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Although testosterone replacement therapy (TRT) is the first-choice method used worldwide for late-onset hypogonadism (LOH), clinical benefits are not seen in all cases. This study was conducted to determine the predictors of TRT efficacy for LOH. Fifty-six patients who visited our Men's Health Clinic (Kawanishi City Medical Center, Kawanishi and Hyogo Medical University, Nishinomiya, Hyogo, Japan) between November 2003 and June 2021 with data available before and after TRT were enrolled. They were divided into responders (Group 1; n = 45, accounting for 80.4%) and nonresponders (Group 2; n = 11, accounting for 19.6%) based on the clinical response to TRT, including patient satisfaction. Factors noted before TRT included age, body mass index, aging males' symptoms score, sexual health inventory for men, luteinizing hormone, follicular-stimulating hormone, testosterone, free testosterone, prolactin (PRL), estradiol (E2), and testosterone/estradiol (T/E2) ratio in serum. For statistical analysis, a multivariable logistic regression model was used. Univariate analysis revealed PRL (odds ratio [OR]: 0.9624; 95% confidence interval [CI]: 0.9316-0.9943, P < 0.05), E2 (OR: 0.8692; 95% CI: 0.7745-0.9754, P < 0.05), and T/E2 ratio (OR: 1.1312; 95% CI: 1.0106-1.2661, P < 0.05) to be predictive factors. Multivariate analyses showed that T/E2 ratio was an independent predictive factor (OR: 1.1593; 95% CI: 1.0438-1.2875, P < 0.01). The present results suggest that a low value for T/E2 ratio may predict a reduced response to TRT. The T/E2 ratio threshold to predict nonresponders based on receiver-operating characteristics (ROC) curve analysis was shown to be 17.3. Although additional studies with larger number of patients are necessary, we propose the determination of serum E2 level and testosterone level prior to performing TRT., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Earlier research has presumed that the male and female biology is similar in most organs except the reproductive system, leading to major misconceptions in research interpretations and clinical implications, with serious disorders being overlooked or misdiagnosed. Careful research has now identified sex differences in the cardiovascular, renal, endocrine, gastrointestinal, immune, nervous, and musculoskeletal systems. Also, several cardiovascular, immunological, and neurological disorders have shown differences in prevalence and severity between males and females. Genetic variations in the sex chromosomes have been implicated in several disorders at young age and before puberty. The levels of the gonadal hormones estrogen, progesterone and testosterone and their receptors play a role in the sex differences between adult males and premenopausal women. Hormonal deficiencies and cell senescence have been implicated in differences between postmenopausal and premenopausal women. Specifically, cardiovascular disorders are more common in adult men vs premenopausal women, but the trend is reversed with age with the incidence being greater in postmenopausal women than age-matched men. Gender-specific disorders in females such as polycystic ovary syndrome, hypertension-in-pregnancy and gestational diabetes have attained further research recognition. Other gender-related research areas include menopausal hormone therapy, the "Estrogen Paradox" in pulmonary arterial hypertension being more predominant but less severe in young females, and how testosterone may cause deleterious effects in the kidney while having vasodilator effects in the coronary circulation. This has prompted the National Institutes of Health (NIH) initiative to consider sex as a biological variable in research. The NIH and other funding agencies have provided resources to establish state-of-the-art centers for women health and sex differences in biology and disease in several academic institutions. Scientific societies and journals have taken similar steps to organize specialized conferences and publish special issues on gender-based research. These combined efforts should promote research to enhance our understanding of the sex differences in biological systems beyond just the reproductive system, and provide better guidance and pharmacological tools for the management of various clinical disorders in a gender-specific manner., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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; I 2  = 69%, p for heterogeneity  = 0.01) and enclomiphene citrate (mean difference: 7.50 nmol/L; 95% coefficient interval: 6.52, 8.48; I 2  = 4%, p for 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; I 2  = 0%, p for 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., (© 2023 American Society of Andrology and European Academy of Andrology.)

Background: Sexual dysfunctions, particularly erectile dysfunction, are common in men living with HIV, whose organic and psychological components remain to be clarified. The aim of the study is to investigate the impact of risk factors of sexual dysfunctions, including organic, relational, and psychological determinants of erectile function, in men living with HIV younger than 50 years old., Methods: A cross-sectional, observational study was conducted in men living with HIV < 50 years. The questionnaire International Index of Erectile Function-15 was used to assess the prevalence and degree of erectile dysfunction. The structured interview of erectile dysfunction was used to explore the organic (Scale 1), relational (Scale 2), and psychological (Scale 3) components of erectile dysfunction. Total testosterone, estradiol, and dihydrotestosterone were measured by liquid chromatography-tandem-mass spectrometry; free testosterone was calculated by the Vermeulen equation., Results: A total of 313 consecutive men living with HIV were prospectively enrolled (median age 47.0 years; median HIV-infection duration 16.2 years). 187 patients (59.7%) had erectile dysfunction, with a higher prevalence of non-heterosexual (138 out of 187, 73.8%) than heterosexual patients (p = 0.003). Patients with erectile dysfunction showed a worse score of structured interview of erectile dysfunction scale 3 compared to patients without erectile dysfunction (p = 0.025); the International Index of Erectile Function-15 was inversely related to structured interview of erectile dysfunction scale 3 (p = 0.042). No difference was found for sex steroids (total testosterone, estradiol, free testosterone, and dihydrotestosterone) between men living with HIV with and without erectile dysfunction. In the multivariate analysis sexual orientation, and lack of stable relationships were major determinants for erectile dysfunction. Only 35 of 187 patients with erectile dysfunction (18.7%) reported the use of erectile dysfunction medications., Conclusions: Within the multidimensional network of erectile dysfunction in men living with HIV, the psychological component is predominant, highlighting the contribution of peculiar factors related to HIV distress (e.g., fear of virus transmission, stigma) rather than gonadal status and other classical risk factors. In contrast to the high prevalence, only a few patients reported the use of erectile dysfunction medications suggesting a general under-management of such issues., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Middle-aged and older men have typically accumulated comorbidities, are increasingly sedentary, and have lower testosterone concentrations (T) compared to younger men. Reduced physical activity (PA) and lower T both are associated with, and may predispose to, metabolically adverse changes in body composition, which contribute to higher risks of cardiometabolic disease. Exercise improves cardiometabolic health, but sustained participation is problematic. By contrast, rates of T prescription have increased, particularly in middle-aged and older men without organic diseases of the hypothalamus, pituitary, or testes, reflecting the unproven concept of a restorative hormone that preserves health. Two recent large randomized trials of T, and meta-analyses of randomized trials, did not show a signal for adverse cardiovascular (CV) events, and T treatment on a background of lifestyle intervention reduced type 2 diabetes by 40% in men at high risk. Men with both higher endogenous T and higher PA levels have lower CV risk, but causality remains unproven. Exercise training interventions improve blood pressure and endothelial function in middle-aged and older men, without comparable benefits or additive effects of T treatment. Therefore, exercise training improves cardiometabolic health in middle-aged and older men when effectively applied as a supervised regimen incorporating aerobic and resistance modalities. Treatment with T may have indirect cardiometabolic benefits, mediated via favorable changes in body composition. Further evaluation of T as a pharmacological intervention to improve cardiometabolic health in aging men could consider longer treatment durations and combination with targeted exercise programs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

According to World Health Organization estimates, 5% of the adult population worldwide suffers from depression. In addition to the affective, psychomotor and cognitive symptoms which characterize this mood disorder, sexual dysfunction has been frequently reported among men suffering from depression. The most common sexual manifestations are decreased libido, erectile dysfunction and orgasmic disorder. In addition, epidemiological studies have documented a reduction of testosterone concentrations in men with depression and, for these reasons, depressive disorders appear as one possible cause of male functional hypogonadism. Moreover, some largely used antidepressant medications can cause or worsen sexual complaints, thus depression and its treatments rise several andrological-relevant issues. The other way round, men with hypogonadism can manifest depressed mood, anxiety, insomnia, memory impairment which, if mild, may respond to testosterone replacement therapy (TRT). However, the prevalence of functional hypogonadism in depression, and of depressive symptoms in hypogonadal men, is not known. Severe depressive symptoms do not respond to TRT, while the effect of treating major depression on functional hypogonadism, has not been investigated. Overall, the clinical relevance of each condition to the other, as well as the physiopathological underpinnings of their relationship, are still to be clarified. The present review summarizes current evidence on the influence of testosterone on mood and of depression on the hypothalamic-pituitary-testis axis; the clinical association between male hypogonadism and depression; and the reciprocal effects of respective treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Indirli, Lanzi, Arosio, Mantovani and Ferrante.)

Background: Relugolix is the newest form of androgen deprivation therapy (ADT) approved for prostate cancer. However, as an oral drug, several real-world concerns exist, particularly medication compliance, safety with other androgen receptor-targeted agents, and financial burden to patients., Methods: A single institution retrospective chart review was conducted evaluating all patients who were prescribed relugolix for any prostate cancer indication from January 1, 2021 to January 31, 2022. Demographic data, cardiac risk factors, concomitant therapy usage, and PSA/testosterone levels, were abstracted from the chart review. Adverse effects were obtained by examining progress notes. Compliance was assessed by clinic notes as well as prescription fills by specialty pharmacy records. The reasons patients did not fill or discontinued the medication were noted., Results: Hundred and one patients were prescribed relugolix, and 91 patients consented to research. Seventy-one (78%) patients filled the prescription to relugolix, with a median follow-up of 5 months. Prescription fill data were available for 45 (63%) patients, with 94% of days covered. The most commonly reported reason not to fill was cost at 50%. Sixty-six (93%) patients reported never missing a dose. PSA levels were available in 71 (100%) patients with 69 (97%) showing stable or improved PSA. Testosterone levels were available in 61 (86%) of patients, which showed 61 (100%) stable or successful castration. Twenty-four (34%) patients used relugolix in combination. No new major safety signals were seen in combination therapy. Nineteen (27%) patients had switched to another form of ADT. Fifteen of these (79%) felt similar or better on relugolix therapy., Conclusions: Compliance with relugolix seemed acceptable. No major new safety signals were seen, even in combination. Among patients who switched therapy, most tolerated relugolix similarly or better than the previous form of ADT. The cost was a major reason for patients not initiating and for discontinuing therapy., (© The Author(s) 2023. Published by Oxford University Press.)

Approximately 0.6% of adults (1 to 1.4 million adults) in the United States identify as transgender, and 2% of high school-aged individuals (150,000 to 300,000 individuals). Gender-affirming care for transgender and gender- diverse patients can include support with social transition or physical presentation, legal steps, and medical treatments (eg, hormone therapy) and surgeries. Adolescent and adult patients who request gender-affirming hormone therapy must meet several criteria. One is confirmed persistence of gender dysphoria or gender incongruence. Also, the patient must have reached the age of legal medical consent and be able to consent to therapy. For adolescent patients who are minors, meeting of additional criteria is recommended. In eligible adolescent patients, gender-affirming hormone therapy consists of two phases, pubertal suppression and then feminizing or masculinizing hormone therapy. Before puberty, hormone therapy is not recommended. When puberty begins, patients can receive a gonadotropin-releasing hormone agonist to suppress puberty (ie, puberty blocker). Feminizing or masculinizing hormone therapy, which usually is initiated at age 16 years, consists of estradiol or testosterone, respectively. For adult patients requesting gender-affirming hormone therapy, a thorough evaluation should be performed to assess for contraindications and conditions that may increase therapy-associated risks. Feminizing hormone therapy includes estrogen and an antiandrogen, and masculinizing therapy consists of testosterone. These patients should undergo regular monitoring. Cancer screening is based on risk factors, organ inventory, and screening guidelines.

Purpose of Review: The purpose of this review is to summarize the scientific evidence on bone health in transgender and gender diverse (TGD) youth., Recent Findings: Gender-affirming medical therapies may be introduced during a key window of skeletal development in TGD adolescents. Before treatment, low bone density for age is more prevalent than expected in TGD youth. Bone mineral density Z-scores decrease with gonadotropin-releasing hormone agonists and differentially respond to subsequent estradiol or testosterone. Risk factors for low bone density in this population include low body mass index, low physical activity, male sex designated at birth, and vitamin D deficiency. Peak bone mass attainment and implications for future fracture risk are not yet known. TGD youth have higher than expected rates of low bone density prior to initiation of gender-affirming medical therapy. More studies are needed to understand the skeletal trajectories of TGD youth receiving medical interventions during puberty., (© 2023. The Author(s).)

Testosterone replacement therapy is becoming more and more popular in men as "anti-aging medicine". Testosterone has beneficial effects on body mass and muscle gain, and much research has examined testosterone in palliative cancer therapy for oncology patients. In addition to direct effects on weight gain, testosterone improves mood and self-confidence, strength, libido, muscle mass, bone density, and cognitive functions and reduces the risk of cardiovascular disease. Lower testosterone levels are found in 65 % of male patients with progressive tumors compared to only 6 % of men in the general population. We hypothesize that perioperative substitution testosterone therapy (PSTT) together with a balanced diet, may be more effective than balanced diet alone in the overall treatment outcome of patients with head and neck squamous cell carcinomas. Therefore, PSTT in combination with a balanced diet should be considered as an additional tool for head and neck carcinoma treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Testosterone levels decrease as men age. When the testes fail to produce an adequate level of endogenous testosterone, men develop hypogonadism. Although the definition of a low testosterone level varies among guidelines, a serum total testosterone level of less than 300 to 350 ng/dL on two separate morning blood samples is considered a low level. To receive exogenous testosterone replacement therapy (TRT), patients should meet criteria for hypogonadism, which is defined as a low testosterone level and signs or symptoms of hypogonadism. Management discussions should be individualized to address patient needs and goals. Counseling before therapy should include shared decision-making regarding risks, benefits, and expectations. Numerous testosterone formulations are available, ranging from topical gels to intramuscular injections. The choice of formulation depends on factors such as cost and patient preference. Use of TRT is limited by contraindications, adverse effects, and a lack of long-term safety data. Patients receiving this therapy require close monitoring. For patients who wish to avoid use of exogenous hormones, are not candidates for TRT, or are unable to tolerate its adverse effects, several nonhormonal pharmacotherapies are available., (Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.)

Although there has been a dramatic increase in visibility and recognition of transgender and gender-diverse populations, remarkably little has been published on prevalence rates of hypertension within these populations. In addition to summarizing the limited data on prevalence rates, this review compares the prevalence rates with those of cisgender populations and explores whether gender-affirming hormone therapy affects blood pressure and hypertension rates. The studies show that hypertension affects a significant proportion of transgender and gender-diverse people and support the practice of routinely monitoring blood pressure in transgender and gender-diverse people, especially after the initiation of gender-affirming hormone therapy. The two largest studies both found that estrogen plus an antiandrogen was associated with a decrease in systolic blood pressure and that testosterone was associated with an increase in systolic blood pressure., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Testosterone plays a key role in the maintenance of physical and mental functions in men. Age-related testosterone decline is closely associated with sarcopenia and muscle deterioration, while testosterone decline is linked with the etiology and prevention of diseases such as angina pectoris, arteriosclerosis, obesity, metabolic syndrome, and dementia. Late-onset hypogonadism (LOH) is defined as a disease characterized by age-related testosterone decline and associated clinical symptoms. Testosterone replacement therapy improves health-related QOL in patients with LOH.

Male climacteric syndrome (MCS) is a medical condition that can affect middle-aged men whose testosterone levels begin to decline considerably. These symptoms may include fatigue, decreased libido, mood swings, and disturbed sleep. MCS can be managed with lifestyle modifications and testosterone replacement. However, testosterone therapy may cause number of side effects, including an increased risk of cardiovascular issues. This study aims to evaluate the efficacy and safety of unripe black raspberry extract (BRE) against MCS and voiding dysfunction in men with andropause symptoms. A total of 30 subjects were enrolled and randomly assigned to the BRE group (n = 15) or the placebo group (n = 15). Participants were supplemented with 4800 mg BRE or placebo twice daily for 12 weeks. The impact of BRE was assessed using the Aging Male's Symptoms (AMS scale), International Prostate Symptom Score (IPSS) and the IPSS quality of life index (IPSS-QoL). Additionally, male sex hormones, lipid profiles, and anthropometric indices were assessed 6 and 12 weeks after treatment. The AMS scores did not differ significantly between the two groups. In the BRE group, the total IPSS and IPSS-QoL scores decreased significantly after 12 weeks compared to baseline ( p < 0.05), but there was no significant difference compared to the placebo group. However, a significant difference was observed in the IPSS voiding symptoms sub-score compared to the placebo group. Furthermore, LDL-C and TC levels were also significantly lower in the BRE group than in the placebo group ( p < 0.05). Collectively, the study provides strong evidence supporting the safety of BRE as a functional food and its supplementation potentially enhances lipid metabolism and alleviates MCS and dysuria symptoms, limiting the development of BPH.

Objective: To compare between different combined oral contraceptive pills (COCPs) as part of the update of the International Evidence-Based Guidelines on the Assessment and Management of polycystic ovary syndrome (PCOS)., Design: A systematic review and meta-analysis was performed, Prospero CRD42022345640., Methods: MEDLINE, EMBASE, All EBM, CINAHL, and PsycINFO was searched on July, 8, 2022, for studies including women with PCOS, comparing 2 different COCPs in randomized controlled trials., Results: A total of 1660 studies were identified, and 19 randomized controlled trials (RCTs) were included.Fourth-generation COCP resulted in lower body mass index (BMI) (mean difference [MD] 1.17 kg/m2 [95% confidence interval {CI} 0.33; 2.02]) and testosterone (MD 0.60 nmol/L [95% CI 0.13; 1.07]) compared with third-generation agents, but no difference was seen in hirsutism.Ethinyl estradiol (EE)/cyproterone acetate (CPA) was better in reducing hirsutism as well as biochemical hyperandrogenism (testosterone [MD 0.38 nmol/L {95% CI 0.33-0.43}]) and BMI (MD 0.62 kg/m2 [95% CI 0.05-1.20]) compared with conventional COCPs.There was no difference in hirsutism between high and low EE doses. No evidence regarding natural estrogens in COCP was identified., Conclusion: With current evidence, combined regimens containing an antiandrogen (EE/CPA) may be better compared with conventional COCPs in reducing hyperandrogenism, but EE/CPA will not be recommended as a first-line COCP treatment by the pending PCOS guideline update, due to higher venous thrombotic events (VTE) risk in the general population. Later-generation progestins offer theoretical benefits, but better evidence on clinical outcomes is needed in women with PCOS., Trial Registration: The protocol for the systematic review was registered prospectively in Prospero, CRD42022345640., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Statins are lipid-lowering agents with pleiotropic actions. Experts have proposed that in addition to improving the dyslipidaemia associated with polycystic ovary syndrome (PCOS), statins may also exert other beneficial metabolic and endocrine effects, such as reducing testosterone levels. This is an update of a Cochrane Review first published in 2011., Objectives: To assess the efficacy and safety of statin therapy in women with PCOS who are not actively trying to conceive., Search Methods: We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHLs, and four ongoing trials registers on 7 November 2022. We also handsearched relevant conference proceedings and the reference lists of relevant trials for any additional studies, and we contacted experts in the field for any further ongoing studies., Selection Criteria: We included randomised controlled trials (RCTs) that evaluated the effects of statin therapy in women with PCOS not actively trying to conceive. Eligible comparisons were statin versus placebo or no treatment, statin plus another agent versus the other agent alone, and statin versus another agent. We performed statistical analysis using Review Manager 5, and we assessed the certainty of the evidence using GRADE methods., Data Collection and Analysis: We used standard Cochrane methodology. Our primary outcomes were resumption of menstrual regularity and resumption of spontaneous ovulation. Our secondary outcomes were clinical and physiological measures including hirsutism, acne severity, testosterone levels, and adverse events., Main Results: Six RCTs fulfilled the criteria for inclusion. They included 396 women with PCOS who received six weeks, three months, or six months of treatment; 374 women completed the studies. Three studies evaluated the effects of simvastatin and three studies evaluated the effects of atorvastatin. We summarised the results of the studies under the following comparisons. Statins versus placebo (3 RCTs) One trial measured resumption of menstrual regularity as menstrual cycle length in days. We are uncertain if statins compared with placebo shorten the mean length of the menstrual cycle (mean difference (MD) -2.00 days, 95% confidence interval (CI) -24.86 to 20.86; 37 participants; very low-certainty evidence). No studies reported resumption of spontaneous ovulation, improvement in hirsutism, or improvement in acne. We are uncertain if statins compared with placebo reduce testosterone levels after six weeks (MD 0.06, 95% CI -0.72 to 0.84; 1 RCT, 20 participants; very low-certainty evidence), after 3 months (MD -0.53, 95% CI -1.61 to 0.54; 2 RCTs, 64 participants; very low-certainty evidence), or after 6 months (MD 0.10, 95% CI -0.43 to 0.63; 1 RCT, 28 participants; very low-certainty evidence) Two studies recorded adverse events, and neither reported significant differences between the groups. Statins plus metformin versus metformin alone (1 RCT) The single RCT included in this comparison measured resumption of menstrual regularity as the number of spontaneous menses per six months. We are uncertain if statins plus metformin compared with metformin improves resumption of menstrual regularity (MD 0.60 menses, 95% CI 0.08 to 1.12; 69 participants; very low-certainty evidence). The study did not report resumption of spontaneous ovulation. We are uncertain if statins plus metformin compared with metformin alone improves hirsutism measured using the Ferriman-Gallwey score (MD -0.16, 95% CI -0.91 to 0.59; 69 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.31, 95% CI -0.67 to 0.05; 69 participants; very low-certainty evidence), or testosterone levels (MD -0.03, 95% CI -0.37 to 0.31; 69 participants; very low-certainty evidence). The study reported that no significant adverse events occurred. Statins plus oral contraceptive pill versus oral contraceptive pill alone (1 RCT) The single RCT included in this comparison did not report resumption of menstrual regularity or spontaneous ovulation. We are uncertain if statins plus the oral contraceptive pill (OCP) improves hirsutism compared with OCP alone (MD -0.12, 95% CI -0.41 to 0.17; 48 participants; very low-certainty evidence). The study did not report improvement in acne severity. We are also uncertain if statins plus OCP compared with OCP alone reduces testosterone levels, because the certainty of the evidence was very low (MD -0.82, 95% CI -1.38 to -0.26; 48 participants). The study reported that no participants experienced significant side effects. Statins versus metformin (2 RCTs) We are uncertain if statins improve menstrual regularity compared with metformin (number of spontaneous menses per six months) compared to metformin (MD 0.50 menses, 95% CI -0.05 to 1.05; 1 RCT, 61 participants, very low-certainty evidence). No studies reported resumption of spontaneous ovulation. We are uncertain if statins compared with metformin reduce hirsutism measured using the Ferriman-Gallwey score (MD -0.26, 95% CI -0.97 to 0.45; 1 RCT, 61 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.18, 95% CI -0.53 to 0.17; 1 RCT, 61 participants; very low-certainty evidence), or testosterone levels (MD -0.24, 95% CI -0.58 to 0.10; 1 RCT, 61 participants; very low-certainty evidence). Both trials reported that no significant adverse events had occurred. Statins versus oral contraceptive pill plus flutamide (1 RCT) According to the study report, no participants experienced any significant side effects. There were no available data for any other main outcomes., Authors' Conclusions: The evidence for all main outcomes of this review was of very low certainty. Due to the limited evidence, we are uncertain if statins compared with placebo, or statins plus metformin compared with metformin alone, improve resumption of menstrual regularity. The trial evaluating statin plus OCP versus OCP alone reported neither of our primary outcomes. No other studies reported resumption of spontaneous ovulation. We are uncertain if statins improve hirsutism, acne severity, or testosterone. All trials that measured adverse events reported no significant differences between the groups., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Most rheumatic diseases are characterized by sexual dimorphism both in prevalence and in the characteristics of the clinical course. Increased production of pro-inflammatory cytokines that accompanies inflammatory joint diseases may be accompanied by a decrease in the level of male sex hormones, and vice versa, the presence of hypogonadism in men increases the risk of developing certain rheumatic diseases. The review presents data on the relationship between testosterone deficiency and major inflammatory joint diseases, as well as the effect of testosterone replacement therapy on their manifestations.

Background: The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined., Methods: In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo., Results: The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group., Conclusions: In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.)., (Copyright © 2023 Massachusetts Medical Society.)

Objective: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG)., Design: Mediation analysis of a randomised placebo-controlled trial of testosterone., Methods: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed., Results: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001)., Conclusion: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Testicular cancer survivors (TCS) are at risk of Leydig cell insufficiency, which is a condition characterized by elevated luteinising hormone (LH) in combination with low levels of testosterone. It has been suggested that this condition is associated with impaired metabolic profile and low bone mineral density (BMD). The primary aim of the randomized double-blind trial NCT02991209 was to evaluate metabolic profile after 12-months testosterone replacement therapy (TRT) in TCS with mild Leydig cell insufficiency. Here we present the secondary outcomes of changes in BMD and markers of bone turnover., Methodology: In total, 69 TCS with mild Leydig cell insufficiency were randomized 1:1 to 12 months TRT ( n  = 35) (Tostran, gel, 2%, applied transdermally, with a maximum daily dose of 40 mg) or placebo ( n  = 34). BMD and markers of bone turnover were evaluated at baseline, after 6- and 12-months TRT, and 3-months post-treatment. Linear mixed effects models were used to analyse changes in BMD, N-terminal propeptide of type 1 procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX)., Results: After 12 months treatment, TRT was not associated with a statistically significant difference in BMD compared to placebo; total body BMD: 0.01 g/cm2 (95% confidence interval (CI): -0.01 - 0.02), BMD of the lumbar spine: 0.01 g/cm2, (95% CI: -0.01-0.03), BMD of the left femoral neck: 0.00, (95% CI: -0.01-0.02). TRT was associated with a small but statistically significant increase in P1NP: 11.65 µg/L (95% CI: 3.96, 19.35), while there was no difference in CTX., Conclusion: 12 months of TRT did not change BMD, while there was as small and clinically irrelevant increase in P1NP compared to placebo in TCS with mild Leydig cell insufficiency. The findings need validation in a larger cohort.

Testosterone is an important evidence-based therapy for hypoactive sexual desire disorder (HSDD) in postmenopausal women. Clinical practice guidelines based on the most comprehensive meta-analysis of benefits and risks of testosterone therapy to date state that the sole evidence-based indication for testosterone therapy is HSDD in postmenopausal women. The guidelines also provide recommendations regarding identification of patients, dosing, monitoring, and follow-up. This Practice Pearl will discuss evidence-based testosterone therapy for management of HSDD in postmenopausal women., (Copyright © 2023 by The North American Menopause Society.)

Purpose: 49,XXXXY (1:85,000-100,000) is a rare sex chromosome aneuploidy that often presents with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications. Hormonal replacement therapy, or testosterone replacement therapy, is associated with improved neurodevelopmental and behavioral outcomes in males with 49,XXXXY. Two forms of testosterone replacement therapy, early hormonal treatment (EHT) and hormonal booster therapy (HBT), are associated with improved neurodevelopmental and behavioral outcomes in these boys. This study investigates the impact of EHT and HBT on behavioral symptoms in males with 49,XXXXY., Methods: A total of 59 individuals were divided into 4 groups: 19 no testosterone (no-T), 23 EHT, 6 HBT, and 11 EHT and HBT. An analysis of variance examined group differences on the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function ranging from 5 to 18 years., Results: Although no differences were identified on the Behavior Rating Inventory of Executive Function, the 3 hormonal replacement therapy groups presented with decreased complications on numerous variables on the Child Behavior Checklist; these include somatic complaints (P = .0095), somatic problems (P = .041), internalizing problems (P = .034), externalizing problems (P = .0001), and withdrawn/depression (P = .025)., Conclusion: This study presents evidence that HBT may be a beneficial treatment for individuals with 49,XXXXY., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Functional hypogonadism is a condition in which some, but not all, older men have low testosterone levels. Rather than chronological age per se, the causality of hypogonadism includes obesity and impaired general health (e.g., metabolic syndrome). An association between testosterone deficiency and lower urinary tract symptoms (LUTS) has been reported, yet due to prostate safety concerns, men with severe LUTS (IPSS score > 19) have invariably been excluded from entering testosterone trials. Irrespective, exogenous testosterone has not been demonstrated to cause de novo or worsen mild to moderate LUTS., Objective: This study investigated whether long-term testosterone therapy (TTh) could have a protective effect on improving the symptoms of LUTS in hypogonadal men. However, the exact mechanism by which testosterone exerts is beneficial effect remains uncertain., Patients and Methods: In this study 321 hypogonadal patients with an average age of 58.9 ± 9.52 years received testosterone undecanoate in 12-week intervals for 12 years. One hundred and forty-seven of these males had the testosterone treatment interrupted for a mean of 16.9 months before it was resumed. Total testosterone, International Prostate Symptom Scale (IPSS), post-voiding residual bladder volume and aging male symptoms (AMS) were measured over the study period., Results: Prior to TTh interruption, it was observed that testosterone stimulation improved the men's IPSS, AMS and post-voiding residual bladder volume, while their prostate volume significantly increased. During the TTh interruption, there was a significant worsening in these parameters, although the increase in prostate volume continued. When TTh was resumed, these effects were reversed, implying that hypogonadism may require lifelong treatment., (© 2023. The Author(s).)

Research Question: What are the outcomes and experiences of oocyte vitrification treatment in trans masculine individuals (TMI) before and after testosterone use?, Design: This retrospective cohort study was conducted at the Amsterdam UMC in the Netherlands between January 2017 and June 2021. The TMI who had completed an oocyte vitrification treatment were consecutively approached for participation. Informed consent was provided by 24 individuals. Participants (n = 7) who initiated testosterone therapy were advised to stop 3 months before stimulation. Demographic characteristics and oocyte vitrification treatment data were retrieved from medical records. Evaluation of the treatment was collected via an online questionnaire., Results: The median age of participants was 22.3 years (interquartile range 21.1-26.0) and mean body mass index was 23.0 kg/m 2 (SD 3.2). After ovarian hyperstimulation, a mean of 20 oocytes (SD 7) were retrieved and a mean of 17 oocytes (SD 6) could be vitrified. Aside from a lower cumulative FSH dose, there were no significant differences between the prior testosterone users and testosterone naïve TMI. The overall satisfaction of oocyte vitrification treatment in participants was high. Hormone injections were considered the most strenuous part of treatment by 29% of participants, closely followed by oocyte retrieval (25%)., Conclusions: No difference in response to ovarian stimulation was found for oocyte vitrification treatment between the prior testosterone users and testosterone naïve TMI. The questionnaire identified hormone injections as the most burdensome aspect of oocyte vitrification treatment. This information can be used to improve gender sensitive fertility counselling and fertility treatment strategies., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Testosterone, many steroidal androgens, and nonsteroidal ligands that bind to androgen receptor and exert tissue-specific transcriptional activity (selective androgen receptor modulators [SARMs]) are being developed as function-promoting therapies to treat functional limitations associated with aging and chronic diseases. This narrative review describes preclinical studies, mechanisms, and randomized trials of testosterone, other androgens, and nonsteroidal SARMs. Sex differences in muscle mass and strength and empiric use of anabolic steroids by athletes to increase muscularity and athletic performance provide supportive evidence of testosterone's anabolic effects. In randomized trials, testosterone treatment increases lean body mass, muscle strength, leg power, aerobic capacity, and self-reported mobility. These anabolic effects have been reported in healthy men, hypogonadal men, older men with mobility limitation and chronic diseases, menopausal women, and HIV-infected women with weight loss. Testosterone has not consistently improved walking speed. Testosterone treatment increases volumetric and areal bone mineral density, and estimated bone strength; improves sexual desire, erectile function, and sexual activity; modestly improves depressive symptoms; and corrects unexplained anemia in older men with low testosterone levels. Prior studies have not been of sufficient size or duration to determine testosterone's cardiovascular and prostate safety. The efficacy of testosterone in reducing physical limitations, fractures, falls, progression to diabetes, and correcting late-onset persistent depressive disorder remains to be established. Strategies to translate androgen-induced muscle mass and strength gains into functional improvements are needed. Future studies should evaluate the efficacy of combined administration of testosterone (or a SARM) plus multidimensional functional exercise to induce neuromuscular adaptations required for meaningful functional improvements., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. 
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Background: Acne vulgaris is associated with insulin resistance and elevated insulin-like growth factor-1 (IGF-1). Metformin is commonly used for treatment of acne in patients with polycystic ovarian syndrome (PCOS). However, the benefits of metformin in patients with acne in general are not well established., Aim: To study the effectiveness of metformin treatment in patients with acne but who do not have PCOS and to understand the mechanisms of action of metformin in acne not related to PCOS., Method: In this observational study, 30 patients with clinically confirmed acne vulgaris were treated with metformin (1000 mg daily) for 3 months without any other topical or systemic active intervention for their acne. The effect of metformin at the clinical, hormonal and genetic level was assessed., Results: Metformin monotherapy significantly (P < 0.001) decreased the global acne grading score for acne followed by a marginal increase in insulin; with a significant (P = 0.03) increase in insulin-like growth factor-1 (IGF-1). A significant (P < 0.001) decrease in free androgen index resulting from a significant (P < 0.001) increase in sex hormone-binding globulin (SHBG) with decrease in testosterone was observed. Homeostasis model assessment insulin resistance (HOMA-IR) was not significantly changed. Forkhead box protein O1 (FOXO1) expression was significantly (P = 0.006) downregulated with metformin treatment at the mRNA level without any significant changes at protein level. Expression of lipogenic genes, namely HMGCR, SQLE and ACSL5 (P = 0.001, P = 0.03, P = 0.03, respectively) were also downregulated., Conclusion: Metformin monotherapy led to significant clinical improvement in acne, possibly by reducing testosterone, inhibiting FOXO1 and reducing lipid synthesis by decreasing the expression of lipogenic genes., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: The purpose of this study was to evaluate rates of rotator cuff tears (RCTs), repairs (RCRs), and revision RCR in patients who were prescribed testosterone replacement therapy (TRT) and compare these patients with a control group., Methods: The PearlDiver database was queried for patients who were prescribed testosterone for at least 90 days between 2011 and 2018 to evaluate the incidence of RCTs in this population. A second analysis evaluated patients who sustained RCTs using International Classification of Diseases, 9th/10th codes to evaluate these patients for rates of RCR and revision RCR. Chi square analysis and multivariate regression analyses were used to compare rates of RCTs, RCR, and subsequent or revision RCR between the testosterone and control groups, with a P -value of 0.05 representing statistical significance., Results: A total of 673,862 patients with RCT were included for analysis, and 9,168 of these patients were prescribed testosterone for at least 90 days before their RCT. The TRT group had a 3.6 times greater risk of sustaining an RCT (1.14% versus 0.19%; adjusted odds ratio (OR) 3.57; 95% confidence interval (CI) 3.57 to 3.96). A 1.6 times greater rate of RCR was observed in the TRT cohort (TRT, 46.4% RCR rate and control, 34.0% RCR rate; adjusted OR 1.60; 95% CI 1.54 to 1.67). The TRT cohort had a 26.7 times greater risk of undergoing a subsequent RCR, irrespective of laterality, within 1 year of undergoing a primary RCR when compared with the control group (TRT, 47.1% and control, 4.0%; adjusted OR 26.4; 95% CI 25.0 to 27.9, P < 0.001)., Conclusions: There is increased risk of RCTs, RCRs, and subsequent RCRs in patients prescribed testosterone. This finding may represent a musculoskeletal consequence of TRT and is important for patients and clinicians to understand. Additional research into the science of tendon injury in the setting of exogenous anabolic steroids remains of interest., Level of Evidence: Level Ⅲ, retrospective cohort study., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

Testosterone Therapy (TTh) trends have changed as a result of clinical research and market forces over the past several years. Understanding the trends or preferences regarding testosterone prescriptions remains unknown. Our objective was to assess both regional and national trends in TTh prescriptions amongst medical specialties within the United States between 2013 and 2017. Publicly available data from the Center for Medicare and Medicaid Services (CMS) Part D Prescriber database with regards to TTh prescriptions across a 5-year span (January 1, 2013-December 31, 2017) were analyzed. TTh therapies were consolidated into four categories: Topical, Oral, Injection and Pellet. Statistical analysis utilizing R 4.0.2 was performed on the resulting data. Trends in prescription modality claim count and cost were plotted over the study period while statistical analysis evaluated associations between TTh modality and medical specialist. We found that Endocrinologists and Urologists prescribed topical testosterone more than all other specialties (60.4% and 53.5%, respectively), while Family and Internal medicine physicians were more likely to prescribe injections (59.82% and 50.69%, respectively). Oral and pellet testosterone were rarely prescribed across all specialties. In conclusion, the wide variation in modalities of testosterone prescriptions illustrates an opportunity for treatment guidelines to be streamlined across all specialists to improve patient outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: To characterize the impact of concomitant prostate cancer treatments with the use of relugolix, the oral GnRH receptor antagonist, in advanced prostate cancer, a subgroup and pharmacokinetic/pharmacodynamic analyses of the HERO study was undertaken., Patients and Methods: Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide or docetaxel 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant enzalutamide or docetaxel. A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Pharmacokinetic/pharmacodynamic analyses of 20 participants in the relugolix treatment group assessed the net effect of enzalutamide on exposure to relugolix., Results: Overall, 125 patients (13.4%) took concomitant therapies that could impact testosterone levels. Enzalutamide (n = 23) was the most frequently used therapy in the relugolix (2.7%) and leuprolide groups (1.9%). Docetaxel (n = 13) was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. Sensitivity analysis showed concomitant therapy did not impact the testosterone levels. Castration rates were similar with and without concomitant use of enzalutamide or docetaxel. No clinically relevant differences in adverse events were observed between subgroups in either treatment group. No differences in relugolix C trough or testosterone concentrations were observed, suggesting that any induction or inhibition properties of enzalutamide on relugolix metabolism result in a neutral net effect on relugolix exposure and testosterone suppression., Conclusion: Treatment with relugolix was associated with similar efficacy and safety profiles with and without concomitant enzalutamide or docetaxel. Standard-of-care use of relugolix in combination with these agents is supported by these data., Competing Interests: Disclosure DJG: grants from Acerta Pharmaceuticals, other from American Association for Cancer Research, grants and personal fees from Astellas, personal fees from Astrazeneca, personal fees from Axess Oncology, grants, personal fees and nonfinancial support from Bayer H/C Pharmaceuticals, grants and personal fees from BMS, grants from Calithera, grants and personal fees from Capio Biosciences, personal fees from EMD Serona, grants, personal fees and nonfinancial support from Exelixis, Inc, personal fees from Flatiron, personal fees from Ipsen, grants and personal fees from Janssen Pharmaceuticals, personal fees from Merck, Sharp & Dohme, personal fees from Michael J Hennessey Assoc, personal fees from Millennium Medical Publishing, personal fees from Modra Pharmaceuticals B.V., personal fees from Myovant Sciences, Inc, personal fees from NCI Genitourinary, personal fees from Nektar Therapeutics, grants and personal fees from Novartis, personal fees from Physician Education Resource, grants and personal fees from Pfizer, grants, personal fees and nonfinancial support from Sanofi, personal fees from UroGPO, personal fees and nonfinancial support from UroToday, personal fees from Vizuri Health Sciences, personal fees from Platform Q. FS: Advisory roles for Astellas Pharma, AstraZeneca/ MedImmune, Bayer, Janssen Oncology, and Sanofi; has received honoraria from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi; and has received research funding grants provided to the institution from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Pfizer, and Sanofi. MSC: Honoraria: Merck, Janssen Biotech, Bayer, Astellas Pharma, Myovant Sciences Consulting or Advisory Role: Merck, Janssen Biotech, MDxHealth, Bayer, Astellas Pharma, Myovant Sciences, TesoRx Pharma, Genomic Health, Ferring Pharmaceuticals, Precision Biopsy. DRS: No relevant conflicts. RT: No relevant conflicts. AB: No relevant conflicts. BT: grants from Myovant, during the conduct of the study; grants and personal fees from Astellas, grants and personal fees from Bayer, grants and personal fees from Janssen, grants and personal fees from Ferring, grants and personal fees from Sanofi. NDS: Consulting or Advisory Role: Bayer, Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Genentech, Myovant Sciences Speakers' Bureau: Janssen, Bayer, Dendreon. BB, BS, SL, AND DB: employees of Myovant Sciences, Inc., (Copyright © 2023. Published by Elsevier Inc.)

Recent publications of well-conducted population studies have informed us that the syndromic prevalence of age-related low testosterone, also known as late-onset hypogonadism, is quite low. Several well-conducted trials in middle-aged and older men with age-related decline in testosterone levels have revealed that efficacy of testosterone therapy is modest with improvement in sexual function, mood, volumetric bone density, and anemia. Although select older men might benefit from testosterone therapy, its effect on prostate cancer risk and major adverse cardiovascular events remains unclear. The results of the ongoing TRAVERSE trial will likely provide important insights into these risks., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The increased awareness of the transgender population and their medical needs has given rise to a wide array of gender-affirming surgeries and hormonal therapies. To better understand the implication of testosterone therapy on female-to-male gender-affirming mastectomies, we conducted a retrospective cohort study based on the medical histories of 170 transgender males operated on by a single surgeon over 18 years. One hundred and one (59.4%) patients received hormonal therapy. The average age of patients in the testosterone treatment group was 20.6 ± 5.3 (range 14-49) years. The median weight of resected breast tissue was 318 g (IQR 221-515) and 311.5 g (IQR 223-480) in patients treated with testosterone, compared to 380 g (IQR 225-735) and 370 g (IQR 240-700) in patients without testosterone treatment (for the right and left breast, respectively). Supplementary liposuction was performed in 35 patients, of whom 23 (64%) were treated with testosterone. Fifty-four patients (31.7%) experienced surgical complications, and 55.6% of complications were recorded in the group treated with testosterone. Forty-nine patients (28.8%) recorded their satisfaction using the Likert satisfaction scale; the average satisfaction was 4.86 ± 0.35 in the non-testosterone group and 4.63 ± 0.69 in the testosterone group. Opposing previous cohorts, we did not find a statistically significant association between testosterone and increased surgical complications in gender-affirming mastectomies. Possible explanations include our practice of avoiding testosterone therapy several weeks before the operation and vigorous hemostasis methods., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: In the United States, the use of testosterone therapy has increased over recent years. Anabolic steroid use has been associated with tendon rupture, although there is a paucity of evidence evaluating the risk of biceps tendon injury (BTI) with testosterone therapy. The aim of this study was to quantify the risk of BTI after the initiation of testosterone therapy., Methods: This was a retrospective cohort study using the PearlDiver database. Records between 2011 and 2018 were queried to identify patients aged 35-75 years who filled a testosterone prescription for a minimum of 3 months. A control group was created, comprising patients aged 35-75 years who had never filled a prescription for exogenous testosterone. International Classification of Diseases, Ninth Revision, International Classification of Diseases, Tenth Revision, and Current Procedural Terminology codes were used to identify patients with distal biceps injuries and those undergoing surgical repair. Three matching processes were completed: one for the overall cohort, one for the cohort comprising only male patients, and one for the cohort comprising only female patients. Each cohort was matched to its control on age, sex, Charlson Comorbidity Index, diabetes, tobacco use, and osteoporosis. Multivariate logistic regression was used to compare rates of distal BTI and subsequent surgical repair in the testosterone groups with their control groups., Results: A total of 776,974 patients had filled a prescription for testosterone for a minimum of 3 consecutive months. In the overall matched analysis between the testosterone and control groups (n = 291,610 in both), the mean age of the patients was 53.9 years and 23.1% were women. Within 1 year of filling exogenous testosterone prescriptions for a minimum of 3 consecutive months, 650 patients experienced a distal BTI compared with 159 patients in the control group (odds ratio [OR], 4.10; 95% confidence interval [CI], 3.45-4.89; P < .001). At any time after testosterone therapy, patients with testosterone use were more than twice as likely to experience a distal BTI as their matched controls (OR, 2.07; 95% CI, 1.94-2.38). Patients who filled prescriptions for testosterone were more likely to undergo surgical repair within a year of the injury compared with the control group. A similar trend was seen in the cohort comprising male patients (OR, 1.63; 95% CI, 1.29-2.07)., Conclusion: Patients with prior prescription testosterone exposure have an increased rate of BTI and biceps tendon repair compared with patients without such exposure. This finding provides insight into the risk profile of testosterone therapy, and doctors should consider counseling patients about this risk, particularly male patients., (Copyright © 2023 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial., Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone., Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022., Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression., Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing., Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm., Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals., Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Background: Sexual dysfunction may indicate severe endocrine diseases. Recent research has suggested a link between hypothyroidism, low testosterone (T) levels, and erectile dysfunction (ED); however, the exact cause is unknown., Aim: We sought to investigate possible beneficial effects of levothyroxine and T alone or in combination on ED in propylthiouracil (PTU)-induced hypothyroid rats., Methods: Adult Wistar rats (n = 35) were divided into 5 groups: control, PTU-induced hypothyroidism, PTU + levothyroxine, PTU + Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, and decanoate) and PTU + levothyroxine + Sustanon. PTU was given in drinking water for 6 weeks. Four weeks after PTU administration, levothyroxine (20 μg microgram kg/day, oral) and Sustanon (10 mg/kg/week, intramuscular) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3), and thyroxine (T4) were determined. In vivo erectile response and in vitro relaxant responses were measured. Localization of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and phosphodiesterase type 5 (PDE5) were determined using immunohistochemical analysis. The relative area of smooth muscle to collagen was measured using Masson trichrome staining., Outcomes: Outcome variables included in vivo erectile function, in vitro relaxant and contractile responses of corpus cavernosum (CC) strips; protein localization of eNOS, nNOS, and PDE5; and smooth muscle content in penile tissue., Results: The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3, and T4. Levothyroxine increased T3 and T4 levels, whereas Sustanon normalized only total T levels. Combined treatment enhanced all hormone levels. Rats with hypothyroidism displayed the lowest erectile response (P < 0.001 vs controls). Combined treatment returned reduced responses, while partial amelioration was observed after levothyroxine and Sustanon treatment alone. Acetylcholine (P < 0.01 vs controls), electrical field stimulation (P < 0.001 vs controls), and sildenafil-induced relaxant responses (P < 0.05 vs controls) were decreased in the CC strips from hypothyroid rats. The combined treatment increased the reduction in relaxation responses. Levothyroxine and Sustanon restored decreases in eNOS and nNOS expression in the hypothyroid group. There was no significant difference in PDE5 expression among groups. Monotreatment partially enhanced reduced smooth muscle mass, while combined therapy completely recovered., Clinical Implications: The combination of thyroid hormones and T is likely to be a therapeutic approach for treatment of hypothyroidism-induced ED in men., Strengths and Limitations: Beneficial effects of levothyroxine and Sustanon treatment were shown in vitro and in vivo in PTU-induced hypothyroid rats. The main limitation of the study was the lack of measurement of androgen-sensitive organ weights and luteinizing hormone, follicle-stimulating hormone, and prolactin levels., Conclusion: These findings demonstrate that neurogenic and endothelium-dependent relaxation responses are reduced by hypothyroidism, which is detrimental to T levels and erectile responses. Levothyroxine and Sustanon combination medication was able to counteract this effect., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Competing Interests: None declared

Background: Hodgkin's lymphoma (HL) is one of the most common malignant lymphoproliferative diseases. Chemotherapy and radiotherapy used in the treatment of LH induce a number of toxic effects leading to dysfunction of endocrine system. Hormonal disorders in HL and their relationships with the therapy used remain to be clarified., Aim: To assess disorders of the endocrine function of thyroid, parathyroid glands and gonads in HL survivors., Materials and Methods: Screening of endocrine dysfunction of the thyroid, parathyroid glands and gonads was performed in 160 adult patients with HL, 55 men and 105 women, at remission stage induced by chemotherapy or chemoradiotherapy. Forty healthy subjects, matched by age, were acted as control. The levels of TSH, T3, free T4, PTH, FSH, LH, free testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex-hormone binding globulin (SHBG) were measured in blood serum by ELISA. Bone mineral density (BMD) was assessed by DEXA., Results: Hypothyroidism (25%), hyperparathyroidism (15.6%) and hypogonadism (29% of men and 25.3% of women) were the most prevalent endocrine disorders in LH survivors. Hypothyroidism was significantly more common in patients after chemoradiotherapy than in those who received only chemotherapy (χ2=9.4, р=0.002). In patients with hyperparathyroidism, there were negative correlations between PTH levels and BMD in the lumbar spine (r=-0.74, p=0.00002) and in the femoral neck (r=-0.66, p=0.0003). Men with HL demonstrated lower free testosterone concentrations when compared to control (p=0.04); LH and FSH levels were elevated (p=0.0004 and p=0.04, respectively). In men with HL the levels of DHEA-S were reduced (p=0.0009). The increased SHBG concentrations were revealed in 13 (23.6%) men. Women of reproductive age with HL had higher levels of LH in the luteal phase (p=0.05) and FSH in the follicular phase (p=0.02) than controls., Conclusion: The data indicate a high prevalence of the dysfunctions of thyroid, parathyroid glands, and gonads in HL survivors. Screening for endocrine disorders in these patients is highly recommended.

Aim: To evaluate the efficacy and safety of using Androgel in men with endogenous testosterone deficiency and lower urinary tract symptoms (LUTS), associated with benign prostatic hyperplasia (BPH) in routine clinical practice., Materials and Methods: The multicenter, prospective, comparative study "POTOK" included 500 patients aged over 50 years with biochemical signs of testosterone deficiency (morning total testosterone concentration <12.1 nmol/l) and LUTS/BPH (International Prostatic Symptoms Score [IPSS] score of 8-19). The recruitment and monitoring of patients was carried out in 2022 in 40 clinics in Russia. Depending on the therapy, all patients were divided into two groups. The physician's decision to prescribe a specific drug (according to the approved patient information leaflet), as well as the subsequent follow-up scheme and therapy, was made a priori and independently of patient. In the first group (n=250) alpha-blockers and Androgel were prescribed, while in the second group (n=250) patients received monotherapy with alpha-blockers. The follow-up duration was 6 months. The efficiency of the therapy was evaluated after 3 and 6 months according to IPSS, symptoms of androgen deficiency (AMS and IIEF scores), uroflowmetry (peak flow rate, total urination volume), ultrasound study (postvoid residual and prostate volume). Safety was assessed by the total number of adverse events, stratified by severity and frequency. Statistical analysis was carried out using IBM SPSS 26.0., Results: According to the primary end-point (IPSS score), there were significant differences between groups 1 and 2 after 3 months (11 vs. 12 points, p=0.009) and 6 months of therapy (9 vs. 11 points, p<0.001). There were also significant differences in the severity of symptoms of androgen deficiency after 3 and 6 months of therapy according to AMS score of 35 vs. 38 points (p<0.001) and 28 vs. 36 points (p<0.001), respectively. According to IIEF, all domains (erectile and orgasmic functions, libido, sexual satisfaction with and general satisfaction) were better in group 1 (p<0.001). After 6 months, uroflowmetry values also differed. In group 1 Qmax was 16 ml/s compared to 15.2 ml/s in group 2 (p=0.004); postvoid residual was 10 ml vs. 15.5 ml, respectively (p=0.001). The prostate volume in group 1 after 6 months of treatment was significantly lower (39.5 cc) compared with group 2 (43.3 cc; p=0.002). During the study, 18 mild AEs, 2 moderate AEs, and 1 severe AE were identified without significant differences between the groups (p>0.05)., Conclusion: The results of study "POTOK" showed greater efficacy and comparable safety of alpha-blockers in combination with Androgel compared with monotherapy with alpha-blockers in men with LUTS/BPH and endogenous testosterone deficiency in routine clinical practice. The increase in serum testosterone concentrations to normal values in patients with age-related hypogonadism favorably influence on the severity of LUTS and the potentiate the effect of the standard monotherapy with alpha-blockers.

Transmasculine individuals, considering whether to undergo total hysterectomy with bilateral salpingectomy, have the option to have a concomitant oophorectomy. While studies have evaluated hormone changes following testosterone therapy initiation, most of those patients have not undergone oophorectomy. Data are currently limited to support health outcomes regarding the decision to retain or remove the ovaries. We performed a retrospective chart review of transmasculine patients maintained on high-dose testosterone therapy at a single endocrine clinic in Vancouver, British Columbia, Canada. Twelve transmasculine individuals who underwent bilateral oophorectomy and had presurgical and postsurgical serum data were included. We identified 12 transmasculine subjects as controls, who were on testosterone therapy and did not undergo oophorectomy, but additionally matched to the first group by age, testosterone dosing regimen, and body mass index. There was a statistically significant decrease in the estradiol levels of case subjects postoophorectomy, when compared to presurgical estradiol levels (P = 0.02). There was no significant difference between baseline estradiol levels between control and case subjects; however, the difference in estradiol levels at follow-up measurements was significant (P = 0.03). Total testosterone levels did not differ between control and case subjects at baseline and follow-up (both P > 0.05). Our results demonstrate that oophorectomy further attenuates estradiol levels below what is achieved by high-dose exogenous testosterone alone. Correlated clinical outcomes, such as impacts on bone health, were not available. The clinical implications of oophorectomy versus ovarian retention on endocrinological and overall health outcomes are currently limited., Competing Interests: None

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs., (© 2023 The Japanese Urological Association.)

Aromatase enzyme plays an essential role in estrogen-induced tumorigenesis. It is expressed in the normal pituitary and more significantly in prolactinoma tissues. The aim of this study was to investigate the effects of an aromatase inhibitor, letrozole, on MMQ and GH3 rat prolactinoma cell lines and evaluate the possible mechanism of action. MMQ and GH3 cells were characterized with demonstrating aromatase enzyme and estrogen receptor alpha expression by PCR and immunofluorescence staining. After dose optimization for testosterone (T) and letrozole (L), four groups were established: only the testosteron-treated group (T) to detect cell proliferation; only letrozole-treated group (L) to investigate apoptotic effects; testosterone and letrozole concomitant-treated group to demonstrate inhibition of testosterone induced cell proliferation with letrozole treatment s(T + L) and control group (C) with no treatment. The proliferation rate of cells was determined by WST-1. For the detection of apoptotic and necrotic cells, Annexin V and caspase-3 labeling was used. Prolactin and estrogen levels were measured with ELISA, and the mRNA expression of aromatase and Esr1 was also determined. Testosterone induced the proliferation of MMQ and GH3 cells and further increased prolactin and estradiol levels. Adding letrozole to testosterone resulted in decreased cellular proliferation and even induced apoptosis. Also, letrozole administration significantly decreased prolactin and estradiol levels. However, letrozole alone had no effects on proliferation and apoptosis. Gene expression of aromatase and Esr1 was also significantly decreased by letrozole treatment. This in vitro study demonstrated that treatment of testosterone proliferating cells with letrozole resulted in decreased prolactin levels and cell proliferation and induced apoptosis, and further loss of aromatase and Esr1 mRNA expression were observed. Although this is an in vivo study, the results showed unique and novel findings which may easily be adapted to clinical use for further verification., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Relugolix treatment of advanced prostate cancer (APC), like other gonadotropin-releasing hormone-antagonists, results in rapid decrease in testosterone concentrations without the risk of flare, as seen in leuprolide. Despite this benefit over leuprolide, no economic evaluation assessment to ascertain the cost-effectiveness of relugolix has been conducted. Therefore, this study aims to assess the cost-effectiveness of androgen deprivation therapy (ADT) with 120 mg relugolix against 7.5 mg leuprolide for the treatment of APC., Methods: A Markov model was used to assess and compare the costs of APC treatment from a health care payer's perspective and the effectiveness of ADT with relugolix and leuprolide at the 3 lines of APC treatment among modified intent-to-treat patients. Relative progression-free (PFS) and overall survival (OS) rates were estimated. Outcomes measured in the analyses included costs of the drugs and therapies, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), cost-effectiveness acceptability, and probability curves., Results: The cost-effectiveness analysis showed the ICER for ADT with relugolix to be US $49,571.1 per QALY. At the ICER value, the sensitivity analysis indicated that ADT with leuprolide was dominant in 100% of the simulations. ADT acceptance with relugolix was 100% when a willingness-to-pay threshold was set at US $100,000/QALY. At 5-years, the relative PFS and OS rates for relugolix at the first line of therapy were 72.7% and 86.0%, respectively, compared to 61.0% and 85.90% for leuprolide., Conclusion: Though the influence of adverse events was not considered in the analysis, ADT with relugolix was not a cost-effective choice for APC management. While the analysis revealed a slight chance of sustaining testosterone suppression with relugolix, ADT with relugolix provided no significant survival advantages over ADT with leuprolide. Therefore, this analysis confirms no need for further assessment of APC interventions to make informed decisions beneficial to the APC patients, oncologists, and other stakeholders., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The discovery of the benefits of castration for prostate cancer treatment in 1941 led to androgen deprivation therapy, which remains a mainstay of the treatment of men with advanced prostate cancer. However, as early as this original publication, the inevitable development of castration-resistant prostate cancer was recognized. Resistance first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of the androgen receptor axis. Evaluation of clinical specimens demonstrates that castration-resistant prostate cancer cells remain addicted to androgen signalling and adapt to chronic low-testosterone states. Paradoxically, results of several studies have suggested that treatment with supraphysiological levels of testosterone can retard prostate cancer growth. Insights from these studies have been used to investigate administration of supraphysiological testosterone to patients with prostate cancer for clinical benefits, a strategy that is termed bipolar androgen therapy (BAT). BAT involves rapid cycling from supraphysiological back to near-castration testosterone levels over a 4-week cycle. Understanding how BAT works at the molecular and cellular levels might help to rationalize combining BAT with other agents to achieve increased efficacy and tumour responses., (© 2022. Springer Nature Limited.)

Background: Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first-choice treatment for male hypogonadism, with several side effects, that is, subfertility. Clomiphene citrate (CC) is an alternative off-label therapy for a certain group of hypogonadal males, especially for those with an active or future child wish. There is scarce literature in usage of CC for men with hypogonadism. The aim of this retrospective study was to evaluate the effectiveness and safety of CC for hypogonadal males., Methods: In this single-centre study, men treated with CC for hypogonadism were evaluated retrospectively. Primary outcome was hormonal evaluation including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Secondary outcomes were hypogonadal symptoms, metabolic and lipid parameters, haemoglobin (Hb), haematocrit (Ht), prostate specific antigen (PSA), side effects, the effect of a trial without medication and potential predictors for biochemical and clinical response., Results: In total, 153 hypogonadal men were treated with CC. Mean TT, FT, LH and FSH increased during treatment. TT increased from 9 to 16 nmol/L, with a biochemical increase in 89% of the patients. In patients who continued CC treatment, an increased level of TT persisted after 8 years of treatment. With CC treatment, 74% of the patients experienced hypogonadal symptom improvement. LH at the lower normal range before CC treatment was predictive for better TT response. During CC therapy, few side effects were reported and no clinical important changes in PSA, Hb and Ht were found., Conclusion: Clomiphene citrate is an effective therapy on short and long term, improving both clinical symptoms and biochemical markers of male hypogonadism with few side effects and good safety aspects., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)