Management of male obesity-related secondary hypogonadism: A clinical update.

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management.

Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center.

Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.

Hypogonadism is frequent in very old men with multimorbidity and is associated with anemia and sarcopenia.

BACKGROUND: Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS: A total of 167 men aged 65-96 years (mean 81 ± 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy X­ray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS: Hypogonadism was present in 62% (n = 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low T­score). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (p = 0.031) and lower hemoglobin levels (p = 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION: Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.

Effect of oestrogen modulation on semen parameters in men with secondary hypogonadism: Systematic review and meta-analysis.

BACKGROUND: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta-analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism. OBJECTIVES: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism. MATERIALS AND METHODS: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non-randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB-2 and ROBINS-I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non-randomised studies of intervention meta-analysis were conducted using the random-effect model. The certainty of evidence was assessed using GRADE. RESULTS: Five non-randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I2  = 0%) and three non-randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46-19.59, I2  = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m2 . Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found. DISCUSSION AND CONCLUSION: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity.

Endoscopic Enucleation of Prostate Could Increase Testosterone Levels in Hypotestosteronemic Patients with Bladder Outlet Obstruction.

Background: We evaluated the impact of endoscopic enucleation of the prostate on testosterone levels in hypotestosteronemic patients with bladder outlet obstruction. Methods: We enrolled 294 men with lower urinary tract symptoms (LUTS) who received surgery between January 2019 and December 2020 in simple tertiary centre. The inclusion criteria were as follows: being a male patient aged 45−95 years and having recurrent urinary tract infection, having previously failed medical treatment for LUTS or urine retention, and undergoing bipolar or thulium laser enucleation of the prostate. The preoperative and postoperative data were retrospectively reviewed. Results: This study included 112 men with a mean age of 69.4 years. The mean preoperative and postoperative testosterone levels were 4.8 and 4.98, respectively. Of the patients, 88 (78.6%) received ThuLEP and 24 received BipolEP. We divided the patients into two groups according to preoperative serum testosterone levels: normal-testosterone (≥3 ng/mL) and low-testosterone (<3 ng/mL) groups. A significant change in testosterone levels (p = 0.025) was observed in the low-testosterone group. In contrast, no significant difference in testosterone levels was noted in the normal-testosterone group (p = 0.698). Conclusions: Endoscopic enucleation surgery of the prostate could improve postoperative testosterone levels in hypotestosteronemic patients with bladder outlet obstruction.

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice.

In the U.S. about half of the HIV-infected individuals are aged 50 and older. In men living with HIV, secondary hypogonadism is common and occurs earlier than in seronegative men, and its prevalence increases with age. While the mechanisms(s) are unknown, the HIV-1 trans-activator of transcription (Tat) protein disrupts neuroendocrine function in mice partly by dysregulating mitochondria and neurosteroidogenesis. We hypothesized that conditional Tat expression in middle-aged male transgenic mice [Tat(+)] would promote age-related comorbidities compared to age-matched controls [Tat(-)]. We expected Tat to alter steroid hormone milieu consistent with behavioral deficits. Middle-aged Tat(+) mice had lower circulating testosterone and progesterone than age-matched controls and greater circulating corticosterone and central allopregnanolone than other groups. Young Tat(+) mice had greater circulating progesterone and estradiol-to-testosterone ratios. Older age or Tat exposure increased anxiety-like behavior (open field; elevated plus-maze), increased cognitive errors (radial arm water maze), and reduced grip strength. Young Tat(+), or middle-aged Tat(-), males had higher mechanical nociceptive thresholds than age-matched counterparts. Steroid levels correlated with behaviors. Thus, Tat may contribute to HIV-accelerated aging.

Body composition changes following chemotherapy for testicular germ cell tumor: obesity is the long-term problem.

Metabolic syndrome is a long-term complication of systemic chemotherapy for testicular germ cell tumor (TGCT). It is believed to be caused by secondary hypogonadism or toxic medicines because of orchidectomy followed by systemic chemotherapy. In this study, changes in the body composition of patients over time were quantitatively analyzed up to 24 months after chemotherapy. This study retrospectively analyzed 44 patients with TGCT who underwent chemotherapy at our institution from January 2008 to December 2016. Subcutaneous and visceral fat areas and psoas and skeletal muscle areas were measured by computed tomography before and immediately after chemotherapy as well as 3 months, 6 months, 12 months, and 24 months after chemotherapy. The subcutaneous and visceral fat indices and psoas and skeletal muscle indices were calculated as each area divided by body height squared. The total fat area had already significantly increased 3 months after the initiation of chemotherapy (P = 0.004). However, it did not return to prechemotherapeutic levels even at 24 months after chemotherapy. The skeletal muscle area was significantly decreased at the end of chemotherapy (P < 0.001); however, the value returned to baseline within 12 months. In multivariable analysis, the prechemotherapeutic skeletal muscle index and number of chemotherapy cycles were independently associated with the reduction of skeletal muscle at the end of chemotherapy (P = 0.001 and P = 0.027, respectively). In patients with TGCT, skeletal muscle mass decreased during chemotherapy and recovered within 12 months, whereas fat mass progressively increased from the initiation of chemotherapy until 24 months after chemotherapy.

Biochemical predictors of structural hypothalamus-pituitary abnormalities detected by magnetic resonance imaging in men with secondary hypogonadism.

PURPOSE: Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic-pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. METHODS: A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. RESULTS: In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62-0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. CONCLUSION: In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.

Potential Cardiovascular and Metabolic Beneficial Effects of ω-3 PUFA in Male Obesity Secondary Hypogonadism Syndrome.

Long-chain ω-3 polyunsaturated fatty acids (PUFAs) are fundamental biocomponents of lipids and cell membranes. They are involved in the maintenance of cellular homeostasis and they are able to exert anti-inflammatory and cardioprotective actions. Thanks to their potential beneficial effects on the cardiovascular system, metabolic axis and body composition, we have examined their action in subjects affected by male obesity secondary hypogonadism (MOSH) syndrome. MOSH syndrome is characterized by the presence of obesity associated with the alteration of sexual and metabolic functions. Therefore, this review article aims to analyze scientific literature regarding the possible benefits of ω-3 PUFA administration in subjects affected by MOSH syndrome. We conclude that there are strong evidences supporting ω-3 PUFA administration and/or supplementation for the treatment and management of MOSH patients.

Management of Hypopituitarism.

: Hypopituitarism includes all clinical conditions that result in partial or complete failure of the anterior and posterior lobe of the pituitary gland's ability to secrete hormones. The aim of management is usually to replace the target-hormone of hypothalamo-pituitary-endocrine gland axis with the exceptions of secondary hypogonadism when fertility is required, and growth hormone deficiency (GHD), and to safely minimise both symptoms and clinical signs. Adrenocorticotropic hormone deficiency replacement is best performed with the immediate-release oral glucocorticoid hydrocortisone (HC) in 2-3 divided doses. However, novel once-daily modified-release HC targets a more physiological exposure of glucocorticoids. GHD is treated currently with daily subcutaneous GH, but current research is focusing on the development of once-weekly administration of recombinant GH. Hypogonadism is targeted with testosterone replacement in men and on estrogen replacement therapy in women; when fertility is wanted, replacement targets secondary or tertiary levels of hormonal settings. Thyroid-stimulating hormone replacement therapy follows the rules of primary thyroid gland failure with L-thyroxine replacement. Central diabetes insipidus is nowadays replaced by desmopressin. Certain clinical scenarios may have to be promptly managed to avoid short-term or long-term sequelae such as pregnancy in patients with hypopituitarism, pituitary apoplexy, adrenal crisis, and pituitary metastases.

Male Obesity-related Secondary Hypogonadism - Pathophysiology, Clinical Implications and Management.

The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex. Obesity-induced increase in levels of leptin, insulin, proinflammatory cytokines and oestrogen can cause a functional hypogonadotrophic hypogonadism with the defect present at the level of the hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. The resulting hypogonadism by itself can worsen obesity, creating a self-perpetuating cycle. Obesity-induced hypogonadism is reversible with substantial weight loss. Lifestyle-measures form the cornerstone of management as they can potentially improve androgen deficiency symptoms irrespective of their effect on testosterone levels. In selected patients, bariatric surgery can reverse the obesity-induced hypogonadism. If these measures fail to relieve symptoms and to normalise testosterone levels, in appropriately selected men, testosterone replacement therapy could be started. Aromatase inhibitors and selective oestrogen receptor modulators are not recommended due to lack of consistent clinical trial-based evidence.

Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism.

INTRODUCTION: Hypogonadism is an important issue among the male population. Treatments such as exogenous testosterone have become very popular. One of the adverse effects of testosterone is its suppression of fertility. This has lead to the use of alternative therapies such as selective estrogen receptor modulators (SERMs) that aim to correct hypogonadism without reducing fertility. Areas covered: The SERM, clomiphene citrate, which is approved by the FDA for the treatment of ovarian dysfunction, has been shown to have beneficial effects on male hypogonadism. Clomiphene citrate exists as a mixture of both the cis-isomer (zuclomiphene) and the trans-isomer (enclomiphene). The literature has suggested that most of the beneficial effects of clomiphene are due to the trans-isomer enclomiphene. Zuclomiphene contributes little to the intended outcomes. The purpose of this drug profile is to examine the available literature on the trans-isomer enclomiphene. Expert opinion: Enclomiphene has been shown to increase testosterone levels while stimulating FSH and LH production. Initial studies demonstrated that enclomiphene maintains the androgenic benefit of clomiphene citrate without the undesirable effects attributable to zuclomiphene. This article reviews the difficulties associated with the FDA approval of a new molecular entity related to the treatment of hypogonadism.

Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: Prospective results from the EMAS.

OBJECTIVE: Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone-binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). DESIGN: Prospective observational study with a median follow-up of 4.3 years. PATIENTS: Three thousand three hundred sixty-nine community-dwelling men aged 40-79 years from eight European centres. MEASUREMENTS: Subjects were categorized according to baseline and follow-up biochemical status into persistent eugonadal (referent group; n = 1880), incident LNSH (eugonadism to LNSH; n = 101) and incident LLSH (eugonadism to LLSH; n = 38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. RESULTS: The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9%, respectively. Baseline obesity predicted both LNSH and LLSH, but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR = 2.67 (1.27-5.60)], erectile dysfunction [OR = 4.53 (2.05-10.01)] and infrequent morning erections [OR = 3.40 (1.48-7.84)]. CONCLUSIONS: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT.

[Evaluation of testosteronemia in men undergoing surgery for urethral strictures].

INTRODUCTION: Testosterone plays an important role in the functioning of various organs and systems of the male body. Its diagnostic and prognostic values are studied both in urological diseases and in the patients undergoing non-urologic surgery. AIM: To investigate changes in testosterone level in patients with urethral strictures (US) depending on its baseline level, the cause of US, the age of patients and the number of surgeries. MATERIALS AND METHODS: The study comprised 30 patients aged 19-63 years with traumatic (76.7%) and inflammatory (23.3%) US. Primary and recurrent US were diagnosed in 25 (83.3%) and 5 (16.7%) patients, respectively. Nineteen (63.3%) patients underwent excision and primary anastomosis, while replacement urethroplasty was performed in 11 (36.7%) patients. In addition to the standard diagnostic work-up, all patients were tested for total serum testosterone 24 hours prior to surgery and at 1, 3, 7, 14 days after the operation. RESULTS: 33.3% of men with US had a testosterone deficiency in the absence of any testicular or endocrine injuries and diseases. Surgery was associated with a drop in testosteronemia in 83.3% of patients. The degree of postoperative testosterone level decline and its changes were significantly influenced by the age of patients and the number of operations. Men who had baseline testosterone deficiency and underwent repeat surgeries remained in a hypogonadal state throughout the postoperative period. CONCLUSION: Investigating the clinical value of testosterone in men with US and the risks of their surgical treatment associated with testosterone deficiency will provide insight into the role of testosterone in the treatment of this condition and the decision-making regarding pharmacological correction of testosterone deficiency in patients undergoing surgery for US.

S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism.

BACKGROUND: Excess reactive oxygen species and reactive nitrogen species are implicated in male infertility and impaired spermatogenesis. AIM: To investigate the effect of excess reactive nitrogen species and nitrosative stress on testicular function and the hypothalamic-pituitary-gonadal axis using the S-nitrosoglutathione reductase-null (Gsnor-/-) mouse model. METHODS: Testis size, pup number, and epididymal sperm concentration and motility of Gsnor-/- mice were compared with those of age-matched wild-type (WT) mice. Reproductive hormones testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone were compared in Gsnor-/- and WT mice. Immunofluorescence for Gsnor-/- and WT testis was performed for 3ß-hydroxysteroid dehydrogenase and luteinizing hormone receptor (LHR) and compared. Human chorionic gonadotropin and gonadotropin-releasing hormone stimulation tests were performed to assess and compare testicular and pituitary functions of Gsnor-/- and WT mice. OUTCOMES: Evaluation of fertility and reproductive hormones in Gsnor-/- vs WT mice. Response of Gsnor-/- and WT mice to human chorionic gonadotropin and gonadotropin-releasing hormone to evaluate LH and T production. RESULTS: Gsnor-/- mice had smaller litters (4.2 vs 8.0 pups per litter; P < .01), smaller testes (0.08 vs 0.09 g; P < .01), and decreased epididymal sperm concentration (69 vs 98 × 106; P < .05) and motility (39% vs 65%; P < .05) compared with WT mice. Serum T (44.8 vs 292.2 ng/dL; P < .05) and LH (0.03 vs 0.74 ng/mL; P = .04) were lower in Gsnor-/- than in WT mice despite similar follicle-stimulating hormone levels (63.98 vs 77.93 ng/mL; P = .20). Immunofluorescence of Gsnor-/- and WT testes showed similar staining of 3ß-hydroxysteroid dehydrogenase and LHR. Human chorionic gonadotropin stimulation of Gsnor-/- mice increased serum T (>1,680 vs >1,680 ng/dL) and gonadotropin-releasing hormone stimulation increased serum LH (6.3 vs 8.9 ng/mL; P = .20) similar to WT mice. CLINICAL TRANSLATION: These findings provide novel insight to a possible mechanism of secondary hypogonadism from increased reactive nitrogen species and excess nitrosative stress. STRENGTHS AND LIMITATIONS: Limitations of this study are its small samples and variability in hormone levels. CONCLUSION: Deficiency of S-nitrosoglutathione reductase results in secondary hypogonadism, suggesting that excess nitrosative stress can affect LH production from the pituitary gland. Masterson TA, Arora H, Kulandavelu S, et al. S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. J Sex Med 2018;15:654-661.

Testosterone replacement therapy: For whom, when and how?

The finding of low circulating testosterone level in men is relatively frequent. The symptoms of hypogonadism are very frequent in the aging men. However, the diagnosis of hypogonadism is often neglected and the opportunity to replace low testosterone in older men is highly debated. The aim of this narrative review is to summarize the steps necessary to formulate a proper diagnosis and to guide toward an individualized treatment. While universally recognized the need to treat the young adults with known causes of pituitary or testicular failure, there are controversies on the cost-benefit of treating testosterone deficiency in older men. Discrepancies among the several available guidelines do not help to clarify the scenario, however, the recent larger clinical trials have shed some light on the fact that testosterone treatment carries some benefit, that is not free from risks. We provide an updated review of the diagnostic hallmarks, the several treatment modalities, with their advantages and disadvantages, and how to individualize and monitor treatment in order to maximize the benefits and minimize the risks. The treatment of male hypogonadism can no longer be downgraded and must become part of the cultural baggage of the endocrinologist.

Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy.

AIM: To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU). METHODS: A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD). RESULTS: Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR). CONCLUSION: In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition.

Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis.

BACKGROUND: Sexual dimorphism manifests noticeably in obesity-associated gonadal dysfunction. In women, obesity is associated with androgen excess disorders, mostly the polycystic ovary syndrome (PCOS), whereas androgen deficiency is frequently present in obese men in what has been termed as male obesity-associated secondary hypogonadism (MOSH). Obesity-associated gonadal dysfunction, consisting of PCOS in women and MOSH in men, is a frequent finding in patients with severe obesity and it may be ameliorated or even resolve with marked weight loss, especially after bariatric surgery. OBJECTIVE AND RATIONALE: We aimed to obtain an estimation of the prevalence of obesity-associated gonadal dysfunction among women and men presenting with severe obesity and to evaluate the response to bariatric surgery in terms of resolution and/or improvement of this condition and changes in circulating sex hormone concentrations. SEARCH METHODS: We searched PubMed and EMBASE for articles published up to June 2016. After deleting duplicates, the abstract of 757 articles were analyzed. We subsequently excluded 712 articles leaving 45 studies for full-text assessment of eligibility. Of these, 16 articles were excluded. Hence, 29 studies were included in the quantitative synthesis and in the different meta-analyses. Quality of the studies was assessed using the Quality index for prevalence studies and the Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group available from the National Heart, Lung and Blood Institute. For meta-analyses including more than 10 studies, we used funnel and Doi plots to estimate publication bias. OUTCOMES: In severely obese patients submitted to bariatric surgery, obesity-associated gonadal dysfunction was very prevalent: PCOS was present in 36% (95CI 22-50) of women and MOSH was present in 64% (95CI 50-77) of men. After bariatric surgery, resolution of PCOS was found in 96% (95CI 89-100) of affected women and resolution of MOSH occurred in 87% (95CI 76-95) of affected men. Sex hormone-binding globulin concentrations increased after bariatric surgery in women (22 pmol/l, 95CI 2-47) and in men (22 pmol/l, 95CI 19-26) and serum estradiol concentrations decreased in women (-104 pmol/l, 95CI -171 to -39) and to a lesser extent in men (-22 pmol/l, 95CI -38 to -7). On the contrary, sex-specific changes were observed in serum androgen concentrations: for example, total testosterone concentration increased in men (8.1 nmol/l, 95CI 6-11) but decreased in women (-0.7 nmol/l, 95CI -0.9 to -0.5). The latter was accompanied by resolution of hirsutism in 53% (95CI 29-76), and of menstrual dysfunction in 96% (95CI 88-100), of women showing these symptoms before surgery. WIDER IMPLICATIONS: Obesity-associated gonadal dysfunction is among the most prevalent comorbidities in patients with severe obesity and should be ruled out routinely during their initial diagnostic workup. Considering the excellent response regarding both PCOS and MOSH, bariatric surgery should be offered to severely obese patients presenting with obesity-associated gonadal dysfunction.

"Cherchez La Femme": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology.

INTRODUCTION: Selective estrogen receptor modulators (SERMs) have been used off-label in men for more than 50 years. SERMs exert their action on the estrogen receptor agonistically or antagonistically. A fundamental knowledge of the complex molecular action and physiology of SERMs is important in understanding their use and future directions of study in men. AIM: To review the basic science and mechanism of the action of estrogens, the estrogen receptor, and SERMs, and the existing clinical publications on the use of SERMs in men for infertility and hypogonadism with their strengths and weaknesses and to identify the need for future studies. METHODS: After a review of publications on the basic science of estrogen receptors, a chronologic review of published evidence-based studies on the use of SERMs in men for infertility and hypogonadism was undertaken. MAIN OUTCOME MEASURES: Clinical publications were assessed for type of study, inclusion criteria, outcome measurements, and results. Strengths and weaknesses of the publications were assessed and discussed. RESULTS: Few prospective rigorously controlled trials have been undertaken on the use of SERMs in men. Most existing trials are largely retrospective anecdotal studies with inconsistent inclusion and end-point measurements. The SERMs are complex and at times can produce paradoxical results. Their action likely depends on the genetics of the individual, his tissue-specific composition of estrogen receptors, the molecular structure and pharmacodynamics of the SERMs, and their metabolism. CONCLUSION: Rigorously controlled trials of the use of SERMs in men are needed to better identify their clinical benefit and long-term safety in infertile and hypogonadal men. Recent placebo-controlled pharmaceutical industry SERM trials have demonstrated short-term safety and efficacy in men with secondary hypogonadism and eventually might provide an alternative to exogenous testosterone replacement therapy in men with secondary hypogonadism. Helo S, Wynia B, McCullough A. "Cherchez La Femme": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology. Sex Med Rev 2017;5:365-386.

[A CASE OF PROSTATE CANCER WITH SECONDARY HYPOGONADISM].

A 70 year-old man underwent contrast CT, which revealed his swollen left inguinal and pelvic lymph nodes. The lymph nodes reduced in size without any treatments in a follow-up examination. In 2013, the lymph nodes enlarged again, and FDG-PET/CT showed high value at the prostate and multiple lymph nodes. The levels of serum PSA was high (PSA=682 ng/ml), therefore he underwent a prostate biopsy in his previous hospital and was diagnosed prostate cancer with metastasis of lymph nodes (cT2cN1M1a). Androgen deprivation therapy (ADT) was administered; however, the levels of serum PSA didn't reduce and lymph nodes enlarged further. He was referred to our hospital for further evaluation and treatment. The levels of serum total testosterone before ADT administration at his previous hospital was less than 0.05 ng/ml, which meaned that he had been hypogonadism. Brain MRI revealed a pituitary tumor, and he was diagnosed secondary hypogonadism due to the pituitary tumor. This was thought a rare case of a prostate cancer with secondary hypogonadism which had become castration resistant at the time of diagnosis.