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Background and objective: The longitudinal efficacy and clinical utility of Testosterone Therapy (TTh) in ameliorating functional hypogonadism (FH) remain contentious, with long‐term data being scarce. To address this lacuna, a comprehensive long‐term registry study, stratifying patients across a spectrum of hypogonadal etiologies, offers a robust investigative paradigm. Materials and methods: This 9‐year registry, encompassing 650 patients (equivalent to 4,362 cumulative years of treatment), included 188 patients diagnosed with FH (mean age 42.3 ± 11.3 years) and 462 individuals with classical hypogonadism (CH). The cohort segregated into 266 men with primary hypogonadism (PH, mean age 34.0 ± 11.7 years) and 196 with secondary hypogonadism (SH, mean age 31.9 ± 12.0 years). Uniform treatment across the cohort involved intramuscular administration of testosterone undecanoate (1,000 mg). A comparative analysis was conducted focusing on anthropometric, metabolic, and safety parameters. Results: Serum testosterone levels increased from 6.6 ± 2.4 to 19.3 ± 2.9 nmol/L (p < 0.001). TTh was linked with weight reduction and decreased waist circumference (WC) in both CH and FH cohorts (both p < 0.001). Cox regression and Kaplan–Meier analyses delineated disparities: men with FH demonstrated a higher propensity for losing > 10% body weight and > 5% WC compared to CH (hazard ratio [HR] 1.3 [1.1–1.4], p = 0.008 and HR 1.4 [1.3–1.5], p = 0.001). Increases in hematocrit > 50% were uniform across groups, albeit amelioration of anemia was more pronounced in FH versus CH (p = 0.002). Increments of prostate‐specific antigen (PSA) levels were more likely to occur in FH (HR 1.3 [1.1–1.6], p = 0.003). FH patients exhibited pronounced improvements in metabolic parameters and in aging male symptom score (AMS) and IIEF‐EF questionnaire scores. These effects were markedly modulated by age and initial weight. Subgroup analysis of age‐matched obese patients revealed an accentuated impact of TTh in CH compared to FH. Discussion and conclusion: The therapeutic outcomes of TTh across distinct hypogonadal populations demonstrate heterogeneous responses, significantly influenced by diagnostic categorization, age, and baseline risk factor profiles. [ABSTRACT FROM AUTHOR]

Background: Testosterone plays a vital role in maintaining tissue homeostasis, and testosterone deficiency may potentially influence the likelihood of urethral stricture recurrence. Objectives: To evaluate the prognostic value of testosterone levels in the recurrence after direct visual internal urethrotomy in primary short segment bulbar urethral strictures and its clinical reflections. Materials and methods: A total of 723 patients who underwent direct vision internal urethrotomy between January 2000 and October 2022 were retrospectively analyzed. After implying exclusion criteria, 116 patients with available data were enrolled. Patients were divided into two groups as recurrence and no recurrence. Age, stricture length, etiology, time of recurrence, diagnosis of previous diabetes mellitus, hypertension, smoking, body mass index, and total testosterone levels were recorded. Free testosterone and bioavailable testosterone values were calculated using total testosterone, albumin, and sex hormone binding globulin values. Hypogonadism was considered as a total testosterone level less than 300 ng/dL. Demographic characteristics and total testosterone, free testosterone, and bioavailable testosterone levels were compared between the two groups for statistical significance. The recurrence rates of patients with and without hypogonadism were compared. Results: Recurrence was observed in 41.4% of the cases (n = 48). There was no statistically significant difference between the groups in terms of age, body mass index values, diabetes mellitus, hypertension, smoking status, presence of hypogonadism, and etiology (p = 0.745, 0.863, 0.621, 0.622, 0.168, 0.051, and 0.232). In terms of total testosterone levels and bioavailable testosterone levels, the recurrence group had significantly lower values (p = 0.018 and 0.04). There was no significant difference between the two groups in terms of stricture length (p = 0.071). Sixteen of 28 patients with hypogonadism had recurrence, whereas 32 of 88 patients without hypogonadism had recurrence (p = 0.051). Discussion: Testosterone levels have potential to predict recurrence in primary short‐segment bulbar urethral strictures. This study represents the inaugural analysis of the impact of testosterone deficiency on recurrence within the cohort of patients with primary short‐segment bulbar urethral strictures. Conclusion: Testosterone levels and ratios may serve as predictive factors for identifying recurrent cases in primary short‐segment bulbar strictures. For patients at a higher risk of recurrence, urethroplasty may be considered as an initial treatment option, even in cases of primary and short‐segment strictures. [ABSTRACT FROM AUTHOR]

Background Objective Materials and methods Results Discussion and conclusion Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations.The primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality‐of‐life assessments to 1.62% topical testosterone gel (AndroGel 1.62%; AbbVie).In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted by 75 mg/dose at weeks 4 and 8 based on average serum total testosterone concentration and maximum observed serum concentration. The primary endpoint was the proportion of patients receiving oral testosterone undecanoate with serum total testosterone concentration within the eugonadal reference range (300–1140 ng/dL). Secondary endpoints included the proportion of patients with maximum serum total testosterone concentrations within predetermined limits, safety parameters, and quality‐of‐life endpoints including the Short Form‐36v2 Health Survey, Psychosexual Daily Questionnaire, and International Prostate Symptom Score.Overall mean ± SD baseline testosterone was 205.7 ± 71.6 ng/dL. For patients receiving oral testosterone undecanoate, 87.4% demonstrated a 24‐h average serum total testosterone concentration within the reference range following titration. Oral testosterone undecanoate demonstrated a nominal statistically significantly greater mean change from baseline than 1.62% topical testosterone gel for Short Form‐36v2 Health Survey measures of mental health (2.91 vs. ‐0.10; p = 0.035), and mental component summary (3.82 vs. 0.55; p = 0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (‐0.57 vs. ‐0.20; p = 0.021). Safety endpoints were comparable between therapies. No deaths or treatment‐related serious adverse events were reported.Male patients with hypogonadism receiving oral testosterone undecanoate 225 mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration. [ABSTRACT FROM AUTHOR]

Background: Testosterone plays an important role in collagen metabolism, transforming growth factor‐β1 expression, and wound healing, which are all critical factors in pathogenesis of Peyronie's disease. Some clinical studies have suggested an association between Peyronie's disease and hypogonadism. Objective: We sought to investigate whether baseline total testosterone levels influence response to intralesional collagenase clostridium histolyticum in Peyronie's disease. Methods: A retrospective review of patients receiving collagenase clostridium histolyticum injections with available total testosterone levels within 1 year of initial injection was conducted at a single institution. Baseline demographics, hypogonadal status, total testosterone, number of collagenase clostridium histolyticum cycles, and pre‐ and post‐treatment degrees of curvature were collected. Hypogonadism was defined as total testosterone <300 ng/dL. Results and discussion: Thirty‐six men were included with mean age of 58.2 years (SD 10.4) and mean body mass index 26.8 (SD 3.2). The mean total testosterone was 459.2 ng/dL (SD 144.0), and four (11.1%) were hypogonadal. Mean pre‐treatment curvature was 47.6°, and mean post‐treatment curvature was 27.8°, with mean improvement of 19.9° (40.1%). Hypogonadal status was not significantly associated with more severe curvature, 46.4° among hypogonadal men as to 57.5° among eugonadal men (p = 0.32). On linear regression analysis, total testosterone did not significantly predict improvement in degrees (β = –0.02; R2 = 0.06; p = 0.14) or percent (β = 0.0; R2 = 0.05; p = 0.18). Improvement in neither degrees nor percent differed significantly by hypogonadal status (p = 0.41 and 0.82, respectively). The cycle number did significantly predict greater improvement in curvature on both univariate and multivariate analyses (β = 5.7; R2 = 0.34; p < 0.01). Conclusion: Neither total testosterone nor hypogonadism is associated with a degree of improvement after collagenase clostridium histolyticum treatment. [ABSTRACT FROM AUTHOR]

Background: Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle‐aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle‐aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost‐effectiveness of testosterone treatment in such men with low testosterone compared with no treatment. Methods: A cost‐utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10‐year‐time horizon. Clinical outcomes were obtained from an individual patient meta‐analysis of placebo‐controlled, double‐blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality‐adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost‐effectiveness ratios and cost‐effectiveness acceptability curves for selected scenarios. Results: Ten‐year excess treatment costs for testosterone compared with non‐treatment ranged between £2306 and £3269 per patient. Quality‐adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index‐derived quality‐adjusted life years data, testosterone was cost‐effective (incremental cost‐effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost‐effective in men aged >75 years in models assuming increased morbidity and/or mortality. Conclusions and future research: Our data suggest that testosterone is cost‐effective in men <75 years when Beck depression index‐derived quality‐adjusted life years data are considered; cost‐effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer‐term cost‐utility data are needed to verify our conclusion. [ABSTRACT FROM AUTHOR]

Background: Low testosterone (T) levels in men associate with increased risks of obesity, type 2 diabetes, metabolic syndrome, and cardiovascular diseases. However, most studies are cross‐sectional with follow‐up‐time < 10 years, and data on early growth are limited. Objective: To compare prenatal factors and body mass index (BMI) development from birth to age 46 in relation to low T at age 31. Materials and methods: Men with low T (T < 12.1 nmol/L, n = 132) and men with normal T at age 31 (n = 2561) were derived from the Northern Finland Birth Cohort 1966. Prenatal factors, longitudinal weight and height data from birth to age 14, and cross‐sectional weight and height data at ages 31 and 46, and waist‐hip‐ratio (WHR) and T levels at age 31 were analyzed. Longitudinal modeling and timing of adiposity rebound (AR, second BMI rise at age 5–7 years) were calculated from fitted BMI curves. Results were adjusted for mother's pre‐pregnancy BMI and smoking status, birth weight for gestational age, alcohol consumption, education level, smoking status, and WHR at age 31. Results: Neither gestational age nor birth weight was associated with low T at age 31; however, maternal obesity during gestation was more prevalent among men with low T (9.8% vs. 3.5%, adjusted aOR: 2.43 [1.19−4.98]). Men with low T had earlier AR (5.28 vs. 5.82, aOR: 0.73 [0.56−0.94]) and higher BMI (p < 0.001) from AR onward until age 46. Men with both early AR and low T had the highest BMI from AR onward. Conclusions: In men, maternal obesity and early weight gain associate with lower T levels at age 31, independently of adulthood abdominal obesity. Given the well‐known health risks related to obesity, and the rising prevalence of maternal obesity, the results of the present study emphasize the importance of preventing obesity that may also affect the later reproductive health of the offspring. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Testosterone replacement therapy in aging men increases lean body mass and decreases whole‐body fat. The safety of testosterone replacement therapy concerning cardiovascular disease is unresolved and assessment of whole‐body oxidative stress may contribute to future decision making. Objectives: To determine whole‐body oxidative stress during testosterone replacement therapy and placebo in aging men and evaluate if a change in oxidative stress was mediated by changed body composition. Materials and methods: This was a double‐blinded, randomized, placebo‐controlled study for 24 weeks in 38 men aged 60–78 years with bioavailable testosterone <7.3 nmol/L and waist circumference ≥94 cm who were randomized to testosterone replacement therapy (testosterone gel) (N = 20) or placebo (N = 18). At baseline and after 24 weeks, whole‐body oxidative stress was assessed by oxidized derivatives of nucleic acids, 8‐oxoguanosine and 8‐oxo‐2′‐deoxyguanosine in 24‐h urine samples by ultra‐performance liquid chromatography tandem mass spectrometry. Lean body mass and whole‐body fat were measured by dual X‐ray absorptiometry. Subcutaneous and visceral adipose tissue were estimated by magnetic resonance imaging. Testosterone replacement therapy versus placebo was compared by Mann–Whitney tests on ∆‐values (24–0 weeks). Results: Baseline age was 67 (64–72) years (median [interquartile range]), body mass index 29.8 (26.6–33.3) kg/m2, waist 107 (99–117) cm, and bioavailable testosterone 4.7 (3.7–5.9) nmol/L. During testosterone replacement therapy, 8‐oxoguanosine in 24‐h urine samples decreased from 21.6 (19.8; 27.7) nm to 15.0 (12.2; 18.8) nm (p = 0.038 vs. placebo), lean body mass increased (p < 0.01) and whole‐body fat (p = 0.02) and subcutaneous adipose tissue (p < 0.01) decreased. 8‐Oxoguanosine in 24‐h urine samples was inversely associated with Δ‐lean body mass (ρ = –0.38, p = 0.03), which remained significant after adjusting for Δ‐total testosterone. 8‐Oxo‐2′‐deoxyguanosine in 24‐h urine samples was unchanged (p = 0.06) during testosterone replacement therapy and Δ‐8‐oxo‐2′‐deoxyguanosine in 24‐h urine samples was associated with Δ‐whole‐body fat (kg) (ρ = 0.47, p < 0.01). Δ‐Values of oxidative stress biomarkers were not associated with Δ‐fasting insulin or Δ‐homeostatic model assessment of insulin resistance. Discussion: Oxidative stress decreased during testosterone replacement therapy compared to placebo, which could be mediated by changed body composition. Conclusion: Whole‐body oxidative stress decreased during 24 weeks of testosterone replacement therapy in aging men. [ABSTRACT FROM AUTHOR]

The advent of new systemic therapies resulted in a significant decrease in prostate cancer (PCa) death in the past decades. It comes at the cost of an increase in the proportion of men living with long‐term treatment‐induced hypogonadism. In a population of men with no history of PCa, the testosterone replacement therapy (TRT) proved its ability to both improve erectile function and reduce cardiovascular morbidity, translating into an improved overall survival. Whether TRT is safe and efficient in PCa patients remains an open question. Here, we present an overview on the safety of TRT for PCa patients and discuss the optimal population eligible for TRT after the PCa treatment. [ABSTRACT FROM AUTHOR]

Background: Although Klinefelter syndrome (KS) is the most frequent sex‐hormone disorder, there is ongoing uncertainty about the often associated sex‐hormone deficiency, its impact on common comorbidities, and therefore about prevention and treatment. In this study, we focus on bone loss, reported to occur in over 40% of KS patients, and the impact of testosterone replacement therapy (TRT) on this comorbidity. Objectives: This single‐center retrospective cohort study in a tertiary hospital compared the effect of treatment with TRT to no TRT on evolution of bone mineral density (BMD) in KS patients. Methods: After a medical chart review, a total of 52 KS subjects were included in this study. BMD was measured by dual‐energy X‐ray absorptiometry (DXA) and expressed as T‐scores. Results: The subjects were divided into three groups, according to TRT. In the subgroup that only started TRT after baseline measurements (mean age 31 years), we observed significant gain in BMD T‐score at the lumbar spine (0.58 ± 0.60, p = 0.003; mean gain of 0.62% areal BMD per year) and total femur T‐score (0.24 ± 0.39, p = 0.041; mean gain of 0.25% areal BMD per year) after a mean follow‐up period of 7.5 years. Compared to untreated subjects, a significant difference in evolution was demonstrated at the lumbar level (+0.58 ± 0.60 vs. −0.14 ± 0.42, p = 0.007). In untreated subjects with normal testosterone levels, a loss of BMD (−0.27 ± 0.37, p = 0.029; mean loss of 0.49% areal BMD per year) at the femoral neck was measured. This decline was equal to the predicted loss seen in the general male population. Conclusion: TRT results in BMD gain in patients with KS with testosterone deficiency, mainly at the lumbar spine. However, this effect is limited (0.62% per year). Patients who were not treated with TRT because of sufficient endogenous testosterone levels, showed only the predicted age‐related bone loss during follow‐up. The need for TRT in maintaining bone health in KS should be evaluated on an individual basis according to the degree of sex steroid deficiency. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Apo A‐I Leu75Pro amyloidosis is a rare systemic hereditary disease, whose hallmark and earliest involvement is testicular impairment, characterized by hypogonadism and macrorchidism; renal and hepatic involvement are the other characteristics. Objective: To evaluate for the first time the prevalence of osteopenia, osteoporosis and vertebral fractures (VFs) in men with this form of amyloidosis affected by hypogonadism and under long‐term testosterone replacement therapy (TRT). Materials and methods: Retrospective study on 50 men >50 years (median age 64.5) with dual‐energy X‐ray absorptiometry (DXA), hormonal, and biochemical data available at least 3 years after the start of TRT. Serum gonadal hormones and bone markers, lumbar and femoral DXA‐scan with morphometric assay for evaluation of VFs were assessed. Results: At 7.5 years from start of TRT, lumbar and/or femoral osteopenia and osteoporosis were found in 54% and 10% of patients, respectively. Of the men who had the morphometric assay performed, five of 34 (14.7%) had VFs. Compared to patients with normal bone mineral density, men with osteopenia and osteoporosis were older, had lower body mass index, higher sex hormone binding globulin and showed more frequently renal involvement. Multiorgan involvement, without different TRT dosage, was associated with lower testosterone levels. Discussion and conclusion: Men with hypogonadism because of Apo A‐I Leu75Pro amyloidosis under long‐term TRT had a high burden of low bone mass (64%) and VFs (almost 15%). Osteopenia‐osteoporosis was more frequently observed in older patients with multi‐organ disease, which might contribute to impair bone health beyond hypogonadism. [ABSTRACT FROM AUTHOR]

Reduced serum testosterone affects millions of men across the world and has been linked to several comorbidities, metabolic dysfunctions, and quality of life changes. The standard treatment for testosterone deficiency remains testosterone replacement therapy. However, limitations on its use and the risk of significant adverse effects make alternative therapeutics desirable. Studies on the mechanisms regulating and synthesizing testosterone formation in testicular Leydig cells demonstrate numerous endogenous targets that could increase testosterone biosynthesis, which could alleviate reduced testosterone effects. Testosterone biosynthesis is facilitated by a conglomerate of cytosolic and mitochondrial proteins that facilitate cholesterol translocation into the mitochondria, the rate‐limiting step in steroidogenesis. An effective therapeutic approach would be required to increase endogenous testosterone formation by enhancing steroidogenesis in Leydig cells. Numerous ligands for steroidogenic proteins have been developed, which increase steroid hormone formation. However, off‐target effects on neurosteroid and adrenal steroid formation may limit their clinical use. First‐in‐class biologics, such as voltage‐dependent anion channel peptides and transplantation of induced human Leydig‐like cells offer advances in the development of specific strategies that could be used to enhance endogenous steroid formation in hormone deficient patients. [ABSTRACT FROM AUTHOR]

Introduction: Erectile dysfunction is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for erectile dysfunction is phosphodiesterase type 5 inhibitors, but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices and penile prosthetic surgery, should be considered in management of diabetic men with erectile dysfunction refractory to phosphodiesterase type 5 inhibitors. Furthermore, combination therapy of phosphodiesterase type 5 inhibitors and other oral treatments such as arginine or L-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem-cell therapy, which may also be effective in targeted treatment modalities. Furthermore, studies suggest that erectile dysfunction can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidaemia. We present an evidence-based narrative review focusing on the management of erectile dysfunction in diabetic men who have not responded to phosphodiesterase type 5 inhibitors. Conclusions: Both clinicians and patients should be aware of the different management options in diabetic patients who have not responded to phosphodiesterase type 5 inhibitors. [ABSTRACT FROM AUTHOR]

Background: The very low-calorie ketogenic diet (VLCKD) represents an opportunity to attain clinically relevant weight loss in obese patients. Functional hypogonadism represents a frequent hormonal disorder associated with obesity and visceral fat accumulation characterised by low testosterone levels and subnormal luteinising hormone (LH) levels. Aim: To evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients. Methods: Twenty-two obese male patients (mean age 39.3 ± 11.7 years, mean body mass index (BMI) 38.2±6.4 kg/m2) were enrolled and treated for 28 days with VLCKD. Anthropometric and hormonal variables were assessed before, during and after diet intervention. Results: After 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin and homeostasis model assessment index was observed compared with baseline. TT significantly increased after 7 days (+35 ± 64 ng/dl) and 28 days (+74 ± 97 ng/dl) on a VLCKD. In addition to TT, a significant increase in serum sex hormone-binding globulin levels was observed after 7 (+2.1 ± 4.1) and 28 days (+7.7 ± 10.0). However, both calculated free testosterone and LH did not change after 7 or 28 days of VLCKD. Following cessation of VLCKD, hypogonadal subjects achieved a higher percentage of total weight loss (8.5% ± 1.5%), a greater reduction in weight (-9.94 ± 1.66 kg), fat mass (-7 ± 2.1 kg) and waist circumference (-6.31 ± 2.65 cm) and a greater improvement in glycaemia (-8.75 ± 10.92 mg/dl) as compared with eugonadal subjects. Furthermore, hypogonadal subjects exhibited a trend of higher TT increase (+98.12 ± 71.51 ng/dl) as compared with eugonadal subjects. Conclusions: VLCKDresults in rapid improvements in TT levels associated with weight loss in male obese non-diabetic subjects, particularly in the presence of obesity-related hypogonadism. [ABSTRACT FROM AUTHOR]

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 diabetesmellitus on testosterone levels and androgendeficiency-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 and rogen-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. [ABSTRACT FROM AUTHOR]

Background: Most men diagnosed with prostate cancer today have organ‐confined disease and low risk of disease recurrence after radical prostatectomy. Testosterone deficiency in prostate cancer survivors contributes to impaired health‐related quality of life but testosterone treatment is viewed as a contraindication in this population. Objectives: We describe the design of the first randomized trial to determine the safety and efficacy of testosterone treatment in men who have undergone prostatectomy for non‐aggressive prostate cancer and have symptomatic testosterone deficiency. Methods: Surviving Prostate cancer while Improving quality of life through Rehabilitation with Testosterone Trial is a randomized, placebo‐controlled, double‐blind, parallel group trial in 142 men, ≥ 40 years, who have undergone radical prostatectomy for organ‐confined prostate cancer, Gleason score ≤ 7 (3+4), Stage pT2, N0, M0 lesions and have symptomatic testosterone deficiency and undetectable prostate specific antigen for > 2 years after surgery. Eligible participants are randomized to weekly intramuscular injections of 100‐mg testosterone cypionate or placebo for 12 weeks and followed for another 12 weeks. Primary endpoint is change from baseline in sexual activity. Secondary outcomes include change in sexual desire, erectile function, energy, lean and fat mass, physical and cognitive performance. Safety is assessed by monitoring prostate‐specific antigen, lower urinary tract symptoms, hemoglobin, and adverse events. Results: The trial is being conducted at two trial sites in Boston, MA and Baltimore, MD. As of July 30, 2022, 42 participants have been randomized. No prostate‐specific antigen or clinical recurrence has been noted to‐date. Discussion: Recruitment was slowed by coronavirus disease 2019‐related closures, slow subsequent ramp‐up of research activities, and patient concerns about safety of testosterone treatment. Despite these challenges, participant retention has been high. Conclusion: The Surviving Prostate cancer while Improving quality of life through Rehabilitation with Testosterone Trial, a placebo‐controlled, randomized trial, will determine whether testosterone replacement therapy is safe and efficacious in correcting symptoms of testosterone deficiency in prostate cancer survivors, and potentially inform clinical practice. [ABSTRACT FROM AUTHOR]

Background: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied. Objectives: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. Materials and methods: We conducted a population‐based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding. Results: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33–4.59) which was more pronounced in proximal hypospadias. Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08–2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18–2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27–1.71). Discussion: We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies. Conclusion: Hypospadias is associated with an increased risk of androgen‐related comorbidity in adolescence and adulthood. We suggest that this can be considered clinically, while further research is needed, especially in older populations. [ABSTRACT FROM AUTHOR]

Background: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell‐produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin‐like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes. Objectives: To characterize insulin‐like peptide 3 as a biomarker to assess gonadal status in aging men. Methods and materials: A large European multicenter (European Male Aging Study) cohort of community‐dwelling men was analyzed to determine how insulin‐like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters. Results and discussion: Insulin‐like peptide 3 declines cross‐sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin‐like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin‐like peptide 3 is negatively dependent on luteinizing hormone and sex hormone‐binding globulin and positively dependent on follicle‐stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin‐like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin‐like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European‐wide reference range for insulin‐like peptide 3 (95% confidence interval) adjusted for increasing age. Conclusion: Insulin‐like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin‐dependent short‐term regulation and within‐individual variation in testosterone. [ABSTRACT FROM AUTHOR]

Objective: Men with male hypogonadism (MH) experience sexual dysfunction, which improves with testosterone replacement therapy (TRT). However, randomised controlled trials provide little consensus on functional and behavioural symptoms in hypogonadal men; these are often better captured by qualitative information from individual patient experience. Methods: We systematically searched major electronic databases to identify qualitative data from men with hypogonadism, with or without TRT. Two independent authors performed the selection, extraction, and thematic analysis of data. Quality of eligible studies was assessed using the Critical Appraisals Skills Programme and Grading of Recommendations Assessment, Development and Evaluation‐Confidence in the Evidence from Reviews of Qualitative research tools. Results: We analysed data from five studies published in nine reports that assessed a total of 284 participants. Published data were only available within North America, with no ethnic minority or other underserved groups included. In addition to sexual dysfunction, men with MH experienced adverse changes in physical strength, perceptions of masculinity, cognitive function, and quality of life. The experience of MH appeared dependent on the source(s) of educational material. Discussion: We propose a patient‐centred approach to clinician interactions rather than focusing on discreet MH symptoms. Current evidence about the experience of MH is limited to North America and predominantly white ethnicity, which may not be broadly applicable to other geographic regions. Broadening our understanding of the MH experience may improve the targeting of information to patients. In addition, a multidisciplinary approach may better address symptoms neither attributable to MH nor alleviated by TRT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Chronic pain and opioid treatment are associated with increased risk of male hypogonadism and subsequently decreased muscle function. A diagnosis of hypogonadism is based on the presence of low total testosterone and associated symptoms. The effect of testosterone replacement therapy on muscle function in men with chronic pain and low total testosterone remains to be investigated. Objectives: To investigate the effects of testosterone replacement therapy on muscle function and gait performance in men treated with opioids for chronic non‐cancer pain. Materials and methods: A double‐blind, placebo‐controlled study. Forty‐one men (>18 years) with opioid‐treated chronic pain and serum total testosterone < 12 nmol/L were randomized to 24 weeks testosterone replacement therapy (testosterone undecanoate injection three times/6 months, n = 20) or placebo injections (n = 21). Muscle function was measured as leg press maximal voluntary contraction, leg extension power using the Nottingham power rig and handgrip strength using a handheld dynameter. Gait performance was measured at usual and maximal gait speed on a 10‐m track. Body composition (lean body mass and fat mass) was determined by dual‐energy X‐ray absorptiometry. Mann‐Whitney tests were performed on ∆‐values (24‐0 weeks) between testosterone replacement therapy and placebo. Results: At baseline, median (interquartile range) age was 55 ± 13 years and BMI was 30.7 ± 5.2 kg/m2. ∆‐muscle function and ∆‐gait performance were similar between testosterone replacement therapy and placebo. Median ∆‐leg press maximal voluntary contraction was 174.2 ± 406.7 Newton, following testosterone replacement therapy, and 7.6 ± 419.1 Newton, after placebo, p = 0.091. ∆‐lean body mass was significantly higher following testosterone replacement therapy compared to placebo, 3.6 ± 2.7 versus 0.1 ± 3.5 kg, respectively (p < 0.001). Discussion: Testosterone replacement therapy, compared to placebo, did not improve muscle function or gait performance despite increased lean body mass. Changes in body composition did not infer any changes in muscle function. Conclusion: 24 weeks testosterone replacement therapy in opioid‐treated men with pain‐related male hypogonadism did not improve muscle function. [ABSTRACT FROM AUTHOR]

Background: Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first‐choice therapy, with several side effects, including negative feedback of the hypothalamic–pituitary–gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off‐label therapy. This systematic review and meta‐analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism. Methods: The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects. Results: We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta‐analysis, with a total of 1279 patients. Therapy and follow‐up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82–3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone‐binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported. Conclusion: Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects. [ABSTRACT FROM AUTHOR]

Background: A potential role of testosterone among sex hormones has been hypothesized in identifying sex‐related differences in the clinical consequences of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. Due to the high global prevalence of hypogonadism, the relationship between hypogonadism and SARS‐CoV‐2 infection outcomes deserves an in‐depth study. Objective: The present study aimed to investigate the relationship of serum testosterone with other laboratory parameters on the prognosis of coronavirus disease‐19 (COVID‐19) in male patients with COVID‐19 diagnosis. Materials and methods: This prospective cohort study included 358 male patients diagnosed with COVID‐19 and 92 COVID‐19 negative patients admitted to the urology outpatient clinics as a control group. The COVID‐19 patients were divided into groups according to prognosis (mild‐moderate and severe group), lung involvement in chest computed tomography (<50% and >50%), intensive care unit needs, and survival. Results: The measured serum total testosterone level of the COVID‐19 patients group was found to be significantly lower than that of the control group (median, 140 ng/dl; range, 0.21–328, 322 ng/dl; range, median, 125–674, p < 0.001, respectively). The serum TT levels were statistically significantly lower in severe COVID‐19 patients compared to mild‐moderate COVID‐19 patients (median, 85.1 ng/dl; range, 0.21–532, median, 315 ng/dl; range, 0.88–486, p < 0.001, respectively), in COVID‐19 patients in need of intensive care compared to COVID‐19 patients who did not need intensive care (median, 64.0 ng/dl; range, 0.21–337, median, 286 ng/dl; range, 0.88–532 p < 0.001, respectively), and in COVID‐19 patients who died compared to survivors (median, 82.9 ng/dl; range, 2.63–165, median, 166 ng/dl; range, 0.21–532, p < 0.001, respectively). Discussion and conclusion: Our data are compatible with low TT levels playing a role on the pathogenesis of the disease in Covid‐19 patients with poor prognosis and a mortal course and may guide clinicians in determining the clinical course of the disease. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 receptor agonists (GLP1‐RAs) are novel anti‐hyperglycemic drugs efficacious on glucose control, weight loss, and cardiovascular prevention. These drugs may also be effective in modulating testicular function. In fact, they increase serum testosterone levels in diabetic and/or obese patients with functional hypogonadism on a dysmetabolic basis. Although part of this effect can be ascribed to weight loss, some evidence suggests that there is a direct effect at the testicular level. Indeed, human Leydig, Sertoli, and germ cells express GLP1 receptors. GLP1‐RAs improve sperm metabolism, motility, and insulin secretion in vitro. Likewise, GLP1‐RAs exert positive effects on the metabolism of human Sertoli cells in vitro. Finally, GLP1 is secreted by mouse Leydig cells and this suggests the presence of a paracrine mechanism by which these cells could support the metabolism of Sertoli cells. Therefore, the widespread use of GLP1‐RAs in clinical practice may reveal an important role in the management of male infertility in obese and/or diabetic patients given the negative impact of these diseases on testicular steroidogenesis and spermatogenesis. This should suggest the design of randomized controlled studies aimed at evaluating the effects of these drugs on testicular function. [ABSTRACT FROM AUTHOR]

Background: While previous studies have demonstrated testosterone's beneficial effects on glycemic control in men with hypogonadism and Type 2 Diabetes, the extent to which these improvements are observed based on the degree of treatment adherence has been unclear. Objectives: To evaluate the effects of long‐term testosterone therapy in A1C levels in men with Type 2 Diabetes Mellitus and hypogonadism, controlling for BMI, pre‐treatment A1C, and age among different testosterone therapy adherence groups. Materials and methods: We performed a retrospective analysis of 1737 men with diabetes and hypogonadism on testosterone therapy for 5 years of data from 2008–2018, isolating A1C, lipid panels, and BMI results for analysis. Subjects were categorized into adherence groups based on quartiles of the proportion of days covered (> 75% of days, 51–75% of days, 26–50% of days and 0–25% of days), with >75% of days covered considered adherent to therapy. Results: Pre‐treatment median A1C was 6.8%. Post‐treatment median A1C was 7.1%. The adherent group, >75%, was the only group notable for a decrease in A1C, with a median decrease of −0.2 (p = 0.0022). BMI improvement was associated with improved post‐treatment A1C (p = 0.007). When controlling for BMI, age, and pre‐treatment A1C, the >75% adherence group was associated with improved post‐treatment A1C (p < 0.001). Discussion: When controlling for all studied variables, testosterone adherence was associated with improved post‐treatment A1C. The higher the initial A1C at the initiation of therapy, the higher the potential for lowering the patient's A1C with >75% adherence. Further, all groups showed some reduction in BMI, which may indicate that testosterone therapy may affect A1C independent of weight loss. Conclusion: Even when controlling for improved BMI, pre‐treatment A1C, and age, testosterone positively impacted glycemic control in diabetes patients with hypogonadism, with the most benefit noted in those most adherent to therapy (>75%). [ABSTRACT FROM AUTHOR]

Background: Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. Objectives: Uncover the effects of Glucagon‐Like Peptide‐1 receptor agonist (GLP‐1 RA) therapy on serum testosterone. Material and Methods: Prospective cohort study of men starting GLP‐1 RA therapy for type 2 diabetes mellitus. Results: 51 men lost 2.27 kg (p = 0.00162) and their HbA1c values improved by 0.7% (p = 0.000503) after 6 months of GLP‐1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone <320 ng/dL (238.5 ± 56.5 ng/dL to 272.2 ± 82.3 ng/dL) compared to higher values (438 ± 98.2 ng/dL to 412 ± 141.2 ng/dL) (p = 0.0172);free testosterone increased if the baseline total testosterone was <320 ng/dL (55.2 ± 12.8 pg/mL to 57.2 ± 17.6 pg/mL) and decreased if >320 ng/dL (74.7 ± 16.3 pg/mL to 64.2 ± 17.7 pg/mL) (p = 0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6 ± 123.9 ng/dL to 394.4 ± 136.5 ng/dL) compared to men with HbA1c changes <1% (331.8 ± 128.6 ng/dL to 316.1 ± 126.2 ng/dL) (p = 0.0413). Conclusion: GLP‐1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits. [ABSTRACT FROM AUTHOR]

Background: Trends of male factor causes of couples' infertility over time have been poorly investigated. Objective: We investigated trends in the causes of pure male factor infertility (MFI) throughout the last 10 years in a tertiary‐referral academic andrology center. Material and Methods: Baseline characteristics at first presentation from a cohort of 1647 consecutive male factor infertility patients belonging to primary infertile couples between 2008 and 2018 have been comprehensively collected over time. Seven major causes of male factor infertility were identified: varicocoele; history of cryptorchidism; hypogonadism (primary and secondary); obstructive azoospermia; genetic abnormalities; other causes (large group including the remnant conditions of known causes); and idiopathic infertility. Rates of different male factor infertility causes over the study period were analyzed. Multivariable logistic regression models tested the likelihood of male factor infertility causes over time. Estimated trends were explored graphically. Results: Of all, varicocoele was found in 615 (37.3%), cryptorchidism in 124 (7.5%), genetic abnormalities in 61 (3.7%), hypogonadism in 165 (10%), obstructive conditions in 55 (3.3%), other causes in 129 (7.8%) patients, and idiopathic infertility in 498 (30.3%) patients, respectively. Over time, a reduction in the proportions of cryptorchidism and varicocoele (all P < 0.001) cases was observed, along with an increase in the proportions of hypogonadism, other causes of MFI and idiopathic cases (all P ≤ 0.01). Rates of genetic and obstructive cases remained stable. The observed trends were confirmed at logistic regression models. Discussion and Conclusions: A decreasing trend in the proportions of varicocoele and cryptorchidism at first presentation was observed over the last 10 years; conversely, the proportions of idiopathic cases, hypogonadal patients, and infertile men presenting with other male factor infertility causes significantly increased over the same time frame at a single tertiary‐referral academic andrology center. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether the neurovascular bundle (NVB) sparing could improve post‐operative urinary continence and potency. Furthermore, concern remains regarding the impact of nerve‐sparing (NS) radical cystectomy (RC) on oncological outcomes. Objectives: The primary objective of this meta‐analysis was to evaluate whether in men undergoing NS RC could improve post‐operative urinary continence and potency. The secondary objective was to assess whether NS RC could compromise the oncological control. Materials and methods: A systematic search of the PubMed and Web of Science was performed in February 2020, yielding 1446 unique records. A total of 13 comparative cohort studies were included. Risk of bias in each study was assessed separately by two authors using the Newcastle‐Ottawa Scale (NOS). Results: Data from 921 participants in 12 studies were synthesized in the present meta‐analysis. Meta‐analysis revealed that NS compared with non–nerve sparing (NNS) results in improved post‐operative potency, daytime continence, and nocturnal continence. RRs were 9.35 (P <.00001) in potency, 1.11 (P =.045) in daytime continence, and 1.33 (P =.002) in nocturnal continence, respectively. Furthermore, no differences were found in the included studies reporting oncological outcomes. RRs were 0.88 (P =.61) in local and/or distant recurrence between two groups. A sensitivity analysis of prospective studies indicated consistent results. Discussion and conclusion: This meta‐analysis indicates that NS RC can improve post‐operative potency, and daytime and nocturnal urinary continence, without compromising oncological control, compared with NNS RC in men. [ABSTRACT FROM AUTHOR]

Genetic dissection of spermatogenic arrest through exome analysis - clinical implications for... A. RIERA-ESCAMILLA SP 1 sp , D. MORENO-MENDOZA SP 1 sp , K. HOLLEMAN SP 2 sp , F. CIOPPI SP 3 sp , F. ALGABA SP 1 sp , M. PYBUS SP 1 sp , C. FRIEDRICH SP 4 sp , M. J. WYRWOLL SP 4 sp , E. CASAMONTI SP 3 sp , S. PIETROFORTE SP 3 sp , L. NAGIRNAJA SP 5 sp , A. M. LOPES SP 6 sp , S. KLIESCH SP 7 sp , A. PILATZ SP 8 sp , D. T. CARRELL SP 9 sp , D. F. CONRAD SP 5,10 sp , E. ARS SP 1 sp , E. RUIZ-CASTAÑÉ SP 1 sp , K. I. ASTON SP 9 sp , W. M. BAARENDS SP 2 sp , F. TÜTTELMANN SP 4 sp , C. KRAUSZ SP 1,3 sp SP 1 sp Fundació Puigvert, Barcelona, Spain; SP 2 sp Erasmus MC University Medical Centre, Rotterdam, Netherlands; SP 3 sp University of Florence, Florence, Italy; SP 4 sp University of Münster, Münster, Germany; SP 5 sp Oregon Health & Science University, Portland, United States; SP 6 sp Universidade do Porto, Porto, Portugal; SP 7 sp University Hospital Münster, Münster, Germany; SP 8 sp Justus Liebig University, Giessen, Germany; SP 9 sp University of Utah School of Medicine, Salt Lake City, United States; SP 10 sp Washington University School of Medicine, St. Louis, United States B Introduction: b Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). The panel encloses 34 genes for male infertility, 15 genes for female infertility and 2 genes causing both male and female infertility. B Patients and Methods: b RNA sequencing was performed to compare the genetic profile of testicular biopsies from patients with (KS and testis atrophy patients) and without (Sertoli cell only patients and fertile controls) testicular fibrosis. [Extracted from the article]

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 β1‐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. [ABSTRACT FROM AUTHOR]

Background: Cognitive decline and impairment of physical performance and mobility are age‐related clinical problems with major negative impact on quality of life of elderly men. In how far the decline of testosterone production contributes to these problems in older men and whether testosterone therapy can contribute to slow down, prevent, or reverse their development remains subjects of debate. Objectives: This narrative review presents the current knowledge on association of sex steroid status with cognitive decline and impairment of physical function and mobility in elderly men and on the effects of testosterone therapy on cognition and on physical performance and mobility in elderly men. Materials and Method: The review is based on electronic database searches with primary focus on evidence from larger prospective observational studies and from controlled randomized trials, respectively. Results: In most observational studies, testosterone levels do not predict cognitive decline or development of Alzheimer's disease. In randomized trials, testosterone therapy did not significantly affect cognition in men with low or low‐to‐normal serum testosterone, regardless of whether they have preexisting cognitive impairment. Overall, observational data indicate that the usually moderate decline of androgen exposure in older men cannot fully account for the parallel decline of physical performance and mobility. Trials of testosterone therapy in older men with low or low‐normal serum testosterone, whether they were generally healthy or suffered from physical function impairments, either did not show any effect on mobility and physical performance or showed limited effects of uncertain clinical relevancy. Discussion and Conclusions: The whole of the evidence tends to downplay the role of sex steroid status in the decline of cognitive function and impairment of physical function and mobility in older men. Based on the available evidence, prevention or treatment of cognitive decline or of impairment of mobility and physical function are not valid indications for testosterone treatment in older men with low or low‐to‐normal serum testosterone levels. [ABSTRACT FROM AUTHOR]

Background: Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non‐genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied. Objectives: To compare the effects of various concentrations of T on nitric oxide (NO)‐dependent and nitric oxide‐independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway. Materials and methods: Human corpus cavernosum (HCC) samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150 ng/dL), eugonadal (400 ng/dL), and hypergonadal (600 ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS, and phosphodiesterase type 5 (PDE5) were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays. Results: Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil‐induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP, and NOx levels, along with reduced PDE5 protein expression. Conclusion: This study reveals an important role of short‐term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression, and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function in hypogonadal men. [ABSTRACT FROM AUTHOR]

Background: Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking. Objective: To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS. Materials and methods: Eighty‐seven patients with KS (median age 41 years, range 18‐64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty‐five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool. Results: Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with "low BMD per age" (subject < 50 years with Z‐score ≤−2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1‐9). Prevalence of VFs was similar between healthy and low‐BMD patients (15.9% vs 13.6%; P =.80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P =.039), without significant differences in age at the time of observation (P =.162), body mass index (P =.234), testosterone replacement therapy (P =.432), duration of testosterone therapy (P =.409), vitamin D therapy (P = 681), and serum testosterone levels (P =.338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P =.047). In 55 cases evaluated by the FRAX® tool, no significant differences in 10‐year risk of major fracture (P =.270) and hip fracture (P =.860) were found between fractured and non‐fractured patients. Conclusions: This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Exercise and weight loss have been shown to improve serum testosterone (T) in obese individuals. However, the association between low T levels and guideline‐based exercise thresholds has not been determined. Objective: Using the recently updated Physical Activity Guidelines Advisory Committee (PAGAC) recommendations, we sought to investigate the relationship between recommended activity levels and the prevalence of low T levels. Materials and Methods: The2011‐2016 National Health and Nutrition Examination Survey (NHANES) was used to identify men ages 18 to 80 years who answered the physical activity questionnaire and underwent serum T testing. Men were categorized based on PAGAC activity level: less than recommended, recommended and greater than recommended. Multivariable logistic regressions were used to determine the association between low T (<300 ng/dL) and activity level across body mass index (BMI) categories while adjusting for potential confounders. Results: Of the 7372 men who met the inclusion criteria, the majority (4372, 59.3%) exceeded the recommended amount of activity, whereas only 2326 (31.6%) exercised less than the recommended amount. On multivariable analysis, obese men whose activity exceeded the recommended amount were less likely to have low T (OR 0.523, 95% CI 0.409‐0.669, P <.001) compared with men who did not meet the recommended activity level. Discussion and Conclusions: Using a large, nationally representative cohort, we demonstrated that obese men whose activity exceeded PAGAC recommendations had a decreased likelihood of having low T levels. Given the numerous benefits of exercise, these data provide a basis for counseling obese patients regarding the association between exercise and decreased prevalence of low T. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Adult patients with Klinefelter syndrome (KS) may present with testicular volume loss and a decrease in circulating testosterone (T) levels. However, the actual rate of hypogonadism in adult KS men is unknown. We aimed to (a) assess the prevalence of different forms of hypogonadism in a cohort of KS patients with non‐obstructive azoospermia (NOA); and (b) investigate potential preoperative predictor of positive sperm retrieval (SR) at surgery in the same cohort of men. Methods: Complete data from 103 KS men with NOA who underwent testicular sperm extraction (TESE) between 2008 and 2019 at five centers were analyzed. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients were categorized into four groups of hypogonadism as follows: eugonadism [normal total T (tT) (≥3.03 ng/mL) and normal luteinizing hormone (LH) (≤9.4 mUI/mL)], secondary hypogonadism [low tT (≤3.03 ng/mL) and low/normal LH (≤9.4 mUI/mL)], primary hypogonadism [low tT (≤3.03 ng/mL) and elevated LH (≥9.4 mUI/mL)], and compensated hypogonadism [normal tT (≥3.03 ng/mL) and elevated LH (≥9.4 mUI/mL)]. Descriptive statistics tested the association between clinical characteristics and laboratory values among the four groups. Results: Median (IQR) patients age was 32 (24, 37) years. Baseline follicle‐stimulating hormone and tT levels were 29.5 (19.9, 40.9) mUI/mL and 3.8 (2.5, 11.0) ng/mL, respectively. Eugonadism, primary hypogonadism, and compensated hypogonadism were found in 16 (15.6%), 34 (33.0%), and 53 (51.4%) men, respectively. No patients had secondary hypogonadism. Positive SR rate at TESE was 21.4% (22 patients); of 22, 15 (68.2%) patients underwent assisted reproductive technology and five (22.7%) ended in live birth children. Patients' age, BMI, CCI, FSH levels, and positive SR rates were comparable among hypogonadism groups. No preoperative parameters were associated with positive SR at logistic regressions analysis. Conclusions: Findings from this cross‐sectional study showed that 15.6% of adult KS men have normal tT values at presentation in the real‐life setting. Most KS patients presented with either compensated or primary hypogonadism. Sperm retrieval rates were not associated with different forms of hypogonadism. [ABSTRACT FROM AUTHOR]

Background: Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency. Objective: To review the metabolic impact of late‐onset hypogonadism. Methods: Comprehensive literature search with emphasis on recent publications. Results: Obesity is one of the strongest modifiable risk factors for late‐onset hypogonadism, and coexisting diabetes leads to further hypothalamic‐pituitary‐testicular axis suppression. The hypothalamic‐pituitary‐testicular axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that hypothalamic‐pituitary‐testicular axis suppression is mediated by dysregulation of pro‐inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the paradigm that estradiol excess is a major contributor to hypothalamic‐pituitary‐testicular axis suppression. Instead, relative estradiol signaling deficiency may contribute to metabolic dysregulation in men with diabesity. While weight loss and optimization of comorbidities can reverse functional hypothalamic‐pituitary‐testicular axis suppression, testosterone treatment leads to metabolically favorable changes in body composition and to improvements in insulin resistance. Discussion: The relationship between diabesity and late‐onset hypogonadism is bidirectional. Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects. Conclusions: While recent research has provided new insights into mechanistic and clinical aspects of diabesity‐associated late‐onset hypogonadism, more evidence from well‐designed large trials is needed to guide the optimal clinical approach to such men. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Late‐onset hypogonadism (LOH) is a condition defined by low levels of testosterone (T), occurring in advanced age. LOH is promoted by senescence, which, in turn, has negative effects on male fertility. Interestingly, the impact of metabolic disorders on the male reproductive system has been the topic of several studies, but the association with LOH is still debatable. Objectives: Herein, we discuss the hypothesis that the prevalence of metabolic abnormalities potentiates the effects of LOH on the male reproductive system, affecting the reproductive potential of those individuals. Material and methods: We analyzed the bibliography available, until June 2019, about LOH in relation to metabolic and hormonal dysregulation, sperm quality profiles and assisted‐reproduction treatment outcomes. Results: LOH affects the hypothalamic‐pituitary testis (HPT) axis. Additionally, metabolic disorders can also induce T deficiency, which is reflected in decreased male fertility, highlighting a possible connection. Indeed, T replacement therapy (TRT) is widely used to restore T levels. Although this therapy is unable to reverse all deleterious effects promoted by LOH on male reproductive function, it can improve metabolic and reproductive health. Discussion and Conclusions: Emerging new evidence suggests that metabolic disorders may aggravate LOH effects on the fertility potential of males in reproductive age, by enhancing T deficiency. These results clearly show that metabolic disorders, such as obesity and diabetes, have a greater impact on causing hypogonadotropic hypogonadism than tissue senescence. Further, TRT and off‐label alternatives capable of restoring T levels appear as suitable to improve LOH, while also counteracting comorbidities related with metabolic diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Testicular ultrasound (US) is routinely employed in the evaluation of reproductive and sexual function. However, its use for characteristics other than testicular volume is hampered by a lack of information on the prognostic value of its findings, which to date have only been incorporated in a score proposed by Lenz et al in 1993. Objectives: We sought to explore whether testicular US examination can predict the quality of spermatogenesis and provide information on testicular endocrine function. Materials and methods: We retrospectively reviewed 6210 testicular US examinations, finally selecting examinations from 2230 unique men. The following variables were considered: bitesticular volume and testicular asymmetry, parenchymal echotexture, echogenicity and presence of microlithiasis, solid lesions and varicocoele. Concurrent fasting hormonal data were available for 1160 men, while 979 had a semen sample available from the same day as the US examination. Results: We derived a new US score, termed TU score, that can predict both impaired spermatogenesis (AUC 0.73, sensitivity 72%, specificity 61%, P <.001) and hypogonadism (AUC 0.71, sensitivity 71%, specificity 53%, P <.001) more accurately than the Lenz's score. In a multivariate analysis, a reduced sperm composite index (defined as total spermatozoa × total motility × normal forms) was independently predicted by bitesticular volume and by inhomogeneous echotexture, while hypogonadism was independently predicted also by reduced echogenicity and presence of microlithiasis. Discussion and conclusions: We describe the testicular US characteristics that are independently associated with impaired spermatogenesis and hypogonadism and propose the TU score as a simple screening method for use in subjects referred for testicular US. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding functional hypogonadism, previously referred to as 'late‐onset' hypogonadism, has increased substantially during the last 10 year. Objective: To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. Methods: Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results: The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well‐validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%‐50% represent relative contraindications for TRT. Prostate‐specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. Conclusion: TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long‐term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision‐making. [ABSTRACT FROM AUTHOR]

Background: This case control study aimed to investigate whether symptoms of sexual dysfunction are more common in males from infertile couples than in the general population and to explore whether symptoms of sexual dysfunction are associated to hypogonadism. Objectives: Participants were 165 subfertile men in infertile heterosexual relationships, 18–50 years of age, with sperm concentrations < 15 × 106/mL. The controls were 199 men from a population‐based group, matched for age. Material and methods: Logistic regression was applied in order to calculate odds ratios (ORs) for seven different symptoms of sexual dysfunction. In a multivariate model, we tested independent effects of infertility and primary as well as secondary hypogonadism. Results: Statistically significant association between subfertility and symptoms of sexual dysfunction was found for lack of ability to control ejaculation (OR 2.2, 95% CI: 1.2–4.2). For hypogonadism, statistical significance was seen both in relation to low sexual interest/desire for sex (OR 2.3, 95% CI: 1.0–5.5) and for being worried about the size or shape of the penis (OR 3.6, 95% CI: 1.3–9.5). These associations remained statistically significant in males with primary but not those with secondary hypogonadism. Discussion: Our study showed that men from infertile couples have an increased risk of symptoms of sexual dysfunction and this risk is linked to androgen deficiency. Conclusion: Assessment of reproductive hormone levels and sexual function should routinely be done in this group of males. [ABSTRACT FROM AUTHOR]

Background: Obesity-induced hypogonadism, which manifests as erectile dysfunction and a lack of libido, is a less visible and under-recognized obesity-related disorder in men., Objective: We examined the impact of weight loss on total (TT) and free testosterone (FT) levels, and constructed nomograms to provide an easy-to-use visual aid for clinicians., Materials and Methods: Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean differences (SMD) for testosterone. Parallel-scale nomograms were constructed from baseline and target body mass index values to estimate the gain in testosterone., Results: In total, 44 studies were included, comprising 1,774 participants and 2,159 datasets, as some studies included several datasets at different time points. Weight loss was controlled by low calorie diet (LCD) in 19 studies (735 participants, 988 datasets), by bariatric surgery (BS) in 26 studies (1,039 participants, 1,171 datasets), and by both in one study. The median follow-up was 26 weeks (interquartile range = 12-52). The range of baseline mean age was 21-68 yr, BMI: 26.2-71.2 kg/m 2 , TT: 7-20.2 nmol/L and FT: 140-583 pmol/L. TT levels increased after weight loss by LCD: SMD (95%CI) = 2.5 nmol/L (1.9-3.1) and by BS: SMD = 7.2 nmol/L (6.0-8.4); the combined TT gain was 4.8 nmol/L (3.9-5.6). FT levels increased after weight reduction by LCD: SMD = 19.9 pmol/L (7.3-32.5) and by BS: SMD = 58.0 pmol/L (44.3-71.7); the combined gain was 42.2 pmol/L (31.4-52.9). Greater amounts of total and free testosterone could be gained by weight loss in men with higher baseline BMI, or lower levels of SHBG, TT and FT, while gain in TT was relatively greater in older and FT in younger age. Age-stratified nomograms revealed that compared to older men (> 40 yr), younger men (≤ 40 yr) gained less TT but more FT for a given weight loss., Discussion and Conclusion: Both TT and FT levels increased after weight loss, relatively greater with higher baseline BMI, or lower levels of SHBG, TT and FT. Nomograms constructed from a large number of participants with a wide range of BMI and testosterone values provide an evidence-based and simple-to-use tool in clinical practice., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)