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 longterm management.

Resveratrol Modulates Bone Mineral Density and Bone Mineral Content in A Rat Model of Male Hypogonadism

Objective: To determine whether resveratrol(Res) can correct osteoporosis induced in a rat model of male hypogonadism. Methods: Thirty-two rats were randomly divided into 4 groups, 8 in each group;1) a control sham group: underwent a similar surgical procedure for induction of orchiectomy(ORCD) without ligation of any arteries or veins or removal of the testis and epididymis;2) a control + Res-treated group(Con+Res):underwent sham surgery similar to the control, but was then treated with Res, as described below;3) an ORCDinduced group: bilateral ORCD surgery as described above, and 4) a ORCD+Res-treated group: bilateral ORCD surgery followed by Res treatment. Res treatment began 4 weeks after ORCD and continued for 12 weeks. After 12 weeks, bone mineral density(BMD) and bone mineral content(BMC) were measured in the tibia and femur of each rat’s right hind leg. Blood levels of bone turnover indicators such as deoxypyridinoline(Dpd), N-telopeptide of type Ⅰ collagen(NTXⅠ), alkaline phosphatase(ALP), and osteocalcin(OC), as well as receptor activator of nuclear factor kappa B(RANK) and osteoprotegerin(OPG) were assessed. Results: ORCD significantly decreased BMD(P<0.01) and significantly increased bone resorption, manifested by increased RANK. In addition, it inhibited serum levels of OPG and OC. Res treatment after ORCD effectively increased serum levels of bone formation markers such as OPG and OC, compared with testisectomized rats(P<0.05). Conclusion:Res could ameliorate bone loss induced by male hypogonadism, possible via restoration of the normal balance between RANK and OPG.

Secondary male hypogonadism： a prevalent but overlooked comorbidity of obesity

Male hypogonadism associated with obesity is a very prevalent condition and is increasing in parallel with the epidemic prevalence of obesity. Low testosterone levels promote higher fat mass with reduced lean mass. Male hypogonadism is related to an increase in associated cardiometabolic complications, such as hypertension, type 2 diabetes mellitus, the metabolic syndrome, and cardiovascular disease. Its influence as a comorbidity of obesity is becoming more evident and should be evaluated and treated in at-risk patients. Mechanisms involved in this relationship include body composition changes, the presence of adipokines, insulin resistance, and other factors, some of which are still unknown. Weight loss and treatment to replace testosterone levels improve the metabolic profile and quality of life in patients with obesity and hypogonadism; these beneficial effects depend on treatment modality and duration of therapy. The use of testosterone replacement therapy may be indicated, as it has not been shown to increase cardiovascular risk, and retrospective studies suggest a reduction in events in men with metabolic syndrome and type 2 diabetes.

How to recognize late-onset hypogonadism in men wit sexual dysfunction

Late-onset hypogonadism （LOH） has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone （T） levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T （different thresholds）, sexual parameters, medical history data （delayed puberty, pituitary disease or cryptorchidism） and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels.

Leydig cell transplantation restores androgen production in surgically castrated prepubertal rats

Prepubertal testicular dysfunction and the subsequent development of hypogonadism affects an estimated one in 200 children worldwide. As the testosterone levels are dynamic during development and puberty, traditional hormone treatment regimens are often inadequate, thereby leaving associated physiological conditions unresolved. Therefore, we have investigated the potential therapeutic effect of mature Leydig cell transplantation for the treatment of prepubertal primary hypogonadism through the use of a surgically induced hypogonadistic rat model system. In the experiment, Leydig cells were surgically isolated from mature Sprague-Dawley rats and transplanted into prepubertal recipients. Serum testosterone levels and microscopic analysis of the stained testicular interstitium were compared with sham-treated controls, as well as with castrated and intact rats during sexual development. At 4 weeks post-implantation, serum testosterone was detectable in Leydig cell recipients, but not in surgical controls, and progressively increased as a function of time until reaching levels comparable with sexually mature males at 12 weeks post-implantation. Histological analysis revealed a high rate of Leydig cell survival as well as steroidogenic secretory activity. Therefore, we conclude that mature Leydig cell transplantation in prepubertal hypogonadism recipients has therapeutic potential in rats and merits further investigation for clinical application.

Androgens and prostate disease

A growing body of literature has established the anabolic benefits of testosterone （T） therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently find a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5α-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease.

Apoptotic Sertoli cell death in hypogonadic(hgn/hgn)rat testes during early postnatal development

Aim： To determine the involvement of apoptotic cell death in postnatal pathogenesis in mutant strain of hypogonadic （hgn/hgn） rats testes. We evaluated the numbers and types of cells undergoing apoptotic cell death. Methods： Tissue sections were stained by the TUNEL method for in situ detection of apoptotic cells, with specific antibodies used as markers of testicular somatic and germ cells. Results： We found that apoptosis in the hgn/hgn testes during the early postnatal period occurred primarily in Sertoli cells, which should actively proliferate during this stage of differentiation. These findings strongly suggest that the normal allele of hgn is involved in the direct or indirect control of differentiation and proliferation of Sertoli cells. Conclusion： To our knowledge, this is the first report demonstrating early postnatal apoptosis of Sertoli cells, suggesting that the hgn/hgn rat is a unique model for the study of Sertoli cell deficiency.

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

AIMTo determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men.METHODSWe studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual.RESULTSAge was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality.CONCLUSIONWe show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men.

Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice

Twenty-four-month-old male C57BU6 mice with low serum testosterone levels were used as a late-onset hypogonadism （LOH） animal model for examining the effects of velvet antler polypeptide （VAP） on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg-1 body weight per day （n = 10 mice per dose）. Control animals （n = 10） received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein （STAR）, cytochrome P450 cholesterol side-chain cleavage enzyme （P450scc）, and 3β-hydroxysteroid dehydrogenase （3βHSD） in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone （ITT） concentration also increased in the VAP-treated groups. The expression of STAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis （STAR, P450scc, and 3β-HSD） and the following promotion of testosterone syothesis in vivo.

Late-onset hypogonadism： beyond testosterone

Late-onset hypogonadism is defined as a combination of low testosterone （T） levels and typical symptoms and signs. A major area of uncertainty is whether T concentrations are always really sufficient to fully reflect Leydig cell （dys）function. Mild testicular alteration could be diagnosed only by additional biochemical markers, such as luteinizing hormone （LH） and 25-hydroxyvitamin D levels. These markers help in identifying the so-called ＂subclinical＂ hypogonadism （normal T, high LH levels）. Patients with hypogonadism have frequently low levels of 25-hydroxyvitamin D due to impairment of the hydroxylating enzyme CYP2R1 in the testis. However, no data have been published dealing with the best treatment option （cholecalciferol - the Vitamin D precursor, or calcidiol - 25-hydroxylated form of Vitamin D） in these patients. We studied 66 patients with classic hypogonadism （total T [TT] 〈12 nmol I-~, LH 〉 8 IU 1-1） （n = 26） and subclinical hypogonadism （TT 〉 12 nmol I-＊, LH 〉 8 IU I-~） （n = 40） and low 25-hydroxyvitamin D （〈50 nmol I-1）. Subjects received cholecalciferol （5000 IU per week） （n = 20） or calcidiol （4000 IU per week） （n -- 46）, and 25-hydroxyvitamin D and parathyroid hormone （PTH） were evaluated after 3 months of therapy. Supplementation with calcidiol significantly increased 25-hydroxyvitamin D and significantly decreased PI＂H levels in both groups of men with hypogonadism （primary, n = 16 and subclinical, n = 30）, whereas supplementation with cholecalciferol did not modify their levels. This study shows for the first time that the administration of the 25-hydroxylated form of Vitamin D （calcidiol）, and not the administration of the precursor cholecalciferol, restores 25-hydroxyvitamin D levels in subjects with hypogonadism.

Androgen receptor deficiency in monocytes/ macrophages does not alter adiposity or glucose homeostasis in male mice

Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor （AR） is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages （M-ARKO） were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type （WT） and M-ARKO mice （12-22 weeks of age, n = 12 per group） were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake （3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice） or total energy expenditure （0.6 ± 0.1 Kcal h-1 for WT mice vs 0.5 ± 0.1 Kcal h-1 for M-ARKO mice） were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice （1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02）. Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.

Testicular ultrasound inhomogeneity is an informative parameter for fertility evaluation

Testicular volume(TV)is proposed to be a positive predictor of male fertility status,because of the relation known between the TV and the seminiferous tubule content.Independently of the measurement methodology,the role of TV and testicular ultrasound(US)assessments is still debated in andrological clinical practice.In this retrospective cohort study,we evaluated TV and testis US role in the diagnostic workup of andrological patients.All consecutive outpatients undergoing single-operator testis US(Modena,Italy)from March 2012 to March 2018 were enrolled,matching sonographic,hormonal,and seminal data.A total of 302 men were referred and evaluated for gynecomastia,suspected hypogonadism,couple infertility(Cl),or sexual dysfunction.In the hypogonadal group,TV was lower compared to that in other groups(P<0.001),and a significant,direct correlation between TV and testosterone level was observed in nonandrogen-treated patients(R=0.911,P<0.001),suggesting that testicular size could be related to the testosterone-secreting compartment.In the Cl group,normozoospermic patients showed higher TV compared to men with impaired semen quality(P=0.003)and azoospermia(P=0.003).However,TV was not able to discriminate between patients presenting normal and altered semen quality.On the contrary,testis US inhomogeneity was more frequent in patients with impaired sperm quality(55.0%;P=0.007)and azoospermia(40.0%;P=0.012),compared to patients with normozoospermia(5%),identifying thereby the sonographic pattern as an informative parameter of the fertility status.Therefore,in the Cl workup,US evaluation seems to be more informative than the TV assessment alone.