Reproductive outcomes of microdissection testicular sperm extraction in hypogonadotropic hypogonadal azoospermic men after gonadotropin therapy.

PURPOSE: Male infertility caused by hypogonadotropic hypogonadism (HH) is not common. The main treatment is gonadotropins for 12 months or longer. If the patient is still azoospermic, conventional or microdissection testicular sperm extraction (mTESE) may further help in sperm retrieval. We aimed to analyze the fertility outcomes of HH men treated at our institute. METHODS: From 2008 to 2020, infertile men with hormone profile showing HH were enrolled. Gonadotropin therapy was prescribed if parenthood was being considered. Assisted reproductive technology was available to help patients attain fertility depending on the results of sperm analysis. Patient outcomes, including sperm retrieval, pregnancy and live birth rates, were analyzed. RESULTS: Seventeen initially azoospermic patients were administered gonadotropins for an average of 11.1 months, and sperm was subsequently found in the ejaculate of seven patients (41%). mTESE was performed on the other ten (59%) who were still azoospermic. For these 10 patients, they had collectively undergone an average 12.1 months (range 6-23 months) of gonadotropin therapy. Sperm was retrieved in nine (90.0%) cases. After 11 cycles of TESE-ICSI, six (54.5%) successful pregnancies were recorded, resulting in five (55.6%) cases with live-born babies, including two sets of twins, and one case of missed abortion at 9 weeks of gestation. CONCLUSION: Gonadotropin therapy reversed azoospermia in a portion of the HH male patients studied. Of men who were still azoospermic after gonadotropin treatment, a majority could still have testicular sperm retrieved by mTESE for use in assisted reproductive technology, subsequently resulting in live births.

Sleeve Gastrectomy and Gastric Bypass Decrease the Carotid Intima-Media Thickness in Obese Men: Association with Weight Loss, Cardiovascular Risk Factors, and Circulating Testosterone.

BACKGROUND: Obesity surgery has shown to decrease the carotid intima-media thickness (IMT), but studies that compare different surgical techniques are scarce, especially in men. OBJECTIVE: To evaluate the changes in IMT in men after laparoscopic Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) and its association with circulating testosterone. SETTING: Academic Hospital. METHODS: We studied 40 men with severe obesity, of whom 20 were submitted to laparoscopic RYGB and 20 to SG. Twenty control men matched for age and degree of obesity were also included. Both patients and controls were evaluated at baseline and 6 months after surgery or conventional treatment with diet and exercise, respectively. RESULTS: The mean carotid IMT decreased after surgery irrespective of the surgical technique whereas no changes were observed in the control men submitted to conventional therapy (Wilks' λ = 0.745, P < 0.001 for the interaction, P < 0.001 for RYGB vs. controls, P = 0.001 for SG vs. controls, P = 0.999 for RYGB vs. SG). The decrease in the carotid IMT correlated with the increase in total testosterone (r = 0.428, P = 0.010) and lost BMI (r = 0.486, P < 0.001). Multivariate linear regression retained only the decrease in BMI (ß = 0.378, P = 0.003) after adjustment (R2 = 0.245, F = 9.229, P = 0.001). CONCLUSION: Both RYGB and SG decrease carotid IMT in men with obesity compared with conventional treatment with diet and exercise.

Prolactinomas in males: any differences?

CONTEXT: Prolactinomas in men are usually large and invasive, presenting with signs and symptoms of hypogonadism and mass effects, including visual damage. Prolactin levels are high, associated with low testosterone, anemia, metabolic syndrome and if long-standing also osteoporosis. RESULTS: Medical treatment with the dopamine agonist, cabergoline, became the preferred first-line treatment for male prolactinomas as well as for giant tumors, leading to prolactin normalization in ~ 80% of treated men, and tumor shrinkage, improved visual fields and recovery of hypogonadism in most patients. Multi-modal approach including surgery and occasionally radiotherapy together with a high-dose cabergoline is saved for resistant and invasive adenomas. Experimental treatments including temozolomide or pasireotide may improve clinical response in men harboring resistant prolactinomas. CONCLUSIONS: Compared to other pituitary adenomas, secreting and non-secreting, where pituitary surgery is the recommended first-line treatment, men with prolactinomas will usually respond to medical treatment with no need for any additional treatment.

A Phenotypic Female Adolescent with Primary Amenorrhea and Dysmorphic Features.

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495-e500.].

Extended indications for varicocelectomy.

The relationship between varicoceles and subfertility is well-established, but recent evidence suggests that varicoceles may cause global testicular dysfunction. This has led to exploration into expanding the indications for varicocelectomy. This review examines the literature regarding varix ligation as a treatment for non-obstructive azoospermia, elevated DNA fragmentation, and hypogonadism.

Effects of Bariatric Surgery in Male Obesity-Associated Hypogonadism.

INTRODUCTION: The prevalence of obesity has grown exponentially over the last several decades. Research has linked male obesity to changes in the gonadal axis, which can induce functional hypogonadism. Bariatric surgery provides sustained weight loss and metabolic improvement. This was a retrospective cohort study to evaluate the male gonadal axis and metabolic profiles of obese individuals during the bariatric pre- and post-operative periods while comparing them to a normal body mass index (BMI) group. METHODS: Twenty-nine obese men, who underwent bariatric surgery between 2012 and 2016 at the Federal University of Santa Catarina Hospital and a control group (CG) of 29 age-matched men with normal BMI, were analyzed. Bariatric pre- and 6-month post-operative data were compared with the CG. RESULTS: The study group (G1) presented an average age, weight, and BMI of 42.8 ± 9.5 years, 155.2 ± 25.8 kg, and 50.6 ± 7.1 kg/m2, respectively. The pre-operative total testosterone (TT) G1 values were different from the CG (229.5 ± 96.4 versus 461.5 ± 170.8 ng/dL, p < 0.01). Bariatric surgery promoted a statistically significant improvement in weight, TT, and metabolic profiles in surgical patients. CONCLUSION: Functional hypogonadism is prevalent in obese men, and we must be aware of this diagnosis. Although studies defining the best diagnostic parameters and indication of adequate hormone replacement therapy are lacking, an increase in TT levels during the first 6 months after bariatric surgery was identified in our study. Previous studies have shown that gonadal function can normalize after metabolic improvement.

ENDOCRINE HISTORY: The history of discovery, synthesis and development of testosterone for clinical use.

As the most important male hormone, testosterone has an impact on almost all organs and body functions. The biological effects of testosterone and the testes have been known since antiquity, long before testosterone was identified as the active agent. Practical applications of this knowledge were castration of males to produce obedient servants, for punishment, for preservation of the prepubertal soprano voice and even for treatment of diseases. Testes were used in organotherapy and transplanted as treatment for symptoms of hypogonadism on a large scale, although these practices had only placebo effects. In reaction to such malpractice in the first half of the 20th century science and the young pharmaceutical industry initiated the search for the male hormone. After several detours together with their teams in 1935, Ernst Laqueur (Amsterdam) isolated and Adolf Butenandt (Gdansk) as well as Leopold Ruzicka (Zürich) synthesized testosterone. Since then testosterone has been available for clinical use. However, when given orally, testosterone is inactivated in the liver, so that parenteral forms of administration or modifications of the molecule had to be found. Over 85 years the testosterone preparations have been slowly improved so that now physiological serum levels can be achieved.

Lack of Improvement of Sperm Characteristics in Obese Males After Obesity Surgery Despite the Beneficial Changes Observed in Reproductive Hormones.

BACKGROUND: Even though obesity surgery normalizes circulating testosterone concentrations in males with obesity-associated secondary hypogonadism, its impact on spermatogenesis remains controversial. We aimed to evaluate sperm characteristics in obese men after bariatric surgery as well as changes in reproductive hormones. METHODS: Twenty severely obese men (body mass index (BMI) ≥ 35 kg/m2) were evaluated before and 2 years after bariatric surgery. The serum was assayed for insulin, leptin, kisspeptin, and inhibin B, among other hormones. Homeostasis model assessment of insulin resistance (HOMA-IR) was estimated. We used World Health Organization reference values for sperm analysis. RESULTS: After surgery, serum total testosterone, calculated free testosterone, inhibin B, and kisspeptin increased, whereas fasting insulin, HOMA-IR, and leptin concentrations decreased. Despite these improvements, sperm volume showed a small decrease after surgery, while the rest of sperm characteristics remained mostly unchanged. Abnormal sperm concentration persisted in 60% of the patients. CONCLUSIONS: Sperm characteristics may not improve after bariatric surgery despite the beneficial changes of reproductive hormones.

Varicocele Repair Versus Testosterone Therapy for Older Hypogonadal Men with Clinical Varicocele and Low Testosterone.

As men age, serum testosterone levels decrease. This reduction in testosterone levels may cause symptoms leading to hypogonadism. In addition, the presence of a varicocele can impair Leydig cell function, resulting in decreased testosterone production in men. Varicocelectomy and testosterone replacement therapy are both viable treatment options for hypogonadism in elderly male patients. The correct modality of treatment will vary for each patient, but education is essential in order to help men understand their options. Testosterone therapy (TTh) with laboratory monitoring will likely appeal to many men who want to avoid surgery, but for men with hypogonadism and a varicocele, a one-time low-risk microsurgery with the potential to negate the need for further therapy presents an attractive alternative to lifelong TTh. PATIENT SUMMARY: Varicocelectomy and testosterone therapy (TTh) are viable treatment options for hypogonadism in elderly male patients. Treatment modality will vary for each patient, but education is essential to help them understand their options. Although TTh with laboratory monitoring may appeal to men wanting to avoid surgery, those with hypogonadism and a varicocele would likely prefer a one-time low-risk microsurgery to lifelong TTh.

Primary adrenal insufficiency due to hereditary apolipoprotein AI amyloidosis: endocrine involvement beyond hypogonadism.

Several mutations in the gene encoding apolipoprotein AI (apoAI) have been described as a cause of familial amyloidosis. Individuals with apoAI-derived (AApoAI) amyloidosis frequently manifest with liver, kidney, laryngeal, skin and myocardial involvement. Although primary hypogonadism (PH) is considered almost pathognomonic of this disease, until now, primary adrenal insufficiency (PAI) has not been described as a common clinical feature. Here, we report the first kindred with AApoAI amyloidosis in which PAI is well-documented. All family members with the Leu60_Phe71delins60Val_61Thr heterozygous mutation who were regularly followed-up at our centre were considered. Nineteen individuals had the confirmed APOA1 deletion/insertion mutation, with detailed medical records available in 11 cases. Of these, 6 had PAI and 3 (all males) had PH. Among them, one 47-year-old man, not previously diagnosed with PAI, developed adrenal crisis after liver transplantation, precipitated by an opportunistic infection. Transplantation due to organ failure, which necessitates use of immunosuppressive medication such as corticosteroids, is frequently required during the course of hereditary amyloidosis. Consequently, PAI can remain masked, being discovered only when an adrenal crisis develops. Therefore, according to the present evidence, patients with AApoAI amyloidosis should be submitted to regular testing of corticotrophin and cortisol levels in order to avoid delaying corticosteroid replacement.

Decreased visceral fat area correlates with improved total testosterone levels after Roux-en-Y gastric bypass in obese Chinese males with type 2 diabetes: a 12-month follow-up.

BACKGROUND: Obesity and type 2 diabetes (T2D) are recognized as risk factors for hypogonadism in males. Serum sex hormone profiles have not been assessed adequately in obese Chinese males with T2D who have undergone Roux-en-Y gastric bypass (RYGB). OBJECTIVE: This study was conducted to examine the changes in sex hormone profiles, anthropometric parameters, and metabolic indexes before and after RYGB. SETTING: University Hospital, China. METHODS: There were 45 obese males with T2D who had undergone RYGB enrolled in this retrospective study, focusing on anthropometric parameters, metabolic indexes, and sex hormone profiles before and after surgery. RESULTS: The baseline prevalence of hypogonadism (defined by total testosterone [TT] levels<8 nM) was 33.33%. After surgery, both the levels of TT and sex hormone-binding globulin increased, while the levels of estradiol decreased. However, the calculated free testosterone, follicle-stimulating hormone, and luteinizing hormone levels remained unchanged. Multiple linear regression analysis showed that the visceral fat area was the only significant and independent parameter associated with TT levels at baseline (ß = -.479, P = .001). After surgery, decreases in the visceral fat area continued to be negatively associated with increases in TT (r = -.411, P = .024). CONCLUSION: These preliminary results demonstrated that TT could be significantly increased in obese Chinese males with T2D after RYGB; this occurs in part via a reduction in adipose tissue, especially visceral fat. Therefore, RYGB might be a promising therapy to treat hypogonadism in obese men with T2D.

Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery.

Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial. This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5 years. Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P = 0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels. Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation.

Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with clinical varicocele: A meta-analysis.

To reassess the efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males, we carried out a meta-analysis of clinical trials and retrospective studies that compared the pre-operative and postoperative serum testosterone. We searched Embase and PubMed (1980 to May 2016) for studies. Eight studies and 712 patients were included. The combined analysis of seven studies discovered that the mean serum testosterone of patients post-operation improved by 34.3 ng/dl (95% CI: 22.57-46.04, p < .00001, I² = 0.0%) compared with their pre-operative levels. In subgroup analysis, testosterone improvements in the hypogonadal treated subgroup were more significant (improved by 123 ng/dl, 95% CI: 114.61-131.35, p < .00001, I2  = 37%) than in the eugonadals, or the untreated controls. In an analysis of surgery versus untreated control (three studies included), results showed that mean testosterone among hypogonadals increased by 105.65 ng/dl (95% CI: 77.99-133.32), favouring varicocelectomy, as the differences were significant (p < .00001), However, there were insignificant differences in eugonadals (p = .36). In conclusion, varicocelectomy significantly improved testosterone in hypogonadal men with subfertility. Active surgical treatment of varicocele might have a benefit of maintaining healthy androgen levels in subfertile men.

Clomiphene citrate treatment for late onset hypogonadism: rise and fall

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.

Prediction of Long-term Post-operative Testosterone Replacement Requirement Based on the Pre-operative Tumor Volume and Testosterone Level in Pituitary Macroadenoma.

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.

Hypogonadism as an additional indication for bariatric surgery in male morbid obesity?

OBJECTIVE: Male obesity is often associated with reduced levels of circulating total (TT) and calculated free testosterone (cFT), with normal/reduced gonadotropins. Bariatric surgery often improves sex steroid and sex hormone-binding globulin (SHBG) levels. The aim of this study was to assess the effects of bariatric surgery on waist circumference (WC) and BMI, and on TT levels, in morbidly obese men, stratified, according to the gonadal state, in eugonadal and hypogonadal (TT<8 nmol/l) subjects. DESIGN: A cohort of morbidly obese patients (29 with hypogonadism (HG) and 26 without) undergoing bariatric surgery (37, 10, 6, and 2, with Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, biliopancreatic diversion and gastric sleeve, respectively) was studied at 6 and 12 months from the operation. METHODS: Anthropometric parameters (weight, BMI, WC) and sex hormones (gonadotropins, TT, cFT, estradiol (E2), SHBG) were assessed. RESULTS: WC was the only parameter significantly correlated with androgens, but not with E2, SHBG, and gonadotropins, at baseline. After surgery, a significant increase in TT, cFT, and SHBG, accompanied by a decrease in E2, was evident in the two groups. However, both TT and cFT, but not E2, SHBG, and gonadotropin variations, were significantly higher in the hypogonadal group at follow-up, with an overall 93% complete recovery from HG. Reduction in WC, but not BMI, was significantly greater in hypogonadal men (ΔWC=-29.4±21.6 vs -14.4±17.4 at 12 months, P=0.047). CONCLUSIONS: Recovery from obesity-associated HG is one of the beneficial effects of bariatric surgery in morbidly obese men. The present findings suggest that the gonadal state is a predictor of WC decrease after bariatric surgery.

[Risks and benefits: new concepts of treatment of late-onset hypogonadism].

Late-onset hypogonadism (LOH) is a clinical and bio-chemical syndrome associated with advancing age in males and seriously affects the quality of life of some of the patients. A classical therapeutic option for LOH is testosterone supplementary treatment (TST). Its effectiveness has been verified, whereas its long-term safety remains to be further evaluated. With deeper insights into LOH, many new therapeutic strategies have been proposed, which include the treatments with gonadotropins, testosterone precursors (such as dehydroepiandrosterone [DHEA]), non-aromatizable androgens (such as dihydrotestosterone [DHT]), antiestrogens (such as aromatase inhibitors and estrogen receptor antagonists), and Chinese medicine. Meanwhile, studies on the transplantation of Leydig stem cells, selective androgen receptor modulators (SARMs), and selective estrogen receptor beta (ERbeta) agonists have shed new light on the treatment of LOH.