterone concentrations were 3.6 +/- 0.6 nmol/L at the end of the wash-out phase and 9.4 +/- 0.6 nmol/L 3 weeks after each injection. There were no differences in hormone concentrations between centers. There were no adverse toxicological effects. There were only minor differences between the two treatments
Zhang, Manna; Tong, Guoyu; Liu, Yanling; Mu, Yiming; Weng, Jianping; Xue, Yaoming; Luo, Zuojie; Xue, Yuanming; Shi, Lixin; Wu, Xueyan; Sun, Shouyue; Zhu, Yanhua; Cao, Ying; Zhang, Jie; Huang, Hong; Niu, Ben; Li, Hong; Guo, Qinghua; Gao, Yan; Li, Zhibin; Ning, Guang; Zhu, Dalong; Li, Xiaoying
Gonadotropin therapy using a human chorionic gonadotropin (hCG) and FSH preparation is an effective regimen in inducing masculinization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, the high cost of medication and frequent injections affect compliance. The aim of this study was to determine the efficacy of sequential use of highly purified urinary FSH (uFSH)/hCG in men with IHH. A randomized, open-label, prospective, controlled noninferiority trial with an 18-month follow-up was conducted in 9 tertiary hospitals. A total of 67 Chinese men with IHH were randomly allocated into group A receiving continual uFSH (75 U, 3 times a week) and hCG (2000 U, twice a week) injection and group B receiving sequential uFSH (75 U, 3 times a week every other 3 months) and hCG (2000 U, twice a week) injection. The primary outcome was the proportion of subjects with a sperm concentration of ≥ 1.0 × 10(6)/mL during the 18 months. The efficacy between groups A and B was compared for noninferiority. Of the patients, 17/33 (51.5%) receiving continual uFSH/hCG and 19/34 (55.9%) receiving sequential uFSH/hCG achieved sperm concentrations of ≥ 1.0 × 10(6)/mL. The efficacy in the sequential uFSH/hCG group was not inferior to that in the continual uFSH/hCG group (noninferiority, P = .008) by intention-to-treat analysis. The efficacy of the sequential uFSH/hCG regimen is not inferior to that of the continual uFSH/hCG regimen in inducing spermatogenesis and masculinization of patients with IHH.
Pitteloud, Nelly; Acierno, James S; Meysing, Astrid; Eliseenkova, Anna V; Ma, Jinghong; Ibrahimi, Omar A; Metzger, Daniel L; Hayes, Frances J; Dwyer, Andrew A; Hughes, Virginia A; Yialamas, Maria; Hall, Janet E; Grant, Ellen; Mohammadi, Moosa; Crowley, William F
Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nIHH). Mixed pedigrees containing both KS and nIHH have also been described; however, the genetic cause of these rare cases is unknown. We examined the FGFR1 gene in seven nIHH subjects who either belonged to a mixed pedigree (n = 5) or who had associated midline defects (n = 2). Heterozygous FGFR1 mutations were found in three of seven unrelated nIHH probands with normal MRI of the olfactory system: (i) G237S in an nIHH female and a KS brother; (ii) (P722H and N724K) in an nIHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q680X in a nIHH male with cleft lip/palate and missing teeth, his brother with nIHH, and his father with delayed puberty. We show that these mutations lead to receptor loss-of-function. The Q680X leads to an inactive FGFR1, which lacks a major portion of the tyrosine kinase domain (TKD). The G237S mutation inhibits proper folding of D2 of the FGFR1 and likely leads to the loss of cell-surface expression of FGFR1. In contrast, the (P722H and N724K) double mutation causes structural perturbations in TKD, reducing the catalytic activity of TKD. We conclude that loss-of-function mutations in FGFR1 cause nIHH with normal MRI of the olfactory system. These mutations also account for some of the mixed pedigrees, thus challenging the current idea that KS and nIHH are distinct entities.
Finkelstein, J.S.; Klibanski, A.; Neer, R.M.; Doppelt, S.H.; Rosenthal, D.I.; Segre, G.V.; Crowley, W.F. Jr. )
To assess the effects of gonadal steroid replacement on bone density in men with osteoporosis due to severe hypogonadism, we measured cortical bone density in the distal radius by 125I photon absorptiometry and trabecular bone density in the lumbar spine by quantitative computed tomography in 21 men with isolated GnRH deficiency while serum testosterone levels were maintained in the normal adult male range for 12-31 months (mean +/- SE, 23.7 +/- 1.1). In men who initially had fused epiphyses (n = 15), cortical bone density increased from 0.71 +/- 0.02 to 0.74 +/- 0.01 g/cm2 (P less than 0.01), while trabecular bone density did not change (116 +/- 9 compared with 119 +/- 7 mg/cm3). In men who initially had open epiphyses (n = 6), cortical bone density increased from 0.62 +/- 0.01 to 0.70 +/- 0.03 g/cm2 (P less than 0.01), while trabecular bone density increased from 96 +/- 13 to 109 +/- 12 mg/cm3 (P less than 0.01). Cortical bone density increased 0.03 +/- 0.01 g/cm2 in men with fused epiphyses and 0.08 +/- 0.02 g/cm2 in men with open epiphyses (P less than 0.05). Despite these increases, neither cortical nor trabecular bone density returned to normal levels. Histomorphometric analyses of iliac crest bone biopsies demonstrated that most of the men had low turnover osteoporosis, although some men had normal to high turnover osteoporosis. We conclude that bone density increases during gonadal steroid replacement of GnRH-deficient men, particularly in men who are skeletally immature.
Ros, Cristina; Alobid, Isam; Centellas, Silvia; Balasch, Juan; Mullol, Joaquim; Castelo-Branco, Camil
To assess the impact of Turner's syndrome (TS) and other congenital hypogonadisms (OCH) on the sense of smell and taste. An analytical study of three independent cohorts was designed: patients affected by TS, OCH, and a control group of healthy women taking contraception. Gynaecological Endocrinology Unit and Smell Clinic in Rhinology Unit of Hospital Clinic of Barcelona. Thirty TS patients between 20 and 50 years of age receiving hormone replacement treatment (HT) were included as the exposed cohort; fourteen age-matched women with OCH taking HT were recruited; forty-three age-matched healthy controls receiving hormone contraception treatment were selected as the control group. This group was matched with an historical cohort of forty healthy women without contraception, used to validate BAST-24 in Hospital Clinic of Barcelona. Clinical history, presence of nasal symptoms, general physical examination, nasal endoscopy, and Barcelona Smell Test-24 (BAST-24) and gustometry were carried out on all patients. TS physical dysmorphology features, intensity of nasal symptoms and signs of nasal obstruction were collected. BAST-24 test included 24 odours to assess both sensory (detection, memory and forced choice) and sensitivity (intensity, irritability, freshness and pleasantness) odour characteristics, as well as 4 tastes to evaluate taste domains (detection and forced choice). Healthy women taking hormone contraception felt odours with more intensity (p=0.002) and less irritability (p<0.001) than the historical cohort. TS patients showed a significant impairment in smell memory (p<0.005) and forced-choice (p<0.001) compared with controls taking contraception, whereas no differences were found in odour sensitivity. Detection of taste was successful in 100% of patients. When considering only individual tastes, none of them showed statistically significant differences between groups. Patients with TS show the impairment of smell but not of taste, compared to OCH and
Mao, Jiang-Feng; Xu, Hong-Li; Duan, Jin; Chen, Rong-Rong; Li, Li; Li, Bin; Nie, Min; Min, Le; Zhang, Hong-Bing; Wu, Xue-Yan
Although idiopathic hypogonadotropic hypogonadism (IHH) has traditionally been viewed as a life-long disease caused by a deficiency of gonadotropin-releasing hormone neurons, a portion of patients may gradually regain normal reproductive axis function during hormonal replacement therapy. The predictive factors for potential IHH reversal are largely unknown. The aim of our study was to investigate the incidence and clinical features of IHH male patients who had reversed reproductive axis function. In this retrospective cohort study, male IHH patients were classified into a reversal group (n = 18) and a nonreversal group (n = 336). Concentration of gonadotropins and testosterone, as well as testicle sizes and sperm counts, were determined. Of 354 IHH patients, 18 (5.1%) acquired normal reproductive function during treatment. The median age for reversal was 24 years old (range 21–34 years). Compared with the nonreversal group, the reversible group had higher basal luteinizing hormone (LH) (1.0 ± 0.7 IU l-1 vs 0.4 ± 0.4 IU l−1, P < 0.05) and stimulated LH (28.3 ± 22.6 IU l−1 vs 1.9 ± 1.1 IU l−1, P < 0.01) levels, as well as larger testicle size (5.1 ± 2.6 ml vs 1.5 ± 0.3 ml, P < 0.01), at the initial visit. In summary, larger testicle size and higher stimulated LH concentrations are favorite parameters for reversal. Our finding suggests that reversible patients may retain partially active reproductive axis function at initial diagnosis. PMID:25578938
La Vignera, Sandro; Condorelli, Rosita Angela; Cimino, Laura; Russo, Giorgio Ivan; Morgia, Giuseppe; Calogero, Aldo E
The traditional pharmacological treatment of patients with late onset hypogonadism (LOH) is represented by different formulations of testosterone (T) or alternatively by the extractive human chorionic gonadotropin (HCG). The hormone replacement treatment (HRT) is associated with the potential increase of hematocrit, serum concentrations of prostate-specific antigen (PSA) and prostate volume. Moreover, the gynecomastia represent a condition frequently associated with HRT. Recent evidences showed the role of leydig cells in the 25-hydroxylation of vitamin D and the elevated frequency of hypovitaminosis D among LOH patients. Finally, another important aspect of LOH is represented by the frequency of secondary infertility due to age or to traditional HRT. This study evaluated 40 LOH patients treated for 6 months with extractive HCG (n = 10 patients) and three different formulations of T: transdermal (n = 10 patients), undecaonate (n = 10 patients) and enantate (n = 10 patients). Hormonal, anthropometric, metabolic and sperm parameters were evaluated and compared. Moreover, the main safety parameters and the results of the main questionnaires were evaluated. After treatment, HCG group showed serum concentrations of 25-OH-vitamin D significantly higher (p < 0.05) and serum concentrations of oestrogens significantly lower (p < 0.05) compared with other groups. Moreover, they showed a mean value of hematocrit, PSA and prostate volume significantly lower (p < 0.05) compared with other groups. Finally, all the groups treated with T showed a significant reduction (p < 0.05) of sperm density and of percentage of spermatozoa with progressive motility compared with HCG group.
Yau, Ivan; Vuong, Te Garant, Aurelie; Ducruet, Thierry; Doran, Patrick; Faria, Sergio; Liberman, Sender; Richard, Carole; Letellier, Francois; Charlebois, Patrick; Loungnarath, Rasmy; Stein, Barry; Devic, Slobodan
Purpose: Recent studies have reported fluctuations in sex hormones during pelvic irradiation. The objective of this study was to observe the effects of radiation on hormonal profiles for two treatment modalities: conventional external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDRBT) given neoadjuvantly for patients with rectal cancer. Methods and Materials: Routine serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were collected from 119 consecutive male patients receiving either EBRT, using 45.0-50.4 Gy in 25-28 fractions with concurrent 5-fluorouracil chemotherapy or HDRBT using 26 Gy in 4 fractions. Results: Thirty patients with initially abnormal profiles were excluded. Profiles included in this study were collected from 51 patients treated with EBRT and 38 patients treated with HDRBT, all of whom had normal hormonal profiles before treatment. Mean follow-up times were 17 months for the entire patient cohort-14 and 20 months, respectively-for the EBRT and HDRBT arms. Dosimetry results revealed a mean cumulative testicular dose of 1.24 Gy received in EBRT patients compared with 0.27 Gy in the HDRBT group. After treatment, FSH and LH were elevated in all patients but were more pronounced in the EBRT group. The testosterone-to-LH ratio was significantly lower (p = 0.0036) in EBRT patients for tumors in the lower third of the rectum. The 2-year hypogonadism rate observed was 2.6% for HDRBT compared with 17.6% for EBRT (p = 0.09) for tumors in the lower two thirds of the rectum. Conclusion: HDRBT allows better hormonal sparing than EBRT during neoadjuvant treatment of patients with rectal cancer.
Heidari, R; Sajadi, H; Pourmand, A; Pourmand, G
Androgens are essential for the development and growth of the genitalia. They regulate the erectile physiology by multiple mechanisms. Several studies have examined associations among sex hormones' serum levels, erectile function and sex drive. We sought to identify a protocol for using testosterone in men with erectile dysfunction and late-onset hypogonadism (LOH). During a 16-month period, men with erectile dysfunction who presented to the andrology clinic were selected. They underwent a complete physical examination and filled out the International Index of Erectile Function-5 questionnaire. Serum luteinising hormone (LH) and testosterone levels were evaluated. Patients received a single intramuscular injection of 250 mg testosterone. Thereafter, serum levels of LH and testosterone were measured 3 weeks later. The mean age was 53 years old. After treating patients with testosterone, 45 (94%) showed improvement in LOH symptoms including libido, loss of energy, irritability and quality of life. The mean International Index of Erectile Function was 9 and 13.1, prior to and after treatment respectively. Mean serum testosterone levels before and after treatment were 4.2 and 4.1 ng ml(-1) respectively (P = 0.849). Mean serum LH revealed a significant decrease after the study (P = 0.004) (6.12 and 5.1 ng ml(-1) , before and after the study respectively). Our findings suggested that testosterone replacement therapy improves libido and LOH symptoms in individuals with almost normal or lower limit normal value of serum testosterone levels. © 2014 Blackwell Verlag GmbH.
Fuentes-Pastor, J; Pellejero, P; Ortiz, I; Ramírez-Backhaus, M; de Gracia, A; Marrugo, C; Gomez-Ferrer, A; Calatrava, A; Rubio-Briones, J; Rodriguez-Torreblanca, C; Solsona-Narbón, E
To assess the relationship between prostate cancer (PC) and the presence of metabolic syndrome and late-onset hypogonadism (LOH) syndrome. A retrospective study was conducted on 686 patients who underwent prostate biopsy. We analysed the demographic variables, clinical data and biopsy results. To diagnose metabolic syndrome, we employed the criteria of the American Heart Association. For the diagnosis of LOH syndrome, we employed the Androgen Deficiency in the Aging Male questionnaire and testosterone levels (TT). We evaluated the relationship between free testosterone (FT) and bioavailable testosterone (BT) on one hand and PC and its aggressiveness on the other, as well as the usefulness of the TT to prostate specific antigen (TT/PSA) ratio in the PC diagnosis. The patient's median age was 65 years. Metabolic syndrome is not associated with PC (39.4% vs. 35%; P=.1) but is associated with a PC Gleason score >7 (50.4% vs. 29.44%; P=.002). LOH, low FT and low BT are associated with an increased presence of PC (51% vs. 35%, P=.02; 44.86% vs. 33.33%, P=.03; and 46.46% vs. 33.08%, P=.01, respectively) and with an increased probability of a PC Gleason score >7 (61.54% vs. 37.5%, P=.02; 54.17% vs. 34.12%, P=.02; 54.35% vs. 34.48%, P=.02, respectively). Additionally, the median TT/PSA ratio was significantly lower in patients with positive biopsies (P=.022). Metabolic syndrome was not associated with the probability of having PC but was associated with a PC Gleason score >7. Moreover, LOH syndrome had a higher percentage of PC and a greater presence of PC Gleason scores >7, as did low levels of FT and low levels of BT. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.
Corona, Giovanni; Vignozzi, Linda; Sforza, Alessandra
Late-onset hypogonadism (LOH) is a syndromic condition that has a well-recognized association with sexual and reproductive failure. LOH is frequently associated with chronic conditions including cardiovascular diseases (CVD), obesity, osteoporosis, HIV infection, renal failure, and obstructive pulmonary diseases. Despite this evidence, in patients with these conditions, LOH is still only rarely investigated and testosterone replacement therapy (TRT) rarely considered. In this paper, we critically reviewed the available evidence on LOH treatment focusing on possible risks and benefits. Medical therapy of LOH should be individualized depending on the etiology of the disease and the patient's expectations. The fear of prostate cancer and the risk of erythrocytosis probably represent the main limitations of TRT in aging men. However, TRT in healthy older men in near physiological doses does not appear to incur serious adverse events, although regular monitoring of prostate-specific antigen and hematocrit levels is required. Available evidence also suggests that TRT might ameliorate central obesity and glycometabolic control in patients with metabolic syndrome and type 2 diabetes. In addition, TRT has been associated with an increase in bone mineral density in men with osteoporosis, with an improvement in lean body mass in subjects with human immunodeficiency virus infection or chronic obstructive pulmonary disease, as well as with peripheral oxygenation in patients with chronic kidney diseases. Despite this evidence, however, it should be recognized that the results of these trials were heterogeneous and limited by small sample sizes. Hence, further research is required regarding the long-term benefits and adverse effects of TRT in LOH. PMID:24044106
To determine the incidence of hypogonadism in men with human immunodeficiency virus (HIV)/acquired immunodeficiency virus (AIDS), the most useful serum testosterone measurement and threshold for diagnosing hypogonadism, and the comparative efficacy of 2 testosterone replacement therapy (TRT) 1% gels (AndroGel® [Abbott Laboratories] and Testim® [Auxilium Pharmaceuticals, Inc.]). This was a 2-stage observational study. In stage 1, patient records from 2 medical practices specializing in HIV/AIDS were reviewed. Eligible patients were aged ≥ 18 years; had HIV-seropositive status confirmed by enzyme-linked immunosorbent assay and western blot test or HIV-1 viremia confirmed by HIV-1 RNA polymerase chain reaction; and had prior baseline testosterone assessments for hypogonadism (ie, presence of signs/symptoms of hypogonadism as well as total testosterone [TT] and free testosterone [FT] level measurements). Stage 2 included the evaluation of patients from stage 1 who were treated with 5 to 10 g/day of TRT. The stage 2 inclusion criteria were a diagnosis of low testosterone (defined as TT level < 300 ng/dL and/or FT level < 50 pg/mL, as per The Endocrine Society guidelines and presence/absence of hypogonadal signs and symptoms); ≥ 12 months of evaluable sign and symptom assessments and TT/FT level measurements while on TRT with either Testim® or AndroGel®; and ≥ 4 weeks on initial TRT if the initial TRT was switched or discontinued. Four hundred one of 422 patients met the stage 1 inclusion criteria and 167 of 401 patients (AndroGel®, n = 92; Testim®, n = 75) met the stage 2 inclusion criteria. Total testosterone level < 300 ng/dL alone identified 24% (94 of 390) of patients as hypogonadal, but failed to diagnose an additional 111 patients (67.7%) with FT levels < 100 pg/mL and hypogonadal symptoms. Through month 12, AndroGel® increased mean TT levels by +42.8% and FT levels by +66.9%, compared with +178.7% (P = 0.017) and +191% (P = 0.039), respectively, for
Page, Stephanie T; Hirano, Lianne; Gilchriest, Janet; Dighe, Manjiri; Amory, John K; Marck, Brett T; Matsumoto, Alvin M
Benign prostatic hyperplasia and hypogonadism are common disorders in aging men. There is concern that androgen replacement in older men may increase prostate size and symptoms of benign prostatic hyperplasia. We examined whether combining dutasteride, which inhibits testosterone to dihydrotestosterone conversion, with testosterone treatment in older hypogonadal men with benign prostatic hyperplasia reduces androgenic stimulation of the prostate compared to testosterone alone. We conducted a double-blind, placebo controlled trial of 53 men 51 to 82 years old with symptomatic benign prostatic hyperplasia, prostate volume 30 cc or greater and serum total testosterone less than 280 ng/dl (less than 9.7 nmol/l). Subjects were randomized to daily transdermal 1% T gel plus oral placebo or dutasteride for 6 months. Testosterone dosing was adjusted to a serum testosterone of 500 to 1,000 ng/dl. The primary outcomes were prostate volume measured by magnetic resonance imaging, serum prostate specific antigen and androgen levels. A total of 46 subjects completed all procedures. Serum testosterone increased similarly into the mid-normal range in both groups. Serum dihydrotestosterone increased in the testosterone only but decreased in the testosterone plus dutasteride group. In the testosterone plus dutasteride group prostate volume and prostate specific antigen (mean ± SEM) decreased 12% ± 2.5% and 35% ± 5%, respectively, compared to the testosterone only group in which prostate volume and prostate specific antigen increased 7.5% ± 3.3% and 19% ± 7% (p = 0.03 and p = 0.008), respectively, after 6 months of treatment. Prostate symptom scores improved in both groups. Combined treatment with testosterone plus dutasteride reduces prostate volume and prostate specific antigen compared to testosterone only. Coadministration of a 5α-reductase inhibitor with testosterone appears to spare the prostate from androgenic stimulation during testosterone replacement in older
Jones, T. Hugh; Arver, Stefan; Behre, Hermann M.; Buvat, Jacques; Meuleman, Eric; Moncada, Ignacio; Morales, Antonio Martin; Volterrani, Maurizio; Yellowlees, Ann; Howell, Julian D.; Channer, Kevin S.
OBJECTIVE This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0−6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6−12). RESULTS TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA1c: treatment difference, −0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate. CONCLUSIONS Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS. PMID:21386088
Nieschlag, Eberhard; Kumar, Narender; Sitruk-Ware, Régine
Testosterone is an essential part of all regimens for hormonal male contraception tested to date. Initial efficacy trials revealed that the half-life of the testosterone preparations available at that time was too short to be used for male contraception. The ensuing search for long-acting preparations yielded testosterone buciclate and undecanoate as well as 7α-methyl-19-nortestosterone (MENT). Following description of the principle of male hormonal contraception and the efficacy trials performed to date, the systematic development of MENT for substitution of male hypogonadism and use in male contraception by the Population Council is reviewed here.
Alejandra Samaniego, Yanina; Cecilia Fornari, María; Reyes Toso, Carlos; Juan Ponzo, Osvaldo
Background. There is a gender disparity in the incidence, prevalence, and progression of renal disease. The object of this paper is to evaluate the presence and type of renal lesion in normogonadic and hypogonadic male rats in a mild hyperuricemia induced condition and exposed to a high-fructose diet. Methods. 56 adult male Wistar rats were used. Animals were divided into two groups, one normogonadic (NGN) and one hypogonadic (HGN), and each group was divided into four subgroups in accordance with the treatment: control with only water (C), fructose (F), oxonic acid (OA), and fructose + oxonic acid (FOA). Renal changes were evaluated by measuring glomerulosclerosis, fibrosis, and arteriolar media/lumen (M/L) ratio. Results. The OA and FOA groups presented significantly hypertension (p < 0.001). The OA group significantly increased (p < 0.05) the percentage of glomerulosclerosis as well as the FOA group (p < 0.001). When comparing NGN versus HGN, we observed a trend to a lower glomerulosclerosis in the latter. A higher arteriolar M/L ratio was observed in the OA (p < 0.05) and FOA (p < 0.001). Conclusion. Hyperuricemia conditions and a high-fructose diet favor blood pressure increase together with changes in the arteriolar media/lumen ratio and renal glomerular damage. These changes were more apparent in normogonadic animals. PMID:28293259
Heráček, Jiří; El Balouly, Karim; Sobotka, Vladimír; Šnajderová, Marta; Kalvachová, Božena; Urban, Michael
The aim of the study was to evaluate prostate transrectal ultrasonography findings in men with congenital hypogonadism treated by long term testosterone replacement therapy. We have gradually included 31 men with congenital hypogonadism in period of 2001-2011. The average follow-up was 7.3 years (2 months - 10.8 years). We have used Sustanon® 250 i.m. every 3 weeks or Nebido® i.m. every 3 months for continual testosterone replacement therapy. We performed to all patients the transrectal ultrasonography of prostate and seminal vesicles by biplanar rectal probe every 6 months. During the transrectal ultrasonography we observed in 22 (71.0 %) patients changes in prostatic tissue. In case of 12 patients were diagnosed asymptomatic prostatic cysts, in 9 patients prostatolithiasis and in 5 patients changes in echogenity of prostatic tissue. In 2 patients was found simultaneous occurrence of prostatic cyst and prostolithiasis, in further 2 patients simultaneous occurrence of hyperechogenic prostatic lesion and prostatolithiasis. The above described findings were diagnosed in 5 patients in the treatment lasting from 3 to 5 years, for the other 17 men with hormone replacement therapy longer than 5 years. The study presents long term results of complex treatment in patients with disorders of sexual development, onset and progress of puberty. The long term treatment of these patients in interdisciplinary cooperation of endocrinologist and andrologist may significantly contribute to clarify an impact of testosterone replacement therapy on prostate development.
Heaton, Jeremy P W
Andropause is a problem that can be identified in some men as distinct from the changes associated with aging or chronic disease. These men have mild hypogonadism and a clinical picture that is well within the scope of urologists to identify and manage. Andropause is neither life threatening nor trivial and there are clinical guidelines published that will help to refine the understanding and definition of this condition. The character of andropause is distinct from profound hypogonadism in its relation to age, the scope and degree of contributing symptoms and the marginal reduction in testosterone. Testosterone is the established treatment for some men with andropause and the links between testosterone and cancer of the prostate create an overlap in management that places a premium on urological expertise. Obviously men with cancer of the prostate must not be given testosterone and some men may have clinical andropause and undetected cancer of the prostate. However, current understanding points to the fact that there is no additional risk from re-establishing a normal androgen environment (androgen replacement) in terms of initiating a new cancer of the prostate while testosterone will encourage growth of an established cancer. Therefore, the natural good practice of urology, and only urology, intrinsically encompasses the major issues inherent in the medical collision of cancer of the prostate and testosterone replacement. The good practice of urology includes the use of androgen replacement therapy in men who need it and have been assessed for the presence of cancer of the prostate.
Jeong, K-H; Bakowska, J C; Song, I O; Fu, N; Breakefield, X O; Kaiser, U B
One of the challenges of gene targeting is to achieve regulated transgene expression in specific target cells. The hypogonadal (hpg) mice are genetically deficient in hypothalamic gonadotropin-releasing hormone (GnRH) production due to a deletion in the GnRH gene, resulting in hypogonadotropic hypogonadism. Here we show an improvement in reproductive parameters of adult female homozygous hpg mice by direct infusion into the hypothalamic preoptic area (POA) of a herpes simplex virus (HSV)-based amplicon vector containing a 13.5 kb genomic fragment encoding the GnRH gene together with its cognate promoter and regulatory elements. Following vector injection, GnRH-expressing neurons were detected in the POA, and pituitary and plasma gonadotropin levels as well as ovarian and uterine weights increased. In addition, a subset of injected hpg mice demonstrated cyclic estrous changes, consistent with regulated control of GnRH production. Administration of kisspeptin-10 resulted in an increase in plasma luteinizing hormone levels, further supporting appropriate regulation of the introduced GnRH transgene. These findings indicate that delivery of the GnRH gene resulted in selective neuronal expression of GnRH and regulated hypothalamic GnRH release. To our knowledge, this is the first example of the correct targeting of a gene under its cognate promoter to neurons resulting in selective and regulated synthesis of a biologically active peptide, and thus may have a wide range of applications in the treatment of human disorders.
Nair, Sandhya; Jadhav, Swati; Lila, Anurag; Jagtap, Varsha; Bukan, Amol; Pandit, Reshma; Ekbote, Alka; Dharmalingam, Mala; Kumar, Prasanna; Kalra, Pramila; Gandhi, Pramod; Walia, Rama; Sankhe, Shilpa; Raghavan, Vijaya; Shivane, Vyankatesh; Menon, Padma; Bandgar, Tushar; Shah, Nalini
Congenital isolated hypogonadotropic hypogonadism (IHH) is caused due to defect in GnRH neuronal development, migration and action. Although genetic aetiology of IHH is increasingly being studied, Asian Indian data on phenotypic spectrum and genetic basis are scarce. To investigate the phenotypic and genotypic spectrum of IHH in Asian Indian subjects. A cohort of 135 IHH probands were characterized phenotypically for reproductive and nonreproductive features and screened for rare sequence variations (RSVs) in five genes KAL1, FGFR1, FGF8, GNRHR and KISS1R. Of 135 probands [56 normosmic IHH (nIHH) and 79 Kallmann syndrome (KS)], 20 were familial cases. KS group had more male dominance (M:F ratio of 8:1) as compared to nIHH group (M:F ratio of 1·5:1). Complete absence of puberty was more prevalent in KS probands (81% in KS vs 46% in nIHH). The prevalence of MRI abnormalities was more in anosmic group (92·8%) as compared to hyposmic (37·5%) and normosmic groups (15·4%). No particular nonreproductive phenotypic predominance was seen in any group. Genotyping revealed rare sequence variation (RSV) detection rate of 15·5% in five genes studied: (KAL1 - 4·4%, FGFR1 - 4·4%, GNRHR - 6·7%, oligogenicity - 1·5%). Prevalence of RSV was more common in familial cases (35%) as compared to sporadic (12·2%). GNRHR RSV p.C279Y (not reported in patients of ethnicities other than south Asians) was recurring in four unrelated patients. In our cohort, 60% were KS with majority of males and a severe reproductive phenotype as against nIHH. Contribution of the genetic burden for the five genes studied was 15·5%. RSV p.C279Y in GNRHR may have a founder effect originating from south Asia. This study provides a model for molecular and phenotypic representation of Asian Indian subjects with IHH. © 2015 John Wiley & Sons Ltd.
Della Valle, Elisa; Vezzani, Silvia; Rochira, Vincenzo; Granata, Antonio Raffaele Michele; Madeo, Bruno; Genovese, Elisabetta; Pignatti, Elisa; Marino, Marco; Carani, Cesare; Simoni, Manuela
Introduction: Hypogonadotropic hypogonadism (HH) is a heterogeneous disease caused by mutations in several genes. Based on the presence of hyposmia/anosmia it is distinguished into Kallmann syndrome (KS) and isolated HH. The prevalence of other developmental anomalies is not well established. Methods: We studied 36 patients with HH (31 males, 5 females, mean age 41.5), 9 with familial and 27 with sporadic HH (33 congenital, 3 adult-onset), by physical examination, smell test (BSIT Sensonics), audiometry, renal ultrasound, and magnetic resonance imaging of the olfactory structures. Results: Based on the smell test, patients were classified as normosmic (n = 21, 58.3%) and hypo/anosmic (n = 15, 41.6%). Hypoplasia/agenesis of olfactory bulbs was found in 40% of patients (10/25; 75% hypo/anosmic, 7.6% normosmic, p < 0.01, Fisher’s test). Remarkably, olfactory structures were normal in two anosmic patients, while one normosmic patient presented a unilateral hypoplastic bulb. Fourteen of 33 patients (42.4%) presented neurosensorial hearing loss of various degrees (28.5% hypo/anosmic, 52.6% normosmic, p = NS). Renal ultrasound revealed 27.7% of cases with renal anomalies (26.6% hypo/anosmic, 28.5% normosmic, p = NS). At least one midline defect was found in 50% of the patients (53.3% hypo/anosmic, 47.6% normosmic, p = NS), including abnormal palate, dental anomalies, pectus excavatum, bimanual synkinesis, iris coloboma, and absent nasal cartilage. Anamnestically 4/31 patients reported cryptorchidism (25% hypo/anosmic, 5.2% normosmic, p = NS). Conclusion: Hypo/anosmia is significantly related to anatomical anomalies of the olfactory bulbs/tracts but the prevalence of other developmental anomalies, especially midline defects and neurosensorial hearing loss, is high both in HH and KS and independent of the presence of anosmia/hyposmia. From the clinical standpoint KS and normosmic HH should be considered as the same complex, developmental
Yassin, Aksam; Nettleship, Joanne E; Talib, Raidh A; Almehmadi, Yousef; Doros, Gheorge
Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function - erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.
Sinnesael, Mieke; Callewaert, Filip; Morreels, Maarten; Kumar, Narender; Sitruk-Ware, Regine; Van Proeyen, Karen; Hespel, Peter; Boonen, Steven; Claessens, Frank; Vanderschueren, Dirk
Purpose Overt male hypogonadism induces not only osteoporosis but also unfavorable changes in body composition, which can be prevented by testosterone (T) replacement. In this preclinical study, the potential of synthetic androgen 7α-methyl-19-nortestosterone (MENT) as alternative treatment for male hypogonadism was evaluated in comparison with T. Methods 11-month-old male rats were orchidectomized (orch) and left untreated for 2-months. Subsequently, the effects of 4-months MENT (12 µg/day) and T (72µg/day) treatment on bone, muscle and fat were analyzed by microcomputed tomography, dual-energy X-ray absorptiometry, dynamic bone histomorphometry and muscle fiber typing. Results At the onset of treatment orch rats were clearly hypogonadal. This was evidenced by significant reductions of androgen-sensitive organ weight, lean mass, cortical thickness and trabecular bone volume compared with sham-operated aged-matched controls (sham). MENT and T restored weight of androgen-sensitive organs to a similar extent, with a superior anabolic action of MENT on levator ani muscle. Both androgens not only fully rescued hypogonadal loss of lean mass, but also restored muscle fiber type composition and trabecular bone volume. Cortical bone loss was similarly prevented by MENT and T, but without full recovery to sham. Both androgens stimulated periosteal bone formation, but with a stronger effect of T. In contrast, MENT more strongly suppressed endocortical bone formation and bone turnover rate and reduced fat mass and serum leptin to a greater extent than T. Conclusion MENT and T are both effective replacement therapies to stimulate bone and muscle in hypogonadal rats, with stronger lipolytic action of MENT. PMID:21790658
Sinnesael, M; Callewaert, F; Morreels, M; Kumar, N; Sitruk-Ware, R; Van Proeyen, K; Hespel, P; Boonen, S; Claessens, F; Vanderschueren, D
Overt male hypogonadism induces not only osteoporosis but also unfavourable changes in body composition, which can be prevented by testosterone (T) replacement. In this preclinical study, the potential of synthetic androgen 7α-methyl-19-nortestosterone (MENT) as alternative treatment for male hypogonadism was evaluated in comparison with T. Eleven-month-old male rats were orchidectomized (orch) and left untreated for 2-months. Subsequently, the effects of 4-month MENT (12 μg/day) and T (72 μg/day) treatment on bone, muscle and fat were analysed using microcomputed tomography, dual-energy X-ray absorptiometry, dynamic bone histomorphometry and muscle fibre typing. At the onset of treatment, orch rats were clearly hypogonadal. This was evidenced by significant reductions of androgen-sensitive organ weight, lean mass, cortical thickness and trabecular bone volume compared with sham-operated aged-matched controls (sham). MENT and T restored weight of androgen-sensitive organs to a similar extent, with a superior anabolic action of MENT on levator ani muscle. Both androgens not only fully rescued hypogonadal loss of lean mass but also restored muscle fibre type composition and trabecular bone volume. Cortical bone loss was similarly prevented by MENT and T, but without full recovery to sham. Both androgens stimulated periosteal bone formation, but with a stronger effect of T. By contrast, MENT more strongly suppressed endocortical bone formation and bone turnover rate and reduced fat mass and serum leptin to a greater extent than T. MENT and T are both effective replacement therapies to stimulate bone and muscle in hypogonadal rats, with stronger lipolytic action of MENT.
Blick, Gary; Khera, Mohit; Bhattacharya, Rajib K; Kushner, Harvey; Miner, Martin M
Although hypogonadism is common in men with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), testosterone levels after testosterone replacement therapy (TRT) in this population have not been reported. The Testim Registry in the United States (TRiUS) was the first prospective, observational registry of men with hypogonadism who were prescribed TRT. The TRiUS cohorts with (n = 82) and without (n = 767) HIV/AIDS were followed during 12 months of treatment with Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.). Total testosterone (TT) and free testosterone levels, symptoms of depression, sexual function, body composition profiles, and prostate-specific antigen levels were evaluated. The HIV/AIDS and non-HIV/AIDS cohorts differed at baseline in age (48.3 vs 52.5 years), TT level (13.0 vs 9.6 nmol/L), duration of hypogonadism (27.1 vs 14.6 months), prior TRT (36.6% vs 22.6%), body mass index (26.5 vs 32.0 kg/m2), and antidepressant (29% vs 15%) and opioid (20% vs 10%) use (P ≤ 0.01 for all comparisons). During the 12 months, both cohorts experienced significant elevations in TT and free testosterone levels to within normal ranges. Sexual function and depression scores improved and antidepressant medication use decreased in both cohorts. Body composition profiles improved significantly (P ≤ 0.05) in men without HIV/AIDS and remained stable in men with HIV/AIDS during the 12 months of follow-up. This 12-month, non-placebo-controlled, observational study of Testim® use in men with and without HIV/AIDS suggests that TRT may provide clinical benefits irrespective of the patient's HIV/AIDS status. This conclusion is supported by the higher testosterone levels, better sexual function, lower depression scores, and better body composition profiles found in both groups. However, given the loss of patients to follow-up, these results may reflect a bias toward drug responders.
De Sanctis, Vincenzo; Elsedfy, Heba; Soliman, Ashraf T; Elhakim, Ihab Zaki; Pepe, Alessia; Kattamis, Christos; Soliman, Nada A.; Elalaily, Rania; El Kholy, Mohamed; Yassin, Mohamed
Introduction In males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function, and strength, a worsened sense of well-being and degraded quality of life (QOL). Patients and methods We studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy. Fasting venous blood samples were collected two weeks after transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*. Bone mineral density was measured at the lumbar spine (L1–L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine. Results The mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH showed azoospermia in 3 and oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml (severe iron load) was significantly higher in AHH patients compared to controls, 5/11 (45
Kim, Edward D; McCullough, Andrew; Kaminetsky, Jed
To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism. Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel(®) 1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18-60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2-10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study. TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group. Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.
Jones, Amanda; Hwang, Dong-Jin; Narayanan, Ramesh; Miller, Duane D; Dalton, James T
Glucocorticoids are the most widely used antiinflammatory drugs in the world. However, prolonged use of glucocorticoids results in undesirable side effects such as muscle wasting, osteoporosis, and diabetes. Skeletal muscle wasting, which currently has no approved therapy, is a debilitating condition resulting from either reduced muscle protein synthesis or increased degradation. The imbalance in protein synthesis could occur from increased expression and function of muscle-specific ubiquitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF1), or decreased function of the IGF-I and phosphatidylinositol-3 kinase/Akt kinase pathways. We examined the effects of a nonsteroidal tissue selective androgen receptor modulator (SARM) and testosterone on glucocorticoid-induced muscle atrophy and castration-induced muscle atrophy. The SARM and testosterone propionate blocked the dexamethasone-induced dephosphorylation of Akt and other proteins involved in protein synthesis, including Forkhead box O (FoxO). Dexamethasone caused a significant up-regulation in the expression of ubiquitin ligases, but testosterone propionate and SARM administration blocked this effect by phosphorylating FoxO. Castration induced rapid myopathy of the levator ani muscle, accompanied by up-regulation of MAFbx and MuRF1 and down-regulation of IGF-I, all of which was attenuated by a SARM. The results suggest that levator ani atrophy caused by hypogonadism may be the result of loss of IGF-I stimulation, whereas that caused by glucocorticoid treatment relies almost solely on up-regulation of MAFbx and MuRF1. Our studies provide the first evidence that glucocorticoid- and hypogonadism-induced muscle atrophy are mediated by distinct but overlapping mechanisms and that SARMs may provide a more effective and selective pharmacological approach to prevent glucocorticoid-induced muscle loss than steroidal androgen therapy.
Strollo, Felice; Strollo, Giovanna; Morè, Massimo; Magni, Paolo; Macchi, Chiara; Masini, Maria Angela; Carucci, Iarba; Celotti, Fabio; Ruscica, Massimiliano; Gentile, Sandro
An open-label follow-up study of low-to-intermediate dose testosterone replacement therapy (TRT) was conducted in 64 overweight patients (aged 65-75 years) with late onset hypogonadism (LOH) and increased fasting plasma glucose (FPG). Patients were subdivided into four treatment groups: oral testosterone (T) (T undecanoate, 80 mg/d), transmucosal T (60 mg/d), transdermal T (30 mg/d) or no treatment (control), and evaluated at 0 and 6 months. FPG, hemoglobin (Hb), prostate-specific antigen (PSA) and total T were measured and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated. Body mass index (BMI), waist circumference, fitness level (6-min walking test), Aging Males' Symptoms (AMS) scale, handgrip strength and energy expenditure with physical activity (Minnesota questionnaire for Leisure Time Physical Activity (LTPA)) were evaluated and a "frailty score" (based on: grip strength, gait speed and LTPA) was calculated. T levels increased in all treatment groups; the oral T group had values still in the hypogonadal range (5.9 ± 1.1 nmol/L). PSA and Hb concentrations did not change in any group. BMI, waist circumference, FPG and HOMA-IR improved in all T-treated groups after 6 months, with a greater effect seen with transmucosal and transdermal T compared with oral T. This study indicates that low-to-intermediate dose TRT may be safely utilized in LOH patients to ameliorate somatic and psychological frailty symptoms in association with improved anthropometric and glycometabolic parameters in aging, overweight men with LOH and impaired fasting glucose.
Cunningham, Glenn; Belkoff, Laurence; Brock, Gerald; Efros, Mitchell; Gittelman, Marc; Carrara, Dario; Neijber, Anders; Ando, Masakazu; Mitchel, Jules
Testosterone replacement therapy is indicated for male hypogonadism. This study aimed to evaluate the efficacy and safety of testosterone gel 2% (Tgel) over 90 days. This phase 3, open-label, noncomparator study was conducted in adult hypogonadal men (2 consecutive fasting serum testosterone values <300 ng/dL and >86% subjects with symptoms consistent with testosterone deficiency). Subjects applied Tgel 23 mg/day (single pump-actuation using a hands-free cap applicator). The dose was uptitrated to 46 mg/day after 2 weeks if the 4-hour serum total testosterone level was <500 ng/dL. The dose could be further up- or downtitrated to 23, 46, and 69 mg on Days 21, 42, and 63. The primary endpoint included the percentage of subjects with average testosterone concentration (Cave (0-24)) between 300 and 1,050 ng/dL on Day 90. Safety endpoints were adverse events (AEs), laboratory parameters, and vital signs. Of the 159 who enrolled, 139 men completed the study. Approximately three-quarters (76.1%) of subjects met Cave criteria on Day 90. Most AEs were mild to moderate. There were 5 serious AEs, and 1 (myocardial infarction) was judged as possibly related to Tgel. Confirmed excessive increases in prostate-specific antigen or hematocrit levels were rare. Tgel had a favorable local skin tolerability profile. Overall, 76% of subjects achieved Cave between 300 and 1,050 ng/dL with Tgel. Symptoms of testosterone deficiency improved with few safety concerns. AE = adverse event Cave(0-24) = average testosterone concentration CI = confidence interval Cmax = maximum concentration IIEF = International Index of Erectile Function MAF = Multidimensional Assessment of Fatigue PK = pharmacokinetic PSA = prostate-specific antigen SAE = serious adverse event SF-12 = Short Form 12 Health Survey Tgel = testosterone gel 2% Tmax = time to achieve maximum concentration TRT = testosterone replacement therapy.
Coutant, Régis; Biette-Demeneix, Estelle; Bouvattier, Claire; Bouhours-Nouet, Natacha; Gatelais, Frédérique; Dufresne, Sylvie; Rouleau, Stéphanie; Lahlou, Najiba
The diagnosis of isolated hypogonadotropic hypogonadism (IHH) in boys with delayed puberty is challenging, as may be the diagnosis of hypogonadotropic hypogonadism (HH) in boys with combined pituitary hormone deficiency (CPHD). Yet, the therapeutic choices for puberty induction depend on accurate diagnosis and may influence future fertility. The aim was to assess the utility of baseline inhibin B (INHB) and anti-Mullerian hormone (AMH) measurements to discriminate HH from constitutional delay of puberty (CDP). Both hormones are produced by Sertoli cells upon FSH stimulation. Moreover, prepubertal AMH levels are high as a reflection of Sertoli cell integrity. We studied 82 boys aged 14 to 18 yr with pubertal delay: 16 had IHH, 15 congenital HH within CPHD, and 51 CDP, as confirmed by follow-up. Subjects were genital stage 1 (testis volume<3 ml; 9 IHH, 7 CPHD, and 23 CDP) or early stage 2 (testis volume, 3-6 ml; 7 IHH, 8 CPHD, and 28 CDP). Age and testis volume were similar in the three groups. Compared with CDP subjects, IHH and CPHD subjects had lower INHB, testosterone, FSH, and LH concentrations (P<0.05), whereas AMH concentration was lower only in IHH and CPHD subjects with genital stage 1, likely reflecting a smaller pool of Sertoli cells in profound HH. In IHH and CPHD boys with genital stage 1, sensitivity and specificity were 100% for INHB concentration of 35 pg/ml or less. In IHH and CPHD boys with genital stage 2, sensitivities were 86 and 80%, whereas specificities were 92% and 88%, respectively, for an INHB concentration of 65 pg/ml or less. The performance of testosterone, AMH, FSH, and LH measurements was lower. No combination or ratio of hormones performed better than INHB alone. Discrimination of HH from CDP with baseline INHB measurement was excellent in subjects with genital stage 1 and fair in subjects with genital stage 2.
De Sanctis, Vincenzo; Soliman, Ashraf T.; Elsedfy, Heba; Albu, Alice; Al Jaouni, Soad; Anastasi, Salvatore; Bisconte, Maria Grazia; Canatan, Duran; Christou, Soteroula; Daar, Shahina; Di Maio, Salvatore; El Kholy, Mohamed; Khater, Doaa; Elshinawy, Mohamed; Kilinc, Yurdanur; Mattei, Roberto; Mosli, Hala H.; Quota, Alessandra; Roberti, Maria Grazia; Sobti, Praveen; Yaarubi, Saif AL; Canpisi, Saveria; Kattamis, Christos
Background Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists. The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed. Methods In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network. Results The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients’ compliance to treatment was reported as good in 81.2 % of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating
Role of peritoneal macrophages and lymphocytes in the development of hypogonadal osteoporosis in an ovariectomized rat model: possible phytoestrogenic efficacy of oil extract of garlic to preserve skeletal health.
Mukherjee, M; Das, A S; Das, D; Mukherjee, S; Mitra, S; Mitra, C
This study was to examine whether skeletal health deterioration in the hypogonadal situation is a consequence of an alteration in the functional status of peripheral mononuclear cells and its amelioration, if any, by an oil extract of garlic. The results suggest that hypogonadism-induced oxidative stress of peritoneal macrophages and lymphocytes could be reduced by supplementation with an oil extract of garlic. However, estrogen deficiency did not cause any significant change in DNA fragmentation of peritoneal macrophages. The hypogonadism-induced increase in the serum levels of IL-6 and TNF-alpha were significantly reduced by an oil extract of garlic. Further, such supplementation could revive the hypogonadism-induced decrease in serum estrogen titer and counter-balance the increase in bone turnover as determined by low bone tensile strength and alterations in bone related biochemical variables such as urinary calcium, hydroxyproline, calcium to creatinine ratio and serum tartrate resistant acid phosphatase activity (TRAP). The garlic oil supplemented partial recovery of the serum estrogen titer in hypogonadal rats was found to be persistently associated with reduced oxidative stress of peritoneal macrophages and lymphocytes, reduced serum interleukins and better preservation of bone mass. This study proposes that the hypogonadism-induced bone loss has a direct correlation with the functional status of lymphocytes and peritoneal macrophages, and garlic can prevent this. Copyright (c) 2007 John Wiley & Sons, Ltd.
Aydogan, Umit; Aydogdu, Aydogan; Akbulut, Halil; Sonmez, Alper; Yuksel, Servet; Basaran, Yalcin; Uzun, Ozcan; Bolu, Erol; Saglam, Kenan
Hypogonadotropic hypogonadism is defined as the failure in production of gonadal hormones, thus resulting in lower amounts of testosterone. Depression, anxiety and decreased quality of life are the most common psychopathological conditions in young hypogonadal men. The aim of the present study was to assess the still debated relationship with testosterone levels and psychological symptoms in young male patients with congenital hypogonadotropic hypogonadism (CHH). Thirty-nine young male patients with CHH and 40 age-matched healthy males were enrolled in the present study. The impact of testosterone replacement treatment (TRT) on the patients' anxiety and depression levels, sexual function and quality of life were assessed before and after 6 months of treatment using valid and reliable scales, including the Short Form-36 (SF-36), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Arizona Sexual Experiences (ASEX). Patients with CHH had significantly higher scores for BDI, BAI, and ASEX than the control subjects at baseline (p=0.011, p=0.036, p<0.001, respectively). The ASEX and BDI scores significantly improved after the TRT (p<0.001 for both), while the improvement in the BAI score was not statistically significant (p=0.135). When compared to the control group, treatment naïve hypogonadal patients had more severe symptoms of sexual dysfunction, anxiety, depression, and worse quality of life. After 6 months of TRT, we observed improvements in the above parameters, suggesting that low endogenous levels of testosterone might be related to the increased incidence of psychological symptoms.
Bauman, William A; La Fountaine, Michael F; Cirnigliaro, Christopher M; Kirshblum, Steven C; Spungen, Ann M
To determine whether favorable changes to lean tissue mass (LTM), resting energy expenditure (REE), and testosterone (T) that occurred with 12 months of physiological testosterone replacement therapy (TRT) were retained 6 months after discontinuing treatment. Prospective, open-label, controlled drug intervention trial. Metropolitan area hospitals. Eugonadal (n = 11) and hypogonadal (n = 13) men with chronic spinal cord injury (SCI). Hypogonadal subjects received a 5 or 10 mg transdermal T patch daily for 12 months, with adjustment of the dose to normalize the serum T concentration; TRT was discontinued after 12 months (TRT-12M) and subjects were followed for an additional 6 months and re-evaluated (Post-TRT). Total body dual energy X-ray absorptiometry and blood draws were performed at baseline (BL) prior to TRT, TRT-12M, and Post-TRT. Eugonadal subjects did not receive treatment and were evaluated at comparable time points. There were no significant differences between groups prior to TRT at BL for any of the study endpoints. In the hypogonadal group, a significant increase in LTM was observed from BL to TRT-12M (50.2 ± 7.4 vs. 52.9 ± 6.8 kg, P < 0.01), which persisted Post-TRT compared to BL (52.2 ± 7.8 kg, P < 0.05). The increase in REE from BL to TRT-12M (1283 ± 246 vs. 1410 ± 250 kcal/day) was also retained at Post-TRT (1393 ± 220 kcal/day). These sustained improvements in LTM and REE after termination of anabolic hormonal therapy may be associated with persistent beneficial effects on health and physical function of hypogonadal men with chronic SCI.
Yassin, Aksam; Almehmadi, Yousef; Saad, Farid; Doros, Gheorghe; Gooren, Louis
In addition to primary and secondary ('classical') hypogonadism, hypogonadism occurring in middle-aged and elderly men has been recognized. There is evidence that restoring T levels to normal improves body weight, serum lipids and glucose levels. Observational registry study. Two hundred and sixty-two hypogonadal, middle-aged and elderly, men received testosterone replacement treatment (TRT). After having been on TRT for a mean duration of 65·5 months, TRT was temporarily intermitted in 147 patients for a mean of 16·9 months (Group I) due to cost reimbursement issues and in seven men due to prostate cancer. All these men resumed TRT for a mean period of 14·5 months. Of the cohort, 115 men were treated continuously (designated as Group C). To compare on-treatment to off-treatment periods, three periods of equal duration were defined: pre-intermission (on TRT), during intermission (off TRT) and post-intermission (on TRT after resumption of TRT). For proper comparison, the same periods were analysed for those patients who continued TRT throughout (Group C). Variables of body weight, glucose metabolism, lipids, blood pressure and C-reactive protein (CRP). In Group C there was a continuous improvement of body weight, serum lipids, glucose, HbA1c , blood pressure and CRP. In Group I there was a similar initial improvement which was reversed upon intermission of T administration but which appeared again when T treatment was reinstated. Our observation indicates that T administration improves body weight and metabolic factors in men with hypogonadism but withdrawal of T reverses these beneficial effects to appear again when TRT is resumed. © 2015 John Wiley & Sons Ltd.
Tirabassi, G; delli Muti, N; Gioia, A; Biagioli, A; Lenzi, A; Balercia, G
The relationship between androgen receptor (AR) CAG polymorphism and bone metabolism is highly controversial. We, therefore, aimed to evaluate the independent role of AR CAG repeat polymorphism on bone metabolism improvement induced by testosterone replacement therapy (TRT) in male post-surgical hypogonadotropic hypogonadism, a condition frequently associated with hypopituitarism and in which the effects of TRT have to be distinguished from those resulting from concomitant administration of pituitary function replacing hormones. 12 men affected by post-surgical hypogonadotropic hypogonadism [mean duration of hypogonadism 8.3 ± 2.05 (SD) months] were retrospectively assessed before and after TRT (from 74 to 84 weeks after the beginning of therapy). The following measures were studied: parameters of bone metabolism [serum markers and bone mineral density (BMD)], pituitary dependent hormones and genetic analysis (AR CAG repeat number). Total testosterone, estradiol, free T4 (FT4) and insulin-like growth factor-1 (IGF-1) increased between the two phases, while follicle stimulating hormone (FSH) decreased. While serum markers did not vary significantly between the two phases, BMD improved slightly but significantly in all the studied sites. The number of CAG triplets correlated negatively and significantly with all the variations (Δ-) of BMDs. Conversely, Δ-testosterone correlated positively and significantly with all studied Δ-BMDs, while Δ-FSH, Δ-estradiol, Δ-FT4, and Δ-IGF-1 did not correlate significantly with any of the Δ-BMDs. Multiple linear regression analysis, after correction for Δ-testosterone, showed that CAG repeat length was negatively and significantly associated with ∆-BMD of all measured sites. Our data suggest that, in post-surgical male hypogonadotropic hypogonadism, shorter AR CAG tract is independently associated with greater TRT-induced improvement of BMD.
Bacevičienė, Rasa; Valonytė, Laura; Ceponis, Jonas
The aim of this study was to analyze whether the addition of physiotherapy to testosterone replacement therapy provides added benefit in improving functional capacity of the motor system in men with hypogonadism. The study involved 3 groups of subjects: group 1, healthy men (n=20); group 2, men with hypogonadism who underwent testosterone replacement therapy with physiotherapy (TRT+PT) (n=8); and group 3, men with hypogonadism who underwent testosterone replacement therapy alone (TRT) (n=10). Physical activity (International Physical Activity Questionnaire [IPAQ]) and body composition (X-SCAN analysis) were analyzed; the vertical jump test (Leonardo Mechanography®) was applied. The application of testosterone replacement therapy together with physiotherapy for 6 months significantly increased the maximum and relative power of jump in the subjects in the TRT+PT group; however, in the TRT group, no statistically significant difference was observed. The maximum jump height for the subjects in the TRT+PT group significantly increased 6 months after the intervention; however, in the TRT group, this index remained unaltered. The lean body mass of the subjects in the TRT+PT group increased (P<0.05); however, in the TRT group, it did not change. The relative fat body mass in the TRT+PT group decreased significantly (P<0.05), but, in the TRT group, it had a tendency to increase, though insignificantly. Our results suggest that the application of testosterone replacement therapy together with physiotherapy (1 hour twice weekly) in men with hypogonadism may lead to earlier and better results in comparison with testosterone replacement therapy applied alone.
Obesity is an increasing public health problem, with two-thirds of the adult population in many Western countries now being either overweight or obese. Male obesity is associated with late onset hypogonadism, a condition characterised by decreased serum testosterone, sperm quality plus diminished fertility and quality of life. In this paper we propose a novel theory underlying the development of obesity related hypogonadism- the GELDING theory (Gut Endotoxin Leading to a Decline IN Gonadal function). Several observational studies have previously reported an association between obesity related hypogonadism (low testosterone) and systemic inflammation. However, for the first time we postulate that the trans-mucosal passage of bacterial lipopolysaccharide (LPS) from the gut lumen into the circulation is a key inflammatory trigger underlying male hypogonadism. Obesity and a high fat/high calorie diet are both reported to result in changes to gut bacteria and intestinal wall permeability, leading to the passage of bacterial endotoxin (lipopolysaccharide- LPS) from within the gut lumen into the circulation (metabolic endotoxaemia), where it initiates systemic inflammation. Endotoxin is known to reduce testosterone production by the testis, both by direct inhibition of Leydig cell steroidogenic pathways and indirectly by reducing pituitary LH drive, thereby also leading to a decline in sperm production. In this paper we also highlight the novel evolutionary benefits of the GELDING theory. Testosterone is known to be a powerful immune-suppressive, decreasing a man's ability to fight infection. Therefore we postulate that the male reproductive axis has evolved the capacity to lower testosterone production during times of infection and resulting endotoxin exposure, decreasing the immunosuppressive influence of testosterone, in turn enhancing the ability to fight infection. While this response is adaptive in times of sepsis, it becomes maladaptive in the setting of "non
Lunenfeld, B; Saad, F; Hoesl, C E
Prescription sales for testosterone products have substantially increased over the last several years reflecting the growing awareness of physicians for the potential benefits of testosterone replacement therapy in men with hypogonadism. Indiscriminate administration of testosterone poses a risk and has to be deprecated. Testosterone supplementation to treat late-onset hypogonadism (LOH), a term for androgen deficiency in elderly men, is still controversially discussed mainly due to a lack of large, controlled clinical trials on efficacy and safety. To provide guidance for physicians primarily dealing with aging men, ISSAM is periodically updating and publishing its recommendations as new data become available [Morales A, Lunenfeld B. International Society for the Study of the Aging Male. Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. International Society for the Study of the Aging Male. Aging Male 2002;5:74-86 and Morales A, Lunenfeld B. Androgen replacement therapy in aging men with secondary hypogonadism. Draft recommendations for endorsement by ISSAM. Aging Male 2001;4:1]. Following a panel discussion at the 4th ISSAM Congress in Prague in February 2004, the International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM) and the European Association of Urology (EAU) revised existing recommendations on the definition, diagnosis and management of LOH. The recommendations are based on the currently available scientific data on androgen supplementation therapy and should be regarded as provisional until larger-scale, long-term studies are available. While certainly not intending to be exhaustive, this review will highlight some relevant background information and provide the underlying scientific rationale for the ISA, ISSAM and EAU recommendations on LOH published in this issue.
Bardin, C. Wayne; Ross, Griff T.; Rifkind, Arleen B.; Cargille, Charles M.; Lipsett, Mortimer B.
Pituitary and gonadal function was studied in seven chromatin-negative men, ages 15-27 yr, with retarded sexual and somatic development, skeletal anomalies, and hyposmia. These hyposmic patients were compared with normal men, prepuberal boys and hypogonadal patients with hypopituitarism. The urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels of hyposmic subjects were the same as those of normal boys and hypopituitary patients but significantly lower than those of normal men. Clomiphene citrate did not cause an increase in plasma FSH and LH levels in either hypogonadal group as it does in normal men. In contrast to hypopituitary patients, thyroid and adrenocortical function and release of growth hormone in the hyposmic subjects were normal. The plasma testosterone levels were equally low in prepuberal, hypopituitary, and hyposmic patients but were increased to a greater extent by human chorionic gonadotropin (HCG) treatment in prepuberal and hypopituitary subjects than in the hyposmic patients. Prolonged treatment with HCG has failed to return plasma testosterone levels to normal in two hyposmic patients. These observations suggest that there are defects of both pituitary and Leydig cell function in men with the syndrome of hypogonadism, skeletal anomalies, and hyposmia. They have impaired secretion of FSH and LH and a Leydig cell insensitivity to gonadotropin. Images PMID:4390462
Shigehara, Kazuyoshi; Konaka, Hiroyuki; Koh, Eitetsu; Nakashima, Kazufumi; Iijima, Masashi; Nohara, Takahiro; Izumi, Koji; Kitagawa, Yasuhide; Kadono, Yoshifumi; Sugimoto, Kazuhiro; Iwamoto, Teruaki; Mizokami, Atsushi; Namiki, Mikio
We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis. From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n = 35) and control (n = 34) groups. The TRT group was administered 250 mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated. At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0 ± 5.0 vs. 3.0 ± 3.2; p = .0434) and in adiponectin value (-0.90 ± 3.33 vs. 0.10 ± 2.04; p = .0192). There were no significant changes in other parameters. TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis.
Shigehara, Kazuyoshi; Konaka, Hiroyuki; Koh, Eitetsu; Izumi, Koji; Kitagawa, Yasuhide; Mizokami, Atsushi; Nakashima, Takao; Shimamura, Masayoshi; Iwamoto, Teruaki; Namiki, Mikio
We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia. From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n = 31) and controls (n = 33), were included in this analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups. At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group. Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.
Tirabassi, G; delli Muti, N; Buldreghini, E; Lenzi, A; Balercia, G
Little is known about the effect of androgen receptor (AR) gene CAG repeat polymorphism in conditioning body composition changes after testosterone replacement therapy (TRT). In this study, we aimed to clarify this aspect by focussing our attention on male post-surgical hypogonadotropic hypogonadism, a condition often associated with partial or total hypopituitarism. Fourteen men affected by post-surgical hypogonadotropic hypogonadism and undergoing several replacement hormone therapies were evaluated before and after TRT. Dual-energy X-ray absorptiometry (DEXA)-derived body composition measurements, pituitary-dependent hormones and AR gene CAG repeat polymorphism were considered. While testosterone and insulin-like growth factor-1 (IGF-1) levels increased after TRT, cortisol concentration decreased. No anthropometric or body composition parameters varied significantly, except for abdominal fat decrease. The number of CAG triplets was positively and significantly correlated with this abdominal fat decrease, while the opposite occurred between the latter and Δ-testosterone. No correlation of IGF-1 or cortisol variation (Δ-) with Δ-abdominal fat was found. At multiple linear regression, after correction for Δ-testosterone, the positive association between CAG triplet number and abdominal fat change was confirmed. In male post-surgical hypogonadotropic hypogonadism, shorter length of AR CAG repeat tract is independently associated with a more marked decrease of abdominal fat after TRT. Copyright © 2014 Elsevier B.V. All rights reserved.
Salman, Mahmoud; Yassin, Dany-Jan; Shoukfeh, Huda; Nettleship, Joanne Elisabeth; Yassin, Aksam
We and others have previously shown that testosterone replacement therapy (TRT) results in sustained weight loss in the majority of middle-aged hypogonadal men. Previously, however, a small proportion failed to lose at least 5% of their baseline weight. The reason for this is not yet understood. In the present study, we sought to identify early indicators that may predict successful long-term weight loss, defined as a reduction of at least 5% of total body weight relative to baseline weight (T0), in men with hypogonadism undergoing TRT. Eight parameters measured were assessed as potential predictors of sustained weight loss: loss of 3% or more of baseline weight after 1 year of TU treatment, severe hypogonadism, BMI, waist circumference, International Prostate Symptom Score (IPSS), glycated hemoglobin (HbA1C), age and use of vardenafil. Among the eight measured parameters, three factors were significantly associated with sustained weight loss over the entire period of TU treatment: (1) a loss of 3% of the baseline body weight after 1 year of TRT; (2) baseline BMI over 30; and (3) a waist circumference >102 cm. Age was not a predictor of weight loss.
Yassin, A A; Nettleship, J E; Salman, M; Almehmadi, Y
Waist circumference is considered a useful predictor of obesity-associated cardiovascular risk, but its use as an indicator of sexual health status and quality of life (QoL) in hypogonadal men is unknown. We investigated whether three measurements of obesity, weight, body mass index and waist circumference, correlate with the International Index of Erectile Function-5 (IIEF-5), the Aging Males' Symptoms (AMS) and the International Prostate Symptom Score (IPSS) questionnaires. A total of 261 patients were enrolled in a prospective study on hypogonadism treatment with intramuscular long-acting testosterone undecanoate. Patients with total testosterone ≤3.5 ng ml(-1) were enrolled, and baseline demographic data were recorded. Patient's response to IIEF, IPSS and AMS standardised questionnaires was recorded to evaluate health-related QoL. The mean length of treatment and follow-up was 4.7 years (max 6 years). ANOVA regression analysis showed that waist circumference was significantly inversely proportional to IIEF-5 and directly proportional to AMS and IPSS. Weight was inversely proportional to IIEF and directly proportional to IPSS but not associated with AMS. BMI had no proportionality to measurements of sexual function and quality of life. These results suggest that among weight, BMI and waist circumference, the latter is the best predictor of health-related QoL in men with hypogonadism.
Langdahl, Jakob H; Frederiksen, Anja L; Nguyen, Nina; Brusgaard, Klaus; Juhl, Claus B
Boucher Neuhäuser Syndrome (BNS) is a rare clinical syndrome with autosomal recessive inheritance defined by early-onset ataxia, hypogonadism and chorioretinal dystrophy. We present two siblings diagnosed with BNS in late adult life identified with compound heterozygous state of two novel PNPLA6 mutations. Five healthy siblings were non- or heterozygous carriers of the mutations. The cases, which presented with ataxia in childhood and hypogonadotropic hypogonadism (HH), were diagnosed at age 17 and 25, respectively, when examined for delayed puberty. The youngest case, a 55-year old male, was referred to our department in 2006 for evaluation of secondary causes of osteoporosis, which he developed despite adequate testosterone replacement therapy. The unusual medical history with childhood ataxia and hypogonadotropic hypogonadism lead to further examinations and eventually the diagnosis of BNS. The older sister of the proband also displayed the triad of ataxia, HH and chorioretinal dystrophy accompanied by cerebellar atrophy and in 2014, we found the mutations in PNPLA6. BNS is a rare cause of HH and secondary osteoporosis, but should be considered in patients presenting with one or more of the key features. Genetic screening is becoming increasingly available and inexpensive and accordingly this may be considered earlier and by broader indication in unusual phenotypic presentations. The increasing knowledge of causes for inherited diseases should extend the use of genetic screening, as the correct diagnosis will benefit the patients.
Kang, De-Ying; Li, Hong-Jun
Abstract Testosterone replacement therapy is used for the treatment of age-related male hypogonadism, and prostate-specific antigen (PSA) is a primary screening tool for prostate cancer. The systematic review and meta-analysis aimed to determine the effect of testosterone replacement therapy on PSA levels. Medline, Cochrane Library, EMBASE, and Google Scholar databases were searched until February 28, 2014, and inclusion criteria were as follows: randomized controlled trial; intervention group received testosterone/androgen replacement therapy; control group did not receive treatment; and no history of prostate cancer. The primary outcome was change of PSA level between before and after treatment. Secondary outcomes were elevated PSA level after treatment, and the number of patients who developed prostate cancer. After initially identifying 511 articles, 15 studies with a total of 739 patients that received testosterone replacement and 385 controls were included. The duration of treatment ranged from 3 to 12 months. Patients treated with testosterone tended to have higher PSA levels, and thus a greater change than those that received control treatments (difference in means of PSA levels = 0.154, 95% confidence interval [CI] 0.069 to 0.238, P < 0.001). The difference in means of PSA levels were significant higher for patients that received testosterone intramuscularly (IM) than controls (difference in means of PSA levels = 0.271, 95% CI 0.117–0.425, P = 0.001). Elevated PSA levels after treatment were similar between patients that received treatment and controls (odds ratio [OR] = 1.02, 95% CI 0.48–2.20, P = 0.953). Only 3 studies provided data with respect to the development of prostate cancer, and rates were similar between those that received treatment and controls. Testosterone replacement therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given IM and even the increase with IM administration
Smith, J C; Bennett, S; Evans, L M; Kynaston, H G; Parmar, M; Mason, M D; Cockcroft, J R; Scanlon, M F; Davies, J S
Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0
Yin, Anthony; Alfadhli, Eman; Htun, Michelle; Dudley, Robert; Faulkner, Sandra; Hull, Laura; Leung, Andrew; Bross, Rachelle; Longstreth, James; Swerdloff, Ronald; Wang, Christina
This study investigates the effect of dietary fat on the testosterone (T) pharmacokinetics in hypogonadal men following administration of a self-emulsifying capsule formulation of oral T undecanoate (TU). In an open-label, 2-center, 5-way crossover study, a single oral dose of TU containing 300-mg equivalents of T (maximum anticipated human dose per administration) was administered to 16 hypogonadal men with a washout period of at least 5 days between doses. All participants were randomized to receive the TU capsules fasting or 30 minutes after an approximately 800-calorie meal containing 10%, 20%, 30%, or 50% fat. Serial blood samples were collected from 2 hours predose to 25 hours postdose to determine serum T and dihydrotestosterone (DHT) by liquid chromatography tandem mass spectrometry. Administering TU with a meal increased serum T concentrations, with the magnitude of the increase being directly dependent on the amount of fat in the meal. Average and peak serum T concentrations and area under the curve increased as the fat content of the meal was increased. Neither the high-fat meal (50% fat) nor the lower-fat meal (20% fat) showed a significant food effect relative to the normal-fat (Western diet) meal (30% fat). However, administering TU while fasting resulted in 50% or less of the cumulative exposure obtained when administered with 20%- to 50%-fat meals (albeit still substantial). A very-low-fat meal (10% fat) showed a significant food effect relative to the normal meal, but still exceeded the fasting condition by approximately 50%. Serum DHT concentrations showed corresponding increases to the serum T. As expected with the maximum anticipated clinical dose of TU (300 mg T), oral administration of this new formulation with food containing 20% to 50% dietary fat produced T levels at or above the upper range of adult men, and T levels trended higher as dietary fat content increased. Only with a very-low-fat diet (10%) or in a fasted state did a clinically
Yin, Anthony; Alfadhli, Eman; Htun, Michelle; Dudley, Robert; Faulkner, Sandra; Hull, Laura; Leung, Andrew; Bross, Rachelle; Longstreth, James; Swerdloff, Ronald; Wang, Christina
This study investigates the effect of dietary fat on the testosterone (T) pharmacokinetics in hypogonadal men following administration of a self-emulsifying capsule formulation of oral T undecanoate (TU). In an open-label, 2-center, 5-way crossover study, a single oral dose of TU containing 300-mg equivalents of T (maximum anticipated human dose per administration) was administered to 16 hypogonadal men with a washout period of at least 5 days between doses. All participants were randomized to receive the TU capsules fasting or 30 minutes after an approximately 800-calorie meal containing 10%, 20%, 30%, or 50% fat. Serial blood samples were collected from 2 hours predose to 25 hours postdose to determine serum T and dihydrotestosterone (DHT) by liquid chromatography tandem mass spectrometry. Administering TU with a meal increased serum T concentrations, with the magnitude of the increase being directly dependent on the amount of fat in the meal. Average and peak serum T concentrations and area under the curve increased as the fat content of the meal was increased. Neither the high-fat meal (50% fat) nor the lower-fat meal (20% fat) showed a significant food effect relative to the normal-fat (Western diet) meal (30% fat). However, administering TU while fasting resulted in 50% or less of the cumulative exposure obtained when administered with 20%- to 50%-fat meals (albeit still substantial). A very-low-fat meal (10% fat) showed a significant food effect relative to the normal meal, but still exceeded the fasting condition by approximately 50%. Serum DHT concentrations showed corresponding increases to the serum T. As expected with the maximum anticipated clinical dose of TU (300 mg T), oral administration of this new formulation with food containing 20% to 50% dietary fat produced T levels at or above the upper range of adult men, and T levels trended higher as dietary fat content increased. Only with a very-low-fat diet (10%) or in a fasted state did a clinically
Background The CyberKnife is an appealing delivery system for hypofractionated stereotactic body radiation therapy (SBRT) because of its ability to deliver highly conformal radiation therapy to moving targets. This conformity is achieved via 100s of non-coplanar radiation beams, which could potentially increase transitory testicular irradiation and result in post-therapy hypogonadism. We report on our early experience with CyberKnife SBRT for low- to intermediate-risk prostate cancer patients and assess the rate of inducing biochemical and clinical hypogonadism. Methods Twenty-six patients were treated with hypofractionated SBRT to a dose of 36.25 Gy in 5 fractions. All patients had histologically confirmed low- to intermediate-risk prostate adenocarcinoma (clinical stage ≤ T2b, Gleason score ≤ 7, PSA ≤ 20 ng/ml). PSA and total testosterone levels were obtained pre-treatment, 1 month post-treatment and every 3 months thereafter, for 1 year. Biochemical hypogonadism was defined as a total serum testosterone level below 8 nmol/L. Urinary and gastrointestinal toxicity was assessed using Common Toxicity Criteria v3; quality of life was assessed using the American Urological Association Symptom Score, Sexual Health Inventory for Men and Expanded Prostate Cancer Index Composite questionnaires. Results All 26 patients completed the treatment with a median 15 months (range, 13-19 months) follow-up. Median pre-treatment PSA was 5.75 ng/ml (range, 2.3-10.3 ng/ml), and a decrease to a median of 0.7 ng/ml (range, 0.2-1.8 ng/ml) was observed by one year post-treatment. The median pre-treatment total serum testosterone level was 13.81 nmol/L (range, 5.55 - 39.87 nmol/L). Post-treatment testosterone levels slowly decreased with the median value at one year follow-up of 10.53 nmol/L, significantly lower than the pre-treatment value (p < 0.013). The median absolute fall was 3.28 nmol/L and the median percent fall was 23.75%. There was no increase in biochemical hypogonadism
Bauman, W A; Cirnigliaro, C M; La Fountaine, M F; Jensen, A M; Wecht, J M; Kirshblum, S C; Spungen, A M
Men with spinal cord injury are at an increased risk for secondary medical conditions, including metabolic disorders, accelerated musculoskeletal atrophy, and, for some, hypogonadism, a deficiency, which may further adversely affect metabolism and body composition. A prospective, open label, controlled drug intervention trial was performed to determine whether 12 months of testosterone replacement therapy increases lean tissue mass and resting energy expenditure in hypogonadal males with spinal cord injury. Healthy eugonadal (n = 11) and hypogonadal (n = 11) outpatients with chronic spinal cord injury were enrolled. Hypogonadal subjects received transdermal testosterone (5 or 10 mg) daily for 12 months. Measurements of body composition and resting energy expenditure were obtained at baseline and 12 months. The testosterone replacement therapy group increased lean tissue mass for total body (49.6 ± 7.6 vs. 53.1 ± 6.9 kg; p < 0.0005), trunk (24.1 ± 4.1 vs. 25.8 ± 3.8 kg; p < 0.005), leg (14.5 ± 2.7 vs. 15.8 ±2.6 kg; p = 0.005), and arm (7.6 ± 2.3 vs. 8.0 ± 2.2 kg; p < 0.005) from baseline to month 12. After testosterone replacement therapy, resting energy expenditure (1328 ± 262 vs. 1440 ± 262 kcal/d; p < 0.01) and percent predicted basal energy expenditure (73 ± 9 vs. 79 ± 10%; p < 0.05) were significantly increased. In conclusion, testosterone replacement therapy significantly improved lean tissue mass and energy expenditure in hypogonadal men with spinal cord injury, findings that would be expected to influence the practice of clinical care, if confirmed. Larger, randomized, controlled clinical trials should be performed to confirm and extend our preliminary findings. Georg Thieme Verlag KG Stuttgart · NewYork.
Saad, F; Haider, A; Gooren, L
Psoriasis is increasingly recognised as a skin disease with far-reaching systemic effects, associated with a high prevalence of comorbid disease such as cardiometabolic dysfunction, shifting the focus from a single organ disease confined to the skin to a systemic inflammatory condition. Chronic and systemic inflammation plays a major role in the development of these diseases, and there are striking similarities between the molecular and inflammatory pathways in psoriasis and atherosclerosis. In a single-centre, cumulative, prospective registry study of 347 hypogonadal men (total testosterone ≤12.1 nmol l(-1) ), fifteen men with psoriasis could be studied. Upon testosterone administration, the skin disease improved considerably. Scores on the Psoriasis Area and Severity Index and Physician Global Assessment for Psoriasis showed significant improvement for the first 24 months. Thereafter, these improvements were sustained. Upon testosterone treatment, C-reactive protein declined significantly. There were significant improvements of obesity and of lipid profiles. Adipose tissue is now regarded as a source of inflammatory factors. These preliminary results deserve to be studied in a specifically designed study to investigate the effects of testosterone on psoriasis and its associated immunopathology.
Méndez, Juan Pablo; Zenteno, Juan Carlos; Coronel, Agustín; Soriano-Ursúa, Marvin Antonio; Valencia-Villalvazo, Elith Yazmín; Soderlund, Daniela; Coral-Vázquez, Ramón Mauricio; Canto, Patricia
Purpose/aim of the study: To date, different genes have been identified as responsible for the presence of normosmic congenital hypogonadotropic hypogonadism (nCHH). Herein, we report the molecular findings regarding the analysis of PROK2, in two brothers with nCHH. Two siblings with nCHH, in whom mutations in GNRHR, PROKR2 and FGFR1 had been investigated previously, as well as their family were studied. DNA was amplified by PCR and sequenced for the PROK2 gene. Controls were analyzed by restriction fragment-length polymorphism. The structure of PROK2 and its mutant protein were compared using a protein molecular model. Both affected siblings exhibited a heterozygous p.R117W mutation in PROK2, while their mother was a heterozygous carrier and their father, an unaffected brother and their sister were homozygous wild type. Besides, both patients presented a homozygous p.E90K mutation in GNRHR that had been previously reported. We found a novel mutation in PROK2 in two siblings in whom a mutation in the GNRHR gene had been previously reported.
Duvan, Candan İltemir; Pekel, Aslıhan; Ercan, Ummu Gulsum; Arıkan, Yuksel Onaran
This study aimed to report the case of a successful live birth from a woman having oocytes with abnormally large cytoplasmic inclusions. The patient described in this case is a 28 year-old woman with hypogonadotropic hypogonadism (HH) with a history of two previous unsuccessful in vitro fertilization (IVF) attempts offered an antagonist protocol. Stimulation was performed with human menopausal gonadotropin 300 IU/day. The intracytoplasmic sperm injection (ICSI) procedure was performed 4-6 hours after oocyte aspiration for all mature oocytes. Six oocytes were retrieved, five of which mature (MII). All oocytes had abnormal cytoplasmic structures. Two were fertilized after ICSI and two top quality embryos were transferred on Day 2. Our case report suggests that HH patients with refractile bodies/lipofuscin in their oocytes may not have their pregnancies negatively affected. While there have been several reports of successful births from dysmorphic oocytes, no cases of successful pregnancies followed by live births from young women with HH and oocytes with large cytoplasmic inclusions had been reported to date.
Beneduzzi, Daiane; Trarbach, Ericka B; Latronico, Ana Claudia; Mendonca, Berenice Bilharinho de; Silveira, Letícia F G
We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation.
Ohtaka, Kohnosuke; Fujisawa, Yasuko; Takada, Fumio; Hasegawa, Yukihiro; Miyoshi, Tatsuya; Hasegawa, Tomonobu; Miyoshi, Hideaki; Kameda, Hiraku; Kurokawa-Seo, Misuzu; Fukami, Maki; Ogata, Tsutomu
Heterozygous loss-of-function mutations of FGFR1 (fibroblast growth factor receptor 1) cause various disorders including hypogonadotropic hypogonadism with split-hand/foot malformation (HH-SHFM). We examined FGFR1 in four Japanese patients with HH-SHFM (cases 1-4) and the mother of case 4 with HH only. Cases 1 and 2 had heterozygous loss-of-function mutations with no dominant negative effect (c.289G>A, p.[G97S]; and c.2231G>C, p.[R744T]), and case 3 had a splice donor site mutation (c.1663+1G>T). Notably, case 4 had a maternally inherited 8,312 bp microdeletion that involved noncoding exon 1U and impaired FGFR1 expression. Furthermore, consistent with the presence of transcription-related histone marks (e.g., H3K4Me3, H3K4Me1, and H3K27Ac) and multiple transcription factor-binding sites around exon 1U, functional studies demonstrated a marked transactivation function of a 414-bp segment harboring the transcription start site. These results support the relevance of FGFR1 mutations to HH-SHFM, and argue for the presence of the FGFR1 core-promoter elements around exon 1U.
Korematsu, Seigo; Uchiyama, Shin-ichi; Honda, Akira; Izumi, Tatsuro
Cholesterol is one of the main components of human cell membranes and constitutes an essential substance in the central nervous system, endocrine system, and its hormones, including sex hormones. A 19-year-old male patient presented with failure to thrive, psychomotor deterioration, intractable epilepsy, hypogonadism, and cerebro-cerebello-bulbar degeneration. His serum level of cholesterol was low, ranging from 78.7 to 116.5 mg/dL. The serum concentrations of intermediates in the cholesterol biosynthesis pathway, such as 7-dehydrocholesterol, 8-dehydrocholesterol, desmosterol, lathosterol, and dihydrolanosterol, were not increased. In addition, the levels of the urinary cholesterol biosynthesis marker mevalonic acid, the serum cholesterol absorption markers, campesterol and sitosterol, and the serum cholesterol catabolism marker, 7α-hydroxycholesterol, were all low. A serum biomarker analysis indicated that the patient's basic abnormality differed from that of Smith-Lemli-Opitz syndrome and other known disorders of cholesterol metabolism. Therefore, this individual may have a new metabolic disorder with hypocholesterolemia because of decreased biosynthesis and absorption of cholesterol. Copyright © 2014 Elsevier Inc. All rights reserved.
Miller, Christopher M.; Rindflesch, Thomas C.; Fiszman, Marcelo; Hristovski, Dimitar; Shin, Dongwook; Rosemblat, Graciela; Zhang, Han; Strohl, Kingman P.
Study Objectives: Sleep quality commonly diminishes with age, and, further, aging men often exhibit a wider range of sleep pathologies than women. We used a freely available, web-based discovery technique (Semantic MEDLINE) supported by semantic relationships to automatically extract information from MEDLINE titles and abstracts. Design: We assumed that testosterone is associated with sleep (the A-C relationship in the paradigm) and looked for a mechanism to explain this association (B explanatory link) as a potential or partial mechanism underpinning the etiology of eroded sleep quality in aging men. Measurements and Results: Review of full-text papers in critical nodes discovered in this manner resulted in the proposal that testosterone enhances sleep by inhibiting cortisol. Using this discovery method, we posit, and could confirm as a novel hypothesis, cortisol as part of a mechanistic link elucidating the observed correlation between decreased testosterone in aging men and diminished sleep quality. Conclusions: This approach is publically available and useful not only in this manner but also to generate from the literature alternative explanatory models for observed experimental results. Citation: Miller CM; Rindflesch TC; Fiszman M; Hristovski D; Shin D; Rosemblat G; Zhang H; Strohl KP. A closed literature-based discovery technique finds a mechanistic link between hypogonadism and diminished sleep quality in aging men. SLEEP 2012;35(2):279-285. PMID:22294819
Yarrow, Joshua F.; Conover, Christine F.; Nseyo, Unyime; Meuleman, John R.; Lipinska, Judyta A.; Braith, Randy W.; Beck, Darren T.; Martin, Jeffrey S.; Morrow, Matthew; Roessner, Shirley; Beggs, Luke A.; McCoy, Sean C.; Cannady, Darryl F.; Shuster, Jonathan J.
Testosterone acts directly at androgen receptors and also exerts potent actions following 5α-reduction to dihydrotestosterone (DHT). Finasteride (type II 5α-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men could produce musculoskeletal benefits without prostate enlargement. Sixty men aged ≥60 yr with a serum testosterone concentration of ≤300 ng/dl or bioavailable testosterone ≤70 ng/dl received 52 wk of treatment with testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8–14% (P = 0.015 to <0.001), fat-free mass 4.04 kg (P = 0.032), lumbar spine bone mineral density (BMD) 4.19% (P < 0.001), and total hip BMD 1.96% (P = 0.024) while reducing total body fat −3.87 kg (P < 0.001) and trunk fat −1.88 kg (P = 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P < 0.001). Coadministration of finasteride did not alter any of these effects. Over 12 mo, testosterone also increased prostate volume 11.4 cm3 (P = 0.0051), an effect that was completely prevented by finasteride (P = 0.0027). We conclude that a higher-than-replacement TE combined with finasteride significantly increases muscle strength and BMD and reduces body fat without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement but is not required for benefits in musculoskeletal or adipose tissue. PMID:24326421
Calderón, Berniza; Galdón, Alba; Calañas, Alfonso; Peromingo, Roberto; Galindo, Julio; García-Moreno, Francisca; Rodriguez-Velasco, Gloria; Martín-Hidalgo, Antonia; Vazquez, Clotilde; Escobar-Morreale, Héctor F; Botella-Carretero, José I
Bariatric surgery results in the complete resolution of male obesity-associated secondary hypogonadism (MOSH) in many patients. However, the effects of different bariatric surgical procedures on male sexual hormone profiles and sexual dysfunction have not been compared to date. We compared the pre- and post-operative (at least 6 months after initial surgery) sex hormone profiles of 20 severely obese men submitted to laparoscopic gastric bypass (LGB) with 15 similar patients submitted to restrictive techniques (sleeve gastrectomy in 10 and adjustable gastric banding in 5). We calculated free testosterone (FT) levels from total testosterone (TT) and sex hormone binding globulin (SHBG) concentrations. Fasting glucose and insulin levels served for homeostatic model assessment of insulin resistance (HOMAIR). MOSH was present in 25 and 16 of the 35 patients when considering TT and FT concentrations respectively, resolving after surgery in all but one of them. When considering all obese men as a whole, patients submitted to LGB or restrictive procedures did not differ in terms of excess weight loss, in the decrease of fasting glucose and insulin, HOMAIR and waist circumference, or in the increase of serum 25-hydroxyvitamin D, TT and FT levels. The improvement in TT correlated with the decrease in fasting glucose (r = -0.390, P = 0.021), insulin (r = -0.425, P = 0.015) and HOMAIR (r = -0.380, P = 0.029), and with the increase in SHBG (r = 0.692, P < 0.001). The increase in FT correlated with the decrease in fasting glucose (r = -0.360, P = 0.034). LGB and restrictive techniques are equally effective in producing a remission of MOSH.
Calderón, Berniza; Gómez-Martín, Jesús M; Vega-Piñero, Belén; Martín-Hidalgo, Antonia; Galindo, Julio; Luque-Ramírez, Manuel; Escobar-Morreale, Héctor F; Botella-Carretero, José I
To study the prevalence of male obesity-secondary hypogonadism (MOSH) in patients with moderate to severe obesity, we performed a prospective prevalence study including 100 male patients with moderate to severe obesity at a university tertiary hospital. Total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations among others were assayed in all patients. Serum-free testosterone (FT) concentration was calculated from TT and SHBG levels. Semen analysis was conducted in 31 patients. We found a prevalence of 45% (95% CI: 35-55%) when considering decreased TT and/or FT concentrations. Serum concentrations of TT were correlated negatively with glucose (r = -0.328, p < 0.001) and insulin resistance (r = -0.261, p = 0.011). The same occurred with FT and glucose (r = -0.340, p < 0.001) and insulin resistance (r = -0.246, p = 0.016). Sixty-two percent (95% CI: 39-85%) of the patients with seminogram also presented abnormal results in semen analysis. The frequencies of low TT or low FT values were similar in patients with abnormal or normal semen analysis (p = 0.646 and p = 0.346, respectively). Ejaculate volume inversely correlated with BMI (ρ = -0.400, p = 0.029) and with excess body weight (ρ = -0.464, p = 0.010). Our data show the prevalence of MOSH in patients with moderate to severe obesity is high. Low circulating testosterone is associated with insulin resistance and low ejaculate volume with higher BMI and excess body weight. Semen analysis must be performed in these patients when considering fertility whether or not presenting low circulating testosterone. © 2015 American Society of Andrology and European Academy of Andrology.
Borst, Stephen E; Yarrow, Joshua F; Conover, Christine F; Nseyo, Unyime; Meuleman, John R; Lipinska, Judyta A; Braith, Randy W; Beck, Darren T; Martin, Jeffrey S; Morrow, Matthew; Roessner, Shirley; Beggs, Luke A; McCoy, Sean C; Cannady, Darryl F; Shuster, Jonathan J
Testosterone acts directly at androgen receptors and also exerts potent actions following 5α-reduction to dihydrotestosterone (DHT). Finasteride (type II 5α-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men could produce musculoskeletal benefits without prostate enlargement. Sixty men aged ≥60 yr with a serum testosterone concentration of ≤300 ng/dl or bioavailable testosterone ≤70 ng/dl received 52 wk of treatment with testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8-14% (P = 0.015 to <0.001), fat-free mass 4.04 kg (P = 0.032), lumbar spine bone mineral density (BMD) 4.19% (P < 0.001), and total hip BMD 1.96% (P = 0.024) while reducing total body fat -3.87 kg (P < 0.001) and trunk fat -1.88 kg (P = 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P < 0.001). Coadministration of finasteride did not alter any of these effects. Over 12 mo, testosterone also increased prostate volume 11.4 cm(3) (P = 0.0051), an effect that was completely prevented by finasteride (P = 0.0027). We conclude that a higher-than-replacement TE combined with finasteride significantly increases muscle strength and BMD and reduces body fat without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement but is not required for benefits in musculoskeletal or adipose tissue.
Trabado, Séverine; Lamothe, Sophie; Maione, Luigi; Bouvattier, Claire; Sarfati, Julie; Brailly-Tabard, Sylvie; Young, Jacques
Men with Kallmann syndrome (KS) and those with congenital isolated hypogonadotropic hypogonadism with normal olfaction share a chronic, usually profound deficit, in FSH and LH, the two pituitary gonadotropins. Many studies indicate that this gonadotropin deficiency is already present during fetal life, thus explaining the micropenis, cryptorchidism and marked testicular hypotrophy already present at birth. In addition, neonatal activation of gonadotropin secretion is compromised in boys with severe CHH/Kallmann, preventing the first phase of postnatal testicular activation. Finally, CHH is characterized by the persistence, in the vast majority of cases, of gonadotropin deficiency at the time of puberty and during adulthood. This prevents the normal pubertal testicular reactivation required for physiological sex steroid and testicular peptide production, and for spermatogenesis. CHH/KS thus represents a pathological paradigm that can help to unravel, in vivo, the role of each gonadotropin in human testicular exocrine and endocrine functions at different stages of development. Recombinant gonadotropins with pure LH or FSH activity have been used to stimulate Leydig's cells and Sertoli's cells, respectively, and thereby to clarify their paracrine interaction in vivo. The effects of these pharmacological probes can be assessed by measuring the changes they provoke in circulating testicular hormone concentrations. This review discusses the impact of chronic gonadotropin deficiency on the endocrine functions of the interstitial compartment, which contains testosterone-, estradiol- and INSL3-secreting Leydig's cells. It also examines the regulation of inhibin B and anti-Mullerian hormone (AMH) secretion in the seminiferous tubules, and the insights provided by studies of human testicular stimulation with recombinant gonadotropins, used either individually or in combination.
Dhindsa, Sandeep; Ghanim, Husam; Batra, Manav; Kuhadiya, Nitesh D.; Abuaysheh, Sanaa; Sandhu, Sartaj; Green, Kelly; Makdissi, Antoine; Hejna, Jeanne; Chaudhuri, Ajay; Punyanitya, Mark
OBJECTIVE One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. RESEARCH DESIGN AND METHODS A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. RESULTS Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (−3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all). CONCLUSIONS Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat. PMID:26622051
Dhindsa, Sandeep; Ghanim, Husam; Batra, Manav; Kuhadiya, Nitesh D; Abuaysheh, Sanaa; Sandhu, Sartaj; Green, Kelly; Makdissi, Antoine; Hejna, Jeanne; Chaudhuri, Ajay; Punyanitya, Mark; Dandona, Paresh
One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all). Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Versiani, Beatriz R; Trarbach, Ericka; Koenigkam-Santos, Marcel; Dos Santos, Antonio Carlos; Elias, Lucila L K; Moreira, Ayrton C; Latronico, Ana Claudia; de Castro, Margaret
The pathogenesis of idiopathic hypogonadotrophic hypogonadism (IHH) is mostly unclear. We characterized the clinical findings and molecular analysis of GnRHR and KAL1 genes in 26 Brazilian males with IHH with and without hyposmia/anosmia. Design Clinical assessment was performed for endocrine status, olfactory structure and function, renal lesion, and mirror movement. The diagnosis of Kallmann syndrome (KS) included HH and the clinical complaint of hyposmia/anosmia or decreased olfactory acuity obtained by the Smell Identification Test (SIT). We analysed GnRHR and KAL1 genes using the polymerase chain reaction (PCR) direct sequencing method. A variable degree of HH was observed, including various clinical abnormalities, such as cryptorchidism, hearing loss, strabismus, cleft lip/palate, high-arched palate, dental agenesis, psychiatric disorders, learning dysfunction, and bimanual synkinesia. Twenty-two out of 26 patients with IHH (85%) were classified as KS. Abnormalities of olfactory bulbs/sulci were observed in 79% of KS patients. One-third of KS patients had renal defects and 45.5% had a positive family history. GnRHR gene sequence analysis showed no mutations. KAL1 sequence analysis identified two novel missense mutations: c.1061A to G in exon 7 (N304S) and c.1583C to A in exon 10 (S478X). We also observed a 14-bp deletion within exon 11 that caused a premature termination. According to the National Center for Biotechnology Information (NCBI)-Single Nucleotide Polymorphism (SNP) database, two previously described polymorphisms (rs808119 and rs809446) were detected. KAL1 mutations accounted for 12% of KS patients. This low prevalence of KAL1 mutations indicates that other genes, such as the fibroblast growth factor receptor 1 (FGFR1) gene or other as yet undiscovered genes, epigenetic events and/or environmental factors might be involved in the aetiology and phenotypic variability of KS.
Sukumar, Suja P; Bhansali, Anil; Sachdeva, Naresh; Ahuja, Chirag Kamal; Gorsi, Ujjwal; Jarial, Kush Dev Singh; Walia, Rama
Differentiation between constitutional delay in puberty (CDP) and isolated hypogonadotropic hypogonadism (IHH) during adolescence is a great clinical challenge, and the available diagnostic tests are of limited value. To study the effect of withdrawal of short-term, low-dose testosterone therapy (testosterone priming) on the discriminatory power of dynamic tests for hypothalamo-pituitary-testicular axis to differentiate CDP from IHH. A prospective study (n = 30) consisting of 20 boys with delayed puberty (group A) and 10 patients with IHH (group B). Patients in groups A and B underwent Triptorelin and hCG stimulation tests, prior to and 2 months after withdrawal of 'testosterone priming' (100 mg intramuscularly 4 weekly for 3 months) and were followed up until the onset of puberty or 18 years of age, whichever was earlier. At baseline, Triptorelin-stimulated 4 h LH, with a cut-off of 2·8 IU/l, and hCG-stimulated day 7 testosterone with a cut-off of 3·8 nmol/l had sensitivities of 80% each, and specificities of 93% and 87%, respectively, to diagnose CDP. After withdrawal of testosterone, a 4 h LH cut-off of 14·7 IU/l and day 7 testosterone cut-off of 10·3 nmol/l had sensitivities of 93% and 88% respectively, and specificity and positive predictive value of 100% each. A basal inhibin B > 94·7 ng/l was discriminatory for diagnosing CDP after withdrawal of testosterone priming. Inhibin B levels or 4 h LH after Triptorelin stimulation are the best discriminatory tests to differentiate CDP from IHH, when performed after withdrawal of 'testosterone priming'. © 2017 John Wiley & Sons Ltd.
Gill, John C; Wang, Oulu; Kakar, Shelley; Martinelli, Enzo; Carroll, Rona S; Kaiser, Ursula B
Kisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to
de Smith, Adam J.; Purmann, Carolin; Walters, Robin G.; Ellis, Richard J.; Holder, Susan E.; Van Haelst, Mieke M.; Brady, Angela F.; Fairbrother, Una L.; Dattani, Mehul; Keogh, Julia M.; Henning, Elana; Yeo, Giles S.H.; O'Rahilly, Stephen; Froguel, Philippe; Farooqi, I. Sadaf; Blakemore, Alexandra I.F.
Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader–Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a ∼187 kb microdeletion at chromosome 15q11–13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11–13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11–13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction. PMID:19498035
Tancredi, Annalisa; Reginster, Jean-Yves; Schleich, Florence; Pire, Georges; Maassen, Philippe; Luyckx, Francoise; Legros, Jean-Jacques
To date, serum free testosterone measurement is considered to be the gold standard for the diagnosis of hypogonadism in elderly males but it is not available to all subjects suspected of a decrease in testicular function. Therefore, we evaluated whether the Androgen Deficiency in Aging Males (ADAM) questionnaire, in its original or in a modified 'quantitative' version (qADAM), could be used as a surrogate to biochemical determinations for the identification of hypogonadism in elderly males. 5028 men, aged 50-70 years, spontaneously consulting for the assessment of their gonadal function were studied. ADAM and qADAM, allocating a value of 1 point for any positive answer to each of the 10 questions of the ADAM test, were assessed for their ability to discriminate between males with free testosterone levels below or above 70 ng/l. The sensitivity and specificity of the ADAM score were 81% and 21.6% respectively. The use of ADAM resulted in an appropriate classification of our population in normal or hypogonadal subjects in 44.5% of the cases. The area under the receiver operating characteristics (ROC) curve for the qADAM (0.529) revealed a highly marginal interest of this quantitative approach compared with the original scoring system. The ADAM test has a high sensitivity to identify aging males with low free testosterone levels. However, due to its lack of specificity, this test cannot be used as a surrogate to serum free testosterone testing for the identification of androgen deficiency in elderly, community-dwelling males.
Tirabassi, Giacomo; Delli Muti, Nicola; Corona, Giovanni; Maggi, Mario; Balercia, Giancarlo
Few and contradictory studies have evaluated the possible influence of androgen receptor (AR) gene CAG repeat polymorphism on male sexual function. In this study we evaluated the role of AR gene CAG repeat polymorphism in the recovery of sexual function after testosterone replacement therapy (TRT) in men affected by postsurgical hypogonadotropic hypogonadism, a condition which is often associated with hypopituitarism and in which the sexual benefits of TRT must be distinguished from those of pituitary-function replacement therapies. Fifteen men affected by postsurgical hypogonadotropic hypogonadism were retrospectively assessed before and after TRT. Main outcome measures included sexual parameters as assessed by the International Index of Erectile Function questionnaire, levels of pituitary dependent hormones (total testosterone, free T3, free T4, cortisol, insulin-like growth factor-1 [IGF-1], prolactin), and results of genetic analysis (AR gene CAG repeat number). Plasma concentrations of free T3, free T4, cortisol, and prolactin did not vary significantly between the two phases, while testosterone and IGF-1 increased significantly after TRT. A significant improvement in all sexual parameters studied was found. The number of CAG triplets was negatively and significantly correlated with changes in all the sexual parameters, while opposite correlations were found between changes in sexual parameters and changes in testosterone levels; no correlation of change in IGF1 with change in sexual parameters was reported. On multiple linear regression analysis, after correction for changes in testosterone, nearly all the associations between the number of CAG triplets and changes in sexual parameters were confirmed. Shorter length AR gene CAG repeat number is associated with the recovery of sexual function after TRT in postsurgical male hypogonadotropic hypogonadism, independently of the effects of concomitant pituitary-replacement therapies. © 2014 International Society
Lašaitė, L; Čeponis, J; Preikša, R T; Žilaitienė, B
The aim of the study was to examine the effects of two-year testosterone replacement therapy on cognitive functioning, emotional state and quality of life in young and middle-aged men with hypogonadotropic hypogonadism. Nineteen males diagnosed with hypogonadotropic hypogonadism participated in the study. Cognitive functions were assessed by Trail Making Test and Digit Span Test of Wechsler Adult Intelligence Scale. Emotional state was evaluated by Profile of Mood States. Quality of life was evaluated by WHO Brief Quality of Life Questionnaire. Changes after two-year testosterone replacement therapy were detected in Trail Making A (42.9 ± 22.3 vs. 36.2 ± 22.5, p = .050) and B (90.6 ± 55.3 vs. 65.6 ± 21.4, p = .025) tests, showing improvement in attention and visual scanning abilities, executive function and psychomotor speed, as well as in Digit Span Test forward score (5.4 ± 2.0 vs. 6.1 ± 2.6, p = .046), showing improvement in attention capacity and psychomotor speed. No significant differences were observed in emotional state and quality of life. In conclusion, beneficial effect in cognitive functioning (improved attention and visual scanning ability, executive function and psychomotor speed), but not in emotional state and quality of life, was observed in young and middle-aged hypogonadal men after two-year testosterone replacement therapy. © 2016 Blackwell Verlag GmbH.
Cai, Xiang; Tian, Ye; Wu, Tao; Cao, Chen-Xi; Li, Hong; Wang, Kun-Jie
This systematic review was aimed at assessing the metabolic effects of testosterone replacement therapy (TRT) on hypogonadal men with type 2 diabetes mellitus (T2DM). A literature search was performed using the Cochrane Library, EMBASE and PubMed. Only randomized controlled trials (RCTs) were included in the meta-analysis. Two reviewers retrieved articles and evaluated the study quality using an appropriate scoring method. Outcomes including glucose metabolism, lipid parameters, body fat and blood pressure were pooled using a random effects model and tested for heterogeneity. We used the Cochrane Collaboration's Review Manager 5.2 software for statistical analysis. Five RCTs including 351 participants with a mean follow-up time of 6.5-months were identified that strictly met our eligibility criteria. A meta-analysis of the extractable data showed that testosterone reduced fasting plasma glucose levels (mean difference (MD): −1.10; 95% confidence interval (CI) (−1.88, −0.31)), fasting serum insulin levels (MD: −2.73; 95% CI (−3.62, −1.84)), HbA1c % (MD: −0.87; 95% CI (−1.32, −0.42)) and triglyceride levels (MD: −0.35; 95% CI (−0.62, −0.07)). The testosterone and control groups demonstrated no significant difference for other outcomes. In conclusion, we found that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM. Considering the limited number of participants and the confounding factors in our systematic review; additional large, well-designed RCTs are needed to address the metabolic effects of TRT and its long-term influence on hypogonadal men with T2DM. PMID:24369149
Cai, Xiang; Tian, Ye; Wu, Tao; Cao, Chen-Xi; Li, Hong; Wang, Kun-Jie
This systematic review was aimed at assessing the metabolic effects of testosterone replacement therapy (TRT) on hypogonadal men with type 2 diabetes mellitus (T2DM). A literature search was performed using the Cochrane Library, EMBASE and PubMed. Only randomized controlled trials (RCTs) were included in the meta-analysis. Two reviewers retrieved articles and evaluated the study quality using an appropriate scoring method. Outcomes including glucose metabolism, lipid parameters, body fat and blood pressure were pooled using a random effects model and tested for heterogeneity. We used the Cochrane Collaboration's Review Manager 5.2 software for statistical analysis. Five RCTs including 351 participants with a mean follow-up time of 6.5-months were identified that strictly met our eligibility criteria. A meta-analysis of the extractable data showed that testosterone reduced fasting plasma glucose levels (mean difference (MD): -1.10; 95% confidence interval (CI) (-1.88, -0.31)), fasting serum insulin levels (MD: -2.73; 95% CI (-3.62, -1.84)), HbA1c % (MD: -0.87; 95% CI (-1.32, -0.42)) and triglyceride levels (MD: -0.35; 95% CI (-0.62, -0.07)). The testosterone and control groups demonstrated no significant difference for other outcomes. In conclusion, we found that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM. Considering the limited number of participants and the confounding factors in our systematic review; additional large, well-designed RCTs are needed to address the metabolic effects of TRT and its long-term influence on hypogonadal men with T2DM.
Tirabassi, G; Chelli, F M; Ciommi, M; Lenzi, A; Balercia, G
Functional hypercortisolism (FH) is generated by clinical states able to chronically activate the hypothalamic-pituitary-adrenal (HPA) axis [e.g. diabetes mellitus (DM)]. No study has evaluated FH influence in worsening the metabolic profile of male patients affected by DM-associated hypogonadism. In this retrospective work, we assess the possible association between HPA axis-dysregulation and cardiovascular risk factors in men simultaneously affected by DM and late-onset hypogonadism (LOH). Fourteen DM and LOH subjects affected by FH (Hypercort-DM-LOH) and fourteen DM and LOH subjects who were not suffering from FH (Normocort-DM-LOH) were retrospectively considered. Clinical, hormonal and metabolic parameters were retrieved. All metabolic parameters, except for systolic blood pressure, were significantly worse in Hypercort-DM-LOH than in Normocort-DM-LOH. After adjustment for body mass index, waist and total testosterone, Hypercort-DM-LOH subjects showed significantly worse metabolic parameters than Normocort-DM-LOH ones. In Normocort-DM-LOH, no significant correlation between general/hormonal parameters and metabolic variables was present. In Hypercort-DM-LOH, positive and significant correlations of cortisol area under the curve (AUC) after corticotropin releasing hormone with glycemia, triglycerides and blood pressure were evident; on the other hand, negative and significant correlation was present between cortisol AUC and high density lipoprotein (HDL) cholesterol. The associations of AUC cortisol with glycemia, HDL cholesterol and diastolic blood pressure (DBP) were further confirmed at quantile regression after adjustment for therapy. FH may determine a worsening of the metabolic profile in DM-associated hypogonadism. Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by
Francomano, D; Bruzziches, R; Barbaro, G; Lenzi, A; Aversa, A
Modifications of cardiovascular and metabolic parameters during testosterone (T) replacement and withdrawal have never been investigated in severely obese hypogonadal men. Twenty-four severely obese (mean BMI 42; mean age 54.5) hypogonadal men (mean T = 245 ± 52 ng/dL) were enrolled in an observational, parallel-arm, open-label, 54-week study of hypocaloric diet plus physical activity (DPE; n = 12) or DPE plus T injections (DPE + T; n = 12), followed by 24 weeks of DPE alone. Primary endpoints were variations from baseline of cardiovascular (cardiac performance, blood pressure, endothelial function, carotid intima-media thickness, CIMT; epicardial fat thickness, EF) and body composition (fat/lean mass) parameters. Secondary endpoints were variations from baseline of hormonal (T and GH) and metabolic (oral glucose tolerance test, lipids, fibrinogen) parameters. At 54 weeks, DPE + T showed improvements in EF, ejection fraction, diastolic function, CIMT and endothelial function (p < 0.01 vs. controls). Also, hormonal (T, p < 0.0001; GH, p < 0.01), metabolic (HOMA, p < 0.01; microalbuminuria, p < 0.01), lipid (total cholesterol, p < 0.05) and inflammatory (fibrinogen, p < 0.05) parameters improved. After 24 weeks from T withdrawal, all cardiac and hormonal parameters returned to baseline, while fat but not lean mass and blood pressure ameliorations were maintained. An inverse relationship either between EF vs. endothelial function and EF vs. T levels was found (r (2) = -0.46, p < 0.001 and r (2) = -0.56, p < 0.0005, respectively) while direct relationship between T vs. endothelial function occurred (r (2) = 0.43, p < 0.005) in DPE + T. A 33 % dropout rate was reported in DPE without serious adverse events. In middle-aged hypogonadal obese men, 1-year T treatment was safe and improved cardio-metabolic and hormonal parameters. We firstly demonstrated that T withdrawal determines a return back to hypogonadism within 6 months, with loss of cardiovascular and some body
Debruyne, Frans M J; Behre, Hermann M; Roehrborn, Claus G; Maggi, Mario; Wu, Frederick C W; Schröder, Fritz H; Jones, Thomas Hugh; Porst, Hartmut; Hackett, Geoffrey; Wheaton, Olivia A; Martin-Morales, Antonio; Meuleman, Eric; Cunningham, Glenn R; Divan, Hozefa A; Rosen, Raymond C
To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time. The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS. Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men. Results support prostate safety of TRT in newly diagnosed men with HG. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.
Nielsen, J; Pelsen, B
A 20-year follow-up study of 50 hypogonadal males has been made. Of these 34 had Klinefelter's syndrome with the karyotype 47,XXY and 16 had the karyotype 46,XY. These males have been examined at mean ages of 27 and 37 and in the present study at a mean age of 47. At the first examination the following conditions were found in the Klinefelter males to a significantly higher degree than in the hypogonadal males with 46,XY: immaturity, below average school performance, few or no friends, previous mental illness, little energy and initiative, few or no spare time interests, occupation as an unskilled labourer. Psychological testing showed a full scale IQ of 103 in the Klinefelter males and 115 in the hypogonadal males. The follow-up studies have shown that in spite of these findings the Klinefelter males have managed far better than could have been expected at the time of the first investigation. The improvement in a number of conditions such as mental health, working capacity, social adjustment, relations with other people, and activity level was considerable between the ages of 27 and 37. The present examination shows a further improvement at the age of 47 with the only significant difference between the Klinefelter males and the hypogonadal males with 46,XY being a higher frequency of single Klinefelter males. The present examination also showed that there was no significant difference between the two groups in occupation, working capacity, social adjustment, mental and physical disorders or criminality. The results of the examination at the mean age of 27 would probably have been considerably more favourable for the Klinefelter males if diagnosis had been made in childhood, and information, counselling, support and hormone treatment had been given from an early age. The fact that the great majority of the Klinefelter males have managed quite well in spite of this and that no remarkable differences were found between them and a control group is of great importance
Corrales, J J; Almeida, M; Martín-Martín, L; Miralles, J M; Orfao, A
Accumulated experimental data indicates that androgen therapy has effects on inflammation and protects from autoimmune disorders. Despite this, the in vivo effects of testosterone replacement therapy on human antigen-presenting cells-for example, monocytes and dendritic cells- remain unknown. We monitored the effects of testosterone replacement therapy on the number and the functionality -as assessed by the expression of CD107b (lysosome-associated membrane protein 2, LAMP-2)- of resting and in vitro-stimulated peripheral blood (classical and nonclassical) monocytes and dendritic cells (myeloid and plasmacytoid) from hypogonadal men. Our results show that testosterone replacement therapy induces overexpression of CD107b by circulating monocytes and dendritic cells from hypogonadal men, both under resting (i.e. nonstimulated) conditions and after in vitro stimulation. CD107b overexpression mostly involved monocytes and in vitro stimulation with CpG oligodeoxynucleotides. Of note, a strong correlation was found between CD107b expression on monocytes and serum gonadotrophins levels. These results support the existence of an effect of testosterone therapy, and potentially also of gonadotrophins, on circulating antigen-presenting cells. © 2013 John Wiley & Sons Ltd.
Tambi, M I B M; Imran, M K; Henkel, R R
In most countries, millions of people are relying on herbal medicines as remedy for numerous ailments. In South-East Asia, Eurycoma longifolia Jack, also known as 'Malaysian ginseng' or Tongkat ali, is used to combat stress and disease and to improve physical strength. Moreover, the compounds of the roots of this plant are reported to have aphrodisiac and testosterone enhancing effects in the rat. Considering that human studies are not available, 76 of 320 patients suffering from late-onset hypogonadism (LOH) were given 200 mg of a standardised water-soluble extract of Tongkat ali for 1 month. The Ageing Males' Symptoms (AMS) according to the standardised rating scale and the serum testosterone concentration were taken. Results show that treatment of LOH patients with this Tongkat ali extract significantly (P < 0.0001) improved the AMS score as well as the serum testosterone concentration. While before treatment only 10.5% of the patients did not show any complaint according to the AMS scale and 35.5% had normal testosterone levels, after the completed treatment 71.7% and 90.8% of the patients showed normal values, respectively. Thus, Tongkat ali extract appears to be useful as a supplement in overcoming the symptoms of LOH and for the management of hypogonadism.
Meitinger, T; Heye, B; Petit, C; Levilliers, J; Golla, A; Moraine, C; Dalla Piccola, B; Sippell, W G; Murken, J; Ballabio, A
Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism and anosmia. Six families in which the disorder followed an X-linked inheritance were investigated by linkage analysis. Diagnostic criteria were uniformly applied and included tests for hypogonadotropic hypogonadism and anosmia. Close linkage was found by using the hypervariable repeated sequence CRI-S232 (DXS278) previously mapped to Xp22.3. At a maximum lod score of 6.5, the recombination fraction was calculated as .03. Of 30 fully informative meioses, one recombination between the disease locus and the loci recognized by probe CRI-S232 was observed. When an independent approach is used, these results confirm the X-linked Kallmann syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome to the Xp22.3 region. This opens the way to carrier detection and to the identification of a gene responsible for this disorder. Images Figure 2 PMID:1977309
Sato, Naoko; Hasegawa, Tomonobu; Hasegawa, Yukihiro; Arisaka, Osamu; Ozono, Keiichi; Amemiya, Shin; Kikuchi, Toru; Tanaka, Hiroyuki; Harada, Shohei; Miyata, Ichiro; Tanaka, Toshiaki
Abstract Male hypogonadotropic hypogonadism (MHH), a disorder associated with infertility, is treated with testosterone replacement therapy (TRT) and/or gonadotropins replacement therapy (GRT) (TRT and GRT, together with HRT hormone replacement therapy). In Japan, guidelines have been set for treatment during adolescence. Due to the risk of rapid maturation of bone age, low doses of testosterone or gonadotropins have been used. However, the optimal timing and methods of therapeutic intervention have not yet been established. The objective of this study was to investigate the current situation of treatment for children with MHH in Japan and to review a primary survey involving councilors of the Japanese Society for Pediatric Endocrinology and a secondary survey obtained from 26 facilities conducting HRT. The subjects were 55 patients with MHH who reached their adult height after HRT. The breakdown of the patients is as follows: 7 patients with Kallmann syndrome, 6 patients with isolated gonadotropin deficiency, 18 patients with acquired hypopituitarism due to intracranial and pituitary tumor, 22 patients with classical idiopathic hypopituitarism due to breech delivery, and 2 patients with CHARGE syndrome. The mean age at the start of HRT was 15.7 yrs and mean height was 157.2 cm. The mean age at reaching adult height was 19.4 yrs, and the mean adult height was 171.0 cm. The starting age of HRT was later than the normal pubertal age and showed a significant negative correlation with pubertal height gain, but it showed no correlation with adult height. As for spermatogenesis, 76% of the above patients treated with hCG-rFSH combined therapy showed positive results, though ranging in levels; impaired spermatogenesis was observed in some with congenital MHH, and favorable spermatogenesis was observed in all with acquired MHH. From the above, we propose the establishment of a treatment protocol for the start low-dose testosterone or low-dose gonadotropins by dividing
Zhang, Li Tao; Shin, Yu Seob; Kim, Ji Yong; Park, Jong Kwan
In this study we investigated if testosterone undecanoate attenuates anemia and the risk of cardiovascular disease in patients with hypogonadism. A registry study consisted of 58 participants with a subnormal total testosterone level (less than 2.35 ng/ml) and at least mild symptoms of testosterone deficiency. All patients received an injection of 1,000 mg testosterone undecanoate at the initial visit, followed by injection at 6, 18, 30, 42 and 54 weeks. Serum hormones, hemoglobin, hematocrit, anemia risk factors, lipid profiles, whole blood viscosity and anthropometry were measured. Total testosterone (from mean ± SD 1.87 ± 1.09 to 5.52 ± 1.92 ng/ml, p <0.001) and free testosterone (from 3.04 ± 2.03 to 7.23 ± 2.90 pg/ml, p <0.001) were restored by testosterone undecanoate therapy. Hemoglobin and hematocrit significantly increased after testosterone undecanoate therapy by an average of 2.46 gm/dl (p <0.001) and 3.03% (p <0.001), respectively. The prevalence of anemia (from 29.6% to 10.0%) significantly decreased (p <0.001) and patients with anemia showed a significant increase in erythropoietin after testosterone undecanoate therapy (p = 0.047). A reduction in total cholesterol (from 165.89 ± 39.16 to 153.80 ± 154.27 mg/dl, p = 0.002), increased whole blood viscosity and increased hematocrit were observed until 54 weeks compared with baseline. However, whole blood viscosity and hematocrit stabilized after 18 weeks. After 54 weeks testosterone undecanoate decreased the prevalence of anemia and components of the metabolic syndrome. A longer duration of testosterone undecanoate therapy of more than 18 weeks may be effective and safe in reducing blood viscosity and improving anemia. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Voican, Adela; Amazit, Larbi; Trabado, Séverine; Fagart, Jérôme; Meduri, Geri; Brailly-Tabard, Sylvie; Chanson, Philippe; Lecomte, Pierre; Guiochon-Mantel, Anne; Young, Jacques
Context TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. Objective To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. Results From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. Conclusion The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations. PMID:22031817
Khera, Mohit; Bhattacharya, Rajib K; Blick, Gary; Kushner, Harvey; Nguyen, Dat; Miner, Martin M
We measured prostate specific antigen after 12 months of testosterone replacement therapy in hypogonadal men. Data were collected from the TRiUS (Testim® Registry in the United States), an observational registry of hypogonadal men on testosterone replacement therapy (849). Participants were Testim naïve, had no prostate cancer and received 5 to 10 gm Testim 1% (testosterone gel) daily. A total of 451 patients with prostate specific antigen and total testosterone values were divided into group A (197 with total testosterone less than 250 ng/dl) and group B (254 with total testosterone 250 ng/dl or greater). The groups differed significantly in free testosterone and sex hormone-binding globulin, but not in age or prostate specific antigen. In group A but not group B prostate specific antigen correlated significantly with total testosterone (r=0.20, p=0.005), free testosterone (r=0.22, p=0.03) and sex hormone-binding globulin (r=0.59, p=0.002) at baseline. After 12 months of testosterone replacement therapy, increase in total testosterone (mean±SD) was statistically significant in group A (+326±295 ng/dl, p<0.001; final total testosterone 516±28 ng/dl) and group B (+154±217 ng/dl, p<0.001; final total testosterone 513±20 ng/dl). After 12 months of testosterone replacement therapy, increase in prostate specific antigen was statistically significant in group A (+0.19±0.61 ng/ml, p=0.02; final prostate specific antigen 1.26±0.96 ng/ml) but not in group B (+0.28±1.18 ng/ml, p=0.06; final prostate specific antigen 1.55±1.72 ng/ml). The average percent prostate specific antigen increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall the greatest prostate specific antigen was observed after 1 month of treatment and decreased thereafter. Patients with baseline total testosterone less than 250 ng/dl were more likely to have an increased prostate specific antigen after testosterone replacement therapy than those with baseline total
Selmer, Christian; Østergren, Peter Busch; Pedersen, Karen Boje; Schou, Morten; Gustafsson, Finn; Faber, Jens; Juul, Anders; Kistorp, Caroline
Aims Abuse of anabolic androgenic steroids (AAS) is highly prevalent among male recreational athletes. The objective of this study was to investigate the impact of AAS abuse on reproductive hormone levels and symptoms suggestive of hypogonadism in current and former AAS abusers. Methods This study had a cross-sectional case-control design and involved 37 current AAS abusers, 33 former AAS abusers (mean (95%CI) elapsed duration since AAS cessation: 2.5 (1.7; 3.7) years) and 30 healthy control participants. All participants were aged 18–50 years and were involved in recreational strength training. Reproductive hormones (FSH, LH, testosterone, inhibin B and anti-Müllerian hormone (AMH)) were measured using morning blood samples. Symptoms of hypogonadism (depressive symptoms, fatigue, decreased libido and erectile dysfunction) were recorded systematically. Results Former AAS abusers exhibited significantly lower median (25th –75th percentiles) total and free testosterone levels than control participants (total testosterone: 14.4 (11.9–17.7) nmol/l vs. 18.8 (16.6–22.0) nmol/l) (P < 0.01). Overall, 27.2% (13.3; 45.5) of former AAS abusers exhibited plasma total testosterone levels below the lower reference limit (12.1 nmol/l) whereas no control participants exhibited testosterone below this limit (P < 0.01). Gonadotropins were significantly suppressed, and inhibin B and AMH were significantly decreased in current AAS abusers compared with former AAS abusers and control participants (P < 0.01). The group of former AAS abusers had higher proportions of participants with depressive symptoms ((24.2%) (11.1; 42.2)), erectile dysfunction ((27.3%) (13.3; 45.6)) and decreased libido ((40.1%) (23.2; 57.0)) than the other two groups (trend analyses: P < 0.05). Conclusions Former AAS abusers exhibited significantly lower plasma testosterone levels and higher frequencies of symptoms suggestive of hypogonadism than healthy control participants years after AAS cessation
Martin, Malcolm M; Martin, Arline L A
Forty-six male teenagers 13-19 years old with delayed puberty (DP) underwent gonadotropin releasing hormone (GnRH) and human chorionic gonadotropin (HCG) stimulation as part of their work-up. All were followed to age 18 and beyond. Thirty-seven had constitutional delayed puberty (CDP). Nine had hypogonadotropic hypogonadism (HH). At referral 34 youngsters with CDP were properly diagnosed when the lower limit for the luteinizing hormone (LH) response to GnRH (Factrel 0.1 mg i.v.) was set at 12 IU/l. Three boys with CDP failed to reach that level and were not assigned appropriately. All nine patients with HH had basal serum testosterone (T) < 50 ng/dl when first seen and LH responses to GnRH stimulation < 8.0 IU/l. In the late 1970s, five subjects with DP were given HCG 3,000 IU (two patients daily for 5 days; three on 3 alternate days). Serum T was measured before the first, and 48 hours after the last injection (day 7). With recognition of the long biological half-life of injected HCG and receptor downregulation by daily doses, the protocol was changed. In the early 1980s, the dose of HCG was randomized to either 500 IU or 1,000 IU given on 3 alternate days. T was measured before the first injection (basal), 48 hours later (day 3) and 48 hours after the third injection (day 7). At referral 35 patients with CDP, including one GnRH failure, met the criterion for a positive response to HCG stimulation based on their own reactions (T > 170 ng/dl on day 3; > 200 on day 7). Eleven patients with DP failed the test. Nine had HH and two had CDP. The nine patients with HH included the two given daily injections and the three given HCG 3,000 IU on 3 alternate days. Of the two with CDP, one, an obese boy with a normal GnRH test, only received 500 IU HCG (5.6 IU/kg), which may have been inadequate. The other failed both tests. Of the 35 responders, 17 (group 1) were given HCG 500 IU and 18 (group 2) were given 1,000 IU i.m. on 3 alternate days. Seven boys in group 1 and 12 in
Oktenli, C; Yesilova, Z; Ozata, M; Yaman, H; Tuzun, A; Dundar, S; Sanisoglu, S Y; Musabak, U; Erbil, M K; Dagalp, K
The main objective of the present study was to examine the alterations in plasma total homocysteine (tHcy) concentrations during a testosterone-deficient state and after gonadotropin treatment for 6 Months in patients with idiopathic hypogonadotropic hypogonadism (IHH). Thirty-five newly diagnosed male patients with IHH (mean age 21.34+/-1.53 years) and 29 age- and body mass index-matched healthy males (mean age 21.52+/-1.77 years) were recruited into the study. Pretreatment levels of free testosterone (1.51+/-0.66 pg/ml), estradiol (21.37+/- 4.37 pg/ml), FSH (0.91+/-0.24 IU/l) and LH (1.25+/- 0.53 IU/l) were lower than controls (25.17+/-3.06 pg/ml, 31.00+/-4.96 pg/ml, 3.14+/-1.62 IU/l and 4.83+/-1.65 IU/l respectively) (P<0.001). They increased significantly after treatment (18.18+/-1.59 pg/ml, 27.97+/- 4.25 pg/ml, 2.41+/-0.27 IU/l and 2.79+/-0.19 IU/l respectively) (P<0.001). Patients with IHH had lower tHcy levels than controls (10.14+/-1.34 and 12.58+/- 2.29 micro mol/l respectively) (P<0.001). Plasma tHcy concentrations increased significantly (12.63+/-1.44 micromol/l) after 6 months of treatment (P<0.001). As compared with the controls, pretreatment levels of serum creatinine (63.54+/-13.01 vs 82.84+/-16.69 micromol/l), hemoglobin (12.98+/-0.56 vs 13.83+/-0.71 g/dl) and hematocrit (39.29+/-2.01 vs 41.38+/-1.95%) were significantly lower (P<0.001), and they increased significantly following treatment (80.24+/-11.93 micromol/l, 13.75+/-0.49 g/dl and 41.26+/-1.78% respectively) (P<0.001). The pretreatment folic acid and vitamin B(12) levels were significantly higher in patients when compared with controls (14.87+/-5.68 vs 12.52+/-4.98 nmol/l, P=0.034 and 289.75+/-92.34 vs 237.59+/-108.17 pmol/l, P=0.002 respectively). They decreased significantly after treatment (11.29+/-3.31 nmol/l and 228.51+/-54.33 pmol/l respectively) (P<0.001). The univariate and multivariate regression analysis results showed that only changes in creatinine, creatinine clearance, vitamin B
Buxton, Jessica L.; Zekavati, Anna; Sosinsky, Alona; Yiorkas, Andrianos M.; Holder, Susan; Klaber, Robert E.; Bridges, Nicola; van Haelst, Mieke M.; le Roux, Carel W.; Walley, Andrew J.; Walters, Robin G.; Mueller, Michael; Blakemore, Alexandra I. F.
Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans. PMID:26120850
Quintos, J B; Krotz, Stephan; Vogiatzi, Maria G; Kralickova, Milena; New, Maria I
We describe a patient with partial hypogonadotropic hypogonadism caused by a compound heterozygous GnRH-R mutation. She is a 20-year-old tall, eunuchoid female referred for evaluation of primary amenorrhea. Spontaneous thelarche occurred at the age of 15 years. Breast and pubic hair were at Tanner stages 3 and 4, respectively. Evaluation revealed low plasma estradiol level and absence of withdrawal bleeding after progestin challenge. Pelvic ultrasonography showed a small uterus and ovaries. Bone age was delayed at 14.5 years. Bone mineral density showed osteopenia. Endogenous LH secretory pattern was abnormal with low amplitude and frequency, but responded to pulsatile GnRH administration. The coding exons of the GnRH-R gene were amplified and the PCR products were sequenced bidirectionally. Two different mutations were identified: one in exon 1 (Gln106Arg) and the other in exon 3 (Leu266Arg).
Krysiak, Robert; Gilowski, Wojciech; Okopien, Bogusław
Oral testosterone was found to reduce plasma levels of HDL cholesterol. No previous study has examined the effect of fibrates, known to increase HDL cholesterol, in patients with low testosterone levels requiring testosterone replacement. The study included three age-, weight-, and lipid-matched groups of older men with atherogenic dyslipidemia and late-onset hypogonadism, treated with oral testosterone undecanoate (120 mg daily, n = 15), micronized fenofibrate (200 mg daily, n = 15), or testosterone plus fenofibrate (n = 18). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were assessed before and after 16 weeks of therapy. Apart from an increase in plasma testosterone and a reduction in HDL cholesterol, testosterone undecanoate tended to decrease hsCRP and to improve insulin sensitivity. Fenofibrate administered alone increased HDL cholesterol, reduced triglycerides, decreased insulin resistance, reduced circulating levels of uric acid, hsCRP, and fibrinogen, as well as increased plasma levels of homocysteine. The strongest effect on testosterone, HOMA1-IR, uric acid, hsCRP, and fibrinogen was observed if fenofibrate was administered together with testosterone. Testosterone-fenofibrate combination therapy was also devoid of unfavorable effect on HDL cholesterol and homocysteine. Our study shows that fenofibrate produces a stronger effect on cardiometabolic risk factors in men with late-onset hypogonadism and atherogenic dyslipidemia than oral testosterone undecanoate. The obtained results suggest that this group of patients may benefit the most from the combined treatment with oral testosterone undecanoate and micronized fenofibrate. © 2015 John Wiley & Sons Ltd.
Yassin, Dany-Jan; El Douaihy, Yousef; Yassin, Aksam A; Kashanian, James; Shabsigh, Ridwan; Hammerer, Peter G
Many men with "late-onset hypogonadism" (LOH) experience lower urinary tract symptoms (LUTS) that can be distressing and may decrease quality of life. LUTS often appear in men when testosterone levels begin to decline, which could be a significant association. We investigated whether testosterone replacement could alleviate LUTS in men with LOH. Two hundred and sixty-one hypogonadal patients (mean age 59.5 years) presenting with erectile dysfunction, having also been evaluated for LUTS, received a single testosterone undecanoate injection at day 1, at week 6 and quarterly thereafter. Parameters, including International Prostate Symptom Score (IPSS), post-voiding residual urine volume, transrectal ultrasound, prostate volume and prostate-specific antigen were measured at each treatment visit. Two hundred and fifty-nine patients were included in the full analysis set. These were subsequently divided into weight losers (L ≥ 5 % weight loss at last visit from baseline) and non-losers (NL). t test analyses were used to compare the IPSS means of these subgroups. The potentially confounding effect on IPSS of using the phosphodiesterase-5 inhibitor (PDE5i) vardenafil was also accounted for. Mean IPSS showed a significant decrease with time following initiation of testosterone treatment (p < 0.05). No significant differences were observed in either IPSS between L and NL groups or in mean IPSS between vardenafil users and non-users. Testosterone replacement is associated with improvements in LUTS which are not confounded by weight loss or PDE5i. The mechanisms of this association require further investigation.
Efros, M; Carrara, D; Neijber, A
Pharmacokinetics, pharmacodynamics and safety of a novel hydroalcoholic testosterone gel 2% (TG) were evaluated in phase II sequential dose escalation studies using 3 application sites (thigh, abdomen and shoulder/upper arm) and 2 application methods. Hypogonadal men (n = 40), 18-75 years, with serum testosterone <300 ng dl(-1) were included in both studies. Study 1 evaluated hand-applied multiple doses of TG 1.25, 2.50 and 3.75 ml (23, 46 and 70 mg of testosterone, respectively), once daily for 10 days to shoulder/upper arm. Study 2 evaluated applicator-applied (TG 1.25, 2.50 and 3.75 ml) versus hand-applied (TG 2.5 ml) doses, once daily for 7 days to shoulder/upper arm. Primary endpoint for both studies was responder rate (Cave testosterone levels between 298 and 1050 ng dl(-1) ). In Study 1 following multiple applications, >70% participants in each group were responders. Dose-dependent increase was observed in PK values for total testosterone, free testosterone and DHT. In Study 2, responder rate was dose proportional: 16.7%, 50.0% and 77.8% responders in TG 1.25, 2.50 and 3.75 ml groups respectively. The bioavailability was highest for the shoulder application. There was a significant improvement in almost all the domains of sexual functioning. Applicator-application was preferred over hand-application by majority of the participants. TG was found to be safe and well tolerated in hypogonadal men.
Condorelli, Rosita A; Calogero, Aldo E; Di Mauro, Maurizio; Mongioì, Laura M; Russo, Giorgio I; Morgia, Giuseppe; La Vignera, Sandro
To investigate a possible relation between penile Doppler ultrasound examination (PDUE) parameters and efficacy of chronic therapy with tadalafil (TAD) combined with a protocol of aerobic physical activity (PA) in patients with late onset hypogonadism (LOH). The study evaluated 30 patients consecutively enrolled with LOH and erectile dysfunction which present contraindication to hormonal replacement therapy for concomitant prostate disease. These patients were subjected to a combined protocol with phosphodiesterase V selective inhibitors (TAD 5 mg daily) and aerobic PA. After three months, we observed significant improvements in erectile function [IIEF-5, median (IQR) = 13.0 (7.0-18.0) versus 6.0 (5.0-6.75); p < 0.01] and of the main metabolic [homeostatic model assessment index, median (IQR) = 2.5 (1.62-3.37) versus 3.0 (2.0-3.75); p < 0.01; body mass index, median (IQR) = 27.0 (24.0-28.75) versus 27.5 (24.0-29.5)] and vascular parameters [peak systolic velocity, median (IQR) = 29.5 (24.25-31.0) versus 28.0 (23.0-24.25); acceleration time, median (IQR) = 114 (105.25-134.0) versus 115.0 (106.5-134.0)], assessed by PDUE. PA in association with phosphodiesterase V inhibitors could compensate the effects of hypogonadism on erectile function and facilitate the clinical response to these drugs even in the absence of adequate serum concentrations of total testosterone.
Kytövuori, Laura; Lipponen, Joonas; Rusanen, Harri; Komulainen, Tuomas; Martikainen, Mika H; Majamaa, Kari
Defects in the respiratory chain or mitochondrial ATP synthase (complex V) result in mitochondrial dysfunction that is an important cause of inherited neurological disease. Two of the subunits of complex V are encoded by MT-ATP6 and MT-ATP8 in the mitochondrial genome. Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease. We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism. As the phenotype was suggestive of mitochondrial disease, mitochondrial DNA was sequenced and a novel heteroplasmic mutation m.8561C>G in the overlapping region of the MT-ATP6 and MT-ATP8 was found. The mutation changed amino acids in both subunits. Mutation heteroplasmy correlated with the disease phenotype in five family members. An additional assembly intermediate of complex V and increased amount of subcomplex F1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected. Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production. We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
Hickey, Scott E; Walters-Sen, Lauren; Mosher, Theresa Mihalic; Pfau, Ruthann B; Pyatt, Robert; Snyder, Pamela J; Sotos, Juan F; Prior, Thomas W
In 1979 a "new" syndrome characterized by X-linked inheritance, hypogonadism, gynecomastia, intellectual disability, obesity, and short stature was described. The now-36-year-old propositus was recently referred to the genetics clinic for profound intellectual disability. Fragile X testing initially demonstrated a duplication of the FMR1 region, and upon further testing we identified an Xq27.3-q28 8.05 Mb-long duplication responsible for a syndrome. Our report describes the molecular and clinical aspects of the X-linked syndrome. Our results suggest that male patients with intellectual disability, hypogonadism, short stature, and gynecomastia should be further investigated for rearrangements in the Xq27.3-q28 region. In the future, when more cases of the duplication are identified, it may become possible to more accurately determine the specific genes affected by overexpression and responsible for the phenotype.
Saad, Farid; Yassin, Aksam; Almehmadi, Yousef; Doros, Gheorghe; Gooren, Louis
Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone ≤ 12 nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.
Guo, Changcheng; Gu, Wenyu; Liu, Min; Peng, B O; Yao, Xudong; Yang, Bin; Zheng, Junhua
The purpose of the present meta-analysis was to evaluate the efficacy and safety of testosterone replacement therapy in men with hypogonadism. A search was conducted for appropriate randomized controlled trials and the data from 16 trials were pooled. The intended primary outcome of the present study was to determine the efficacy and safety of testosterone replacement therapy. The current data demonstrated that scores for Aging Male Symptoms (AMS) were significantly reduced following testosterone replacement therapy, with a mean decrease in AMS score of 1.52 [95% confidence interval (CI), 0.72 to 2.32; P=0.0002]. Testosterone replacement therapy increased lean body mass [mean difference (MD), 1.22; 95% CI, 0.33 to 2.11; P=0.007], reduced fat mass in a non-significantly manner (MD, -0.85; 95% CI, -1.74 to 0.04; P=0.06) and significantly reduced total cholesterol (MD, -0.16; 95% CI, -0.29 to -0.03; P=0.01). No significant differences were identified in body weight (MD, 0.09; 95% CI, -1.13 to 1.31; P=0.89), body mass index (MD, 0.10; 95% CI, -0.62 to 0.82; P=0.78) or bone mineral density (MD, -0.01; 95% CI, -0.03 to 0.02; P=0.60). Average prostate volume increased (MD, 1.58; 95% CI, 0.6 to 2.56; P=0.002) following testosterone replacement therapy, but the levels of prostate-specific antigen (PSA) (MD, 0.10; 95% CI, -0.03 to 0.22; P=0.14) and the International Prostate Symptom Scores (MD, 0.01; 95% CI, -0.37 to 0.39; P=0.96) did not change. In conclusion, testosterone replacement therapy improves quality of life, increases lean body mass, significantly decreases total cholesterol, and is well-tolerated and safe for men with hypogonadism who are exhibiting PSA levels of <4 ng/ml.
Kang, De-Ying; Li, Hong-Jun
Testosterone replacement therapy is used for the treatment of age-related male hypogonadism, and prostate-specific antigen (PSA) is a primary screening tool for prostate cancer. The systematic review and meta-analysis aimed to determine the effect of testosterone replacement therapy on PSA levels.Medline, Cochrane Library, EMBASE, and Google Scholar databases were searched until February 28, 2014, and inclusion criteria were as follows: randomized controlled trial; intervention group received testosterone/androgen replacement therapy; control group did not receive treatment; and no history of prostate cancer. The primary outcome was change of PSA level between before and after treatment. Secondary outcomes were elevated PSA level after treatment, and the number of patients who developed prostate cancer.After initially identifying 511 articles, 15 studies with a total of 739 patients that received testosterone replacement and 385 controls were included. The duration of treatment ranged from 3 to 12 months. Patients treated with testosterone tended to have higher PSA levels, and thus a greater change than those that received control treatments (difference in means of PSA levels = 0.154, 95% confidence interval [CI] 0.069 to 0.238, P < 0.001). The difference in means of PSA levels were significant higher for patients that received testosterone intramuscularly (IM) than controls (difference in means of PSA levels = 0.271, 95% CI 0.117-0.425, P = 0.001). Elevated PSA levels after treatment were similar between patients that received treatment and controls (odds ratio [OR] = 1.02, 95% CI 0.48-2.20, P = 0.953). Only 3 studies provided data with respect to the development of prostate cancer, and rates were similar between those that received treatment and controls.Testosterone replacement therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given IM and even the increase with IM administration is minimal.
Hoffmann, Hanne M; Trang, Crystal; Gong, Ping; Kimura, Ikuo; Pandolfi, Erica C; Mellon, Pamela L
Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates mammalian fertility. Herein we demonstrate a critical role for the homeodomain transcription factor ventral anterior homeobox 1 (VAX1) in GnRH neuron maturation and show that Vax1 deletion from GnRH neurons leads to complete infertility in males and females. Specifically, global Vax1 knock-out embryos had normal numbers of GnRH neurons at 13 d of gestation, but no GnRH staining was detected by embryonic day 17. To identify the role of VAX1 specifically in GnRH neuron development,Vax1(flox)mice were generated and lineage tracing performed in Vax1(flox/flox):GnRH(cre):RosaLacZ mice. This identified VAX1 as essential for maintaining expression of Gnrh1 The absence of GnRH staining in adult Vax1(flox/flox):GnRH(cre)mice led to delayed puberty, hypogonadism, and infertility. To address the mechanism by which VAX1 maintains Gnrh1 transcription, the capacity of VAX1 to regulate Gnrh1 transcription was evaluated in the GnRH cell lines GN11 and GT1-7. As determined by luciferase and electrophoretic mobility shift assays, we found VAX1 to be a direct activator of the GnRH promoter through binding to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P), and able to compete with the homeoprotein SIX6 for occupation of the identified ATTA sites in the GnRH promoter. We conclude that VAX1 is expressed in GnRH neurons where it is required for GnRH neuron expression of GnRH and maintenance of fertility in mice. Infertility classified as idiopathic hypogonadotropic hypogonadism (IHH) is characterized by delayed or absent sexual maturation and low sex steroid levels due to alterations in neuroendocrine control of the hypothalamic-pituitary-gonadal axis. The incidence of IHH is 1-10 cases per 100,000 births. Although extensive efforts have been invested in identifying genes giving rise to IHH, >50% of cases have unknown genetic origins
Haider, Ahmad; Saad, Farid; Doros, Gheorghe; Gooren, Louis
Treatment of obesity with diet and exercise may have short-term success but longer-term maintenance of weight loss is less successful. Obesity is associated with a reduction of serum testosterone, and, vice versa, a reduction in serum testosterone is associated with obesity and features of the metabolic syndrome. To investigate whether restoring serum testosterone to normal in hypo-gonadal obese men is beneficial with regard to weight loss and improvement of the metabolic syndrome. A prospective registry accumulated to 181 men over five years (mean serum testosterone 10.06±1.3 nmol/L (N>12.1), body mass index (BMI) ≥30 kg/m2. Of these men, 72 had diabetes mellitus type 2. All received parenteral testosterone undecanoate 1000 mg/12 weeks for up to five years. Waist circumference (cm) decreased from 111.2±7.54 to 100.46±7.1, weight (kg) from 114.71±11.59 to 93.2±8.49, BMI (kg/m2) from 36.72±3.72 to 30.2±2.59 (all variables statistically significant vs. baseline (p<0.0001) and each year compared to the previous year (p<0.0001)). In the 72 diabetic men, waist circumference (cm) decreased from 112.93±7.16 to 101.48±7.24, weight (kg) from 116.94±11.62 to 94.42±9.42, BMI (kg/m2) from 37.71±3.5 to 30.95±2.69 (all variables statistically significant vs. baseline (p<0.0001) and each year compared to the previous year (p<0.0001)). In all men serum glucose, HbA1c, lipid profiles and blood pressure improved significantly. Testosterone treatment as assessed by hemoglobin, hematocrit, serum prostate specific antigen (PSA) and occurrence of prostate cancer was acceptably safe. Normalizing serum testosterone in obese hypogonadal men, also in those with diabetes type 2, improved their metabolic state. Copyright © 2013 Asian Oceanian Association for the Study of Obesity. All rights reserved.
Vicari, E; Mongioi, A; Recupero, D; Coniglione, F; Macchi, M; Sipione, C; Calogero, A; D'Agata, R
Gonadotropin-releasing hormone analogues (GnRH-A) induce inhibition of testicular function and reduction of serum testosterone (T) in man, but the mechanism involved is still debatable. To elucidate it we studied six patients with hypogonadotropic hypogonadism (HH) in chronic substitution with hCG for correction of androgen deficiency symptoms, and evaluated the effect of addition of GnRH-A to the hCG therapy on plasma levels of T and 17 alpha-hydroxyprogesterone (17 OHP). All patients were treated with 1000 U of hCG in every 3rd day for 24 weeks. After 8 weeks of this regimen, GnRH-A, Buserelin (D-Ser-TBU-EA-LHRH), 200 micrograms per day sc, was added and given for 8 weeks. After cessation of analogue administration patients were followed for 8 further weeks. The levels of the two steroids did not differ markedly in the pre- and post-GnRH-A period. GnRH-A given for two months did not lower T or 17 OHP levels as in eugonadal men after similar treatment. The median T concentrations during GnRH-A tended to be increased, with plasma values higher (P less than 0.025) than the peak values observed during hCG alone. Since administration of Buserelin did not inhibit hCG-sustained steroid levels in these HH patients, it is conceivable that GnRH-A may have lacked a direct inhibitory gonadal effect in such experimental conditions.
Sumii, K; Miyake, H; Enatsu, N; Matsushita, K; Fujisawa, M
The objective of this study was to characterise the status of health-related quality of life (HRQOL) in Japanese men with late-onset hypogonadism (LOH) treated with testosterone replacement therapy (TRT). HRQOL in 69 consecutive Japanese men with LOH undergoing TRT for at least 6 months was prospectively evaluated before and 6 months after the initiation of TRT using the Medical Outcomes Study 8-Item Short-Form Health Survey (SF-8). All eight-scale scores except for bodily pain (BP) in the 69 patients at 6 months after the introduction of TRT significantly improved compared with those before TRT; however, all scale scores except for BP in the 69 patients were significantly inferior to those in age-matched Japanese controls irrespective of the timing of SF-8. Multivariate analyses of several parameters revealed that both age and Aging Male Symptom (AMS) score had an independent impact on mental health (MH), despite the lack of an independent association between any score and the remaining factors examined. TRT appeared to significantly improve the status of HRQOL in men with LOH; however, even after the introduction of TRT, HRQOL associated with MH remained significantly impaired in elderly men and/or those with a high AMS score. © 2015 Blackwell Verlag GmbH.
Nian, Y; Ding, M; Hu, S; He, H; Cheng, S; Yi, L; Li, Y; Wang, Y
Although testosterone replacement therapy can restore serum testosterone concentrations to normal level in late-onset hypogonadism patients, whether it can improve patients' quality of life remains uncertain. Therefore, we perform a meta-analysis of randomized controlled trials on this issue. Five randomized controlled trials total 1,212 patients were included. Fixed-effect model was used to calculate the weighted mean difference of score of Aging Males' Symptom rating scale. Our result reveals that testosterone replacement therapy improves patients' health-related quality of life in terms of the decrease in the AMS total score [WMD = -2.96 (-4.21, -1.71), p < .00001] and the psychological [WMD = -0.89 (-1.41, -0.37), p = .0008], somatic [WMD = -0.89 (-1.41, -0.37), p = .0008] and sexual [WMD = -1.29 (-1.75, -0.83), p < .00001] subscale score. © 2016 Blackwell Verlag GmbH.
Traish, A M; Haider, A; Doros, G; Saad, F
Aim The goal of this study was to determine if long-term testosterone (T) therapy in men with hypogonadism, henceforth referred to as testosterone deficiency (TD), ameliorates or improves metabolic syndrome (MetS) components. Methods We performed a cumulative registry study of 255 men, aged between 33 and 69 years (mean 58.02 ± 6.30) with subnormal plasma total T levels (mean: 9.93 ± 1.38; range: 5.89–12.13 nmol/l) as well as at least mild symptoms of TD assessed by the Aging Males' symptoms scale. All men received treatment with parenteral T undecanoate 1000 mg (Nebido®, Bayer Pharma, Berlin, Germany), administered at baseline and 6 weeks and thereafter every 12 weeks for up to 60 months. Lipids, glucose, liver enzymes and haemoglobin A1c analyses were carried out in a commercial laboratory. Anthropometric measurements were also made throughout the study period. Results Testosterone therapy restored physiological T levels and resulted in reductions in total cholesterol (TC) [7.29 ± 1.03 to 4.87 ± 0.29 mmol/l (281.58 ± 39.8 to 188.12 ± 11.31 mg/dl)], low-density lipoprotein cholesterol [4.24 ± 1.07 to 2.84 ± 0.92 mmol/l (163.79 ± 41.44 to 109.84 ± 35.41 mg/dl)], triglycerides [3.14 ± 0.58 to 2.16 ± 0.13 mmol/l (276.16 ± 51.32 to 189.78 ± 11.33 mg/dl)] and increased high-density lipoprotein levels [1.45 ± 0.46 to 1.52 ± 0.45 mmol/l (56.17 ± 17.79 to 58.85 ± 17.51 mg/dl)] (p < 0.0001 for all). There were marked reductions in systolic and diastolic blood pressure, blood glucose, haemoglobin A1c, C-reactive protein (6.29 ± 7.96 to 1.03 ± 1.87 U/l), alanine aminotransferase and aspartate aminotransferase (p < 0.0001 for all). Conclusions Long-term T therapy, at physiological levels, ameliorates MetS components. These findings strongly suggest that T therapy in hypogonadal men may prove useful in reducing the risk of cardiometabolic diseases. PMID:24127736
Snyder, Christin N.; Clark, Richard V.; Caricofe, Ralph B.; Bush, Mark A.; Roth, Mara Y.; Page, Stephanie T.; Bremner, William J.; Amory, John K.
Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current “immediate-release” formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency. PMID:20378927
Calder, Michele; Chan, Yee-Ming; Raj, Renju; Pampillo, Macarena; Elbert, Adrienne; Noonan, Michelle; Gillio-Meina, Carolina; Caligioni, Claudia; Bérubé, Nathalie G.; Bhattacharya, Moshmi; Watson, Andrew J.; Seminara, Stephanie B.
The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1−/− female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1+/− embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1−/− uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1−/− female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans. PMID:24877624
Mumusoglu, Sezcan; Ata, Baris; Turan, Volkan; Demir, Berfu; Kahyaoglu, Inci; Aslan, Kiper; Seyhan Ata, Ayse; Yilmaz, Bulent; Yakin, Kayhan; Avci, Berrin; Uncu, Gurkan; Bozdag, Gurkan
In this retrospective multicenter cohort study, women with congenital hypogonadotrophic hypogonadism (CHH) (n = 57) who underwent intra-cytoplasmic sperm injection in-between 2010-2014 were compared to age-matched controls with tubal factor infertility (n = 114) to assess ovarian stimulation cycle and pregnancy outcomes. Live birth rates (LBRs) per started cycle were 31.6 and 24.6% in CHH and controls groups, respectively (p = 0.36). Comparable success rates were also confirmed with the logistic regression analysis (OR: 1.44, 95% CI: 0.78-2.67, p = 0.24). Of the 57 women with CHH, 19 were stimulated with the gonadotropin-releasing hormone (GnRH) antagonist protocol, 13 with the long-GnRH-agonist protocol. Pituitary suppression (PS) was not employed in the remaining 25 cases. Compared to women with PS, women without PS had significantly higher embryo implantation rates (21.6 versus 52.6%, p = 0.03). Although there was a trend favoring no PS, LBRs (25.0 versus 40.0%, p = 0.26) per cycle were short of statistical significance. LBRs per cycle (57.1 versus 31.2%, p = 0.11) and miscarriage rates (11.1 versus 16.7%, p = 0.75) were similar between CHH women who were given estrogen + progesterone and progesterone alone to support the luteal phase. In conclusion, the optimal stimulation protocol appears to be exogenous gonadotropin stimulation alone, without PS, and progesterone-only luteal phase support in CHH patients.
Suzuki, Hiroetsu; Yagi, Mio; Saito, Kenichi; Suzuki, Katsushi
Congenital hypoplasia and dysplasia affect the postnatal development of organs, their physiological functioning in adulthood and the incidence of related diseases at an advanced age. Hypogonadic (hgn/hgn) rats are characterized by male sterility, reduced female fertility, progressive renal insufficiency and growth retardation, all controlled by a single recessive allele (hgn) located on chromosome 10. Since our previous studies indicated that the hypoplasia (dysplasia) of the affected organs was present at birth, we examined the embryonic pathogenesis. We mated hgn/hgn females to Brown Norway males and backcrossed F(1) males to hgn/hgn females. The resulting N(1) fetuses were genotyped using a hgn-linked microsatellite. Both sexes of hgn/hgn fetuses showed low body weight after embryonic day (ED) 15.5 and renal hypoplasia after ED 17.5. Their kidneys contained a reduced number of nephrons in a poorly formed nephrogenic zone and renal cortex. The hgn/hgn ovaries contained a small number of oogonia at ED 15.5 and oocytes after ED 17.5. Testicular growth defects were obvious after ED 17.5, and reduced numbers of Sertoli cells were detected at ED 19.5 and 21.5. The seminiferous cords in hgn/hgn testes contained more apoptotic and mitotic cells than those in +/hgn testes. These findings suggest that the phenotypes described in adult hgn/hgn rats result from embryonic hypogenesis, which continues to early postnatal stage and causes a reduction in functional tissues and cells. Since hgn/hgn rats have an insertion mutation in the microtubule-associated protein Spag5 gene, the embryonic hypogenesis described in hgn/hgn rats might result from defective cell proliferation.
Badiu, Corin; Bonomi, Marco; Borshchevsky, Ivan; Cools, Martine; Craen, Margarita; Ghervan, Cristina; Hauschild, Michael; Hershkovitz, Eli; Hrabovszky, Erik; Juul, Anders; Kim, Soo-Hyun; Kumanov, Phillip; Lecumberri, Beatriz; Lemos, Manuel C; Neocleous, Vassos; Niedziela, Marek; Djurdjevic, Sandra Pekic; Persani, Luca; Phan-Hug, Franziska; Pignatelli, Duarte; Pitteloud, Nelly; Popovic, Vera; Quinton, Richard; Skordis, Nicos; Smith, Neil; Stefanija, Magdalena Avbelj; Xu, Cheng; Young, Jacques; Dwyer, Andrew A
Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers. Co-created patient education materials reached the target 6(th) grade reading level according to 2/6 (33%) algorithms (range: grade 5.9-9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1). Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a
Wang, Q; Jiang, W; Li, G; Tang, L; Hu, Y
Hypogonadotropic hypogonadism (HH) is common in pituitary stalk interruption (PSI) patients. However, the optimal timing and effective regimen in the management of the pituitary-gonadal axis deficiency is still controversial. This study involved a retrospective review of 38 male patients with HH resulting from PSI. The HH patients were subdivided according to their ages into 2 experiment groups: Group I (adolescents, 14-18 years old, 25 cases) and Group II (young adults, 18-24 years old, 13 cases). To compare the therapeutic response to exogenous gonadotropin, a control analysis was carried out in the experimental groups with age-matched control groups. Before gonadotropin therapy, no significant increases in gonadal hormones were noted in either of the 2 experimental groups. After treatment with human chorionic gonadotropin (hCG) for less than 6 months, the hormone levels of pituitary-gonadal axis significantly increased in group I than in group II. After adding the human menopause gonadotropin (hMG) for 6 months, the gonadal hormone levels of group II were significantly increased. In addition, the Tanner stage and penis lengths in group I were significantly improved. There was no significant adverse impact on BMI and height velocity (HV) after less than one year therapy. A prolonged hypogonadotropic period without treatment may be responsible for testicular dysfunction in HH males caused by PSI. Early supplementary therapy with hCG and hMG is beneficial for the recovery of gonadal hormone and development of secondary sexual characteristics. © Georg Thieme Verlag KG Stuttgart · New York.
Pinto, M; Jepsen, K J; Terranova, C J; Buffenstein, R
Sex steroid hormones are major determinants of bone morphology and quality and are responsible for sexually dimorphic skeletal traits. Hypogonadism results in suboptimal skeletal development and may lead to an increased risk of bone fracture later in life. The etiology of delayed puberty and/or hypothalamic amenorrhea is poorly understood, and experimental animal models addressing this issue are predominantly based upon short-term experimental induction of hormonal suppression via gonadotropin releasing hormone antagonists (GnRH-a). This acute change in hormone profile does not necessarily emulate the natural progression of hypogonadic bone disorders. We propose a novel animal model with which to explore the effects of chronic hypogonadism on bone quality, the naked mole-rat (NMR; Heterocephalus glaber). This mouse-size rodent may remain reproductively suppressed throughout its life, if it remains as a subordinate within the eusocial mole-rat colony. NMRs live in large colonies with a single dominant breeding female. She, primarily by using aggressive social contact, naturally suppresses the hypothalamic gonadotropic axis of subordinate NMRs and thereby their reproductive expression. However, should an NMR be separated from the dominant breeder, within less than a week reproductive hormones may become elevated and the animal attains breeding status. We questioned if sexual suppression of subordinates impact upon the development and maintenance of the femora and lead to a sexually indistinct monomorphic skeleton. Femora were obtained from male and female NMRs that were either non-breeders (subordinate) or breeders at the time of sacrifice. Diaphyseal cross-sectional morphology, metaphyseal trabecular micro-architecture and tissue mineral density of the femur were measured using microcomputed tomography and diaphyseal mechanical properties were assessed by four-point bending tests to failure. Subordinates were sexually monomorphic and showed no significant
Pinto, M; Jepsen, K J; Terranova, C J; Buffenstein
Sex steroid hormones are major determinants of bone morphology and quality and are responsible for sexually dimorphic skeletal traits. Hypogonadism results in suboptimal skeletal development and may lead to an increased risk of bone fracture later in life. The etiology of delayed puberty and/or hypothalamic amenorrhea is poorly understood, and experimental animal models addressing this issue are predominantly based upon short-term experimental induction of hormonal suppression via gonadotropin releasing hormone antagonists (GnRH-a). This acute change in hormone profile does not necessarily emulate the natural progression of hypogonadic bone disorders. We propose a novel animal model with which to explore the effects of chronic hypogonadism on bone quality, the naked mole-rat (NMR; Heterocephalus glaber). This mouse-size rodent may remain reproductively suppressed throughout its life, if it remains as a subordinate within the eusocial mole-rat colony. NMRs live in large colonies with a single dominant breeding female. She, primarily by using aggressive social contact, naturally suppresses the hypothalamic gonadotropic axis of subordinate NMRs and thereby their reproductive expression. However should an NMR be separated from the dominant breeder, within less than a week reproductive hormones may become elevated and the animal attains breeding status. We questioned if sexual suppression of subordinates impact upon the development and maintenance of the femora, and lead to a sexually indistinct monomorphic skeleton. Femora were obtained from male and female NMRs that were either non-breeders (subordinate) or breeders at the time of sacrifice. Diaphyseal cross-sectional morphology, metaphyseal trabecular micro-architecture and tissue mineral density of the femur was measured using MicroComputed tomography and diaphyseal mechanical properties were assessed by four-point bending tests to failure. Subordinates were sexually monomorphic and showed no significant differences
Testosterone therapy has positive effects on anthropometric measures, metabolic syndrome components (obesity, lipid profile, Diabetes Mellitus control), blood indices, liver enzymes, and prostate health indicators in elderly hypogonadal men.
Canguven, O; Talib, R A; El Ansari, W; Yassin, D-J; Salman, M; Al-Ansari, A
To alleviate late-onset hypogonadism, testosterone treatment is offered to suitable patients. Although testosterone treatment is commonly given to late-onset hypogonadism patients, there remains uncertainty about the metabolic effects during follow-ups. We assessed the associations between testosterone treatment and wide range of characteristics that included hormonal, anthropometric, biochemical features. Patients received intramuscular 1,000 mg testosterone undecanoate for 1 year. Patient anthropometric measurements were undertaken at baseline and at each visit, and blood samples were drawn at each visit, prior to the next testosterone undecanoate. Eighty-eight patients (51.1 ± 13.0 years) completed the follow-up period. Testosterone treatment was associated with significant increase in serum testosterone levels and significant stepladder decrease in body mass index, total cholesterol, triglycerides and glycated haemoglobin from baseline values among all patients. There was no significant increase in liver enzymes. There was an increase in haemoglobin and haematocrit, as well as in prostate-specific antigen and prostate volume, but no prostate biopsy intervention was needed for study patients during 1-year testosterone treatment follow-up. Testosterone treatment with long-acting testosterone undecanoate improved the constituents of metabolic syndrome and improved glycated haemoglobin in a stepladder fashion, with no adverse effects.
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for simultaneous measurement of salivary testosterone and cortisol in healthy men for utilization in the diagnosis of late-onset hypogonadism in males.
Matsui, Futoshi; Koh, Eitetsu; Yamamoto, Kenrou; Sugimoto, Kazuhiro; Sin, Ho-Su; Maeda, Yuji; Honma, Seijiro; Namiki, Mikio
It is well known that late-onset hypogonadism in males can cause a variety of symptoms, and the differential diagnosis is relatively difficult, including psychological disorders, stress, and mood disturbances. The level of serum cortisol can be measured to reflect a patient's level of stress. Salivary hormones facilitate the evaluation of physiological hormonal actions based on free hormone assay. For the simultaneous measurement of testosterone and cortisol levels in saliva, we validate a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Concerning accuracy and precision, the lower limit of quantification of salivary testosterone and cortisol were established as 5 and 10 pg/mL, respectively. Testosterone and cortisol in saliva is stable for 2 days, 14 days, and 28 days at room temperature, refrigeration and frozen, respectively. Freezing and thawing for 3 cycles and stimulation of salivation with gum chewing do not alter the measured values of testosterone and cortisol. Total, bioavailable, and free serum testosterone showed slight diurnal changes, but total and bioavailable serum cortisol showed marked diurnal changes. Salivary testosterone levels negatively correlate with age, regardless of the time of saliva collection (r=0.64, p<0.05). However, there is no relationship between salivary cortisol and age (r=0033, p>0.05). LC-MS/MS allows rapid, simultaneous, sensitive, and accurate quantification of testosterone and cortisol in saliva for the diagnosis late-onset hypogonadism or other hormone related disease.
Nieschlag, Eberhard; Bouloux, Pierre-Marc G; Stegmann, Barbara J; Shankar, R Ravi; Guan, Yanfen; Tzontcheva, Anjela; McCrary Sisk, Christine; Behre, Hermann M
Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 μg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 10(6)/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 10(6)/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. Corifollitropin alfa 150 μg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. ClinicalTrials.gov: NCT01709331 .
Kelch, R P; Jenner, M R; Weinstein, R; Kaplan, S L; Grumbach, M M
The role of the human testis in the production of 17beta-estradiol (E(2)) was investigated by determining the concentration of E(2) and testosterone in peripheral and spermatic vein plasma samples. Specimens were obtained from eight normal men, three men with hypogonadism, and two patients with the incomplete form of the feminizing testes syndrome. For comparison, similar studies were performed in four monkeys, 10 mongrel dogs, and 4 additional dogs who were given 1000 IU of human chorionic gonadotropin/day for 5 days. Plasma E(2) was measured by radioimmunoassay utilizing sheep anti-E(2) serum preceded by ether extraction and thin layer chromatographic separation of plasma steroids. Procedural blanks, which were subtracted from all reported values were 14.1+/-0.74 (SEM) pg for deionized water and 13.1+/-0.66 pg for charcoaladsorbed pooled male plasma. Pooled male and pooled female control plasmas averaged 17+/-0.71 pg/ml and 95+/-6.9 pg/ml, respectively; individual adult male specimens ranged between 8 and 28 with a mean of 18+/-1.4 pg/ml. In the eight normal men, the mean peripheral vein E(2) concentration was 20+/-1.6 pg/ml, while the spermatic vein concentration was 50 times as great, 1049+/-57 pg/ml. All three patients with testicular abnormalities had low spermatic vein E(2) concentrations (160, 280, and 416 pg/ml). Lesser E(2) gradients were found across the simian (3-fold) and canine (approximately 12-fold) testes. Testicular testosterone gradients (human 110-, simian 10-, and canine 77-fold) were greater than the E(2) gradients in all three species. In four dogs, HCG treatment elicited a 6-fold increase in peripheral and a 9-fold increase in spermatic vein testosterone concentrations; however, peripheral and spermatic vein E(2) concentrations did not differ from control values. Spermatic vein E(2) concentrations were > 4600 and 2210 pg/ml (post-HCG) in two patients with the incomplete form of the feminizing testes syndrome. Postorchiectomy, peripheral E(2
Background Patients with rare diseases such as congenital hypogonadotropic hypogonadism (CHH) are dispersed, often challenged to find specialized care and face other health disparities. The internet has the potential to reach a wide audience of rare disease patients and can help connect patients and specialists. Therefore, this study aimed to: (i) determine if web-based platforms could be effectively used to conduct an online needs assessment of dispersed CHH patients; (ii) identify the unmet health and informational needs of CHH patients and (iii) assess patient acceptability regarding patient-centered, web-based interventions to bridge shortfalls in care. Methods A sequential mixed-methods design was used: first, an online survey was conducted to evaluate health promoting behavior and identify unmet health and informational needs of CHH men. Subsequently, patient focus groups were held to explore specific patient-identified targets for care and to examine the acceptability of possible online interventions. Descriptive statistics and thematic qualitative analyses were used. Results 105 male participants completed the online survey (mean age 37 ± 11, range 19–66 years) representing a spectrum of patients across a broad socioeconomic range and all but one subject had adequate healthcare literacy. The survey revealed periods of non-adherence to treatment (34/93, 37%) and gaps in healthcare (36/87, 41%) exceeding one year. Patient focus groups identified lasting psychological effects related to feelings of isolation, shame and body-image concerns. Survey respondents were active internet users, nearly all had sought CHH information online (101/105, 96%), and they rated the internet, healthcare providers, and online community as equally important CHH information sources. Focus group participants were overwhelmingly positive regarding online interventions/support with links to reach expert healthcare providers and for peer-to-peer support. Conclusion The web
Mao, Jiang-Feng; Wu, Xue-Yan; Lu, Shuang-Yu; Nie, Min
To investigate the values of single or repeated luteinizing hormone (LH) releasing hormone analogue (triptorelin) stimulating test in the differential diagnosis between idiopathic hypogonadotropic hypogonadism (IHH) and constitutional delayed puberty (CDP). Male patients (n = 133) without puberty onset after the age of 14 were recruited for triptorelin stimulating test and were followed up for 24 - 48 months until the diagnosis were confirmed: 86 were IHH and the other 47 were CDP. Repeated triptorelin stimulating tests were conducted in 9 IHH patients and 13 CDP patients one year after the first stimulating tests with an attempt to evaluate the dynamic change of hypothalamus-pituitary-testis axis function. The relationship between the final diagnosis and the peak LH value (LH(max)), and the changes of repeated LH(max) were investigated. In the single triptorelin stimulating test, LH(max) was (1.9 +/- 1.2) U/L in IHH group, which was significantly lower than that in CDP group [(13.7 +/- 8.3) U/L] (P < 0.01); 75 IHH patients (87.2%) had a LH(max) lower than 4 U/L, while only 2 CDP patients (4.3%) had a LH(max) lower than 4 U/L. When LH(max) < 4U/L was used as a criteria for the diagnosis of IHH, the single triptorelin stimulating test had a sensitivity of 87.2%, a specificity of 95.7%, and a positive predictive value of 97.4%. The repeated triptorelin stimulating tests performed one year later showed that the LH(max) in the 9 IHH patients increased from (4.7 +/- 2.5) U/L to (5.1 +/- 3.3) U/L (P = 0.78), while that in the 13 CDP patients increased from (10.7 +/- 3.3) U/L to (24.5 +/- 5.7) U/L (P < 0.05). A single triptorelin stimulating test is highly effective in differentiating IHH from CDP. For some patients without definitive diagnosis, a repeated triptorelin stimulating test performed one year later may provide more valuable information on the dynamic change of the hypothalamus-pituitary-testis axis function.
Sedelaar, J.P. Michiel; Dalrymple, Susan S.; Isaacs, John T.
BACKGROUND Immune deficient male mice bearing human prostate cancer xenografts are used to evaluate therapeutic response to novel androgen ablation approaches and the results compared to surgical castration based upon assumption that testosterone microenvironment in intact and castrated adult male mice mimics eugonadal and castrated aging adult human males. METHODS To test these assumptions, serum total testosterone (TT) and free testosterone (FT) were determined longitudinally in groups (n > 20) of intact versus castrated adult male nude, NOG, and immune competent C57BL/6 mice. RESULTS In adult male mice, TT and FT varies by 30- to 100-fold within the same animal providing a microenvironment that is only equivalent to hypogonadal, not eugonadal, adult human males (TT is 1.7 ± 1.2 ng/ml [5.8 ± 4.1 nM] in nude and 2.5 ± 1.3 ng/ml [8.7 ± 4.4 nM] in NOG mice versus >4.2 ng/ml [14.7 nM] in eugonadal humans). This was confirmed based upon enhanced growth of androgen dependent human prostate cancer xenografts inoculated into mice supplemented with exogenous testosterone to elevate and chronically maintain serum TT at a level (5 ng/ml [18 nM]) equivalent to a 50-year-old eugonadal human male. In castrated mice, TT and FT range from 2 to 20 pg/ml (7–70 pM) and <0.8 pg/ml (<2.6 pM), respectively, which is equivalent to castrate resistant prostate cancer (CRPC) patients treated with abiraterone. This was confirmed based upon the inability of another CYP17A1 inhibitor, ketoconazole, to inhibit the growth of CRPC xenografts in castrated mice. CONCLUSIONS Adult male mice supplemented with testosterone mimic eugonadal human males, while unsupplemented animals mimic standard androgen ablation and castrated animals mimic abiraterone treated patients. These studies confirm what is claimed in Robert Burns’ poem “To a Mouse” that “The best laid schemes of mice and men/often go awry. PMID:23775398
Dwyer, Andrew A; Quinton, Richard; Morin, Diane; Pitteloud, Nelly
Patients with rare diseases such as congenital hypogonadotropic hypogonadism (CHH) are dispersed, often challenged to find specialized care and face other health disparities. The internet has the potential to reach a wide audience of rare disease patients and can help connect patients and specialists. Therefore, this study aimed to: (i) determine if web-based platforms could be effectively used to conduct an online needs assessment of dispersed CHH patients; (ii) identify the unmet health and informational needs of CHH patients and (iii) assess patient acceptability regarding patient-centered, web-based interventions to bridge shortfalls in care. A sequential mixed-methods design was used: first, an online survey was conducted to evaluate health promoting behavior and identify unmet health and informational needs of CHH men. Subsequently, patient focus groups were held to explore specific patient-identified targets for care and to examine the acceptability of possible online interventions. Descriptive statistics and thematic qualitative analyses were used. 105 male participants completed the online survey (mean age 37 ± 11, range 19-66 years) representing a spectrum of patients across a broad socioeconomic range and all but one subject had adequate healthcare literacy. The survey revealed periods of non-adherence to treatment (34/93, 37%) and gaps in healthcare (36/87, 41%) exceeding one year. Patient focus groups identified lasting psychological effects related to feelings of isolation, shame and body-image concerns. Survey respondents were active internet users, nearly all had sought CHH information online (101/105, 96%), and they rated the internet, healthcare providers, and online community as equally important CHH information sources. Focus group participants were overwhelmingly positive regarding online interventions/support with links to reach expert healthcare providers and for peer-to-peer support. The web-based needs assessment was an effective way
Tirabassi, Giacomo; Muscogiuri, Giovanna; Colao, Annamaria; Balercia, Giancarlo
Functional hypercortisolism (FH) is a condition which occurs in some clinical states, such as major depression, eating disorders, numerous psychiatric conditions, and diabetes mellitus (DM) and which exerts several negative systemic effects. No data exist on the potentially harmful role of FH on body composition. In this retrospective study, we evaluated the influence of hypothalamic-pituitary-adrenal (HPA) axis dysregulation on body composition in men affected by DM-associated late-onset hypogonadism (LOH). Fourteen subjects affected by FH (FH-LOH) and 18 subjects not affected (N-LOH) were studied. Clinical, hormonal, and body composition measures were considered. The 2 groups had comparable age and weight. FH-LOH patients had lower levels of total (2 ± 0.27 ng/mL versus 2.31 ± 0.26 ng/mL; P = .003) and free (39.5 ± 6.44 pg/mL versus 46.8 ± 7.23 pg/mL; P = .005) (median, 38.7 [interquartile range, 36.1 to 41.3] pg/mL versus median, 46.1 [interquartile range, 40.4 to 52.7] pg/mL) testosterone compared to N-LOH patients. Abdominal fat amount was greater in FH-LOH than in N-LOH patients, even after adjustment for total testosterone. None of the bivariate correlations between body composition measures and hormonal variables were significant in N-LOH. Conversely, in FH-LOH, cortisol area under the curve (AUC) was found to be positively and significantly correlated with trunk (r = 0.933; P<.001) and abdominal fat (r = 0.852; P<.001) and negatively with lean leg (r = -0.607; P = .021). All of these associations were further confirmed upon linear regression analysis in FH-LOH (respectively, unstandardized β = 10.988 [P<.001]; β = 1.156 [P<.001]; β = -7.675 [P = .021]). Multivariate regression analysis confirmed AUC cortisol as a predictor of trunk and abdominal fat in FH-LOH. Dysregulation of the HPA axis in LOH-associated DM seems to be involved in abdominal fat accumulation.
Hackett, Geoffrey; Cole, Nigel; Saghir, Atif; Jones, Peter; Strange, Richards C; Ramachandran, Sudarshan
To evaluate the sexual function response to 30 weeks' treatment with long-acting testosterone undecanoate (TU) or placebo in 199 men with type 2 diabetes and either severe or mild hypogonadism (HG). Men with HG were identified from seven primary care type 2 diabetes registers. A 30-week randomized placebo-controlled study of TU was carried out in 199 of these men (placebo, n = 107, TU, n = 92). The patient-reported outcome measure was the 15-item International Index of Erectile Function score. Men completing the study (n=189) were stratified, firstly, by baseline total testosterone (TT) or free testosterone (FT) into mild HG (TT 8.1-12 nmol/L or FT 0.18-0.25 nmol/L) and severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L), and secondly, by intervention (placebo or TU), thereby creating four groups: mild HG/placebo; mild HG/TU; severe HG/placebo and severe HG/TU. Changes in sexual function score (a secondary outcome of the study) at each visit within group (from baseline) and between groups (TU vs placebo) at each assessment (6, 18 and 30 weeks) were compared using a Wilcoxon signed-rank and Wilcoxon rank-sum test, respectively. Significant improvement in erectile function was evident only in the severe HG group after 30 weeks of TU treatment; this finding persisted when TU was compared with placebo. Intercourse satisfaction and sexual desire scores were also improved at 6, 18 and 30 weeks in the severe HG group after TU treatment; this increase in scores was also evident when compared with placebo. TU did not appear to alter orgasmic function significantly in any of the patient groups. The present study suggests that benefit in sexual symptoms after TU treatment is evident principally in patients with HG with TT levels ≤8 nmol/L and FT levels ≤0.18 nmol/L. We also suggest that 30 weeks of treatment is necessary before evaluating improvement in erectile function. © 2016 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU
Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups.
Traish, Abdulmaged M; Haider, Ahmad; Haider, Karim Sultan; Doros, Gheorghe; Saad, Farid
In the absence of large, prospective, placebo-controlled studies of longer duration, substantial evidence regarding the safety and risk of testosterone (T) therapy (TTh) with regard to cardiovascular (CV) outcomes can only be gleaned from observational studies. To date, there are limited studies comparing the effects of long-term TTh in men with hypogonadism who were treated or remained untreated with T, for obvious reasons. We have established a registry to assess the long-term effectiveness and safety of T in men in a urological setting. Here, we sought to compare the effects of T on a host of parameters considered to contribute to CV risk in treated and untreated men with hypogonadism (control group). Observational, prospective, cumulative registry study in 656 men (age: 60.7 ± 7.2 years) with total T levels ≤12.1 nmol/L and symptoms of hypogonadism. In the treatment group, men (n = 360) received parenteral T undecanoate (TU) 1000 mg/12 weeks following an initial 6-week interval for up to 10 years. Men (n = 296) who had opted against TTh served as controls. Median follow-up in both groups was 7 years. Measurements were taken at least twice a year, and 8-year data were analyzed. Mean changes over time between the 2 groups were compared by means of a mixed-effects model for repeated measures, with a random effect for intercept and fixed effects for time, group, and their interaction. To account for baseline differences between the 2 groups, changes were adjusted for age, weight, waist circumference, fasting glucose, blood pressure, and lipids. There were 2 deaths in the T-treated group, none was related to CV events. There were 21 deaths in the untreated (control) group, 19 of which were related to CV events. The incidence of death in 10 patient-years was 0.1145 in the control group (95% confidence interval [CI]: 0.0746-0.1756; P < .000) and 0.0092 in the T-treated group (95% CI: 0.0023-0.0368; P < .000); the estimated difference between groups was 0.0804 (95
Zhou, Shao-Hu; Weng, Zhi-Wei; Li, Tang-Lin
To investigate the effect of the method of tonifying the kidney and activating blood circulation on the testosterone secretion index (TSI) in late-onset hypogonadism (LOH) male patients with kidney deficiency and its possible mechanisms. We screened 60 LOH male patients with kidney deficiency based on the scores on Partial Androgen Deficiency in Aging Males (PADAM), the levels of serum total testosterone (TT) and luteinizing hormone (LH), and TSI (TT/LH). We randomly divided the patients into a Nan Geng Ning (NGN) group (n = 40, aged 55.02 +/- 11.37 years) and a control group (n = 20, aged 54.56 +/- 12.12 years) to be treated orally with NGN decoction and testosterone undecanoate capsules, respectively, both for 12 consecutive weeks. We obtained the scores on psychological status, physical status and sexual function and observed the changes in serum TT, LH and TSI after 4, 8 and 12 weeks of treatment. Compared with the baseline, both the NGN and control groups showed a significant reduction after 12 weeks of medication in the LH level ([5.32 +/- 2.08] vs [4.89 +/- 1.46] IU/L and [5.36 +/- 2.07] vs [4.81 +/- 1.75] IU/L, P < 0.05), psychological status score (5.2 +/- 1.3 vs 2.7 +/- 1.4 and 4.8 +/- 2.2 vs 2.9 +/- 1.2, P < 0.05), physical status score (6.9 +/- 2.5 vs 2.9 +/- 1.6 and 7.1 +/- 2.7 vs 3.1 +/- 1.5, P < 0.05) and sexual function score (10.2 +/- 3.3 vs 4.5 +/- 2.9 and 9.8 +/- 3.1 vs 4.8 +/- 3.0, P < 0.05), but a remarkable increase in the TT level ([11.13 +/- 0.69] vs [14.55 +/- 0.75] nmol/L and [10.99 +/- 0.74] vs [14.74 +/- 0.83] nmol/L, P < 0.05) and TSI ([2.14 +/- 0.65] vs [2.99 +/- 0.72] nmol/IU and ([2.05 +/- 0.73] vs [3.11 +/- 0.65] nmol/IU, P < 0.05). However, no significant differences were found between the NGN and control groups at 12 weeks in LH ([4.89 +/- 1.46] vs [4.81 +/- 1.75] IU/L, P > 0.05), TT ([14.55 +/- 0.75] vs [14.74 +/- 0.83] nmol/L, P > 0.05), TSI ([2.99 +/- 0.72] vs [3.11 +/- 0.65] nmol/IU, P > 0.05), psychological status score (2
Francou, Bruno; Paul, Charlotte; Amazit, Larbi; Cartes, Alejandra; Bouvattier, Claire; Albarel, Frédérique; Maiter, Dominique; Chanson, Philippe; Trabado, Séverine; Brailly-Tabard, Sylvie; Brue, Thierry; Guiochon-Mantel, Anne; Young, Jacques; Bouligand, Jérôme
What is the exact prevalence of Kisspeptin Receptor (KISS1R) mutations in the population of patients with normosmic congenital hypogonadotrophic hypogonadism (nCHH) by comparison with other genes, involved in gonadotrophin-releasing hormone (GnRH) release or action? KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases and were less prevalent than GnRH Receptor (GNRHR) mutations. The respective prevalence of each of the genetic causes of nCHH is unclear. Large series of patients are very rare and suffer from heterogeneity of the population of CHH studied. Patients with nCHH were consecutively enrolled in a single French referral centre and were gradually tested for KISS1R between January 2006 and April 2015. A total of 603 patients with nCHH (399 men and 204 women) were diagnosed at the Bicêtre Hospital and underwent KISS1R analysis. The GNRHR, tachykinin receptor 3 (TACR3), gonadotrophin-releasing hormone 1 (GNRH1), tachykinin 3 (TAC3) and KISS1 genes were also sequenced. Functional characterization of KISS1R mutations included a study of signal transduction using a reporter gene (serum response element-luciferase (SRE-Luc) involved in the mitogen-activated protein (MAP) kinase pathway. We detected 15 KISS1R variants (10 novel), in 12 of the 603 patients (2.0%, 95% CI [0.9-3.1]. KISS1R mutations were less prevalent than GNRHR (4.7%) and TACR3 (2.6%) mutations but more prevalent than GNRH1 (1.5%), TAC3 (1.0%) and KISS1 (0%) mutations. KISS1R mutants were present in the biallelic state in 8 of the 12 patients concerned. Among 5 men with biallelic KISS1R mutations, 4 had either micropenis or cryptorchidism. In vitro analysis of the 5 new variants present in the biallelic state (C95W, Y103*, C115W, P176R and A287E) showed a loss of function. The prevalence of TACR3, GNRH1, TAC3 and KISS1 mutations was calculated from a smaller number of nCHH patients than KISS1R and GNRHR. This should prompt caution concerning the reported prevalence
Hypogonadism, diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassaemia major followed from 1980 to 2007 in the Ferrara Centre.
Gamberini, Maria Rita; De Sanctis, Vincenzo; Gilli, Giuseppe
273 patients with thalassaemia major followed from diagnosis in the Ferrara Centre were divided into 3 cohorts (C) according to the year of birth (C1=1954-1964, 85 patients; C2=1965-1974, 129 patients; C3=1975-2001, 59 patients) in order to study the trends of endocrine complications. Menarche occurred in 52 out of 112 patients (46%), without significant differences among the 3 groups, at the mean age of 13.9+/-1.4 years. Sixty-five percent of these patients had secondary amenorrhoea at the mean age of 18.8+/-3.7 years. In males complete pubertal development occurred in 48% of patients (C1:31%, C2: 44%, C3: 63%, p<0.05) followed by secondary hypogonadism in 24% of patients above 21 years of age. Primary (80%) and central 20%) hypothyroidism were diagnosed in 31% of patients (C1: 55%, C2: 31.5%, C3: 13.4%, p<0.05), diabetes mellitus (DM) in 17% of patients (C1: 28.6%, C2: 17.2%, C3: 3.4%, p<0.05), and hypoparathyroidism in 10.6% of cases (C1: 18.7%, C2: 10.1%, C3: 3.4%, p<0.05). No difference was found in patient mean age of diagnosis of hypothyroidism, DM or hypoparathyroidism (20.4+/-8.2 years, 19+/-5 yrs and 18.5+/-5.8 yrs respectively) but in all three groups age at diagnosis significantly increased over time (hypothyroidism and DM: p<0.001; hypoparathyroidism: p<0.01). Over time the prevalence of hypothyroidism, diabetes mellitus and hypoparathyroidism increased to 24.4%, 14.7%, and 6.7%, respectively, at the time of the study. Incidences peaked in the early 1980's, and declined in the following years (primary hypothyroidism from 6.5% in 1981 to 0.9% in 2007, p<0.01; DM from 3.9% in 1986 to 0.8% in 2007, p<0.05; hypoparathyroidism 2.4% in 1984 to 0% in 2007, p<0.01) and correlated with the decrease in annual mean serum ferritin levels in all patients (p<0.001). The main risk factors associated with endocrine complications were high serum ferritin levels, poor compliance with desferioxamine (DFO) therapy, early onset of transfusion therapy (only for hypogonadism
Distinct expression patterns predict differential roles of the miRNA-binding proteins, Lin28 and Lin28b, in the mouse testis: studies during postnatal development and in a model of hypogonadotropic hypogonadism.
Gaytan, Francisco; Sangiao-Alvarellos, Susana; Manfredi-Lozano, María; García-Galiano, David; Ruiz-Pino, Francisco; Romero-Ruiz, Antonio; León, Silvia; Morales, Concepción; Cordido, Fernando; Pinilla, Leonor; Tena-Sempere, Manuel
Lin28 (also termed Lin28a) and Lin28b are related RNA-binding proteins, involved in the control of microRNA synthesis, especially of the let-7 family, with putative functions in early (embryo) development. However, their roles during postnatal maturation remain ill defined. Despite the general assumption that Lin28 and Lin28b share similar targets and functions, conclusive demonstration of such redundancy is still missing. In addition, recent observations suggest a role of Lin28 proteins in mammalian reproduction, which is yet to be defined. We document herein the patterns of RNA expression and protein distribution of Lin28 and Lin28b in mouse testis during postnatal development and in a model of hypogonadotropic hypogonadism as a result of inactivation of the kisspeptin receptor, Gpr54. Lin28 and Lin28b mRNAs were expressed in mouse testis across postnatal maturation, but their levels disparately varied between neonatal and pubertal periods, with peak Lin28 levels in infantile testes and sustained elevation of Lin28b mRNA in young adult male gonads, where relative levels of let-7a and let-7b miRNAs were significantly suppressed. In addition, Lin28 peptides displayed totally different patterns of cellular distribution in mouse testis: Lin28 was located in undifferentiated and type-A1 spermatogonia, whereas Lin28b was confined to spermatids and interstitial Leydig cells. These profiles were perturbed in Gpr54 null mouse testis, which showed preserved but irregular Lin28 signal and absence of Lin28b peptide, which was rescued by administration of gonadotropins, mainly hCG (as super-agonist of LH). In addition, increased relative levels of Lin28, but not Lin28b, mRNA and of let-7a/let-7b miRNAs were observed in Gpr54 KO mouse testes. Altogether, our data are the first to document the divergent patterns of cellular distribution and mRNA expression of Lin28 and Lin28b in the mouse testis along postnatal maturation and their alteration in a model of congenital
Mutations in CUL4B, Which Encodes a Ubiquitin E3 Ligase Subunit, Cause an X-linked Mental Retardation Syndrome Associated with Aggressive Outbursts, Seizures, Relative Macrocephaly, Central Obesity, Hypogonadism, Pes Cavus, and Tremor
Tarpey, Patrick S. ; Raymond, F. Lucy ; O’Meara, Sarah ; Edkins, Sarah ; Teague, Jon ; Butler, Adam ; Dicks, Ed ; Stevens, Claire ; Tofts, Calli ; Avis, Tim ; Barthorpe, Syd ; Buck, Gemma ; Cole, Jennifer ; Gray, Kristian ; Halliday, Kelly ; Harrison, Rachel ; Hills, Katy ; Jenkinson, Andrew ; Jones, David ; Menzies, Andrew ; Mironenko, Tatiana ; Perry, Janet ; Raine, Keiran ; Richardson, David ; Shepherd, Rebecca ; Small, Alexandra ; Varian, Jennifer ; West, Sofie ; Widaa, Sara ; Mallya, Uma ; Moon, Jenny ; Luo, Ying ; Holder, Susan ; Smithson, Sarah F. ; Hurst, Jane A. ; Clayton-Smith, Jill ; Kerr, Bronwyn ; Boyle, Jackie ; Shaw, Marie ; Vandeleur, Lucianne ; Rodriguez, Jayson ; Slaugh, Rachel ; Easton, Douglas F. ; Wooster, Richard ; Bobrow, Martin ; Srivastava, Anand K. ; Stevenson, Roger E. ; Schwartz, Charles E. ; Turner, Gillian ; Gecz, Jozef ; Futreal, P. Andrew ; Stratton, Michael R. ; Partington, Michael
We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority. PMID:17236139
The Ability of Lumbar Spine DXA and Phalanx QUS to Detect Previous Fractures in Young Thalassemic Patients With Hypogonadism, Hypothyroidism, Diabetes, and Hepatitis-B: A 2-Year Subgroup Analysis From the Taranto Area of Apulia Region
Neglia, Cosimo; Peluso, Angelo; di Rosa, Salvatore; Ferrarese, Antonio; Di Tanna, Gianluca; Caiaffa, Vincenzo; Benvenuto, Marco; Cozma, Alexandru; Chitano, Giovanna; Agnello, Nadia; Paladini, Daniele; Baldi, Nicola; Distante, Alessandro; Piscitelli, Prisco
Background: Osteoporosis is a leading cause of morbidity in patients affected by β-thalassemia major or intermediate; we aimed to assess the association between demineralization observed in young thalassemic patients. Methods: A total of 88 patients with β-thalassemia were recruited at Microcitemia Center of Taranto Hospital under the Prevention Osteoporosis and Fractures research project from 2008 to 2010. All the patients were screened with both dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS). T score and Z score values were obtained for each subject. Results: The overall prevalence of demineralization was 84% with DXA and 70% with QUS, whereas normality was found in 16% of patients screened with DXA and in 30% of cases with QUS. Hypogonadism, hypothyroidism, diabetes mellitus, hepatitis-B, and the presence of previous fragility fractures were significantly associated with the demineralization status (lower T scores values) both with DXA and QUS. Conclusion: Our data confirm that DXA and QUS examinations are both useful for detecting bone demineralization in thalassemic patients. PMID:23652868
Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study.
Yassin, A A; Nettleship, J; Almehmadi, Y; Salman, M; Saad, F
Subnormal levels of testosterone are associated with significant negative health consequences, with higher risks of all-cause and cardiovascular mortality. The numbers of studies reporting on the benefits of normalisation of testosterone is increasing but longer-term data on (elderly) men receiving testosterone treatment are almost nonexistent. In this single-centre, cumulative, prospective, registry study, 115 hypogonadal men (mean age 59.05 years) received injections with testosterone undecanoate in 12-week intervals for up to 10 years. Waist circumference, body weight and mean BMI dropped progressively with statistical significance versus previous year for 7 years and, respectively, 8 years for weight and body mass index. Similarly, fasting glucose displayed a significant decrease after the first year continuing to decrease thereafter. A decline in HbA1c , from 6.4% to 5.6% (mean <6%), was observed from year 2 on, together with a decrease in the ratio of triglycerides:high-density lipoprotein (HDL), a surrogate marker of insulin resistance, with an increase in HDL levels. The total cholesterol:HDL ratio and non-HDL cholesterol declined significantly. A decrease was also observed in systolic and diastolic blood pressure, with a decrease in levels of the inflammation marker C-reactive protein. No major adverse cardiovascular events were observed throughout the study.
Chen, Wei; Liu, Zhi-Yong; Wang, Lin-Hui; Zeng, Qin-Song; Wang, Hui-Qing; Sun, Ying-hao
The Aging Male's Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire have been widely used for screening men suspected of late-onset hypogonadism (LOH). We evaluated the consistency of the two questionnaires with sex hormone levels. A total of 985 men completed the two questionnaires, as well as an analysis of the serum levels of total testosterone (TT), bioavailable testosterone (BT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL) and sex hormone-binding globulin (SHBG). No correlation was observed between any hormone level and the psychological or somatic section of the AMS score, whereas the sexual section was correlated with the levels of FT, LH, FSH, SHBG and BT. Significant correlations were observed between the result of the two questionnaires and these hormone levels. When LOH was defined as TT < 300 ng/dl and FT < 5 ng/dl, the sensitivity and specificity of the AMS scale were 54.0% and 41.2% compared with 78.7% and 14.8% for the ADAM questionnaire. Several sex hormone levels correlated with the two questionnaires, but neither of these questionnaires had sufficient sensitivity and specificity. It is necessary to provide a new questionnaire applicable to the Chinese population to screening LOH.
Karavolos, Stamatios; Reynolds, Michael; Panagiotopoulou, Nikoletta; McEleny, Kevin; Scally, Michael; Quinton, Richard
Androgen- or anabolic steroid-induced hypogonadism (ASIH) is no longer confined to professional athletes; its prevalence amongst young men and teenagers using androgens and/or anabolic steroids (AASs) is rising fast, and those affected can experience significant symptoms. Clinicians are increasingly encountering demanding, well-informed men affected by ASIH, yet lacking authoritative information on the subject may struggle to project a credible message. In this article, we overview the methods and drugs that men use in an attempt to counteract ASIH (with a view to either preventing its onset, or reversing it once it has developed) and summarize the scientific evidence underpinning these. The main channel for obtaining these drugs is the Internet, where they can be readily sourced without a valid prescription. An Internet search using relevant terms revealed a huge number of websites providing advice on how to buy and use products to counteract ASIH. Drugs arising repeatedly in our search included human chorionic gonadotrophin (hCG), selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The quality and accuracy of the online information was variable, but review of medical literature also highlighted a lack of scientific data to guide clinical practice. It is important for clinicians to be aware of the AAS user's self-treatment strategies with regard to ASIH side-effect mitigation. By ensuring that they are well-informed, clinicians are more likely to retain the credibility and trust of AAS users, who will in turn likely be more open to engage with appropriate management. © 2014 John Wiley & Sons Ltd.
The rs5934505 single nucleotide polymorphism (SNP) is associated with low testosterone and late-onset hypogonadism, but the rs10822184 SNP is associated with overweight and obesity in a Chinese Han population: a case-control study.
Chen, Y-P; Nie, L-L; Li, H-G; Liu, T-H; Fang, F; Zhao, K; Yang, R-F; Ma, X-L; Kong, X-B; Zhang, H-P; Guan, H-T; Xia, W; Hong, W-X; Duan, S; Zeng, X-C; Shang, X-J; Zhou, Y-Z; Gu, Y-Q; Wu, W-X; Xiong, C-L
Low testosterone is associated with late-onset hypogonadism (LOH) and obesity. Recently, studies have shown that four single nucleotide polymorphisms (SNPs), rs12150660, rs727428, rs5934505, and rs10822184, are associated with testosterone levels in populations of European descent. Therefore, we investigated whether the SNP loci are related to low testosterone, LOH, or obesity in a Chinese Han population. Ruling out co-morbidities, DNA was prepared from 409 men (aged 40-65 years) with low serum testosterone (defined as total testosterone <11.6 nmol/L) and 1 : 1 normal controls (matched age, body mass index (BMI), and the same living area) who were selected from 6898 males. According to the same standards, 310 men with LOH and 1 : 1 normal controls were selected from 6898 males. Excluding the cases with an unreliable sequencing result, genetic analyses were performed. The minor allele frequencies of the SNP loci rs12150660, rs727428, rs5934505, and rs10822184 were 0.1%, 44.6%, 18.7%, and 38.9%, respectively. rs5934505 was associated with the serum total testosterone and calculated free testosterone (CFT) levels (p = 0.045 and p = 0.021). rs5934505 (C>T) was associated with an increased risk of low total testosterone, low CFT, and LOH and adjusted for other factors, with an odds ratio (OR) of 2.01 (1.34-3.01), 2.14 (1.42-3.20), and 1.64 (1.04-2.58). rs10822184 was significantly correlated with weight and BMI (p = 0.035 and p = 0.027). rs10822184 (T>C) was associated with an increased risk of overweight and obesity. We adjusted for other factors, with odds ratios (ORs) of 1.94 (1.36-2.78) and 1.56 (1.00-2.43). In summary, our study provided convincing evidence that rs5934505 (C>T) was associated with the risk of low testosterone and LOH in Chinese populations. We were the first to find that rs10822184 (T>C) was significantly correlated with the risk of overweight and obesity in Chinese populations. However, further large and functional studies are warranted to confirm
Lecomte, P; de Meeus, M C; Lorette, G; Lansac, J; Soutoul, J H
The authors have studied the toxicity of alkylating agents on the gonads in the light of three cases. The more frequent prescription of these products in chemotherapy when treating cases in Nephrology, Dermatology, Neurology and Ophthalmology as well as general systemic diseases, should make the doctor prescribing them look out for the risks that the reproductive function runs in their use. Although of course there is no valid discussion of the use of these drugs when life is at stake one should all the same, seeing how their efficacy is increasing and survival is becoming more likely, ask oneself about their bad effects on the gonads, and in particular when they are being used for less serious indications. The gonads are often attacked early and insidiously, the the effects on them often starting before the more spectacular secondary effects such as alopecia or neutropenia. A review of the literature brings to light the following : there is a more marked effect on the gonad when it is the testis than when it is the ovary, which seems to be progressively affected; the lesions become worse and increase according to the pubertal state of the male. As far as testicular damage is concerned, it seems debatable whether is is dose-related or related to the length of treatment, and the chances of recovery on stopping chemotherapy with alkylating agents seen to be overall poor. On the practical level the use of sperm banks may resolve some of the worries about later infertility. As far as women are concerned, the greater resistance of the ovary to the effects should make one careful to employ contraceptive measures which are necessary during and after treatment (for fear of teratogenicity).
Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, ...
Weinstein, R L; Reitz, R E
An isolated deficiency of pituitary gonadotropins was demonstrated in six 46 XY males, 22 to 36 years of age, with and without anosmia. Undetectable or low levels of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) clearly separated hypogonadotropic from normal adult males. Chronic (8-12 wk) administration of clomiphene citrate caused no increase in serum FSH or LH in gonadotropin-deficient subjects. However, the administration of synthetic luteinizing hormone releasing factor (LRF) resulted in the appearance of serum LH and, to a lesser degree, serum FSH in three subjects tested. While levels of plasma testosterone were significantly lower in gonadotropin-deficient subjects, plasma androstenedione and dehydroepiandrosterone were in a range similar to that of age-matched normal men. Treatment with human chorionic gonadotropin (HCG) increased levels of plasma testosterone to normal adult male values in all gonadotropin-deficient subjects. Cessation of treatment with HCG resulted in the return of plasma testosterone to low, pretreatment levels. That HCG therapy with resultant normal levels of plasma testosterone may somehow stimulate endogenous gonadotropin secretion in gonadotropin-deficient subjects was not evident. The adult male levels of serum FSH and LH after LRF, and plasma testosterone after HCG, confirm pituitary and Leydig cell responsiveness in these subjects. Images PMID:11344554
Rizk, Paul J; Kohn, Taylor P; Pastuszak, Alexander W; Khera, Mohit
Erectile dysfunction and decreased libido are common complaints in the older male population. Recent studies have elucidated the role testosterone therapy (TTh) can play in men with low testosterone levels. The aim of this review is to provide an overview of these findings and the utility of TTh. We specifically examine the role of TTh on erectile function, coadministration with phosphodiesterase type 5 inhibitors, and libido. Recent publications suggest that TTh improves mild erectile dysfunction, though may be less useful in men with more severe erectile dysfunction. In men unresponsive to phosphodiesterase type 5 inhibitors and with mild erectile dysfunction, TTh can further improve erectile function. TTh has also shown consistent benefit in improving libido in men with low testosterone levels at baseline, with no additional improvements once testosterone levels are normalized. The available literature supports a role for TTh in men with low testosterone levels, erectile dysfunction, and low libido, with symptomatic improvement in these men.
d'Anglemont de Tassigny, Xavier; Fagg, Lisa A.; Dixon, John P. C.; Day, Kate; Leitch, Harry G.; Hendrick, Alan G.; Zahn, Dirk; Franceschini, Isabelle; Caraty, Alain; Carlton, Mark B. L.; Aparicio, Samuel A. J. R.; Colledge, William H.
The G protein-coupled receptor GPR54 (AXOR12, OT7T175) is central to acquisition of reproductive competency in mammals. Peptide ligands (kisspeptins) for this receptor are encoded by the Kiss1 gene, and administration of exogenous kisspeptins stimulates hypothalamic gonadotropin-releasing hormone (GnRH) release in several species, including humans. To establish that kisspeptins are the authentic agonists of GPR54 in vivo and to determine whether these ligands have additional physiological functions we have generated mice with a targeted disruption of the Kiss1 gene. Kiss1-null mice are viable and healthy with no apparent abnormalities but fail to undergo sexual maturation. Mutant female mice do not progress through the estrous cycle, have thread-like uteri and small ovaries, and do not produce mature Graffian follicles. Mutant males have small testes, and spermatogenesis arrests mainly at the early haploid spermatid stage. Both sexes have low circulating gonadotropin (luteinizing hormone and follicle-stimulating hormone) and sex steroid (β-estradiol or testosterone) hormone levels. Migration of GnRH neurons into the hypothalamus appears normal with appropriate axonal connections to the median eminence and total GnRH content. The hypothalamic–pituitary axis is functional in these mice as shown by robust luteinizing hormone secretion after peripheral administration of kisspeptin. The virtually identical phenotype of Gpr54- and Kiss1-null mice provides direct proof that kisspeptins are the true physiological ligand for the GPR54 receptor in vivo. Kiss1 also does not seem to play a vital role in any other physiological processes other than activation of the hypothalamic–pituitary–gonadal axis, and loss of Kiss1 cannot be overcome by compensatory mechanisms. PMID:17563351
Bonomi, M; Rochira, V; Pasquali, D; Balercia, G; Jannini, E A; Ferlin, A
Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients' interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.
Muñoz, M T; Argente, J
Anorexia nervosa is a chronic illness that involves a reduction in caloric intake, loss of weight and amenorrhoea, either primary or secondary. In addition to prolonged amenorrhoea, osteopenia and osteoporosis are the most frequent complications. Patients exhibit an alteration in the hypothalamic-pituitary-gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotrophin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotrophin secretion. The loss of fat tissue, as a consequence of the restriction of nutrients, has been associated with hypoleptinaemia, abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotrophin-releasing hormone, among others) and diminution of the amount of total body fat. Despite oestrogen therapy, the severe loss of bone mass may progress. Other factors such as weight loss, duration of amenorrhoea and low insulin-like growth factor-I (IGF-I) levels could contribute to the loss of bone mass in women with anorexia nervosa. The recuperation of weight and, in particular, the amount of total body fat could lead to the spontaneous recuperation of menstruation. Copyright 2002 S. Karger AG, Basel
Kottler, M L; Richard, N; Chabre, O; Alain, S; Young, J
We report a woman with primary amenorrhoea and infertility associated with an isolated deficiency of pituitary FSH that does not respond to GnRH administration. Serum inhibin B was undetectable and antimullerian hormone (AMH) was within the normal range. Ultra sound examination revealed a small uterus and small ovaries with few small follicles. We identified an homozygous 1-bp (G) deletion at codon 79 in FSHbeta gene suggesting a complete loss of function. The patient underwent studies of ovarian responsiveness to recombinant human FSH according to the following protocol: 150UI/d for five days following by 75 UI/d for 10 days. Estradiol plasma level started to increase from day 5 associated to a sharp increase of inhibine B and a decrease of LH. During the same time, we observed an excessive development of multiple follicles resulting in an arrest of the treatment to avoid hyperstimulation. The present study confirm that follicles up to 5 mm in diameter had developed in the absence of FSH and that FSH is required for the growth of follicles beyond the two-layer granulose stage.
Chillarón, Juan J; Fernández-Miró, Mercè; Albareda, Mercè; Fontserè, Sara; Colom, Cristina; Vila, Lluís; Pedro-Botet, Juan; Flores Le-Roux, Juana A
Testosterone deficiency (Td) has been associated with the metabolic syndrome. Few studies have evaluated this condition in type 1 diabetes (T1D). The primary aim of this study was to evaluate the effectiveness of testosterone undecanoate (TU) on insulin sensitivity, glycemic control, anthropometric parameters, blood pressure and lipid profile in patients with Td and T1D. We performed a randomized placebo-controlled multicenter study.
Meyer-Bahlburg, Heino F. L.
The categorization of gender identity variants (GIVs) as “mental disorders” in the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association (APA) is highly controversial among professionals as well as among persons with GIV. After providing a brief history of GIV categorizations in the DSM, this paper presents some of the major issues of the ongoing debate: GIV as psychopathology versus natural variation; definition of “impairment” and “distress” for GID; associated psychopathology and its relation to stigma; the stigma impact of the mental-disorder label itself; the unusual character of “sex reassignment surgery” as a psychiatric treatment; and the consequences for health and mental-health services if the disorder label is removed. Finally, several categorization options are examined: Retaining the GID category, but possibly modifying its grouping with other syndromes; narrowing the definition to dysphoria and taking “disorder” out of the label; categorizing GID as a neurological or medical rather than a psychiatric disorder; removing GID from both the DSM and the International Classification of Diseases (ICD); and creating a special category for GIV in the DSM. I conclude that--as also evident in other DSM categories--the decision on the categorization of GIVs cannot be achieved on a purely scientific basis, and that a consensus for a pragmatic compromise needs to be arrived at that accommodates both scientific considerations and the service needs of persons with GIVs. PMID:19851856
Kahr, W H; Al-Homadhi, A; Meharchand, J; Bailey, D J; Stewart, A K
We present a case of a 55 year old man with multiple myeloma who underwent autologous stem cell transplantation and subsequently developed testicular myeloma. Testicular enlargement was observed only after treatment of an incidental prostatic adenocarcinoma with chemical orchidectomy at a time when myeloma was controlled systemically. A subsequent bilateral surgical orchiectomy revealed plasmacytoma in both testis. Enhanced production of B-lymphocytes after castration has been reported and implicates testosterone as a possible negative regulator of B-cell production. We propose that the androgen deficient state may have contributed to the development of plasmacytoma of the testes in our patient. The regulatory role of sex steroids in B-cell development is discussed.
Hadziselimovic, Faruk; Gegenschatz-Schmid, Katharina; Verkauskas, Gilvydas; Docampo-Garcia, Maria J; Demougin, Philippe; Bilius, Vytautas; Malcius, Dalius; Dasevicius, Darius; Stadtler, Michael B
The whole genome RNA profiling of testicular biopsies by DNA strand-specific RNA sequencing was examined to determine a potential causative role of isolated congenital cryptorchidism in azoospermia and/or infertility in the context of our previously published GeneChip data. Cryptorchid patients, aged 7 months to 5 years and otherwise healthy, were enrolled in this prospective study. During surgery, testicular tissue biopsies were obtained for histological examination and RNA sequencing. Fifteen patients were selected based on the histological results and were divided into 2 groups. Seven were classified as belonging to the high infertility risk (HIR) and 8 to the low infertility risk (LIR) group. Cryptorchid boys in the HIR group lacked transformation of gonocytes into Ad spermatogonia due to impaired mini-puberty. This group of patients will be infertile despite successful surgery. The new important finding was a decreased PROK2, CHD7, FGFR1, and SPRY4 gene expression in the HIR group. Furthermore, identification of multiple differences in gene expression between HIR and LIR groups underscores the importance of an intact hypothalamic-pituitary-gonadal axis for fertility development. Our RNA profiling data strongly support the theory that in the HIR group of cryptorchid boys insufficient PROK2/CHD7/FGFR1/SPRY4 gene expression induces deficient LH secretion, resulting in impaired mini-puberty and infertility. We therefore recommend hormonal treatment for this cohort of cryptorchid boys with defective mini-puberty following a seemingly successful orchidopexy.
Schilling, Stephan; Kohlmann, Stephanie; Bäuscher, Christoph; Sedlmeier, Reinhard; Koch, Birgit; Eichentopf, Rico; Becker, Andreas; Cynis, Holger; Hoffmann, Torsten; Berg, Sabine; Freyse, Ernst-Joachim; von Hörsten, Stephan; Rossner, Steffen; Graubner, Sigrid; Demuth, Hans-Ulrich
Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at the N terminus of peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone and gonadotropin-releasing hormone are essential for regulation of metabolism and fertility in the hypothalamic pituitary thyroid and gonadal axes, respectively. Here, we analyzed the consequences of constitutive genetic QC ablation on endocrine functions and on the behavior of adult mice. Adult homozygous QC knock-out mice are fertile and behave indistinguishably from wild type mice in tests of motor function, cognition, general activity, and ingestion behavior. The QC knock-out results in a dramatic drop of enzyme activity in the brain, especially in hypothalamus and in plasma. Other peripheral organs like liver and spleen still contain QC activity, which is most likely caused by its homolog isoQC. The serum gonadotropin-releasing hormone, TSH, and testosterone concentrations were not changed by QC depletion. The serum thyroxine was decreased by 24% in homozygous QC knock-out animals, suggesting a mild hypothyroidism. QC knock-out mice were indistinguishable from wild type with regard to blood glucose and glucose tolerance, thus differing from reports of thyrotropin-releasing hormone knock-out mice significantly. The results suggest a significant formation of the hypothalamic pGlu hormones by alternative mechanisms, like spontaneous cyclization or conversion by isoQC. The different effects of QC depletion on the hypothalamic pituitary thyroid and gonadal axes might indicate slightly different modes of substrate conversion of both enzymes. The absence of significant abnormalities in QC knock-out mice suggests the presence of a therapeutic window for suppression of QC activity in current drug development. PMID:21330373
Lakshman, Kishore M; Basaria, Shehzad
Transdermal testosterone gels were first introduced in the US in 2000. Since then, they have emerged as a favorable mode of testosterone substitution. Serum testosterone levels reach a steady-state in the first 24 hours of application and remain in the normal range for the duration of the application. This pharmacokinetic profile is comparable to that of testosterone patch but superior to injectable testosterone esters that are associated with peaks and troughs with each dose. Testosterone gels are as efficacious as patches and injectable forms in their effects on sexual function and mood. Anticipated increases in prostate-specific antigen with testosterone therapy are not significantly different with testosterone gels, and the risk of polycythemia is lower than injectable modalities. Application site reactions, a major drawback of testosterone patches, occur less frequently with testosterone gels. However, inter-personal transfer is a concern if appropriate precautions are not taken. Superior tolerability and dose flexibility make testosterone gel highly desirable over other modalities of testosterone replacement. Androgel and Testim, the two currently available testosterone gel products in the US, have certain brand-specific properties that clinicians may consider prior to prescribing. PMID:19966909
Al Attia, Haider M; Jaysundaram, Krishnasamy; Saraj, Fouad
The aim of the study is to study the relationship between androgen levels and bone mineral density (BMD) in elderly Arab males. Forty-five elderly Arab males underwent Dual X-ray absorptiometry for measurement of BMD. The outcomes were defined as per WHO description. Assays for testosterone (T), gonadotropins (LH and FSH) and estradiol (E2), in the serum were carried out. The ratio of T/LH was used as a surrogate for the cFT assay. We excluded patients receiving hormonal ablation for prostatic neoplasm and patients with chronic liver or renal disease and patients receiving corticosteroids. Twelve were osteoporotic (26.5%); 22 osteopenic (49%); and 11(24.5%) had normal outcome. Osteoporotic patients were significantly older (78.17 +/- 7.59 years) than the osteopenic (70.14 +/- 5.92, P
Yassin, Aksam A; Saad, Farid
Recently, testosterone undecanoate (TU), a new parenteral testosterone (T) preparation has been introduced. Two of its distinctive features are (a) its prolonged action: after two initial loading injections 6 weeks apart, usually only one injection every 12 weeks is needed (b) over the full interval between two injections, plasma T levels are in the physiological range. New research presents convincing evidence that T has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, which is, at least, in part reversible upon androgen therapy. Our studies with TU demonstrated that venous leakage could be corrected with T treatment in a number of patients. We further could show that sexual functions, in a substantial number of elderly men, can be restored with treatment with T only. So, these results argue for determination of T levels in elderly men with sexual problems. If the levels are subnormal, T treatment is warranted.
Corona, Giovanni; Rastrelli, Giulia; Monami, Matteo; Saad, Farid; Luconi, Michaela; Lucchese, Marcello; Facchiano, Enrico; Sforza, Alessandra; Forti, Gianni; Mannucci, Edoardo; Maggi, Mario
Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men generally have shown an increase in testosterone levels. The aim of this study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels. Meta-analysis. An extensive Medline search was performed including the following words: 'testosterone', 'diet', 'weight loss', 'bariatric surgery', and 'males'. The search was restricted to data from January 1, 1969 up to August 31, 2012. Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or bariatric surgery, whereas two compared diet and bariatric surgery. Overall, both a low-calorie diet and bariatric surgery are associated with a significant (P<0.0001) increase in plasma sex hormone-binding globulin-bound and -unbound testosterone levels (total testosterone (TT)), with bariatric surgery being more effective in comparison with the low-calorie diet (TT increase: 8.73 (6.51-10.95) vs 2.87 (1.68-4.07) for bariatric surgery and the low-calorie diet, respectively; both P<0.0001 vs baseline). Androgen rise is greater in those patients who lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity. Body weight loss is also associated with a decrease in estradiol and an increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (B=2.50±0.98, P=0.029). These data show that weight loss is associated with an increase in both bound and unbound testosterone levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity.
Bailey, W A; Zwingman, T A; Reznik, V M; Griswold, W R; Mendoza, S A; Jones, K L; Freidenberg, G R
To determine the cause of absent sexual development in a 17-year-old girl with end-stage renal disease. Case study. Seventeen-year-old girl with end-stage renal failure. None. The patient had phenotypically normal external female genitalia, müllerian duct hypoplasia, and no ovaries. Her serum gonadotropin levels were in the castrate range at baseline and after gonadotropin-releasing hormone stimulation. Her karyotype, in lymphocytes and cultured fibroblasts, was 46,XX. Analysis of genomic DNA, following polymerase chain reaction-amplication with oligonucleotide primers corresponding to the Y-encoded zinc finger protein ZFY and the testis-determining SRY gene, showed Y chromosome material in a male control but none in the patient. The results suggest a diagnosis of Frasier syndrome, a disorder characterized by true gonadal dysgenesis and end-stage renal disease occurring in normal phenotypic girls. Although previously reported only in individuals with a 46,XX karyotype, our studies indicate that Frasier syndrome may also occur in 46,XX girls. Delayed puberty is not uncommon in renal failure. This case illustrates the importance of measuring gonadotropin levels in teenage girls with delayed puberty and renal failure, particularly if the origin of the renal disease is obscure.
Schrader, Shannon; Mills, Anthony; Scheperle, Mark; Block, Jon E
Impairment in gonadal function with reduced testosterone (T) levels is commonly associated with HIV infection and patients often complain of diminished libido and sexual dysfunction. The effectiveness of Testim 1% (Auxilium Pharmaceuticals, Inc., Norristown, Pennsylvania) topical T gel was evaluated in HIV-positive males who failed to experience satisfactory symptom relief following prior treatment with AndroGel 1% (Solvay Pharmaceuticals, Inc., Marietta, Georgia). In this open-label study, consecutive subjects were randomly assigned to experimental treatment with Testim 1% (5 g) or to maintenance therapy (control group) with AndroGel 1% (5 g). Twenty-four experimental subjects and 24 control subjects were followed for 4 weeks to evaluate improvements in sexual functioning and satisfaction. Changes from baseline in the 5 domains of the Brief Male Sexual Function Inventory (BMSFI) were compared between groups. The average percentage improvement favored the experimental treatment in all 5 comparisons of the BMSFI, including sexual drive (53% vs 18%, P < 0.001), erectile function (49% vs 7%, P < 0.004), ejaculatory function (15% vs 8%, P < 0.14), problem assessment (59% vs 12%, P < 0.003), and sexual satisfaction (58% vs 9%, P < 0.006). A greater percentage of subjects also reported satisfaction with the experimental treatment (85% vs 48%, P < 0.03), and these subjects were less likely to require upward dose titration at the final follow-up visit (30% vs 74%, P = 0.01). It is hypothesized that the results of the current study may be explained, in part, by an improved pharmacokinetic profile of the experimental intervention. Consideration of Testim 1% gel in HIV patients who have an inadequate response to prior T therapy is encouraged, although it is difficult to estimate the contribution of nonspecific study effects (eg, placebo) in this trial.
Sánchez-Garrido, Miguel Angel; Ruiz-Pino, Francisco; Manfredi-Lozano, Maria; Leon, Silvia; Garcia-Galiano, David; Castaño, Justo P; Luque, Raul M; Romero-Ruiz, Antonio; Castellano, Juan M; Diéguez, Carlos; Pinilla, Leonor; Tena-Sempere, Manuel
Reproduction is sensitive to insufficient body energy reserves, especially in females. Metabolic regulation of the male reproductive axis is less obvious, and the impact of conditions of persistent energy excess has received moderate attention. Yet, the escalating prevalence of obesity and the clinical evidence of its deleterious effects on male fertility have raised considerable concerns. We report here phenotypic and mechanistic studies of the reproductive impact of postnatal nutritional manipulations (mainly overnutrition) coupled to a high-fat diet (HFD) after weaning. Metabolic and hormonal analyses in young (4 months old) and middle-aged (10 months old) animals revealed that HFD caused profound metabolic perturbations, including glucose intolerance, which were worsened by precedent postnatal overfeeding; these were detectable already in young males but aggravated in 10-month-old rats. Impairment of reproductive parameters took place progressively, and HFD alone was sufficient to explain most of these alterations, regardless of postnatal under- or overnutrition. In young males, testosterone (T) levels and steroidogenic enzyme expression were suppressed by HFD, without compensatory increases of LH levels, which were in fact partially inhibited in heavier males. In addition, obese males displayed suppressed hypothalamic Kiss1 expression despite low T, and HFD inhibited LH responses to kisspeptin. Overweight anticipated some of the neuroendocrine effects of aging, such as the suppression of hypothalamic Kiss1 expression and the decline in serum T and LH levels. Nonetheless, HFD per se caused a detectable worsening of key reproductive indices in middle-aged males, such as basal LH and FSH levels as well as LH responses to kisspeptin. Our study demonstrates that nutritional stress, especially HFD, has a profound deleterious impact on metabolic and gonadotropic function as well as on the Kiss1 system and precipitates neuroendocrine reproductive senescence in the male.
Lippincott, Margaret F; True, Cadence; Seminara, Stephanie B
Mutations in the genes encoding the neuropeptides kisspeptin and neurokinin B, as well as their receptors, are associated with gonadotrophin-releasing hormone (GnRH) deficiency and a failure to initiate and/or progress through puberty. Although the total number of patients studied to date is small, mutations in the kisspeptin pathway appear to result in lifelong GnRH deficiency. Mice with mutations in kisspeptin and the kisspeptin receptor, Kiss1(-/-) and Kiss1r(-/-), respectively, appear to be phenocopies of the human with abnormal sexual maturation and infertility. In contrast, mutations in the neurokinin B pathway lead to a more variable adult reproductive phenotype, with a subset of hypogonadotrophic individuals demonstrating paradoxical recovery of reproductive function later in life. While 'reversal' remains poorly understood, the ability to recover reproductive function indicates that neurokinin B may play different roles in the initiation of sexual maturation compared with the maintenance of adult reproductive function. Mice with mutations in the gene encoding the neurokinin B receptor, Tacr3, have abnormal oestrous cycles and subfertility but, similar to their human counterparts, appear less severely affected than mice with kisspeptin deficiency. Further investigations into the interaction between the kisspeptin and neurokinin B pathways will reveal key insights into how GnRH neuronal modulation occurs at puberty and throughout reproductive life.
Schilling, Stephan; Kohlmann, Stephanie; Bäuscher, Christoph; Sedlmeier, Reinhard; Koch, Birgit; Eichentopf, Rico; Becker, Andreas; Cynis, Holger; Hoffmann, Torsten; Berg, Sabine; Freyse, Ernst-Joachim; von Hörsten, Stephan; Rossner, Steffen; Graubner, Sigrid; Demuth, Hans-Ulrich
Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at the N terminus of peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone and gonadotropin-releasing hormone are essential for regulation of metabolism and fertility in the hypothalamic pituitary thyroid and gonadal axes, respectively. Here, we analyzed the consequences of constitutive genetic QC ablation on endocrine functions and on the behavior of adult mice. Adult homozygous QC knock-out mice are fertile and behave indistinguishably from wild type mice in tests of motor function, cognition, general activity, and ingestion behavior. The QC knock-out results in a dramatic drop of enzyme activity in the brain, especially in hypothalamus and in plasma. Other peripheral organs like liver and spleen still contain QC activity, which is most likely caused by its homolog isoQC. The serum gonadotropin-releasing hormone, TSH, and testosterone concentrations were not changed by QC depletion. The serum thyroxine was decreased by 24% in homozygous QC knock-out animals, suggesting a mild hypothyroidism. QC knock-out mice were indistinguishable from wild type with regard to blood glucose and glucose tolerance, thus differing from reports of thyrotropin-releasing hormone knock-out mice significantly. The results suggest a significant formation of the hypothalamic pGlu hormones by alternative mechanisms, like spontaneous cyclization or conversion by isoQC. The different effects of QC depletion on the hypothalamic pituitary thyroid and gonadal axes might indicate slightly different modes of substrate conversion of both enzymes. The absence of significant abnormalities in QC knock-out mice suggests the presence of a therapeutic window for suppression of QC activity in current drug development.
Orshan, Susan A.; Ventura, June L.; Covington, Sharon N.; Vanderhoof, Vien H.; Troendle, James F.; Nelson, Lawrence M.
Objective To test the hypothesis that women with spontaneous primary ovarian insufficiency differ from control women with regard to perceived social support and to investigate the relationship between perceived social support and self-esteem. Design Cross-sectional Setting Mark O. Hatfield Clinical Research Center, National Institutes of Health. Patient(s) Women diagnosed with spontaneous primary ovarian insufficiency (N=154) at a mean age of 27 years and healthy control women (N=63). Intervention(s) Administration of validated self-reporting instruments. Main Outcome Measure(s) Personal Resource Questionnaire-85 (PRQ85), Rosenberg Self-Esteem Scale Result(s) Women with primary ovarian insufficiency had significantly lower scores than controls on the perceived social support scale and the self-esteem scale. The findings remained significant after modeling with multivariate regression for differences in age, marital status, and having children. In patients there was a significant positive correlation between self-esteem scores and perceived social support. We found no significant differences in perceived social support or self-esteem related to marital status, whether or not they had children, or time since diagnosis. Conclusion(s) This evidence supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous primary ovarian insufficiency. PMID:18829005
Hackett, Geoffrey; Cole, Nigel; Bhartia, Mithun; Kennedy, David; Raju, Jessie; Wilkinson, Peter
The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established and current endocrine society guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes or erectile dysfunction. We report the first double-blind, placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess metabolic changes with long-acting testosterone undecanoate (TU). The type 2 diabetes registers of seven general practices identified 211 patients for a 30-week double-blind, placebo-controlled study of long-acting TU 1,000 mg followed by 52 weeks of open-label use. Because of the established impact of age, obesity, and depression on sexual function, these variables were also assessed for influence on metabolic parameters. Changes in glycated hemoglobin (HbA1c) and the level of testosterone at which response are achieved. Treatment with TU produced a statistically significant reduction in HbA1c at 6 and 18 weeks and after a further 52 weeks of open-label medication most marked in poorly controlled patients with baseline HbA1c greater than 7.5 where the reduction was 0.41% within 6 weeks, and a further 0.46% after 52 weeks of open-label use. There was significant reduction in waist circumference, weight, and body mass index in men without depression, and improvements were related to achieving adequate serum levels of testosterone. There were no significant safety issues. Testosterone replacement therapy significantly improved HbA1c, total cholesterol, and waist circumference in men with type 2 diabetes. Improvements were less marked in men with depression at baseline, and therapeutic responses were related to achieving adequate serum testosterone levels. Current advice on 3- to 6-month trials of therapy may be insufficient to achieve maximal response. Patients reported significant improvements in general health. © 2013 International Society for Sexual Medicine.
Doria, Carlo; Leali, Paolo Tranquilli; Solla, Federico; Maestretti, Gianluca; Balsano, Massimo; Scarpa, Robero Mario
Summary Introduction Osteoporosis is a complication of androgen deprivation therapy (ADT) in men with prostate carcinoma. The best defense against osteoporosis in prostate cancer is to identify patients with a high risk for fracture during the first clinical visit, select an effective anti-osteoporosis agent, and advise the patient to change his lifestyle and diet to prevent further bone loss. New agents include denosumab, a human monoclonal antibody that inhibits the RANK ligand (RANKL). RANKL promotes the formation, activity, and survival of osteoclasts and, thus, supports the breakdown of bone. Purpose This is a multicenter, randomized, double-blind prospective study on use of denosumab versus alendronate in the therapy of secondary osteoporosis related to ADT in prostate cancer patients in three European countries (Italy, France, Switzerland). Patients and methods In this 24-month observation study we enrolled 234 patients with diagnosis of osteoporosis underwent ADT for prostate cancer. All patients aged ≥55 years and had a dual-energy X-ray absorptiometry (DEXA) T-score <−1.0 (hip or spine, measured within last 2 years) and ≥ 1 fragility fracture. Patients were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months or alendronate (70 mg weekly) for 2 years. All patient received supplemental vitamin D (600 IU per day) and supplemental calcium to maintain a calcium intake of 1200 mg per day. Effectiveness of therapy in both groups (denosumab group and alendronate group) was assessed by changes in bone turnover markers (BTMs), Bone Mineral Density (BMD), fracture incidence, Visual Analogue Scale (VAS) score for back pain, and Short Form-8 (SF-8TM) health survey score for health-related quality of life (HRQoL). Percent changes from baseline in BTMs and BMD were assessed using the paired t test; a P-value 0.05). Mean changes in BMD at final follow-up differed significantly between two groups. BMD changes at the lumbar spine at 24 months were 5.6% with denosumab vs −1.1% with alendronate (P<0.001). New vertebral fractures developed in fewer patients in the denosumab group than in the alendronate group during the 24-month period, although this difference was not significant (P=0.10). Back pain significantly (P<0.001) improved from baseline at all time points during the study in both study groups. SF-8 health survey scores significantly improved following treatment with both drugs. Incidence of adverse drug reactions were similar in both groups. Conclusion In our study denosumab and alendronate showed similar clinical efficacy in the therapy of ADT-related osteoporosis in men with prostate carcinoma; both drugs provided significant improvements in back pain and general health conditions. Denosumab showed significant increase of BTMs and BMD than alendronate with lower rate of new vertebral fractures. PMID:28228781
Partsch, C J; Pankau, R; Sippell, W G; Tolksdorf, M
A comparison has been made of a case with 45,X/46,XX/47,XXX mosaicism with some 50 cases in the literature. A significant positive correlation was found between height standard deviation scores of mosaic patients from the literature and the frequency of cells with a normal chromosome constitution (n = 21, rs = 0.552, P < 0.01). In contrast, a significant negative correlation was seen between body height and the frequency of cells with a 45,X constitution (n = 21, rs = -0.594, P < 0.01). There was no significant correlation of height standard deviation score with the 47,XXX cell line (n = 21, rs = -0.353). A patient with a rare chromosomal mosaicism (45,X/46,XX/47,XXX) is described. The diagnosis was first made by chromosome analysis in amniotic cells. The patient showed no symptoms suggestive of Turner syndrome and growth followed the 75th height percentile. Basal and gonadotropin-releasing hormone stimulated gonadotropin levels normalized after age 4.8 years and did not subsequently return to hypergonadotropic levels. In blood lymphocytes, there was an increase in the frequency of cells with a normal chromosome constitution over 9 years. This in vivo cell selection is discussed. Chromosome analysis in skin fibroblasts showed the same triple mosaicism with a similar distribution of cell lines as in blood lymphocytes. In conclusion, statistical evidence was demonstrated that the severity of short stature is correlated with the distribution of cell lines in 45,X/46,XX/47,XXX mosaicism. This finding is of importance for the genetic counselling in cases of prenatal diagnosis of mosaic Turner syndrome.
... a long-lasting condition known as hypogonadism (pronounced HI-poe-GO-nad-iz-uhm ) in which the ... Turner syndrome or in individuals with hypogonadotropic (pronounced HI-po-GO-nah-doe-TROH-pik ) hypogonadism, which ...
An assessment of sex chromosome copy number in a phenotypic female patient with hypergonadtropic hypogonadism, primary amenorrhea and growth retardation by GTG-banding and FISH in peripheral blood and skin tissues
Jackson, I.M.D.; DeMoranville, B.; Grollino, M.G.
The present report describes studies performed on an 18-year-old phenotypic female referred because of primary amenorrhea, hypergonadotropic hypoganadism and growth retardation. The clinical features raised the possibility of a gonadal dysgenesis. The ovaries were not identified on either side. Her testosterone was significantly elevated, with serum level at 48 ng/dl, and her free testosterone at 7 pg/ml. A GTG-banding analysis of 33 peripheral blood leukocytes revealed the modal number of chromosomes to be 46 per cell with a male sex constitution and normal appearing banding patterns (46,XY). In view of the clinical findings, additional cells were scored to rule out low percentage mosaicism. Out of 35 additional GTG-banded cells scored for the sex chromosomes, 4 cells (11.5%) were found to contain only one copy of the X chromosome. Fluorescent in situ hybridization (FISH) using dual color biotinylated X and Y probes (Imagenetics) was subsequently performed. Out of approximately 500 cells scored, 87% were found to be XY and 9% were found to be positive for the X signal only, versus 7% and 3% X signal only for 2 XY controls, aged 61 and 46, respectively. As loss of the Y chromosome has been reported in elderly males as well as certain males with leukemia, the age of the controls was important to note. To unequivocally establish the presence of mosaicism, a skin biopsy was obtained for fibroblast culture. Out of 388 total cells scored, 286 (74%) were found to be XY and 46 (12%) were found to be X, versus 99% XY and <1% X in controls. GTG-banding analysis of the same fibroblast culture is currently in progress. Preliminary data on this specimen thus far corroborate results of the FISH study. The presence of XY cells, along with an increased testosterone level, raises the distinct possibility of a gonadoblastoma. In view of this increased risk, arrangements are being made for the patient to have a laparoscopy and surgical removal of her presumptive streak gonads.
Comparison between spontaneous gonadotropin concentration profiles and gonadotropin response to low-dose gonadotropin-releasing hormone in prepubertal and early pubertal boys and patients with hypogonadotropic hypogonadism: assessment by using ultrasensitive, time-resolved immunofluorometric assay.
Goji, K; Tanikaze, S
To assess whether nocturnal gonadotropin concentration profiles in children could be predicted by measurement of peak gonadotropin levels after gonadotropin-releasing hormone (GnRH) administration, we measured spontaneous gonadotropin levels every 20 min and the gonadotropin responses to low-dose GnRH using an ultrasensitive, time-resolved immunofluorometric assay in 61 boys with short stature and/or delayed puberty. Spontaneous nocturnal LH pulses were observed in 58 out of 61 patients. After GnRH administration in a dose of 25 ng/kg, all of the 61 patients had significant LH and FSH responses, and GnRH-stimulated peak LH and FSH levels were highly correlated with maximal spontaneous nocturnal LH and FSH levels, respectively (r = 0.83 for LH and r = 0.91 for FSH; p less than 0.00001). Analysis of individual subjects revealed that GnRH-stimulated peak LH levels were almost identical to maximal nocturnal LH levels in the subjects whose GnRH-stimulated peak LH levels were between 5 and 10 IU/L, whereas GnRH-stimulated peak LH levels tended to be higher than maximal nocturnal levels in the subjects whose GnRH-stimulated peak LH levels were 5 IU/L or lower. To determine if there were any parameters in the gonadotropin response to GnRH that might be useful in distinguishing early pubertal boys from prepubertal boys, we evaluated the gonadotropin response to GnRH in 44 prepubertal and 10 early pubertal normal short boys. Although maximal nocturnal LH levels did not overlap between prepubertal and pubertal groups, GnRH-stimulated LH peak levels overlapped considerably between the two groups. Even the GnRH-stimulated peak LH to peak FSH ratio overlapped between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Wittert, G A; Harrison, R W; Buckley, M J; Wlodarczyk, J
We compared a novel 5% testosterone (T) cream (AndroForte 5, Lawley Pharmaceuticals, Australia) with a 1% T gel (Testogel, Besins Healthcare, Australia). Using an open-label crossover design, subjects were randomized to one of two treatment sequences using either the T gel or T cream first in a 1 : 1 ratio. Each treatment period was 30 days with a 7-14 days washout period between them. On Days 1 and 30 of each treatment period blood was sampled at -15, -5 min, 0, 2, 4, 5, 6, 7, 8, 9, 10, 12 and 16 h post study drug administration. Sixteen men with established androgen deficiency aged between 29 and 73 years, who had undertaken a washout from prior testosterone therapy participated in the study. One subject failed to complete both arms and another was excluded post-completion because of a major protocol violation. Bioequivalence was established based on key pharmacokinetic (PK) variables: AUC, C(avg), C(max), T(max), % fluctuation (with and without baseline correction) for the two formulations of testosterone on Day 1 and Day 30. The ratio and 90% CI of AUC 0.99 (0.86-1.14), C(max) 1.02 (0.84-1.24) and C(avg) 0.99 (0.86-1.14) for T cream/T gel were within the predetermined bio-equivalence criteria of 80% to 125% at Day 30. There were no statistically significant differences between secondary biochemical markers: serum dihydrotestosterone (DHT), oestradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and (FSH). The two testosterone formulations were shown to be bioequivalent.
Afiadata, A; Ellsworth, Pamela
Hypogonadism, defined as a low serum testosterone in the presence of signs and symptoms, is common, particularly in aging men. Testosterone supplementation therapy (TST) is the standard treatment for male hypogonadism. It has been demonstrated to have a significant impact on the signs and symptoms of hypogonadism, but there are concerns about the increase in TST and its potential adverse effects, particularly cardiovascular effects. This review presents health care providers with current information regarding the prevalence and impact of hypogonadism, as well as the diagnosis, evaluation, and treatment of hypogonadism. The beneficial and potential adverse effects are reviewed with a discussion on the current cardiovascular controversy. We reviewed current and "landmark" articles in the English-language literature pertaining to hypogonadism, its prevalence, etiologies, presentation, evaluation, and treatment. Authorities in the field have offered guidelines and recommendations regarding the diagnosis, evaluation, and management of hypogonadism. Although there is a consensus as to the definition of hypogonadism as the presence of a low serum testosterone with signs and symptoms of hypogonadism, there is variability in the definition of "low testosterone." Various testosterone formulations exist, differing in route and frequency of administration as well as in side-effect profiles. Testosterone supplementation therapy should be continued in individuals demonstrating an improvement in signs and symptoms, which may take 3 months to a year for maximum response. Individuals treated with TST require monitoring for adverse effects. Further studies are needed to determine the impact of TST on cardiovascular health. Hypogonadism is common, particularly in aging men. Symptomatic individuals who have no contraindications to TST should be offered treatment. A careful assessment of treatment response after adequate titration and duration of therapy as well as monitoring for
Zhu, Jia; Chan, Yee-Ming
Delayed puberty presenting with low gonadotropins has multiple causes. Self-limited delay (constitutional delay) is generally considered benign, but adult height and bone mineral density may be compromised, and fertility has not been studied. Functional hypogonadotropic hypogonadism due to a stressor is thought to resolve with removal of the stressor, but reproductive endocrine dysfunction can sometimes persist. Most but not all patients with idiopathic hypogonadotropic hypogonadism, a typically long-lasting condition, can achieve fertility with exogenous hormone therapy. Future studies are needed to determine fertility outcomes in self-limited delayed puberty and to more clearly define prognostic factors for fertility in functional and idiopathic hypogonadotropic hypogonadism.
Bloch, Miki; Azem, Foad; Aharonov, Inbar; Ben Avi, Irit; Yagil, Yaron; Schreiber, Shaul; Amit, Ami; Weizman, Abraham
To determine whether the use of a GnRH agonist inducing a hypogonadic state during IVF-ET cycles induces negative mood symptoms, we conducted a prospective randomized study in 108 women comparing two different controlled ovarian stimulation protocols. A significant phase effect was observed for depression and anxiety symptoms during IVF-ET cycles reflecting an increase in symptoms between the hypogonadal phase and the peak in gonadotropin stimulation; however, the hypogonadal phase induced by the GnRH agonist was not associated with a significant increase in any of the studied mood parameters.
Crosstalk among hormones characterizes endocrine function, and assessment of the hypogonadal man should take that into consideration. In men for whom testosterone deficiency is a concern, initial evaluation should include a thorough history and physical exam in which other endocrinopathies are being considered. Hypogonadism can be associated with both pituitary and thyroid dysfunction, for which appropriate biochemical evaluation should be undertaken in certain clinical scenarios. If low serum testosterone is confirmed measurement of luteinizing and follicle stimulating hormones (LH and FSH respectively) is essential to establish whether the hypogonadism is primary or secondary. In secondary hypogonadism measurement of prolactin is always necessary, and measurement of other pituitary hormones, along with pituitary imaging, may be indicated. Checking thyroid function may also be enlightening, and can raise additional therapeutic considerations. Correction of other pituitary axes may attenuate the need for testosterone replacement therapy in some cases. PMID:28078216
... body's sex glands produce little or no hormones) Hypothyroidism (thyroid gland does not make enough thyroid hormone) ... other missing hormones are not replaced, symptoms of hypothyroidism and hypogonadism may develop. When to Contact a ...
... worsen slowly throughout life and can result in blindness or the need for a wheelchair for mobility ... named? Additional Information & Resources MedlinePlus (6 links) Encyclopedia: Blindness and Vision Loss Encyclopedia: Hypogonadotropic Hypogonadism Encyclopedia: Movement- ...
Male menopause; Andropause; Testosterone deficiency; Androgen deficiency of the aging male; Late-onset hypogonadism ... Testosterone makes a man look and feel like a man. In a man, this hormone helps: Keep ...
Caetano de Barros, M; Farias da Silva, W; De Azevedo Filho, H C; Spinelli, C
Sexual impotence is common in patients with basilar impression and/or Arnold-Chiari malformation. There is no evidence of hypogonadism and testicular biopsy is usually normal. An autonomic disturbance is postulated.
... testicles, which can lead to lower production of testosterone. The syndrome may also cause reduced muscle mass, ... caused by Klinefelter syndrome are related to low testosterone (hypogonadism). Testosterone replacement therapy reduces the risk of ...
Payne, J R; Kotwinski, P J; Montgomery, H E
Anabolic steroid abuse in athletes has been associated with a wide range of adverse conditions, including hypogonadism, testicular atrophy, impaired spermatogenesis, gynaecomastia, and psychiatric disturbance. But what effect does steroid abuse have on the cardiovascular system? PMID:15084526
Spinal Cord Injury; Spinal Cord Injuries; Trauma, Nervous System; Wounds and Injuries; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Gonadal Disorders; Endocrine System Diseases; Hypogonadism; Genital Diseases, Male
Herati, Amin S; Cengiz, Cenk; Lamb, Dolores J
The diagnosis of male hypogonadism depends on an assessment of the clinical signs and symptoms of hypogonadism and serum testosterone level. Current clinical laboratory testosterone assay platforms include immunoassays and mass spectrometry. Despite significant advances to improve the accuracy and precision of the currently available assays, limited comparability exists between assays at the lower and upper extremes of the testosterone range. Because of this lack of comparability, there is no current gold standard assay for the assessment of total testosterone levels.
The European Male Aging Study has demonstrated that the hypogonadism of male aging is predominantly secondary. Theoretically with appropriate stimulation from the pituitary, the aging testis should be able to produce eugonadal levels of testosterone. The strategies for the treatment of late onset hypogonadism (LOH) have focused on replacement with exogenous testosterone versus restoration of endogenous production. The purpose of this article is to review existing peer-reviewed literature supporting the concept of restoration of endogenous testosterone in the treatment of LOH.
Villanueva, Carine; Argente, Jesús
Puberty is a complex maturation process that begins during fetal life and persists until the acquisition of reproduction function. The fundamental event that activates puberty occurs in the hypothalamus. A complex neuron network stimulates GnRH secretion, which stimulates pituitary gonadotropin secretion and then gonadal steroid secretion. Pubertal delay is defined as the presentation of clinical signs of puberty 2-2.5 SD later than in the normal population. Three major groups of etiopathogeneses are described: (1) hypogonadotropic hypogonadism, (2) hypergonadotropic hypogonadism, and (3) constitutional delay of puberty (CDP) - the most common cause of delayed puberty in boys. The differential diagnosis between CDP and isolated hypogonadotropic hypogonadism remains difficult. Mechanisms of pubertal timing are now better understood and genetic or epigenetic causes can explain some pubertal delays. However, there are still unexplained mechanisms. Treatment of delayed puberty is necessary to ensure full pubertal development for the adolescent and in case of hypogonadism, to restore fertility. Finally, precocious diagnosis of hypogonadism is primordial but can be difficult during childhood and in cases of partial hypogonadism. The study of genetic pubertal diseases or of different animal models could help to discover new diagnostic or therapeutic tools.
McBride, J. Abram; Carson, Culley C.; Coward, Robert M.
Treatment for hypogonadism is on the rise, particularly in the aging population. Yet treatment in this population represents a unique challenge to clinicians. The physiology of normal aging is complex and often shares the same, often vague, symptoms of hypogonadism. In older men, a highly prevalent burden of comorbid medical conditions and polypharmacy complicates the differentiation of signs and symptoms of hypogonadism from those of normal aging, yet this differentiation is essential to the diagnosis of hypogonadism. Even in older patients with unequivocally symptomatic hypogonadism, the clinician must navigate the potential benefits and risks of treatment that are not clearly defined in older men. More recently, a greater awareness of the potential risks associated with treatment in older men, particularly in regard to cardiovascular risk and mortality, have been appreciated with recent changes in the US Food and Drug Administration recommendations for use of testosterone in aging men. The aim of this review is to provide a framework for the clinician evaluating testosterone deficiency in older men in order to identify correctly and treat clinically significant hypogonadism in this unique population while minimizing treatment-associated harm. PMID:26834840
Lee, Cheng-Chi; Chen, Chung-Ming; Lee, Shih-Tseng; Wei, Kuo-Chen; Pai, Ping-Ching; Toh, Cheng-Hong; Chuang, Chi-Cheng
Non-functioning pituitary macroadenomas (NFPAs) are the most prevalent pituitary macroadenomas. One common symptom of NFPA is hypogonadism, which may require long-term hormone replacement. This study was designed to clarify the association between the pre-operative tumor volume, pre-operative testosterone level, intraoperative resection status and the need of long-term post-operative testosterone replacement. Between 2004 and 2012, 45 male patients with NFPAs were enrolled in this prospective study. All patients underwent transsphenoidal surgery. Hypogonadism was defined as total serum testosterone levels of <2.4 ng/mL. The tumor volume was calculated based on the pre- and post-operative magnetic resonance images. We prescribed testosterone to patients with defined hypogonadism or clinical symptoms of hypogonadism. Hormone replacement for longer than 1 year was considered as long-term therapy. The need for long-term post-operative testosterone replacement was significantly associated with larger pre-operative tumor volume (p = 0.0067), and lower pre-operative testosterone level (p = 0.0101). There was no significant difference between the gross total tumor resection and subtotal resection groups (p = 0.1059). The pre-operative tumor volume and testosterone level impact post-operative hypogonadism. By measuring the tumor volume and the testosterone level and by performing adequate tumor resection, surgeons will be able to predict post-operative hypogonadism and the need for long-term hormone replacement. PMID:26537232
Lee, Cheng-Chi; Chen, Chung-Ming; Lee, Shih-Tseng; Wei, Kuo-Chen; Pai, Ping-Ching; Toh, Cheng-Hong; Chuang, Chi-Cheng
Non-functioning pituitary macroadenomas (NFPAs) are the most prevalent pituitary macroadenomas. One common symptom of NFPA is hypogonadism, which may require long-term hormone replacement. This study was designed to clarify the association between the pre-operative tumor volume, pre-operative testosterone level, intraoperative resection status and the need of long-term post-operative testosterone replacement. Between 2004 and 2012, 45 male patients with NFPAs were enrolled in this prospective study. All patients underwent transsphenoidal surgery. Hypogonadism was defined as total serum testosterone levels of <2.4 ng/mL. The tumor volume was calculated based on the pre- and post-operative magnetic resonance images. We prescribed testosterone to patients with defined hypogonadism or clinical symptoms of hypogonadism. Hormone replacement for longer than 1 year was considered as long-term therapy. The need for long-term post-operative testosterone replacement was significantly associated with larger pre-operative tumor volume (p = 0.0067), and lower pre-operative testosterone level (p = 0.0101). There was no significant difference between the gross total tumor resection and subtotal resection groups (p = 0.1059). The pre-operative tumor volume and testosterone level impact post-operative hypogonadism. By measuring the tumor volume and the testosterone level and by performing adequate tumor resection, surgeons will be able to predict post-operative hypogonadism and the need for long-term hormone replacement.
Ventimiglia, Eugenio; Capogrosso, Paolo; Boeri, Luca; Ippolito, Silvia; Scano, Roberta; Moschini, Marco; Gandaglia, Giorgio; Papaleo, Enrico; Montorsi, Francesco; Salonia, Andrea
To retrospectively validate the American Society for Reproductive Medicine (ASRM) guidelines/recommendations concerning endocrine evaluation in a cohort of white European men presenting for couple's infertility. Retrospective study. Academic reproductive medicine outpatient clinic. Cohort of 1,056 consecutive infertile men (noninterracial infertile couples). Testicular volume was assessed with a Prader orchidometer. Serum hormones were measured (8-10 a.m.) in all cases. Hypogonadism was defined as total T < 3 ng/mL, according to the Endocrine Society definition. Semen analysis values were assessed based on the 2010 World Health Organisation reference criteria. ASRM indications for endocrine assessment in infertile men (sperm concentration <10 million/mL, impaired sexual function, and other clinical ﬁndings suggesting a speciﬁc endocrinopathy) were used to predict hypogonadism in our cohort. Moreover, a clinically user-friendly three-item nomogram was developed to predict hypogonadism and was compared to the ASRM guidelines assessment. Biochemical hypogonadism was diagnosed in 156 (14.8%) men. Overall, 669 (63.4%) patients would have necessitated total T assessment according to the ASRM criteria; of these, only 119 (17.8%) were actually hypogonadal according to the Endocrine Society classification criteria. Conversely, 37 (23.7%) out of 156 patients with biochemical hypogonadism would have been overlooked. The overall predictive accuracy, sensitivity, and specificity of the ASRM guidelines was 58%, 76%, and 39%, respectively. Our nomogram was not reliable enough to predict hypogonadism, despite demonstrating a significantly higher predictive accuracy (68%) than the ASRM guidelines. The current findings show that the ASRM guidelines/recommendations for male infertility workup may not be suitable for application in white European infertile men. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Bobjer, J; Naumovska, M; Giwercman, Y L; Giwercman, A
In men with non-obstructive azoospermia (NOA), the risk of hypogonadism is often overlooked. Testicular sperm extraction (TESE) may increase this risk. The objective of this study was to elucidate the prevalence of hypogonadism in NOA-patients, the impact of TESE on hormone balance and the association between testosterone deficiency and dyslipidaemia. Men with NOA who had undergone TESE during the period 2004-2009 were eligible. Hypogonadism was defined as total testosterone <10 nmol/L and/or LH >10 IU/L and/or ongoing androgen replacement therapy. Sixty-five consecutive men who had undergone TESE owing to NOA and from whom post-TESE serum testosterone levels measured before 1100 h were available. Furthermore, 141 fertile men served as controls. Serum concentrations of testosterone, LH and lipids were assessed. Odds ratios (OR) for biochemical hypogonadism were calculated. Pre- and post-TESE hormone levels were compared. Lipid profile was related to testosterone levels. Hypogonadism was found in 47% (95% CI, 0.36, 0.59) of the NOA-men. As compared with fertile controls, the OR for hypogonadism post-TESE was 17 (95% CI 6.6-45). Serum LH (p = 0.03), but not testosterone (p = 0.43), differed significantly pre- and post-TESE. Compared with eugonadal NOA-men, the OR for having deviations in lipid profile was 3.3 (95% CI 1.3-8.8) for the hypogonadal NOA-men. NOA-men are at very high risk of androgen deficiency, which even in young subjects is associated with dyslipidaemia. Medical management of these men should therefore include endocrinological evaluation and follow-up after completion of infertility treatment.
Dauber, Andrew; Hirschhorn, Joel N; Picker, Jonathan; Maher, Thomas A; Milunsky, Aubrey
We report the case of a 15-year-old girl who presented to a pediatric endocrinology clinic for delayed puberty with no signs of secondary sexual development. Her past medical history was significant for bilateral colobomas, inner-ear anomalies, hearing loss, and anosmia. Genetic testing revealed a novel de novo mutation in the CHD7 gene, one of the causative genes in CHARGE syndrome (coloboma, heart disease, choanal atresia, retarded growth and development and/or central nervous system anomalies, genital anomalies and/or hypogonadism, and ear anomalies and/or deafness). We review the distinction between hypogonadotrophic hypogonadism and hypergonadotrophic hypogonadism and discuss the availability of molecular genetic testing for idiopathic hypogonadotrophic hypogonadism. CHD7 mutations have also been found in some patients with Kallmann syndrome, hypogonadotrophic hypogonadism, and anosmia, and we discuss the overlap between this syndrome and CHARGE syndrome. With the increased availability of genetic testing for a variety of disorders, it is important for pediatricians to become familiar with interpreting genetic test results. Finally, we illustrate that Bayes' theorem is a useful statistical tool for interpreting novel missense mutations of unknown significance.
Doumouchtsis, Konstantinos K; Perrea, Despoina N; Doumouchtsis, Stergios K
In chronic renal failure several factors affect bone homeostasis leading to the development of renal osteodystrophy. Common calcitropic hormone derangements in renal failure play a central role in bone structure and mineral defects, which in turn accompany osteodystrophy frequently resulting in low bone mineral density (BMD) values. However, patients with end-stage renal disease (ESRD) suffer from several comorbidities, which may partly account for renal bone disease lesions. Hypogonadism in particular accompanies chronic renal failure frequently and exerts an additive effect on bone loss potential. Sex hormones contribute to the equilibrium of osteotropic hormones and cytokines, exerting a protective action on bone tissue. Estrogens have a regulatory effect on bone metabolism in women with renal failure as well. Hypogonadal ESRD women experience a higher bone turnover and more significant bone mass decrements than ESRD women with relatively normal hormone profile and menstrual habits. Female hemodialysis patients have lower BMD values than male patients on average, probably because of menstrual cycle irregularities. However, hypogonadal ESRD men may also experience bone mineral deficits and the severity of hypogonadism may correlate to their bone mineral status. Hormone replacement therapy (HRT) appears to reverse bone mineral loss to some extent in both sexes. In conclusion hypogonadism in renal failure contributes to the bone structure and mineral defects as well as the low-energy fracture risk, reflected in BMD measurements. HRT in ESRD patients should therefore not be overlooked in these patients in the face of their significant comorbidities.
Busiah, K; Belien, V; Dallot, N; Fila, M; Guilbert, J; Harroche, A; Leger, J
Puberty is the phenomenon that conducts once to reproductive maturation. Delayed puberty (DP) is defined by the absence of testicular development in boys beyond 14 years old (or a testicular volume lower than 4 ml) and by the absence of breast development in girls beyond 13 years old. DP occurs in approximatively 3% of cases. Most cases are functional DP, with a large amount of constitutional delay of puberty. Others etiologies are hypogonadotrophic hypogonadism like Kallmann syndrome, or hypergonadotrophic hypogonadism. Turner syndrome is a diagnostic one should not forget by its frequency. Treatment is hormonal replacement therapy and of the etiology. During the last decade, many genes have been identified and elucidated the etiological diagnosis of some hypogonadotrophic hypogonadism syndrome. Further studies are required in collaboration with molecular biologists to better understand the mechanism of hypothalamic pituitary gonadal axis abnormalities and of the neuroendocrine physiology of the onset of puberty.
Howard, Sasha; Dunkel, Leo
Male delayed puberty is common, affecting up to 3% of the population. Management of patients with pubertal delay is dependent on the underlying cause. The main differential diagnoses of delayed puberty in males include constitutional delay of growth and puberty (CDGP), idiopathic hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Treatment of isolated CDGP involves expectant observation or short courses of low-dose sex steroid supplementation. More complex and involved management is required in males with hypogonadism to achieve both development of secondary sexual characteristics and to maximise the potential for fertility. This review will cover the options for management involving androgen or gonadotropin therapy, with discussion of benefits, limitations and specific considerations of the different treatment options.
Gronier, H; Peigné, M; Catteau-Jonard, S; Dewailly, D; Robin, G
The hypogonadotropic hypogonadism is an easily treatable form of female infertility. The most common cause of hypogonadotropic hypogonadism is functional hypothalamic amenorrhea. The GnRH pump is a simple and effective treatment to restore fertility of patients with hypothalamic amenorrhea: cumulative pregnancy rate is estimated between 70 and 100% after 6 cycles, compared to a low rate of complications and multiple pregnancies. While only 2.8 cycles are on average required to achieve a pregnancy with a pump, this induction of ovulation stays underused in France. The objective of this paper is to propose a practical manual of pulsatile GnRH, in order to improve the accessibility of pulsatile GnRH for patients with hypogonadotropic hypogonadism.
Wu, Christopher; Kovac, Jason R
There has recently been renewed interest in novel clinical applications of the anabolic-androgenic steroid (AAS) testosterone and its synthetic derivatives, particularly given with the rising popularity of testosterone supplementation therapy (TST) for the treatment of male hypogonadism. In this manuscript, we provide a brief review of the history of AAS and discuss clinical applications of two of the more well-known AAS: nandrolone and oxandrolone. Both agents exhibit favorable myotrophic/androgenic ratios and have been investigated for effectiveness in numerous disease states. We also provide a brief synopsis of selective androgen receptor modulators (SARMs) and postulate how these orally active, non-aromatizing, tissue-selective agents might be used in contemporary andrology. Currently, the applications of testosterone alternatives in hypogonadism are limited. However, it is tempting to speculate that these agents may one day become accepted as alternatives, or adjuncts, to the treatment of male hypogonadism.
Tigas, Stelios; Tsatsoulis, Agathocles
Extraintestinal manifestations from nearly every organ system are common in inflammatory bowel disease (IBD). This review article describes the epidemiology, pathogenesis, diagnosis and management of the main endocrine and metabolic manifestations in IBD, including metabolic bone disease, growth retardation, hypogonadism, pubertal delay, lipid abnormalities and insulin resistance. These clinical problems are commonly interrelated and they share a common basis, influenced by disease-related inflammation and nutritional status. In addition to nutritional support, every effort should be made to achieve and maintain disease remission, thus correcting the underlying chronic inflammation. The criteria for screening and diagnosing osteoporosis are described and treatment options are discussed (lifestyle advice, vitamin D and calcium supplementation, use of bisphosphonates or other specific antiosteoporotic agents, correction of hypogonadism). Chronic glucocorticoid therapy may affect growth as well as predispose to osteoporosis. The diagnosis and management of growth failure, pubertal delay and hypogonadism in IBD are discussed.
Hwang, Kathleen; Miner, Martin
The role of testosterone in the cardiovascular (CV) health of men is controversial. Data suggest that both the condition and treatment of clinical hypogonadism is associated with decreased CV mortality; however, two recent studies suggest that hypogonadal subjects treated with testosterone replacement therapy have a higher incidence of new CV events. There has been increased media attention concerning the risk of CV disease in men treated with testosterone. Until date, there are no long-term prospective studies to determine safety. Literature spanning over the past 30 years has suggested that not only is there a possible increased CV risk in men with low levels of testosterone, but the benefits from testosterone therapy may even lower this risk. We review here the recent studies that have garnered such intense scrutiny. This article is intended as a thorough review of testosterone levels and CV risk, providing the clinician with the facts needed to make informed clinical decisions in managing patients with clinical hypogonadism.
Stoll, Delphine; Puder, Jardena J; Lamy, Olivier
Osteoporosis incidence increases exponentially with age in men and hypogonadism represents a risk factor. Sex steroids levels are correlated to bone mineral density and to fracture prevalence. Most studies demonstrate an improvement in bone mineral density in men with hypogonadism as a result of testosterone therapy. Nevertheless there are no data evaluating the effect of testosterone therapy on fractures in men. Approximately 20% of men older than 60 have a total testosterone level lower than the lower limit of the reference range but there is no true consensus on the definition of hypogonadism in older men. In older men we recommend to treat only if total morning testosterone levels are < 8 nmol/l or even < 6,9 nmol/l on several occasions in the absence of any reversible illness and if there is no contraindication for treatment.
Chou, Sharon H; Mantzoros, Christos
Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin. © 2014 Society for Endocrinology.
Hypogonadism is a common clinical condition affecting men of different age groups. In addition to its sexual consequences, it has several implications posing significant concerns for a man’s health and well-being. Recent advances in testosterone (T) supplementation have facilitated hypogonadism treatment. Despite that, patients complaining of infertility or seeking conception are still hindered by the unfavorable effects supplemental T has on testicular function. Consequently, alternative approaches that can stimulate endogenous T production are favored. Selective estrogen receptor modulators, gonadotropins and aromatase inhibitors (AIs) can be successful in restoring serum T levels, preserving fertility, and providing symptomatic relief. PMID:28078217
Woodhill, Ineke; Cooper, Chris; Zacharin, Margaret; Cukier, Kimberly; Vuillermin, Peter
We present the case of a 16-year-old male who presented reporting a 6-month history of lowered mood, fatigue, anhedonia, disturbed sleep and heightened anxiety. On further questioning he reported restricted eating and weightlifting for at least 1 h on a daily basis. Investigations revealed findings compatible with secondary hypogonadism. The potential causes of secondary hypogonadism including structural lesions, muscle dysmorphia and use of illicit anabolic steroids are discussed. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
Baas, Wesley; Köhler, Tobias S
Contrary to the previous dogma that prostatic growth is directly proportional to testosterone levels, emerging research has suggested a lack of testosterone may be a risk factor for lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). Within this review article, we have demonstrated the current understanding of the physiology of hypogonadism and its interplay with prostatic and lower urinary tract physiology. The current evidence suggests that not only does testosterone replacement therapy (TRT) not worsen LUTS, but that hypogonadism itself is an important risk factor for LUTS/BPH.
Bhattacharya, Rajib K; Khera, Mohit; Blick, Gary; Kushner, Harvey; Miner, Martin M
Testosterone levels naturally decline with age in men, often resulting in testosterone deficiency (hypogonadism). However, few studies have examined hypogonadal characteristics and treatment in older (≥65 years) men. To compare data at baseline and after 12 months of testosterone replacement therapy (TRT) in hypogonadal men ≥65 vs <65 years old. Data for participants 65-74 vs ≥75 years old were also compared. Data were from TRiUS (Testim Registry in the United States), which enrolled 849 hypogonadal men treated with Testim(®) 1% (50-100 mg testosterone gel/day) for the first time. Anthropometric, laboratory, and clinical measures were taken at baseline and 12 months, including primary outcomes of total testosterone (TT), free testosterone (FT), and prostate-specific antigen (PSA) levels. Comparisons of parameters were made using Fisher's exact test or analysis of variance. Nonparametric Spearman's ρ and first-order partial correlation coefficients adjusted for the effect of age were used to examine bivariate correlations among parameters. Of the registry participants at baseline with available age information, 16% (133/845) were ≥65 years old. They were similar to men <65 years old in the duration of hypogonad-ism prior to enrollment (~1 year), TT and FT levels at baseline, TT and FT levels at 12-month follow-up, and in reported compliance with treatment. Older patients were more likely to receive lower doses of TRT. PSA levels did not statistically differ between groups after 12 months of TRT (2.18 ± 2.18 ng/mL for ≥65 vs 1.14 ± 0.84 ng/mL for <65 years old, P = 0.1). Baseline values for the >75-year-old subcohort were not significantly different from subcohorts aged 65-74 years and <65 years. Hypogonadal men ≥65 years old showed significant benefit from TRT over 12 months, similar to that found for hypogonadal men <65 years old. TRT was well tolerated in older patients, successfully increased testosterone level regardless of age, and did not
To assess whether hormone replacement therapy influences longevity, an analysis was made of published life tables allowing for the calculation of the relative benefit of hormone replacement therapy on longevity in men with late onset hypogonadism and in post-menopausal women. It was found that testosterone replacement therapy of men suffering from late onset hypogonadism increased survival rate by 9-10% in 5 years, similar to that of eugonadal, non-LOH men with normal endogenous testosterone secretion. Oestrogen replacement therapy resulted in increased survival by 2.6% in 5 years. It is concluded that hormone replacement therapy increases longevity.
Zinc is an essential nutrients and plays an important role in growth and sexual function. Zinc deficiency has been known to cause growth retardation and hypogonadism. Several mechanisms of growth retardation and hypogonadism due to zinc deficiency have been suggested. Zinc affects growth hormone (GH) metabolism. Conversely, GH affects zinc metabolism. Zinc deficiency may result in reduced GH production and/or insulin-like growth factor-I (IGF-I). Zinc deficiency may also affect bone metabolism and gonadal function. The interrelationships among zinc, growth, gonadal function, and GH-IGF-I axis appears to be complex.
Davis, Shanlee M.; Rogol, Alan D.; Ross, Judith L.
Synopsis Klinefelter syndrome (KS) is the leading genetic cause of primary hypogonadism and infertility in men.1,2 The clinical phenotype has expanded beyond the original description of infertility, small testes and gynecomastia.3 Animal models, epidemiological studies, and clinical research of males with KS throughout the lifespan have allowed us to better characterize the variable phenotype of this condition. This review will provide an overview on what is known of the epidemiology, clinical features, and pathophysiology of KS, followed by a more focused discussion of testicular development and the clinical management of hypogonadism and fertility in men with KS. PMID:26568497
Davis, Shanlee M; Rogol, Alan D; Ross, Judith L
Klinefelter syndrome (KS) is the leading genetic cause of primary hypogonadism and infertility in men. The clinical phenotype has expanded beyond the original description of infertility, small testes, and gynecomastia. Animal models, epidemiologic studies, and clinical research of male subjects with KS throughout the lifespan have allowed the better characterization of the variable phenotype of this condition. This review provides an overview on what is known of the epidemiology, clinical features, and pathophysiology of KS, followed by a more focused discussion of testicular development and the clinical management of hypogonadism and fertility in boys and men with KS.
O'Carrigan, B; Fournier, M; Olver, I N; Stockler, M R; Whitford, H; Toner, G C; Thomson, D B; Davis, I D; Hanning, F; Singhal, N; Underhill, C; Clingan, P; McDonald, A; Boland, A; Grimison, P
This is the first prospective study in a contemporary Australian/New Zealand population to determine the prevalence of testosterone deficiency in testicular cancer survivors at 12 months from treatment, and any association with poorer quality of life. Hormone assays from 54 evaluable patients in a prospective cohort study revealed biochemical hypogonadism in 18 patients (33%) and low-normal testosterone in 13 patients (24%). We found no association between testosterone levels and quality of life (all P > 0.05). Hypogonadal patients should be considered for testosterone replacement to prevent long-term morbidity.
Ben Abdallah, Néjib; Cherif, Lotfi; Khiari, Karima; Hadj Ali, Insaf; Turki, Sami; Mezni, Faouzi; Ben Jilani, Sarrah; Ben Maïz, Hédi
Suprasellar germinomas are frequent in childhood and adolescence, particularly in male sex. The clinical and neuroendocrine abnormalities depend of tumor localization: Increased intracranial pressure, visual disturbances, hypopituitarism, Parinaud syndrome. We report two cases of suprasellar germinoma in young male patients (16 and 18 years old). The first patient hrad corticotorpin insufficiency and clinical signs of hypothyroïdism and hypogonadism. The second had central hypocorticism, hypothyroïdism and hypogonadism associated with central diabetes insipidus and hyperprolactinemia. The diagnosis of germinoma was confirmed after surgery by anatomopathologic examination in the first case and by stereotaxic biopsy in the second case. Treatment by radiotherapy improves prognosis of this disease.
Eckman, Ari; Dobs, Adrian
Gynecomastia is caused by drugs in 10 - 25% of all cases. The pathophysiologic mechanism for some drugs includes exogenous estrogens exposure, medications that cause hypogonadism, anti-androgenic effects and hyperprolactinemia. This manuscript reviews common examples of drug-induced gynecomastia, discussing the mechanisms and possible treatments. Discontinuing the medication is always the best choice; however, if this is not possible, then testosterone replacement therapy may be needed for hypogonadism. When a man is euogonadal, a trial of the anti-estrogen, tamoxifen or an aromatase inhibitor may be an option.
Synofzik, Matthis; Bernard, Geneviève; Lindig, Tobias; Gburek-Augustat, Janina
An 18-year-old German woman presented with progressive cerebellar ataxia since early childhood, delayed cognitive development, and hypogonadotropic hypogonadism. MRI demonstrated diffuse cerebral hypomyelination, cerebellar atrophy, and thin corpus callosum; X-ray revealed persistent milk teeth and hypoplastic crowns and roots (figure), indicative of 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism). POLR3B sequencing(1) revealed 2 compound heterozygous mutations (C527R [C.1579T>C] and the common ancestral V523E [C.1568T>A](2)).
Testosterone replacement therapy (TRT) represents an increasing popular treatment option for men with late-onset hypogonadism (LOH). Because of unsubstantiated beliefs of testosterone’s effect on the prostate, the FDA has recently placed a warning on testosterone products, stating that TRT may worsen benign prostatic hyperplasia (BPH). Within this review article we have demonstrated the current understanding of the physiology of testosterone and its relationship with prostatic and lower urinary tract physiology. The current evidence suggests that not only does TRT not worsen lower urinary tract symptoms (LUTS), but that hypogonadism itself is an important risk factor for LUTS/BPH. PMID:28078221
The incidence of hypogonadism has been steadily increasing over the last few years. Exogenous testosterone has been the standard treatment for hypogonadal men, but is associated with suppression of spermatogenesis as well as other possible adverse effects. There are other medications, currently considered “off label” for androgen replenishment, that exert their effect through modulation of the hypothalamic-gonadal axis. These medications increase endogenous testosterone levels and offer a different therapeutic approach. This review will focus on these alternative (off-label) therapies for androgen replacement in men. PMID:28078215
Fryns, J P; Thiry, P; Geutjens, J; Smeets, E; Vinken, L; Van den Berghe, H
Two profoundly mentally retarded, unrelated males are reported with an unidentified multiple congenital anomaly/mental retardation syndrome, including early balding, patella luxations, small hands and feet, and hypogonadism, similar to a previous publication in this journal of a severely mentally retarded male patient with dysmorphic features. Images PMID:8487281
Bertella, L.; Mori, I.; Grugni, G.; Pignatti, R.; Ceriani, F.; Molinari, E.; Ceccarelli, A.; Sartorio, A.; Vettor, R.; Semenza, C.
Background: Prader-Willi syndrome (PWS) is a congenital alteration of chromosome pair 15. It is characterized by short stature, muscular hypotonia, hyperphagia, obesity, behavioural and emotional disturbances, hypogonadism and partial Growth Hormone (GH) deficiency. The aim of this study was to assess the long-term effect of GH treatment on the…
Forbus, William R., III
A case study focuses on the characteristics and physical management of a 15-year-old with Prader-Willi Syndrome, a birth defect associated with hypotonia, insatiable appetite, hypogonadism, central nervous system dysfunction, and abnormal growth and development . A literature review addresses studies dealing with behavior modification of obesity…
García-Malpartida, Katherine; Gómez-Balaguer, Marcelino; Solá-Izquierdo, Eva; Fuentes-Pardilla, M José; Jover-Fernández, Ana; Sanz-Ruiz, Isabel; Hernández-Mijares, Antonio
The association of primary adrenal insufficiency and hypogonadotropic hypogonadism is extremely infrequent in daily clinical practice. Differential diagnosis includes X-linked adrenal hypoplasia congenita, a genetic disease characterized by an alteration in the formation of the adrenal glands and the hypothalamus-pituitary-gonadal axis. The gene responsible is DAX1 (NR0B1). The most common form of clinical presentation is neonatal primary adrenal insufficiency and complete hypogonadotropic hypogonadism. Members of a single family often present the same clinical form, although there may be relatives affected with different clinical symptoms. The aim of this study is to characterize clinically and genetically a family affected by different forms of hypogonadotropic hypogonadism and/or primary adrenal insufficiency. We describe a family with three members affected, two adults and a neonate. The way of presentation of the adults was neonatal primary adrenal insufficiency and hypogonadotropic hypogonadism (one complete and another presenting as interrupted puberty). The genetic study revealed a new mutation in DAX1, p.Q76X gene (c.C226T), resulting in a truncated protein of 76 amino acids, the same in all three affected male patients and in the asymptomatic women of the family. These cases further expand the number of DAX1 mutations reported, as well as the description of infrequent forms of presentation of this disease as interrupted puberty.
Katz, Nathaniel; Mazer, Norman A
Opioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. A review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.
Hoybye, C; Thoren, M.; Bohm, B.
Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by short stature, muscular hypotonia, hyperphagia, obesity, maladaptive behaviour, hypogonadism and partial growth hormone (GH) deficiency (GHD). Severe GHD of other aetiologies has been shown to affect mood and quality of life negatively, and there are reports of…
Bertella, L.; Mori, I.; Grugni, G.; Pignatti, R.; Ceriani, F.; Molinari, E.; Ceccarelli, A.; Sartorio, A.; Vettor, R.; Semenza, C.
Background: Prader-Willi syndrome (PWS) is a congenital alteration of chromosome pair 15. It is characterized by short stature, muscular hypotonia, hyperphagia, obesity, behavioural and emotional disturbances, hypogonadism and partial Growth Hormone (GH) deficiency. The aim of this study was to assess the long-term effect of GH treatment on the…
Lo, S. T.; Collin, P. J. L.; Hokken-Koelega, A. C. S.
Background: Prader-Willi syndrome (PWS) is characterised by hypotonia, hypogonadism, short stature, obesity, behavioural problems, intellectual disability, and delay in language, social and motor development. There is very limited knowledge about visual-motor integration in children with PWS. Method: Seventy-three children with PWS aged 7-17 years…
Drewa, Tomasz; Olszewska-Słonina, Dorota; Chlosta, Piotr
Controversy surrounds testosterone replacement therapy in obese ageing due to no generally accepted lower limits of normal testosterone level and high prevalence of hypogonadal symptoms in the ageing male population and the non-specific nature of these symptoms. Late onset hypogonadism is a clinical and biochemical syndrome associated with advancing age, often coexisting with obesity and metabolic syndrome. High fat and carbohydrates (fructose) consumption is responsible for development of obesity and metabolic syndrome which is one of risk factors for hypogonadism in older men. High fructose intake has been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Obesity and lack of physical activity negatively influence testosterone level. Low testosterone level should be regarded as an effect of obesity, but reverse relationship has not been proved yet. The management of late-onset hypogonadism symptoms has to be treated by a change of a life style and prevented with healthy nutrition and physical activity. The question related to rational indications for testosterone replacement therapy in obese males seems to be still actual.
Dutta, M K; Gundgurthi, A; Garg, M K; Pakhetr, R
We present a 15 year old boy who was born out of a non consanguineous marriage, and presented with bilateral cryptorchidism, mental retardation, facial dysmorphism, hypergonadotrophic hypogonadism with failure of anatomical and biochemical localisation of testes. Karyotype analysis showed 46 XY with inverted duplication on chromosome 5q22-31.
Layman, Lawrence C.
With the advent of improved molecular biology techniques, the genetic basis of an increasing number of reproductive disorders has been elucidated. Mutations in at least 20 genes cause hypogonadotropic hypogonadism including Kallmann syndrome in about 35–40% of patients. The two most commonly involved genes are FGFR1 and CHD7. When combined pituitary hormone deficiency includes hypogonadotropic hypogonadism as a feature, PROP1 mutations are the most common of the six genes involved. For hypergonadotropic hypogonadism, mutations in 14 genes cause gonadal failure in 15% of affected females, most commonly in FMR1. In eugonadal disorders, activating FSHR mutations have been identified for spontaneous ovarian hyperstimulation syndrome; and WNT4 mutations have been described in mullerian aplasia. For other eugonadal disorders, such as endometriosis, polycystic ovary syndrome, and leiomyomata, specific germline gene mutations have not been identified, but some chromosomal regions are associated with the corresponding phenotype. Practical genetic testing is possible to perform in both hypogonadotropic and hypergonadotropic hypogonadism and spontaneous ovarian hyperstimulation syndrome. However, clinical testing for endometriosis, polycystic ovary syndrome, and leiomyomata is not currently practical for the clinician. PMID:23499866
Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses. PMID:22284844
Various hormonal disorders can influence bone metabolism and cause secondary osteoporosis. The consequence of this is a significant increase of fracture risk. Among pituitary disorders such effects are observed in patients with Cushing's disease, hyperprolactinemia, acromegaly, and hypopituitarism. Severe osteoporosis is the result of the coexistence of some of these disorders and hypogonadism at the same time, which is quite often. PMID:25873948
Hoybye, C; Thoren, M.; Bohm, B.
Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by short stature, muscular hypotonia, hyperphagia, obesity, maladaptive behaviour, hypogonadism and partial growth hormone (GH) deficiency (GHD). Severe GHD of other aetiologies has been shown to affect mood and quality of life negatively, and there are reports of…
Lo, S. T.; Collin, P. J. L.; Hokken-Koelega, A. C. S.
Background: Prader-Willi syndrome (PWS) is characterised by hypotonia, hypogonadism, short stature, obesity, behavioural problems, intellectual disability, and delay in language, social and motor development. There is very limited knowledge about visual-motor integration in children with PWS. Method: Seventy-three children with PWS aged 7-17 years…
Veräjänkorva, Esko; Laato, Matti; Pöllänen, Pasi
To analyse the factors predisposing to male immunological infertility from the hospital records of 508 patients that had been treated for infertility in the Turku University Central Hospital from 1980 to 2000. In addition, the hormonal status was investigated at the beginning of treatment. Patients with a history of mumps, or either a fresh varicocele or a history of varicocele had statistically significant lower levels of MAR antisperm antibodies (ASAs) than patients with no such conditions. Repair of varicocele (either surgical or embolisation), showed a statistically significant enhancement of the total sperm cell counts in ejaculates, but it appeared not to have any influence on other parameters of the semen analysis (mobility and morphology). Of all male infertility patients, 66.3% had normal hormonal status at the beginning of treatment, 12.6% of patients had hypotestosteronemia and 22.1% had subclinical hypogonadism. Patients with subclinical hypogonadism had lower total sperm cell count in ejaculates than patients with normal hormonal status although they had statistically significant more offspring. In addition, it appeared that mumps orchitis as well as smoking and alcohol abuse are risk factors for subclinical hypogonadism. No clear predisposing factor for male immunological infertility could be found. However, patients with subclinical hypogonadism differed from other male infertility patients and thus may form a special group among the male infertility patients.
Akande, A A; Idowu, A A; Jimoh, A K
Biochemical laboratory investigations potentially contribute to the diagnosis of over 50-75% of couples being investigated for infertility. Both hormonal and anti-hormonal treatments have achieved great successes in the treatment of infertility. Our aim therefore was to investigate the pattern of biochemical abnormalities in females diagnosed as infertile form anovulation. One hundred and twenty women diagnosed clinically as primary or secondary infertility from anovulation referred from the gynecological clinic of UITH and private hospitals in Ilorin were investigated by routine fertility test profile. The age ranged between 20-40 years (mean = 32.9, sd +/- 4.7) for the primary infertility and 23-47 years (mean = 34.4, sd +/- 5.4) for the secondary infertility groups respectively. Ninety six (80%) subjects were found to have hormonal abnormalities. Pattern of biochemical diagnosis amongst the 33 (34.4%) primary infertility subjects included hypergonadotrophic hypogonadism 21 (63.6%), hypogonadotrophic hypogonadism 9 (27.3%), and hyperprolactinemia 3 (9.1%). Among the 63 (65.6%) cases of secondary infertility, there were 31 (49.2%) cases of hypergonadotrophic hypogonadism, 30 (47.6%) hypogonadotrophic hypogonadism, and 2 (3.2%) hyperprolactinemia. There was no statistical difference in the mean values in the various biochemical parameters. Hormonal profile should be a goal standard in the diagnosis of anovulation.
Forbus, William R., III
A case study focuses on the characteristics and physical management of a 15-year-old with Prader-Willi Syndrome, a birth defect associated with hypotonia, insatiable appetite, hypogonadism, central nervous system dysfunction, and abnormal growth and development . A literature review addresses studies dealing with behavior modification of obesity…
Dunkel, Leo; Quinton, Richard
Puberty is the period during which we attain adult secondary sexual characteristics and reproductive capability. Its onset depends upon reactivation of pulsative GNRH, secretion from its relative quiescence during childhood, on the background of intact potential for pituitary-gonadal function. This review is intended: to highlight those current practices in diagnosis and management that are evidence based and those that are not; to help clinicians deal with areas of uncertainty with reference to physiologic first principles; by sign-posting relevant data arising from other patient groups with shared issues; to illustrate how recent scientific advances are (or should be) altering clinician perceptions of pubertal delay; and finally, to emphasise that the management of men and women presenting in advanced adult life with absent puberty cannot simply be extrapolated from paediatric practice. There is a broad spectrum of pubertal timing that varies among different populations, separated in time and space. Delayed puberty usually represents an extreme of the normal, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP), but organic defects of the hypothalamo-pituitary-gonadal axis predisposing to hypogonadism may not always be initially distinguishable from it. CDGP and organic, or congenital hypogonadotrophic hypogonadism are both significantly more common in boys than girls. Moreover, around 1/3 of adults with organic hypogonadotrophic hypogonadism had evidence of partial puberty at presentation and, confusingly, some 5-10% of these subsequently may exhibit recovery of endogenous gonadotrophin secretion, including men with Kallmann syndrome. However, the distinction is crucial as expectative ('watch-and-wait') management is inappropriate in the context of hypogonadism. The probability of pubertal delay being caused by organic hypogonadism rises exponentially both with increasing age at presentation and the presence of associated 'red
Kharb, Sandeep; Garg, M. K.; Puri, Pankaj; Brar, Karninder S.; Pandit, Aditi; Srivastava, Sharad
Introduction: Liver is involved with the synthesis of carrier proteins and metabolism of various hormones and liver diseases may, therefore, be associated with various endocrine disturbances. This study was conducted to assess thyroid and gonadal function in subjects with acute hepatitis (AH), chronic liver disease (CLD), and those who had undergone liver transplantation (LT). Materials and Methods: Patients with AH, CLD with Child-Pugh stage A (CLD-1) and Child-Pugh stage B or C (CLD-2), and LT seen at our tertiary level hospital were assessed clinically, biochemically, and for thyroid and gonadal functions besides 25 healthy controls. Results: Thyroid dysfunction and hypogonadism were present in 14 (16%) and 24 (28%) patients with liver diseases respectively. Among thyroid dysfunction, the commonest was sick euthyroid syndrome six (7%), followed by subclinical hypothyroidism in three patients (3.5%), subclinical hyperthyroidism and thyrotoxicosis in two patients each (2.3%) and overt hypothyroidism in one patient. Among patients with LT and AH groups, the only abnormality was significantly lower total T3 compared with healthy controls. The CLD2 group had significantly lower levels of all thyroid hormones compared with controls and CLD1 group. Hypogonadism was commonest in patients with CLD-2 (14; 50%) followed by LT (3; 33%), CLD-1 (4; 20%), and AH (3; 14%). Hypogonadism was predicted by older age, lower levels of serum albumin, total cholesterol, and triglycerides and higher levels of plasma glucose, serum bilirubin, aspartate transaminases, and international normalized ratio. Gonadal functions showed recovery following LT. Conclusions: Thyroid dysfunction and hypogonadism form an important part of the spectrum of acute and CLD, and patients with LT. Deterioration of synthetic functions of liver disease predicts presence of hypogonadism. PMID:25593833
Nishi, Y; Takayanagi, R; Yanase, T; Haji, M; Hasegawa, Y; Nawata, H
To clarify the contribution of the inhibin-like immunoreactivity (inhibin-LI) produced by adrenal glands to the total circulating levels of inhibin-LI, we measured serum inhibin-LI in normal and hypogonadal subjects under ACTH-loading or dexamethasone-loading condition. The mean basal concentration of inhibin-LI in the peripheral serum of the hypogonadal cases was 3.6 +/- 1.3 IU/ml (mean +/- SD, n = 5), which corresponded to 19.5 +/- 5.8% of that of normal controls matched for age and sex. The low levels of inhibin-LI in hypogonadal subjects (n = 7) rose significantly (3.6 +/- 1.1 vs 8.1 +/- 1.7 IU/ml, p < 0.001) after the administration of synthetic 1-24ACTH (40 units/day intramuscular injection) for 2 days, while the levels of serum inhibin-LI were not increased in two cases of Addison's disease with hypogonadism after the administration of ACTH. After the oral administration of a low dose of dexamethasone (1 mg) the serum inhibin-LI level in normal subjects (eight males and eight females) decreased significantly (male, 16.2 +/- 3.3 vs 14.5 +/- 4.1 IU/ml; female, 12.9 +/- 6.3 vs 10.8 +/- 5.6 IU/ml; p < 0.01 each) without significant change in the levels of serum gonadotropin (LH and FSH) and those of gonadal steroid (testosterone or estradiol). These results indicate that a small; but significant amount of inhibin-LI is secreted from the adrenal gland and circulating in vivo, and that the proportion of adrenal-derived inhibin-LI is much higher in patients with hypogonadism.
Blick, Gary; Khera, Mohit; Bhattacharya, Rajib K; Nguyen, Dat; Kushner, Harvey; Miner, Martin M
Among patients with hypogonadism-associated comorbidities, opioid users have the highest incidence of hypogonadism. Data from the Testim Registry in the United States were analyzed to determine the efficacy of testosterone replacement therapy in opioid users vs nonusers. Prospective, 12-month observational cohort registry. Hypogonadal men (N = 849) prescribed Testim (but not necessarily testosterone replacement) for the first time. Testim 1% testosterone gel (5-10 g/day). Total and free testosterone, sex hormone-binding globulin, prostate-specific antigen, sexual function, mood/depression, and anthropometric data were assessed. Changes from baseline were analyzed using repeated measures mixed-effects analysis of variance; multiple linear regressions of changes in testosterone levels with sexual function, mood, and opioid use were computed. 90/849 patients (10.6%) reported opioid use at baseline; 75/90 (83%) used opioids for ≥ 30 days prior to baseline. Baseline total testosterone and prostate-specific antigen were not statistically different between opioid users and nonusers; there was a trend for higher sex hormone-binding globulin (P = 0.08) and lower free testosterone (P = 0.05) in opioid users. After 1 month, both opioid users and nonusers had significant (P < 0.001) increases in total and free testosterone, which continued through 12 months. Sexual function and mood improved significantly in both opioid users and nonusers over 12 months, and significantly correlated with change in total testosterone. Testosterone replacement therapy increased serum testosterone in hypogonadal opioid users and nonusers alike. The data suggest that with testosterone replacement, hypogonadal opioid users might be expected to have similar improvements in sexual function and mood as opioid nonusers. Wiley Periodicals, Inc.
Szulc, P; Claustrat, B; Marchand, F; Delmas, P D
The goal of this study was to identify the clinical and biological patterns of hypogonadism in a cohort of 1040 elderly men. Residual androgenic activity was estimated by total testosterone as well as the apparent free testosterone concentration (AFTC) and free testosterone index (FTI) calculated on the basis of concentrations of SHBG and total testosterone using appropriate formulae. The lower limit of the normal range defined by 2 SD below the mean in 150 healthy, nonobese, and nonsmoking men, aged 19-40 yr, was calculated for total testosterone (9.26 nmol/liter), AFTC (146 pmol/liter), and FTI (0.14 nmol/nmol). The prevalence of hypogonadism increased with ageing. Hypogonadal men were older and heavier (due to a higher fat body mass) and had lower concentrations of 17 beta-estradiol and androstenedione than men with normal androgenic activity. Men with decreased AFTC had a slightly lower bone mineral density (BMD) at certain sites. Men with decreased FTI had lower appendicular skeletal muscle mass and relative skeletal muscle index. For all three measures of androgenic activity, hypogonadal men had increased levels of the markers of bone resorption. In the multiple regression models including both 17 beta-estradiol and testosterone (total, AFTC, or FTI), 17 beta-estradiol was the only significant determinant of BMD. In the multiple regression models including 17 beta-estradiol and AFTC or FTI, only testosterone was a significant determinant of the variability in bone formation markers, whereas both 17 beta-estradiol and testosterone were significant determinants of the variability of the markers of bone resorption. Hypogonadism was associated with an increase in the risk of falls, an impairment of static and dynamic balance, as well as the inability to stand up from a chair and to perform the tandem walk. Decreased AFTC (<146 pmol/liter) discriminated best men with functional disabilities (odds ratio, 1.54-7.95; P < 0.05-0.0001). Hypogonadal elderly men had
Kelly, Daniel F; Chaloner, Charlene; Evans, Diana; Mathews, Amy; Cohan, Pejman; Wang, Christina; Swerdloff, Ronald; Sim, Myung-Shin; Lee, Jihey; Wright, Mathew J; Kernan, Claudia; Barkhoudarian, Garni; Yuen, Kevin C J; Guskiewicz, Kevin
Hypopituitarism is common after moderate and severe traumatic brain injury (TBI). Herein, we address the association between mild TBI (mTBI) and pituitary and metabolic function in retired football players. Retirees 30-65 years of age, with one or more years of National Football League (NFL) play and poor quality of life (QoL) based on Short Form 36 (SF-36) Mental Component Score (MCS) were prospectively enrolled. Pituitary hormonal and metabolic syndrome (MetS) testing was performed. Using a glucagon stimulation test, growth hormone deficiency (GHD) was defined with a standard cut point of 3 ng/mL and with a more stringent body mass index (BMI)-adjusted cut point. Subjects with and without hormonal deficiency (HD) were compared in terms of QoL, International Index of Erectile Function (IIEF) scores, metabolic parameters, and football career data. Of 74 subjects, 6 were excluded because of significant non-football-related TBIs. Of the remaining 68 subjects (mean age, 47.3±10.2 years; median NFL years, 5; median NFL concussions, 3; mean BMI, 33.8±6.0), 28 (41.2%) were GHD using a peak GH cutoff of <3 ng/mL. However, with a BMI-adjusted definition of GHD, 13 of 68 (19.1%) were GHD. Using this BMI-adjusted definition, overall HD was found in 16 (23.5%) subjects: 10 (14.7%) with isolated GHD; 3 (4.4%) with isolated hypogonadism; and 3 (4.4%) with both GHD and hypogonadism. Subjects with HD had lower mean scores on the IIEF survey (p=0.016) and trended toward lower scores on the SF-36 MCS (p=0.113). MetS was present in 50% of subjects, including 5 of 6 (83%) with hypogonadism, and 29 of 62 (46.8%) without hypogonadism (p=0.087). Age, BMI, median years in NFL, games played, number of concussions, and acknowledged use of performance-enhancing steroids were similar between HD and non-HD groups. In summary, in this cohort of retired NFL players with poor QoL, 23.5% had HD, including 19% with GHD (using a BMI-adjusted definition), 9% with hypogonadism, and 50% had Met
Chaloner, Charlene; Evans, Diana; Mathews, Amy; Cohan, Pejman; Wang, Christina; Swerdloff, Ronald; Sim, Myung-Shin; Lee, Jihey; Wright, Mathew J.; Kernan, Claudia; Barkhoudarian, Garni; Yuen, Kevin C.J.; Guskiewicz, Kevin
Abstract Hypopituitarism is common after moderate and severe traumatic brain injury (TBI). Herein, we address the association between mild TBI (mTBI) and pituitary and metabolic function in retired football players. Retirees 30–65 years of age, with one or more years of National Football League (NFL) play and poor quality of life (QoL) based on Short Form 36 (SF-36) Mental Component Score (MCS) were prospectively enrolled. Pituitary hormonal and metabolic syndrome (MetS) testing was performed. Using a glucagon stimulation test, growth hormone deficiency (GHD) was defined with a standard cut point of 3 ng/mL and with a more stringent body mass index (BMI)-adjusted cut point. Subjects with and without hormonal deficiency (HD) were compared in terms of QoL, International Index of Erectile Function (IIEF) scores, metabolic parameters, and football career data. Of 74 subjects, 6 were excluded because of significant non-football-related TBIs. Of the remaining 68 subjects (mean age, 47.3±10.2 years; median NFL years, 5; median NFL concussions, 3; mean BMI, 33.8±6.0), 28 (41.2%) were GHD using a peak GH cutoff of <3 ng/mL. However, with a BMI-adjusted definition of GHD, 13 of 68 (19.1%) were GHD. Using this BMI-adjusted definition, overall HD was found in 16 (23.5%) subjects: 10 (14.7%) with isolated GHD; 3 (4.4%) with isolated hypogonadism; and 3 (4.4%) with both GHD and hypogonadism. Subjects with HD had lower mean scores on the IIEF survey (p=0.016) and trended toward lower scores on the SF-36 MCS (p=0.113). MetS was present in 50% of subjects, including 5 of 6 (83%) with hypogonadism, and 29 of 62 (46.8%) without hypogonadism (p=0.087). Age, BMI, median years in NFL, games played, number of concussions, and acknowledged use of performance-enhancing steroids were similar between HD and non-HD groups. In summary, in this cohort of retired NFL players with poor QoL, 23.5% had HD, including 19% with GHD (using a BMI-adjusted definition), 9% with hypogonadism, and
Chen, Xueyan; Raca, Gordana; Laffin, Jennifer; Babaian, Kara N; Williams, Daniel H
This study investigated the underlying chromosomal abnormalities of testicular failure using molecular cytogenetic analysis. We report 2 cases of rare genetic anomalies that resulted in hypogonadism. The first patient presented with severe hypogonadism. Chromosome analysis revealed a mosaic 46,X,r(Y) (p11.3q11.23)/45,X karyotype, with a ring Y chromosome. A Y chromosome microdeletion assay showed a deletion in the azoospermia factor a region. The second patient presented with infertility and nonobstructive azoospermia. Cytogenetic and fluorescent in situ hybridization analysis revealed a 47,XY,+mar.ish i(15) (D15Z1++,SNRPN2,PML2) karyotype, with a small supernumerary chromosome derived from chromosome 15. These results emphasize the need for molecular cytogenetic evaluation in patients with testicular failure before using advanced reproductive techniques.
Cho, Byoung-Wook; Kwon, Seung-Eun; Kim, Soon-Ki; Lee, Taek; Han, Jee-Young
Klinefelter syndrome (KS) is one of the most common disease entities characterized by X-chromosomal aberration causing the primary hypogonadism in adult men. Patients with KS seem to be typically characterized by tall, slender bodies with delayed puberty and hypergonadotropic hypogonadism. However, it has been known that they have a broad spectrum of phenotype ranging from almost normal external appearances to typical phenotype. Only 25% KS Patients are ever diagnosed because KS remains unrecognized. Also, boys with KS have an onset of pubertal development within the normal range, not delayed onset of puberty. Adolescents with KS are generally diagnosed as having the lack of pubertal progress. Early detection of KS can be difficult without awareness. We report an unusual case of early onset of puberty in obese boy with KS who presented with a unilateral non-hormone secreting testicular teratoma. PMID:27104178
Hammoud, Ahmad O; Carrell, Douglas T; Gibson, Mark; Matthew Peterson, C; Wayne Meikle, A
Obesity has a negative effect on male reproductive function. It is associated with low testosterone levels and alteration in gonadotropin secretion. Male obesity has been linked to reduced male fertility. Data regarding the relation of obesity to sperm parameters are conflicting in terms of the nature and magnitude of the effect. New areas of interest are emerging that can help explain the variation in study results, such as genetic polymorphism and sleep apnea. Sleep disorders have been linked to altered testosterone production and hypogonadism in men. It was also correlated to erectile dysfunction. The relation of sleep disorders to male fertility and sperm parameters remains to be investigated. Men with hypogonadism and infertility should be screened for sleep apnea. Treatment of obesity and sleep apnea improves testosterone levels and erectile function. PMID:22138900
Nohara, Kazunari; Liu, Suhuan; Meyers, Matthew S; Waget, Aurélie; Ferron, Mathieu; Karsenty, Gérard; Burcelin, Rémy; Mauvais-Jarvis, Franck
Polycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. In this study, we determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropin concentrations. Hypothalamic KiSS1 neurons are believed to be critical to the onset of puberty and are the target of leptin. Adult NTM exhibited lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity, and decreased energy expenditure. They displayed a delayed increase in subcutaneous white adipose tissue amounts. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice.
Warburton, Daniel; Hobaugh, Christopher; Wang, Grace; Lin, Haocheng; Wang, Run
Understanding the role of testosterone replacement therapy (TRT) in the development and progression of prostate cancer is an important concept in treating patients with symptoms of hypogonadism. This article revealed a small number of mostly retrospective, observational studies describing the use of TRT in the general population, in men with prostatic intraepithelial neoplasia (PIN), in men with a history of treated prostate cancer, and in men on active surveillance for prostate cancer. The current literature does not report a statistically significant increase in the development or progression of prostate cancer in men receiving testosterone replacement for symptomatic hypogonadism, and the prostate saturation theory provides a model explaining the basis for these results. The use of TRT in men with a history of prostate cancer is considered experimental, but future results from randomized controlled trials could lead to a change in our current treatment approach.
Ahmad, Afzal; D'Souza, Benedicta; Yadav, Charu; Agarwal, Ashish; Kumar, Anand; Nandini, M; D'Souza, Vivian; Poornima, A M; Kamath, Nutan
Alstrom's syndrome (AS) is a rare autosomal recessive ciliopathic condition affecting 1:10,00,000 children. It's a single gene disorder of ALMS1 on chromosome 2 with multisystem involvement with cone-rod retinal dystrophy causing juvenile blindness, obesity, insulin resistance, type 2 Diabetes mellitus, hypogonadism and sensorineural hearing loss. Till now only 800 patients with this disorder has been identified so far. In this report, we describe the case of a 9-year old male boy from south India. He had been initially referred for polyphagia, polyuria, polydipsia, generalized weakness from 1 weeks. On examination he was demonstrated features suggestive of AS, including blindness, obesity, type 2 diabetes, altered lipid profile, hypogonadism, acanthosis nigricans, seborrheic dermatitis, right ear discharge and episodes of respiratory tract infections. So, diagnosis of AS is critical as it can easily be overlooked because of the many features associated with metabolic syndrome starting at age 7, a relatively early age.
Desroches, Bethany; Kohn, Taylor P.; Welliver, Charles; Pastuszak, Alexander W.
The Food and Drug Administration (FDA) introduced changes in labeling and indications for use to testosterone products in 2015 due to a possible increased risk of cardiovascular (CV) events. This decision was made based on six clinical studies—some that supported an increased CV risk, and some that did not. Since this decision, additional studies have been published examining the interplay between hypogonadism, CV risk, and testosterone, demonstrating that the risk may be lower than originally estimated. Clinicians are placed in a difficult position, as studies support an increased mortality risk in hypogonadal men, but also an increased risk of CV events in men on testosterone therapy. As a result, many clinicians will be more selective in their prescribing of testosterone. In this review, we examine how these new guidelines arose and how they may affect prescribing habits. PMID:27141448
Gray, Kendra M; Derosa, Angela
The authors describe the case of a 36-year-old man who presented with hormone level concerns 6 months after a rock climbing accident that resulted in paraplegia. Hypogonadism was diagnosed, and the patient received subcutaneous pellet testosterone replacement therapy. Within 6 months, the patient had substantial improvement in muscle function and was able to take several steps with the assistance of crutches or a walker. This case highlights the potential improvement in quality of life and overall prognosis resulting from the subcutaneous pellet form of testosterone when used as part of the overall treatment plan in such patients. Considering the overwhelming preponderance of hypogonadism in men with spinal cord injuries, the standard of care for such patients should include screening, laboratory hormone evaluation, and prompt treatment for testosterone deficiency.
DeLay, Kenneth J; Haney, Nora
Erectile dysfunction (ED) is prevalent among men and its presence is often an indicator of systemic disease. Risk factors for ED include cardiovascular disease, hypertension, diabetes mellitus (DM), tobacco use, hyperlipidemia, hypogonadism, lower urinary tract symptoms, metabolic syndrome, and depression. Addressing the modifiable risk factors frequently improves a patient's overall health and increases lifespan. The literature suggests that smoking cessation, treatment of hyperlipidemia, and increasing physical activity will improve erectile function in many patients. How the treatment of DM, depression, and hypogonadism impacts erectile function is less clear. Clinicians need to be aware that certain antihypertensive agents can adversely impact erectile function. The treatment of men with ED needs to address the underlying risk factors to ameliorate the disease process. PMID:27574592
Androgens are essential for the development of the penis and it is well known that testosterone play a critical role in the physiology of erectile function. From animal studies, testosterone insufficiency disrupts cellular-signaling pathways and induces pathologic alterations in penile tissues leading to erectile dysfunction. In human, the testosterone threshold for maintaining erection is low which explains the reason why some contracted men still have an erection due to the androgens produced by the adrenal gland. Testosterone alone can improve erectile function in hypogonadic patients. Associated with PDE5-I, testosterone supplementation is a treatment for the hypogonadic patients non responders to therapy. The article reviews the different aspects of the testosterone role in the pathophysiology of erection.
Amore, Mario; Innamorati, Marco; Costi, Sara; Sher, Leo; Girardi, Paolo; Pompili, Maurizio
The aim of this review was to summarize current knowledge on the correlation between depressive symptoms with a syndrome called partial androgen deficiency of the aging male (PADAM) and on the potential benefits of testosterone (T) treatment on mood. Despite, the causative nature of the relationship between low T levels and depression is uncertain, many hypogonadal men suffer from depression and vice versa several depressed patients are affected by hypogonadism. Supplementation with testosterone failed to show sound evidence of effectiveness in the treatment of depression. Nevertheless, testosterone supplementation has proved to be effective on some domains significant for the quality of life of aged patients with PADAM (sexual function and cognitive functions, muscular strengths). PMID:22719760
Abdul Jalil, Mohd Azri; Shuid, Ahmad Nazrun; Muhammad, Norliza
With improvements in living standards and healthcare, life expectancy has been increasing dramatically in most parts of the world. These situations lead to the increase in the reported cases of geriatrics-related diseases such as hypogonadal osteoporosis with skeletal fracture being the ultimate outcome, which eventually causes significant morbidity and mortality. The deficient gonadal hormones, which are the main cause of hypogonadal osteoporosis, could be substituted with hormone replacement therapy to hinder bone loss. However, the artificial hormonal therapy has been linked to grievous conditions such as breast and prostate cancers. In view of the various adverse effects associated with conventional treatment, many researchers are now focusing on finding alternative remedies from nature. This article explores the possibilities of certain medicinal plants native to Malaysia that possess androgenic and antioxidant properties to potentially be used in the treatment of fracture due to osteoporosis in ageing people.
Bolanowski, Marek; Daroszewski, Jacek; Medraś, Marek; Zadrozna-Sliwka, Beata
Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion. GH and insulin-like growth factor-I (IGF-I) exert anabolic activity in bones. Nevertheless, bone mineral density (BMD) loss is not uncommon in patients with acromegaly. It is assumed to be due to hypogonadism associated with the acromegaly. The aim of the study was to examine BMD at various skeletal sites and bone turnover and to assess the influence of impaired gonadal function and disease activity on BMD and turnover changes in acromegaly. A total of 62 patients were studied (40 women, 22 men). Among the women, 22 had active disease and 18 were cured; 16 women had normal gonadal function, and 24 were hypogonadal. Altogether, 12 men presented with active acromegaly, and 10 were cured; normal gonadal function was found in 10 men, and hypogonadism was diagnosed in 12 men. Controls were 30 healthy subjects. Densitometry using dual-energy X-ray absorptiometry of the lumbar spine, proximal femur, forearm, and total body was carried out. Bone turnover was studied based on serum osteocalcin, C-terminal collagen type 1 crosslinks, and bone alkaline phosphatase concentration. A disadvantageous effect of acromegaly on bone density was associated with hypogonadism in the distal radius (in women), the proximal femur (in men), and the total body (both sexes). An anabolic effect of GH during active acromegaly was present in the proximal femur only in men. We confirmed increased bone turnover in the presence of acromegaly, and these changes were similar regarding the activity of the disease and the gonadal status.
Weinberg, U; Kraemer, F B; Kammerman, S
The unique combination of male hypogonadism with hypoparathyroidism, hypoadrenalism, hypothyroidism, diabetes mellitus, and alopecia totalis has been documented in a male patient who has been followed over the past 28 years. In this patient, first seen at the age of six for hypoparathyroidism alone, repeated clinical and laboratory endocrine evaluation detected the sequential development of the additional endocrine deficiencies. The presence of abnormal serum antibodies is consistent with an atuoimmune pathogenesis of this syndrome.
Endocrinol Metab. Jul 2003;285(1):E16-24. 6. Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood...maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. May 2004;89... Reproduction . Mar 2004;127(3):359-366. 23. Andersson DC, Marks AR. Fixing ryanodine receptor Ca leak - a novel therapeutic strategy for contractile
Kumar, Raj; Singhal, Namit
A 15-year-old female presented with primary amenorrhea and delayed onset of secondary sexual characteristics. Earlier she was operated for endoscopic third ventriculostomy (ETV) for a tense suprasellar arachnoid cyst with obstructive hydrocephalus. MRI revealed recurrence of hydrocephalus. Hormonal levels were suggestive of hypogonadism and deficiency of growth hormone. She was operated for fenestration of cyst. In this case, suprasellar arachnoid cyst presented with delayed puberty, which is unusual.
Wei, Christina; Crowne, Elizabeth Clare
Delayed puberty, especially in boys, is a common presentation in paediatrics. Recent advances have improved our understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development, and hence inform the pathophysiology of delayed puberty. The discovery of kisspeptin signalling through its receptor identified neuroendocrine mechanisms controlling the gonadotrophin-releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphism associated with delayed puberty are being identified. Environmental factors, including nutritional factors and endocrine disruptors, have also been implicated in changes in secular trends and abnormal timing of puberty. Despite these advances, the key clinical question is to distinguish delayed puberty associated with an underlying pathology or hypogonadism from constitutional delay in growth and puberty, which remains challenging as biochemical tests are not always discriminatory. The diagnostic accuracies of newer investigations, including 36-hour luteinising hormone releasing hormone (LHRH) tests, GnRH-agonist tests, antimullerian hormone and inhibin-B, require further evaluation. Sex hormone replacement remains the main available treatment for delayed puberty, the choice of which is largely dictated by clinical practice and availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys with idiopathic hypogonadotrophic hypogonadism after a period of sex steroid treatment, highlighting the importance of reassessment at the end of pubertal induction. Novel therapies with a more physiological basis such as gonadotrophins or kisspeptin-agonist are being investigated for the management of hypogonadotrophic hypogonadism. Careful clinical assessment and appreciation of the normal physiology remain the key approach to patients with delayed puberty.
Jha, Shailesh; Garg, Amit
The coincidence or causal incidence of hormonal dysregulation leading to psychotic manifestation had been a point of debate. The interplay of these hormones in pathogenesis of psychotic symptom domains is still inconclusive along with some symptom domains which worsen with antipsychotics. Early detection and treatment with liaison approach is of great help to such patients. We report a case of schizophrenia with primary hypogonadism that responded dramatically to add on testosterone supplement. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Hürlimann, A F; Schnyder, U W
Werner's syndrome is a rare, autosomal recessive inherited disorder with a distinctive clinical picture. The characteristic physiognomy, shortness of stature with thin extremities, and large trophic ulcers are the key signs for the diagnosis. Premature greying of the hair and baldness, juvenile cataracts, a tendency to diabetes mellitus, hypogonadism, calcifications of the blood vessels, osteoporosis, metastatic calcifications of the soft tissue and an elevated incidence of neoplasms are further important features. We describe two patients with this disorder.
Borst, Stephen E; Yarrow, Joshua F
The value of testosterone replacement therapy (TRT) for older men is currently a topic of intense debate. While US testosterone prescriptions have tripled in the past decade (9), debate continues over the risks and benefits of TRT. TRT is currently prescribed for older men with either low serum testosterone (T) or low T plus accompanying symptoms of hypogonadism. The normal range for serum testosterone is 300 to 1,000 ng/dl. Serum T ≤ 300 ng/dl is considered to be low, and T ≤ 250 is considered to be frank hypogonadism. Most experts support TRT for older men with frank hypogonadism and symptoms. Treatment for men who simply have low T remains somewhat controversial. TRT is most frequently administered by intramuscular (im) injection of long-acting T esters or transdermally via patch or gel preparations and infrequently via oral administration. TRT produces a number of established benefits in hypogonadal men, including increased muscle mass and strength, decreased fat mass, increased bone mineral density, and improved sexual function, and in some cases those benefits are dose dependent. For example, doses of TRT administered by im injection are typically higher than those administered transdermally, which results in greater musculoskeletal benefits. TRT also produces known risks including development of polycythemia (Hct > 50) in 6% of those treated, decrease in HDL, breast tenderness and enlargement, prostate enlargement, increases in serum PSA, and prostate-related events and may cause suppression of the hypothalamic-pituitary-gonadal axis. Importantly, TRT does not increase the risk of prostate cancer. Putative risks include edema and worsening of sleep apnea. Several recent reports have also indicated that TRT may produce cardiovascular (CV) risks, while others report no risk or even benefit. To address the potential CV risks of TRT, we have recently reported via meta-analysis that oral TRT increases CV risk and suggested that the CV risk profile for im TRT
Caldas, Amadeus Lima Rocha; Rodrigues, Mecciene Mendes
The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported. PMID:24474111
Doriguzzi, C; Palmucci, L; Mongini, T; Bresolin, N; Bet, L; Comi, G; Lala, R
A 19-year-old man born with thyroprivic hypothyroidism, due to congenital development defect, manifested hypogonadism, stunted growth, chronic progressive external ophthalmoplegia (CPEO), diffuse muscle weakness and wasting, right bundle branch block, cerebral atrophy. Muscle biopsy showed mitochondrial abnormalities. Biochemical investigations on muscle disclosed partial (50%) cytochrome c oxidase deficiency, 58% decrease of cytochrome aa3 and 41% decrease of cytochrome b. Enzyme-linked immunosorbent assay showed decrease of the immunologically active enzyme protein. Images PMID:2540284
Ciana, G.; Fertz, M. C.; Pecile, V.; Demarini, S.
Prader-Willi syndrome in the newborn is essentially characterized by marked hypotonia, feeding difficulties, hypogonadism, and possible characteristic facial features. However, diagnosis at this age may be particularly difficult, and dysmorphic features may be subtle or absent. Prematurity can furthermore delay clinical features recognition and typical complications due to preterm birth may contribute to divert the diagnosis. We describe a preterm baby with a complicated perinatal course later diagnosed as PWS. PMID:22606524
Morley, J E
This article examines in detail the present state of the art concerning androgen deficiency in aging males. There is increasing evidence that testosterone replacement in hypogonadal older males can result in an improvement in quality of life. The major effects of testosterone are on libido, muscles, bone, and cognition. Less information is available concerning the role of testosterone in postmenopausal women, but testosterone replacement may have a role to play in treating disorders of libido and the sarcopenia that occurs at menopause.
Winters, Stephen J
Dose adjustment with transdermal testosterone preparations should recognize the variability of serum total testosterone levels between applications and over the course of 24 h. Dose adjustments are also made difficult by between-laboratory assay variability. Low SHBG with obesity and diabetes lowers the total testosterone level, and free or bioavailable testosterone may prove to be a better choice for monitoring the progress and dosing of testosterone-treated men with adult onset hypogonadism.
Mederos, Michael A; Bernie, Aaron M; Scovell, Jason M; Ramasamy, Ranjith
Low serum testosterone has been associated with obesity, type 2 diabetes, metabolic syndrome, and atherosclerosis. Individuals with these comorbidities are at increased risk of premature death and other adverse health effects. Clinical data portend low testosterone as a risk factor for developing these conditions which are supported by the hypogonadal-obesity-adipocytokine hypothesis. The authors support comprehensive evaluation for these comorbid conditions in men found to have low serum testosterone. PMID:26839520
van Oeveren, Arjan; Motamedi, Mehrnoush; Martinborough, Esther; Zhao, Shuo; Shen, Yixing; West, Sarah; Chang, William; Kallel, Adam; Marschke, Keith B; López, Francisco J; Negro-Vilar, Andrés; Zhi, Lin
A series of selective androgen receptor modulators (SARMs) with a wide spectrum of receptor modulating activities was developed based on optimization of the 4-substituted 6-bisalkylamino-2-quinolinones (3). Significance of the trifluoromethyl group on the side chains and its interactions with amino acid residues within the androgen receptor (AR) ligand binding domain are discussed. A representative analog (9) was tested orally in a rodent model of hypogonadism and demonstrated desirable tissue selectivity.
Michaud, Jason E; Billups, Kevin L; Partin, Alan W
Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH). Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The 'androgen hypothesis' asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered
Michaud, Jason E.; Billups, Kevin L.; Partin, Alan W.
Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH). Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The ‘androgen hypothesis’ asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be
Gu, Wei-Jun; Zhang, Qian; Wang, Ying-Qian; Yang, Guo-Qing; Hong, Tian-Pei; Zhu, Da-Long; Yang, Jin-Kui; Ning, Guang; Jin, Nan; Chen, Kang; Zang, Li; Wang, An-Ping; Du, Jin; Wang, Xian-Ling; Yang, Li-Juan; Ba, Jian-Ming; Lv, Zhao-Hui; Dou, Jing-Tao
Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron–exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients’ sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype–phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights. PMID:26031747
Sänger, C F E; Dietrich, N; Pelivani, N; Borradori, L; de Viragh, P A
Acquired localized hypertrichosis has rarely been reported. Here, we describe a patient with localized hypertrichosis of the pinnae that occurred 4 months after orchiectomy and chemotherapy for a testicular carcinoma. To our knowledge, this is the first case of an acquired hypertrichosis of the pinnae after cancer therapy. We propose that in our patient either hypogonadism or the hormonal imbalance caused by the cancer therapy led to the development of the hairy pinnae, perhaps alongside a genetic predisposition for hairy ears.
Cookson, John; Hodgson, Richard; Wildgust, Hiram J
Hyperprolactinaemia is a common side effect of antipsychotics; markedly raised levels are less common. Higher levels of prolactin result from longer exposure to higher doses, especially with older antipsychotics or with risperidone, sulpiride or amisulpride. Galactorrhoea, gynaecomastia, menstrual abnormalities and sexual dysfunction including hypogonadism and fertility problems are consequences of raised prolactin, and in the longer-term bone demineralisation. Younger patients may be more susceptible to hyperprolactinaemia. Trial reports often fail to state the frequency of raised levels.
Ghazi, Leyla J; Patil, Seema A; Cross, Raymond K
Sexual health is a broad term that encompasses a variety of functions including sexual thoughts, desire, arousal, intercourse, orgasm, and the impact of body image. Sexual dysfunction in individuals with inflammatory bowel disease is multifactorial including the impact of psychosocial factors, disease activity, medical therapies, surgical interventions, body image perceptions and changes, hypogonadism, and pelvic floor disorders. Providers caring for patients with inflammatory bowel disease should be cognizant of these concerns and develop management plans and techniques for earlier diagnosis and treatment.
Potorac, Iulia; Rivero-Müller, Adolfo; Trehan, Ashutosh; Kiełbus, Michał; Jozwiak, Krzysztof; Pralong, Francois; Hafidi, Aicha; Thiry, Albert; Ménagé, Jean-Jacques; Huhtaniemi, Ilpo; Beckers, Albert; Daly, Adrian F
Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.
Levy, C L; Sparkes, R S; Carlson, H E
In 2 adult male patients with 49 chromosomes, an XXXXY sex chromosome constitution was confirmed by trypsin-Giemsa banding sites. Clinical findings as well as fingerprint ridge counts were typical of the syndrome. Primary hypogonadism was documented by finding low serum testosterone and raised serum LH and FSH levels. Several radiological abnormalities, not previously described in this syndrome, were seen in 1 patient. Images PMID:568665
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Ozoemena, Ofn; Ezugworie, Jo; Mbah, Au; Esom, Ea; Ayogu, Bo; Ejezie, Fe
Hormonal derangements potentially contribute to the diagnosis of infertility in over 60%-70% of couples investigated. Use of hormonal and antihormonal agents has achieved great success in the treatment of male infertility. Our aim was to investigate the prevalence of hormonal abnormalities in males diagnosed with infertility. Males diagnosed clinically with infertility and referred from the gynecologic clinics of the University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu State University Teaching Hospital, and some private hospitals in and around Enugu metropolis were recruited for the study. They were grouped according to whether they had primary or secondary infertility on the basis of the World Health Organization definition. Routine fertility test profiles for the subjects were evaluated, and detailed hormonal assays were analyzed. Of 216 men, 173 (80.1%) were found to have a hormonal imbalance. The mean age was 47.7 ± 3.5 (range 30-55) years for primary infertility and 47.2 ± 6.8 (range 33-61) years for secondary infertility. Patterns of hormonal abnormalities diagnosed amongst the 62 (35.80%) primary infertility subjects included hypergonadotrophic hypogonadism in 39 (62.90%), hypogonadotrophic hypogonadism in 18 (29.03%), and hyperprolactinemia in five (8.07%). Among the 111 (64.2%) cases of secondary infertility, there were 55 (49.55%) cases of hypergonadotrophic hypogonadism, 52 (46.85%) of hypogonadotrophic hypogonadism, and four (3.60%) of hyperprolactinemia. There was no statistically significant difference in the mean values between the two groups (χ(2) < 1.414; P > 0.05) for hormonal indices. The hormonal profile should be considered as the gold standard for diagnosis and management of male infertility.
Ozoemena, OFN; Ezugworie, JO; Mbah, AU; Esom, EA; Ayogu, BO; Ejezie, FE
Background Hormonal derangements potentially contribute to the diagnosis of infertility in over 60%–70% of couples investigated. Use of hormonal and antihormonal agents has achieved great success in the treatment of male infertility. Our aim was to investigate the prevalence of hormonal abnormalities in males diagnosed with infertility. Methods Males diagnosed clinically with infertility and referred from the gynecologic clinics of the University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu State University Teaching Hospital, and some private hospitals in and around Enugu metropolis were recruited for the study. They were grouped according to whether they had primary or secondary infertility on the basis of the World Health Organization definition. Routine fertility test profiles for the subjects were evaluated, and detailed hormonal assays were analyzed. Results Of 216 men, 173 (80.1%) were found to have a hormonal imbalance. The mean age was 47.7 ± 3.5 (range 30–55) years for primary infertility and 47.2 ± 6.8 (range 33–61) years for secondary infertility. Patterns of hormonal abnormalities diagnosed amongst the 62 (35.80%) primary infertility subjects included hypergonadotrophic hypogonadism in 39 (62.90%), hypogonadotrophic hypogonadism in 18 (29.03%), and hyperprolactinemia in five (8.07%). Among the 111 (64.2%) cases of secondary infertility, there were 55 (49.55%) cases of hypergonadotrophic hypogonadism, 52 (46.85%) of hypogonadotrophic hypogonadism, and four (3.60%) of hyperprolactinemia. There was no statistically significant difference in the mean values between the two groups (χ2 < 1.414; P > 0.05) for hormonal indices. Conclusion The hormonal profile should be considered as the gold standard for diagnosis and management of male infertility. PMID:24198646
Faraco, J.; Francke, U.; Toledo, S.
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.
Schisler, Jonathan C; Patterson, Cam; Willis, Monte S
Hereditary ataxias are characterized by a slowly progressive loss of gait, hand, speech, and eye coordination and cerebellar atrophy. A subset of these, including hypogonadism, are inherited as autosomal recessive traits involving coding mutations of genes involved in ubiquitination including RNF216, OTUD4, and STUB1. Cerebellar CHIPopathy (MIM 615768) is a form of autosomal recessive spinocerebellar ataxia (SCAR16) and when accompanied with hypogonadism, clinically resembles the Gordon Holmes Syndrome (GHS). A causal missense mutation in the gene that encodes the carboxy terminus of HSP-70 interacting protein (CHIP) protein was reported for the first time in 2014. CHIP-/- mice were found to phenocopy the motor deficiencies and some aspects of the hypogonadism observed in patients with STUB1 mutations. However, mechanisms responsible for these deficits are not known. In a survey of skeletal muscle by transmission electron microscopy. CHIP-/- mice at 6 months of age were found to have morphological changes consistent with increased sarcoplasmic reticulum compartments in quadriceps muscle and gastrocnemius (toxic oligomers and tubular aggregates), but not in soleus. Since CHIP has been implicated in ER stress in non-muscle cells, these findings illustrate potential parallel roles of CHIP in the muscle sarcoplasmic reticulum, a hypothesis that may be clinically relevant in a variety of common muscular and cardiac diseases.
Hill, Simon; Arutchelvam, Vijayaraman; Quinton, Richard
Enclomiphene (Androxal), in development by Repros Therapeutics Inc, is a non-steroidal estrogen receptor antagonist that promotes gonadotropin-dependent testosterone secretion by the testes. Enclomiphene constitutes the trans-stereoisomer of clomiphene citrate, a drug that has been widely prescribed for several decades for the treatment of female ovulatory dysfunction. Because of the antagonistic effects of enclomiphene, the drug has the potential to increase serum testosterone levels in men with secondary hypogonadism by restoring physiological endogenous testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis. In clinical trials conducted to date, enclomiphene demonstrated significant efficacy in the physiological restoration of testosterone levels in males with secondary hypogonadism. The compound also exhibited an unanticipated favorable effect on fasting plasma glucose; this result has been accompanied by rapidly accumulating evidence from other researchers for a bidirectional relationship between low serum testosterone and obesity/metabolic syndrome (syndrome X) in men. Short-term clinical safety data for enclomiphene have been satisfactory and equivalent to safety data for testosterone gels and placebo. Enclomiphene demonstrates promise in the management of secondary hypogonadism associated with obesity, metabolic syndrome and, possibly, infertility, and should undergo placebo-controlled, randomized clinical trials for these indications.
Sokol, Rebecca Z
A normal functioning reproductive endocrine system is a prerequisite for normal male fertility. Any disruption of the delicately coordinated interaction between the components of the hypothalamic-pituitary-testicular axis may lead to hypogonadism and/or infertility. The goal of the clinical evaluation is to determine if the patient has an abnormality of testosterone production or action, the etiology of the abnormality, and if hormone therapy will correct the infertility. Based on a careful history, physical examination, and evaluation of the hormones of the reproductive axis, the physician will ascertain if the patient's hypogonadism is (1) prepubertal or postpubertal in onset; (2) the result of an abnormality in the hypothalamic-pituitary axis, the testes, or the androgen receptor; or (3) associated with another underlying medical condition. This information will place the patient into one of four diagnostic categories: hypogonadotropic hypogonadism, testicular failure, 5alpha-reductase deficiency, or androgen resistance. Within each category are disorders with identifiable pathogenic mechanisms. Recent studies have added to these lists and have provided insights into the molecular basis and inheritance patterns of several of these endocrinopathies.
Hwang, Kathleen; Miner, Martin
The role of testosterone in the cardiovascular (CV) health of men is controversial. Data suggest that both the condition and treatment of clinical hypogonadism is associated with decreased CV mortality; however, two recent studies suggest that hypogonadal subjects treated with testosterone replacement therapy have a higher incidence of new CV events. There has been increased media attention concerning the risk of CV disease in men treated with testosterone. Until date, there are no long-term prospective studies to determine safety. Literature spanning over the past 30 years has suggested that not only is there a possible increased CV risk in men with low levels of testosterone, but the benefits from testosterone therapy may even lower this risk. We review here the recent studies that have garnered such intense scrutiny. This article is intended as a thorough review of testosterone levels and CV risk, providing the clinician with the facts needed to make informed clinical decisions in managing patients with clinical hypogonadism. PMID:25652628
Chatterjee, R; Kottaridis, P D; McGarrigle, H H; Linch, D C
Erectile dysfunction (ED) is a well recognised complication of bone marrow transplantation, which affects quality of life in adult patients. Although the major contributory factors include hypogonadism and psychogenic factors, the best treatment still remains to be established due to the complex aetiopathology of the condition. Here, we report our preliminary results in eight patients treated with testosterone replacement therapy and sildenafil. We studied eight male recipients of BMT aged 22-58 years, presenting with clinical features of hypogonadism, ED, diminished libido and ejaculatory disorders. ED was assessed clinically and by colour flow Doppler studies of the cavernosal vessels. Testicular function was assessed by testicular volume, FSH, LH and testosterone (T) measurements. Erectile performance, libido and ejaculatory function were determined by a structured interview. Patients had severe primary hypogonadism as evidenced by low mean testicular volume, elevated gonadotrophins and low normal mean testosterone levels compared with controls. All had Leydig cell insufficiency (LCI) with or without frank serum testosterone insufficiency. All except one had cavernosal arterial insufficiency. All patients received intramuscular injections of testosterone cypionate (250 mg 4 weekly) for 6 months and 50-100 mg of sildenafil orally, one to two times per week. All patients responded favourably as substantiated from the NIH consensus criteria. Our preliminary results suggest that this combined therapy is a safe and effective therapeutic approach in recipients of high-dose therapy presenting with ED after transplant.
Dillon, E Lichar; Durham, William J; Urban, Randall J; Sheffield-Moore, Melinda
Aging is associated with a gradual decline in circulating testosterone concentrations and decreased musculature in men. While testosterone administration is often considered when symptoms of hypogonadism are presented, the long-term effects of androgen use on muscle physiology are not yet fully understood. The definition of hypogonadism in men remains obscure but is generally indicated by total testosterone concentrations less than a threshold value of 300-500 ng/dL. Androgen replacement therapy is generally safe in men and women with low endogenous testosterone concentrations. The development of selective androgen receptor modulators (SARMs) may provide additional options in treatment of hypogonadism while lowering the potential of side effects often associated with long-term androgen use. Androgen administration, either alone or in combination with other treatments, can be successful in improving muscle mass by increasing protein anabolism and reducing protein catabolism in men and women. Further research is necessary to optimize the anabolic and anticatabolic properties of androgens for treatment and prevention of muscle loss in men and women.
Dillon, E. Lichar; Durham, William J.; Urban, Randall J.; Sheffield-Moore, Melinda
Aging is associated with a gradual decline in circulating testosterone concentrations and decreased musculature in men. While testosterone administration is often considered when symptoms of hypogonadism are presented, the long-term effects of androgen use on muscle physiology are not yet fully understood. The definition of hypogonadism in men remains obscure but is generally indicated by total testosterone concentrations less than a threshold value of 300-500 ng/dL. Androgen replacement therapy is generally safe in men and women with low endogenous testosterone concentrations. The development of selective androgen receptor modulators (SARMs) may provide additional options in treatment of hypogonadism while lowering the potential of side effects often associated with long-term androgen use. Androgen administration, either alone or in combination with other treatments, can be successful in improving muscle mass by increasing protein anabolism and reducing protein catabolism in men and women. Further research is necessary to optimize the anabolic and anticatabolic properties of androgens for treatment and prevention of muscle loss in men and women. PMID:20452103
Bassil, Nazem; Alkaade, Saad; Morley, John E
Increased longevity and population aging will increase the number of men with late onset hypogonadism. It is a common condition, but often underdiagnosed and undertreated. The indication of testosterone-replacement therapy (TRT) treatment requires the presence of low testosterone level, and symptoms and signs of hypogonadism. Although controversy remains regarding indications for testosterone supplementation in aging men due to lack of large-scale, long-term studies assessing the benefits and risks of testosterone-replacement therapy in men, reports indicate that TRT may produce a wide range of benefits for men with hypogonadism that include improvement in libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life and cardiovascular disease. Perhaps the most controversial area is the issue of risk, especially possible stimulation of prostate cancer by testosterone, even though no evidence to support this risk exists. Other possible risks include worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea or severe heart failure. Despite this controversy, testosterone supplementation in the United States has increased substantially over the past several years. The physician should discuss with the patient the potential benefits and risks of TRT. The purpose of this review is to discuss what is known and not known regarding the benefits and risks of TRT. PMID:19707253
Wosnitzer, Matthew S; Paduch, Darius A
47, XXY or Klinefelter syndrome (KS), the most common chromosomal aberration in males, is characterized by either absolute or relative hypogonadism with frequent decline in serum testosterone (T) following the onset of puberty. Decreased T levels are the result of testicular dysfunction with decrease in size of Leydig cells, and loss of germs and Sertoli cells leading to tubular hyalinization. Increase in estradiol results from over-expression of aromatase CYP19. Deficient androgen production and observed varied response of end-organs to T leads to delayed progression of puberty with decreased facial/body hair, poor muscle development, osteoporosis, and gynecomastia. It is possible that hypogonadism and excessive estradiol production contribute to emotional and social immaturity, and specific learning disabilities in KS. Based on the authors' experience and literature review, early fertility preservation and hormonal supplementation may normalize pubertal development, prevent metabolic sequelae of hypogonadism, and have a positive effect on academic and social development. No randomized clinical trials are available studying the effects of T supplementation on reproductive or cognitive issues in KS. Aggressive T supplementation (topical gel) and selective use of aromatase inhibitors may be considered at the onset of puberty with careful follow-up and titration to reach age-specific high-normal physiologic serum values. The decision to institute hormonal therapy should be part of a multidisciplinary approach including physical, speech, behavioral, and occupational therapy. © 2013 Wiley Periodicals, Inc.
Ghosh, Soumitra; Bandyopadhyay, Sanjay K; Bandyopadhyay, Ranjana; Roy, Dipankar; Maisnam, Indira; Ghosh, Moloy K
The aim was to study the prevalence and severity of hormonal imbalance affecting growth, gonadal and thyroid function in thalassaemic patients and to find out whether any correlation exists between the degree of tissue iron-overload and several patients characteristics like age, gender, foetal haemoglobin (HbF) level, type of thalassaemia (beta or E-beta), and the presence of specific endocrine abnormality. Sixty-eight consecutive non-chelated, transfusion-dependent patients of beta and E-beta-thalassaemia with significant tissue iron overload (serum ferritin more than 2000 microg/l) were included. Standing height was noted and clinical features of hypogonadism were recorded. Insulin tolerance test was done to assess growth hormone reserve. Serum oestradiol, T3,T4,TSH were measured in fasting clotted sample, while pooled sera (from 3 consevutive morning samples) was used for testosterone, FSH and LH. Hypogonadism was the commonest abnormality, both in males (52.28%) and females (35.89%) followed by growth retardation (20.58%) and reduced growth hormone reserve (7.35%). There was no significant difference in the prevalence of endocrine dysfunction with regard to patient's age, gender, type of thalassaemia (beta or E-beta) amd HbF level. Hypogonadic females had a significantly elevated mean serum ferritin level. Subclinical hypothyroidism was present in 23.52% of patients, related to the duration of disease. No association was found between pituitarty and thyroid dysfunction.
Burnett, Lisa C.; LeDuc, Charles A.; Sulsona, Carlos R.; Paull, Daniel; Rausch, Richard; Eddiry, Sanaa; Carli, Jayne F. Martin; Morabito, Michael V.; Skowronski, Alicja A.; Hubner, Gabriela; Zimmer, Matthew; Wang, Liheng; Day, Robert; Levy, Brynn; Dubern, Beatrice; Poitou, Christine; Clement, Karine; Rosenbaum, Michael; Salles, Jean Pierre; Tauber, Maithe; Egli, Dieter
Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell–derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p–/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p–/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p–/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH–releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency. PMID:27941249
Laroche, E; Bricaire, L; Christin-Maitre, S
Amenorrhea in adolescents can be primary, with or without breast development, or secondary. Whether amenorrhea is primary or secondary, height, body mass index, food intake, the level of physical activity per week, the presence of hirsutism or galactorrhea, pelvic pain and past history of intercourse need to be investigated. Initially, blood tests should include hCG, FSH, estradiol, testosterone and prolactin serum levels. This screening will discriminate between hypogonadotropic hypogonadism and amenorrhea from primary ovarian insufficiency (POI). In case of primary amenorrhea, hypogonadism may be due to congenital hypogonadotropic hypogonadism (HH) or more rarely acquired HH. If FSH is elevated, amenorrhea is due to primary ovarian failure, mainly related to Turner syndrome. If pubertal development is normal, a pelvic ultrasound should be performed. It may visualize a hindering of menses output or less frequently an absence of uterus, as in Rokitansky syndrome or androgen insentivity syndrome. The most frequent etiologies of secondary amenorrhea are polycystic ovarian syndrome (PCOS), functional hypothalamic amenorrhea and less frequently POI and hyperprolactinemia. The differential diagnoses of PCOS are late-onset 21-hydroxylase deficiency and very rare ovarian or adrenal tumors. When contraception is not necessary, hormonal replacement therapy, including estrogen and progestins should be administered in order to avoid hypoestrogenism. In case of PCOS, sequential progestins can be prescribed. A contraceptive pill can be considered when contraception is needed and/or when hyperandrogenism needs to be treated.
Høst, Christian; Gormsen, Lars C.; Christensen, Britt; Jessen, Niels; Hougaard, David M.; Christiansen, Jens S.; Pedersen, Steen B.; Jensen, Michael D.; Nielsen, Søren; Gravholt, Claus H.
Low testosterone (T) levels in men have been shown to predict development of the metabolic syndrome, but the effects of T on lipid metabolism are incompletely understood. In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy, young males received gonadotropin-releasing hormone agonist treatment 1 month prior to 3 of 4 trial days to induce castrate levels of T. On trial days, T gel was applied to the body containing either high or low physiological T dose or placebo. On the 4th trial day, participants constituted their own eugonadal controls. Each study comprised a 5-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. Short-term hypogonadism did not affect VLDL triglyceride (TG) secretion, nor did it affect VLDL-TG concentrations. It was, however, characterized by lower total lipid oxidation. In addition, acute rescue with high physiological T increased VLDL-TG secretion during both basal and clamp conditions. These data show that T can act through fast nongenomic pathways in the liver. In addition, the early hypogonadal state is characterized by decreased total lipid oxidation, but whether these changes represent early hypogonadal metabolic dysfunction warrants further investigations. T is not a major determinant of resting VLDL-TG kinetics in men. PMID:23193189
Margolese, H C
The objective of this study was to review the literature on the hormonal changes that occur in aging males in order to determine if testosterone declines in relation to depressed mood and if testosterone might prove useful in treatment of depression. Pertinent articles were identified through a MEDLINE search from 1966 to 1999 and by careful review of the bibliographies of articles most relevant to the topic. There is a moderate decline of total testosterone and more significant decline of bioavailable testosterone in aging males. Elderly males who are depressed appear to have the lowest testosterone levels. In eugonadal males, testosterone replacement does not have a significant effect on mood; in hypogonadal males, some studies show an effect whereas others do not. In several small studies of depressed hypogonadal males, testosterone was effective in alleviating depression. Major side effects of testosterone include increased hematocrit and potential effects on the prostate and lipid metabolism. Testosterone replacement as primary or adjuvant treatment of depression may prove useful in elderly, hypogonadal males who fail to respond to conventional antidepressants. Further studies are needed to confirm these initial impressions.
Wu, Frederick; Zitzmann, Michael; Heiselman, Darell; Donatucci, Craig; Knorr, Jack; Patel, Ankur B; Kinchen, Kraig
Evidence from well-designed studies documenting the benefit of testosterone replacement therapy as a function of patient demographic and clinical characteristics is lacking. To determine demographic and clinical predictors of treatment outcomes in hypogonadal men with low sex drive, low energy, and/or erectile dysfunction. Post hoc analysis of a randomized, multicenter, double-blinded, placebo-controlled, 16-week study of 715 hypogonadal men (mean age = 55.3 years, age range = 19-92 years) presenting with low sex drive and/or low energy who received placebo or testosterone solution 2% for 12 weeks. Two levels defined patient-reported improvement (PRI) in sex drive or energy: level 1 was at least "a little better" and level 2 was at least "much better" in energy or sex drive on the Patient Global Impression of Improvement at study end point. PRI in erectile function was stratified by erectile dysfunction severity at baseline as measured by the erectile function domain of the International Index for Erectile Function: mild at baseline (change of 2), moderate at baseline (change of 5), and severe at baseline (change of 7). Associations of demographic and clinical characteristics with PRI were calculated with stepwise forward multiple logistic regression analysis. Odds ratios represented the likelihood of PRI in symptoms among variable categories. Higher levels of end-point testosterone were associated with higher rates of PRI (at levels 1 and 2) in sex drive and energy (P < .001 for the two comparisons). Lower baseline testosterone levels were associated with higher rates of level 1 PRI in sex drive (P = .028); and classic hypogonadism (vs non-classic hypogonadism) was associated with higher rates of level 2 PRI in sex drive (P = .005) and energy (P = .006). When assessing the potential for improvements in men with testosterone deficiency using patient-reported outcome questionnaires, possible predictors of treatment outcomes to consider include the etiology of
Skipworth, Richard J E; Moses, Alastair G W; Sangster, Kathryn; Sturgeon, Catharine M; Voss, Anne C; Fallon, Marie T; Anderson, Richard A; Ross, James A; Fearon, Kenneth C H
Hypogonadism has been linked with systemic inflammation and opioid use in males with advanced cancer. We aimed to investigate the interaction of gonadal status with systemic inflammation and opioids in determining nutrition