Advances in the treatment of functional male hypogonadism.

INTRODUCTION: Functional hypogonadism is frequently found in obese men, particularly those with metabolic complications. Several possible therapeutic approaches could be considered. AREAS COVERED: An extensive search on Medline, Embase, and Cochrane databases was performed to retrieve the available studies assessing the change of testosterone (T) and sexual function upon dieting or physical activity programs, as well as glucagon-like peptide 1 analogues. The role of lifestyle interventions associated with T replacement therapy (TRT) was also evaluated. The expert opinion provided here has been corroborated by meta-analyzing the results of the retrieved studies. EXPERT OPINION: Current evidence supports the beneficial role of lifestyle modifications in increasing T and improving sexual function as a function of weight loss. While dieting programs are associated with greater effects in younger populations, physical exercise has major effects in older ones. Among the dieting programs, a very low-calorie ketogenic diet shows the best results; aerobic or endurance physical exercise perform similarly. The advantages of functional hypogonadism in lifestyle modifications are empowered by the association with TRT. Therefore, TRT may be a valuable complementary strategy to increase muscle mass and facilitate physical exercise while improving sexual symptoms, thus favoring the motivation and compliance for lifestyle interventions.

Positive effects of dietary supplementation with nutraceuticals on male subclinical hypogonadism: a pilot study.

BACKGROUND: Lifestyle modifications (i.e., physical activity [PA] and lower dietary intake) often are not sufficient to improve testosterone (TE) levels and promote weight loss in men with metabolic hypogonadism. The aim of the study was to investigate the effects of a nutraceutical formulation containing myoinositol, alpha lipoic acid, folic acid and SelectSIEVE® as add-on treatment to lifestyle modifications in improving obesity-related subclinical hypogonadism. METHODS: Body composition, insulin resistance, testicular and erectile function were investigated in 15 males (age=39.5±14.5 years; Body Mass Index [BMI]=30.2±3.8 kg/m2, with subclinical hypogonadism (TE levels <14 and normal luteinizing hormone [LH]). After a run-in three months unsupervised PA period (T1), the nutraceutical supplement was administered two-times per day for three additional months (T2). RESULTS: BMI, the percentage fat mass, insulinemia and Homeostasis Model Assessment Index (P<0.01) along with glycemia (P<0.05) were significantly reduced at T2 compared to T1, respectively; fat free mass (FFM) was significantly higher at T2 compared to T1 (P<0.01). Also, TE, LH and 5-item international index of erectile function score were significantly increased at T2 compared to T1 (P<0.01), respectively. CONCLUSIONS: The combination of unsupervised PA and nutraceutical supplement improves body composition, insulin sensitivity and TE production in overweight-obese men with metabolic hypogonadism. Further controlled studies in the long-term are warranted to elucidate potential changes in fertility.

Selective modulation of estrogen receptor in obese men with androgen deficiency: A systematic review and meta-analysis.

BACKGROUND: Although selective estrogen receptor modulators have been proposed as a treatment for men with central functional hypogonadism, only a few data have been produced in men with obesity-related functional androgen deficiency. OBJECTIVE: To determine whether and to what extent selective estrogen receptor modulators are an effective and safe therapy in men with obesity-related functional androgen deficiency. MATERIALS AND METHODS: A thorough search of PubMed, Web of Science, Scopus, and Cochrane Library databases was performed to identify studies comparing testosterone levels before and after treatment. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger's test, and trim-and-fill analysis were used to assess publication bias. RESULTS: Seven studies met the inclusion criteria providing information on 292 men with obesity-related functional androgen deficiency treated with clomiphene citrate (12.5-50 mg daily) or enclomiphene citrate (12.5-25 mg daily) for 1.5-4 months. The pooled estimates indicated a significant increase in testosterone levels both with clomiphene (mean difference: 11.56 nmol/L; 95% coefficient interval: 9.68, 13.43; I2  = 69%, pfor heterogeneity  = 0.01) and enclomiphene citrate (mean difference: 7.50 nmol/L; 95% coefficient interval: 6.52, 8.48; I2  = 4%, pfor heterogeneity  = 0.37). After the exclusion of one study on severely obese men, who exhibited the highest response rate to clomiphene citrate, the heterogeneity disappeared (mean difference: 10.27 nmol/L; 95% coefficient interval: 9.39, 11.16; I2  = 0%, pfor heterogeneity  = 0.66). No publication bias was revealed by Egger's test and trim-and-fill analysis. No treatment-related unexpected findings regarding safety profile were registered. DISCUSSION AND CONCLUSION: Treatment with clomiphene citrate and enclomiphene citrate may be an effective and safe alternative to testosterone replacement therapy in men with obesity-related functional androgen deficiency. Further long-term studies are warranted to define clinical reflections of the selective estrogen receptor modulators-induced increase in testosterone levels and to better clarify the safety profile.

Effects of treatment for diabetes mellitus on testosterone concentrations: A systematic review.

BACKGROUND: Low testosterone levels are frequently present in men with obesity and insulin resistance. Currently available treatment options (testosterone replacement therapy or lifestyle changes) hold possible risks or are insufficient. Since low testosterone levels are closely related to obesity and type 2 diabetes, treatment modalities for these conditions could result into improvement of testosterone levels. OBJECTIVES: To summarize the available evidence on the effects of traditional and recent treatment modalities for diabetes mellitus on testosterone levels and androgen-deficiency-related signs and symptoms. MATERIALS AND METHODS: PubMed was searched from the year 2000 till present using MESH terms: "hypogonadism," "testosterone," "testosterone deficiency," "functional hypogonadism," and the different classes of medications. Studies with observational and experimental designs on humans that evaluated the effect of antidiabetic medications on gonadotropins and testosterone were eligible for inclusion. RESULTS: Current available data show no or only limited improvement on testosterone levels with the classic antidiabetic drugs. Studies with GLP1-receptor analogues show beneficial effects on both body weight and testosterone levels in men with low testosterone levels and obesity with or without type 2 diabetes. However, data are limited to small and heterogeneous study groups and only few studies report data about impact on androgen-deficiency-related signs and symptoms. DISCUSSION AND CONCLUSION: With the recent advances in the knowledge of the pathophysiological pathways in obesity, there is an enormous progress in the development of medications for obesity and type 2 diabetes. Newer incretin-based agents have a great potential for the treatment of functional hypogonadism due to obesity since they show promising weight reducing results. However, before the use of GLP1-receptor analogues can be suggested to treat functional hypogonadism, further studies are needed.

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism.

BACKGROUND: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels. OBJECTIVE: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism. MATERIAL AND METHODS: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration. RESULTS: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events. DISCUSSION AND CONCLUSIONS: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

Functional hypogonadism in middle-aged and older men: testosterone treatment or not?

Clinicians commonly encounter middle-aged and older men who present with functional hypogonadism, that is, with clinical features compatible with androgen deficiency and lowered serum testosterone, but without evidence of organic hypothalamic-pituitary-testicular axis pathology. Whether, and when, testosterone therapy should be offered to such men remains uncertain and controversial, in part due to the lack of definitive evidence regarding long-term patient-important health outcomes with testosterone treatment. In this debate, we address this controversy and provide two opposing points of view on the role of testosterone treatment in older men with functional hypogonadism.

Oncological safety and functional outcomes of testosterone replacement therapy in symptomatic adult-onset hypogonadal prostate cancer patients following robot-assisted radical prostatectomy.

PURPOSE: Testosterone replacement therapy (TRT) remains controversial in men with treated prostate cancer. We assessed its safety and functional impacts in patients after definitive surgical treatment with robotic-assisted radical prostatectomy (RARP). METHODS: We performed a retrospective analysis of 1303 patients who underwent RARP during the years 2006-2019. We identified men with symptoms of andropause and low serum testosterone who received TRT post-RARP; then we divided the cohort into two groups accordingly for comparison. Biochemical recurrence (BCR) was the primary endpoint. Secondary endpoints included functional outcomes. Predictors of BCR, including the effect of TRT on BCR, were evaluated using univariable and multivariable logistic regression. RESULTS: Among the forty-seven men who received TRT, the mean age was 60.83 years with a median follow-up of 48 months. Three (6.4%) and 157 (12.56%) patients experienced BCR in TRT and non-TRT groups, respectively. Baseline characteristics were similar between both groups except for higher mean BMI in the TRT group (p = 0.03). In the multivariate analysis (MVA), higher pre-RARP prostate-specific antigen (PSA) (p = 0.043), higher International Society of Urological Pathology score (p < 0.001), seminal vesical invasion (p = 0.018) and positive surgical margin (p < 0.001) were predictors of BCR. However, TRT was not (p = 0.389). In addition, there was a significant change in the Sexual Health Inventory for Men (p = 0.022), and serum testosterone level (p < 0.001) before and 6 months after initiation of TRT. CONCLUSION: Our findings suggest that TRT, in well-selected, closely followed, symptomatic men post-RARP is an oncologically safe and functionally effective treatment in prostate cancer patients post-RARP.

Risks of Serious Injury with Testosterone Treatment.

BACKGROUND: Injury causes significant morbidity and mortality that is sometimes attributed to testosterone and violence. We hypothesized that prescribed testosterone might be associated with the subsequent risk of serious injury. METHODS: We conducted a self-matched individual-patient exposure-crossover analysis comparing injury risks before and after initiation of testosterone. We selected adults treated with testosterone in Ontario, Canada, from October 1, 2012, to October 1, 2017 (enrollment) and continued until October 1, 2018 (follow-up). The primary outcome was defined as an acute traumatic event that required emergency medical care. RESULTS: A total of 64,386 patients were treated with testosterone of whom 89% were men with a median age of 52 years. We identified 34,439 serious injuries during the baseline interval before starting testosterone (584 per month) and 7349 serious injuries during the subsequent interval after starting testosterone (565 per month). Rates of injuries were substantially above the population norm in both intervals with no significant increased risk after starting testosterone (relative risk = 1.00; 95% confidence interval: 0.96-1.04, P = 0.850). The unchanged risk extended to diverse patients, was observed for different formulations and applied to all injury mechanisms. In contrast, testosterone treatment was associated with a 48% increased risk of a thromboembolic event (relative risk = 1.48; 95% confidence interval: 1.25-1.74, P < 0.001). CONCLUSIONS: Testosterone treatment was associated with a substantial baseline risk of serious injury that did not increase further after starting therapy. Physicians prescribing testosterone could consider basic safety reminders to mitigate injury risks.

Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

Cordyceps militaris Fruit Body Extract Decreases Testosterone Catabolism and Testosterone-Stimulated Prostate Hypertrophy.

The androgens testosterone and dihydrotestosterone (DHT) are essential for a variety of systemic functions in mature males. Alteration of these hormones results in late-onset hypogonadism (LOH) and benign prostate hyperplasia (BPH). The fruit bodies of fungi of the genus Cordyceps have been regarded as folk medicine or health food with tonic and antifatigue effects. The extract from the fruit body of Cordyceps militaris parasitizing Samia cynthia ricini (CM) was evaluated as a novel-candidate natural product for ameliorating male andropause symptoms. To explore the effects of CM on LOH and BPH, CM was applied to rat models and cultured testicular cells and prostate cells. The concentrations of androgens in the serum and culture media were determined by ELISA. Expression of steroidogenic enzymes and androgen-related genes was evaluated by qPCR, and prostatic cell proliferation was assessed with the cell-viability assay. CM maintained the serum levels of testosterone and DHT, but inhibited testosterone-induced prostate hypertrophy. CM also increased the secretion of testosterone and DHT by primary testicular cells, with no changes in the mRNA expression of steroidogenic enzymes, but decreased the growth of prostatic cell lines. Our data suggest that CM could improve both LOH and BPH in males.

Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy.

BACKGROUND: Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). OBJECTIVE: To review the mechanism by which TRT could damage the cardiovascular system. MATERIALS AND METHODS: Comprehensive literature search of recent clinical and experimental studies. RESULTS: The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via ß1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. DISCUSSION: The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. CONCLUSIONS: Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

Critical evaluation of different available guidelines for late-onset hypogonadism.

BACKGROUND: Late-onset hypogonadism (LOH) is a syndrome characterized by clinical and biochemical evidence of low testosterone levels with advancing age. In recent years, several guidelines, position statements and other recommendations have become available. It is unclear whether similar indications are reported in these documents. OBJECTIVE: To review similarities and differences among available documents on the management of hypogonadism, with a special focus on LOH. MATERIALS AND METHODS: PubMed, Google and international societies websites were searched on March 2020 for documents published in the last 10 years on the management of hypogonadism and LOH. RESULTS: Nine documents were found, each developed by: (a) the American Urological Association; (b) the British Society for Sexual Medicine; (c) the Canadian Medical Association; (d) the Endocrine Society; (e) the Endocrine Society of Australia; (f) the European Academy of Andrology; (g) the European Association of Urology; (h) the International Consultation for Sexual Medicine; and (i) the International Society for the Study of Aging Male. DISCUSSION: Despite similar principles, differences were found both for the diagnostic workup and follow-up. Particularly, discrepancies were reported both for total and free testosterone levels for diagnosis and for total testosterone for monitoring. CONCLUSION: Available documents differ in terms of specific recommendations for the management of hypogonadism and LOH. Given the relevant clinical implications of adequate management of these disorders, future guidelines should report more consistent measures to be adopted in clinical practice.

Late-onset Hypogonadism: Bone health.

BACKGROUND: Bone health is underdiagnosed and undermanaged in men. Bone loss occurs in men with hypogonadism and in aging men. Thus, patients with a diagnosis of late-onset hypogonadism (LOH) are at risk of osteoporosis and osteoporotic fractures. OBJECTIVES: To provide an update on research data and clinical implications regarding bone health in men with LOH by reviewing literature articles on this issue. MATERIALS AND METHODS: A thorough search of listed publications in PubMed on bone health in older men with hypogonadism was performed, and other articles derived from these publications were further identified. RESULTS: Late-onset Hypogonadism may be associated with reduced bone mineral density (BMD). In a pathophysiological perspective, the detrimental effects of testosterone (T) deficiency on BMD are partly ascribed to relative estrogen deficiency and both serum T and serum estradiol (E2) need to be above 200 ng/dL and 20 pg/mL to prevent bone loss. The effects of exogenous T on BMD are controversial, but most of the studies confirm that testosterone replacement therapy (TRT) increases BMD and prevents further bone loss in men with hypogonadism. No data are available on TRT and the prevention of fractures. DISCUSSION AND CONCLUSION: In men with documented LOH, a specific clinical workup should be addressed to the diagnosis of osteoporosis in order to program subsequent follow-up and consider specific bone active therapy. TRT should be started according to guidelines of male hypogonadism while keeping in mind that it may also have positive effects also on bone health in men with LOH.

Testosterone replacement in hypogonadal men during inpatient rehabilitation following traumatic brain injury: Results from a double-blind, placebo-controlled clinical pilot study.

BACKGROUND: Endocrinopathy, including hypogonadism, is common following traumatic brain injury (TBI). Prior evidence suggests hypogonadism is associated with poorer function. OBJECTIVE: Determine the feasibility, safety, and efficacy of testosterone (T) therapy in hypogonadal men following TBI in acute rehabilitation. DESIGN: Randomized, double blind, placebo-controlled pilot trial. SETTING: Inpatient rehabilitation brain injury unit. PARTICIPANTS: Men ages 18 -65, post moderate to severe TBI receiving inpatient rehabilitation. INTERVENTIONS: Transdermal T gel or placebo. MAIN OUTCOME MEASURES: Revised FIM™ score, strength, adverse events. RESULTS: Of 498 screened, 70 participants were enrolled, and 22 meeting all criteria were randomized into placebo (n = 10) or physiologic T therapy (n = 12). There was no significant difference between groups in rate of improvement on the FIM™ (intercepts t = -0.31, p = 0.7593, or slopes t = 0.61, p = 0.5472). The Treatment group demonstrated the greatest absolute improvement in FIM™ scores and grip strength compared to Placebo or Normal T groups. There was no difference in adverse events between groups. Percentage of time with agitation or aggression was highest in the Placebo group. CONCLUSIONS: Although there were no significant differences in rates of recovery, treatment group subjects showed greater absolute functional and strength improvement compared to the Placebo or Normal T groups.

Testosterone replacement therapy.

BACKGROUND: The aim of testosterone replacement therapy (TRT) is to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, depressed mood, anaemia, loss of muscle and bone mass, by increasing serum testosterone levels to physiologic range. TRT has been used in the last 70 years, and overtime, numerous preparations and formulations have been developed to improve pharmacokinetics (PKs) and patient compliance. The routes of delivery approved for use in the Western world include buccal, nasal, subdermal, transdermal and intramuscular (IM). OBJECTIVES: The aim of this narrative review was to describe and compare all available and approved testosterone preparations according to pharmacology, PKs and adverse effects. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature on TRT in clinical practice. Contraindications and monitoring of TRT were analyzed by comparing available guidelines released in the last five years. We provide a review of advantages and disadvantages of different modalities of TRT and how to monitor treatment to minimize the risks. RESULTS: TRT is associated with multiple benefits highly relevant to the patient. However, the recommendations given in different guidelines on TRT are based on data from a limited number of randomized controlled trials (RCTs), as well as non-randomized clinical studies and observational studies. This is the case for the safety of a long-term TRT in late-onset hypogonadism (LOH). No evidence is provided indeed on the effects of TRT on endpoints such as deterioration of heart failure suggesting a cautious approach to T replacement in older men with a history of heart failure. CONCLUSION: Clinicians must consider the unique characteristics of each patient and make the necessary adjustments in the management of LOH in order to provide the safest and most beneficial results.

Late-onset hypogonadism: Prostate safety.

BACKGROUND: There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers. OBJECTIVES: The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety. RESULTS: Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late-onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease. CONCLUSION: Testosterone replacement therapy could be considered for most men with late-onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism?

INTRODUCTION: Functional hypogonadism increases in prevalence due to aging as well as an overall increase of obesity. Aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) could be an alternative for testosterone replacement therapy (TRT), but have not yet been established as common clinical practice. METHODS: We conducted a thorough search of the literature published between 2009 and 2018. Only RCTs published in English were included. We assessed the impact of AIs and SERMs on gonadal steroids, sexual function and semen parameters, body composition and glucose homeostasis, physical function, bone mineral density (BMD), anemia, as well as potential adverse effects. RESULTS: Twelve RCTs were included, with a total number of 645 patients. A total of 145 men were included in RCTs comparing AIs versus placebo or TRT and 476 men in RCTs with SERMs versus placebo or TRT. One RCT compared AIs versus SERMs in 24 men. Inclusion criteria were heterogenic. Most studies only included a small number of patients (range 11-256) and follow-up time was relatively short (6 weeks to 12 months). AIs as well as SERMs increased serum testosterone levels. Overall, there was no effect on sexual symptoms nor on semen parameters. Following aromatase inhibition, only minimal improvement of body composition and physical function was observed in some of the trials, but spinal BMD decreased. SERMs only induced a small improvement in body composition. The effect of SERMs on physical function and on BMD was not assessed. No major adverse effects occurred. CONCLUSION: AIs are not recommended as treatment for functional hypogonadism because of insufficient efficacy as well as a decrease in BMD. SERMs might be an alternative for TRT, but more research is needed to evaluate their effect on hypogonadal signs and symptoms, as well as on their long-term safety profile.

Late-onset hypogonadism: a concept comes of age.

The term Late-onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as 'a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)'. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age-related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US-initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that 'in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits'. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.

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.