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Aim: This meta-analysis investigates the association between testosterone replacement therapy [TRT] and carotid artery atherosclerosis. Methods: 3 databases were searched for studies up to June 2023 per the PRISMA guidelines. The eligibility criteria comprised RCTs and observational studies involving hypogonadal males receiving exogenous testosterone, in which CIMT was assessed. CAA was the primary outcome, whereas secondary outcomes included HDL, LDL, CRP, total cholesterol and total testosterone. The statistical analysis was performed using Review Manager. Results: Statistical analysis revealed no association between TRT and assessed outcomes. There was a significant increase in total testosterone levels, depicting indirect anti-atherosclerotic effects of TRT. Conclusion: Meta-analysis shows no relation between TRT and CIMT or other markers, allowing its safe usage for hypogonadal males.

Introduction: There is increasing evidence that gender dysphoria (GD) is more prevalent in the Klinefelter Syndrome (KS) population than in males in the general population; however, the exact incidence is uncertain. The aim of this study was to further explore the prevalence of gender-related issues, the role that physical characteristics play in gender identity, and the issues surrounding Hormone Replacement Therapy (HRT) in KS., Methods: As part of a registered Quality Improvement Project (QIP), one online 23-point questionnaire on KS patient attitudes toward gender identity was shared with members of the Klinefelter Syndrome Association (KSA). In total, 139 anonymous responses were collected between December 2021 and January 2023. The questionnaire was developed with the guidance of multiple clinicians (including gender psychiatrists, urologists, psychosexual medicine specialists, and endocrinologists) and patient Delphi rounds. Data was reviewed and analyzed by 4 independent researchers within the QIP team., Results: Only 53% of KS patients responding to this survey fully identified as male and 19% stated that they did not enjoy living as the sex on their birth certificate, with 43% considering changing aspects of their physical appearance to better match their gender. Regarding HRT, 67% of respondents were receiving Testosterone Replacement Therapy (TRT). 63% wanted TRT and 17% wanted estrogen, including 6% of TRT users who would prefer estrogen instead. 36% that were currently receiving TRT did not identify as male, and 3 participants stated that they have GD., Conclusion: These results indicate that a significant proportion of KS patients do not fully identify with the male gender and are unhappy living as the sex on their birth certificate. Although TRT worked for most, its use should be discussed carefully with those with gender identity concerns.

Context: Klinefelter syndrome (KS) is associated with hypergonadotropic hypogonadism, which contributes to characteristic phenotypical manifestations including metabolic alterations. Extensive research has demonstrated important associations between androgens and liver function., Objectives: Investigation of the association between metabolic parameters, sex hormones and liver function in males with KS, both treated (T-KS) and untreated (U-KS) and healthy control males., Methods: A total of 65 KS males were recruited, of which 32 received testosterone replacement therapy (TRT). Also, 69 healthy controls were recruited. We used alanine aminotransferase (ALAT), alkaline phosphatase and PP (prothrombin-proconvertin time ratio) as the main liver markers. Multivariable regression was performed within the three groups. All statistics were calculated using STATA. Principal component analysis was utilized to demonstrate the interconnected patterns among all measured biomarkers, and to elucidate how the different groups were linked to these patterns., Results: Higher levels of main liver markers were observed in U-KS compared to controls, with no significant differences between U-KS and T-KS. T-KS had lower abdominal fat, total cholesterol, and LDL cholesterol than U-KS. Using multivariable models, variation in ALAT in U-KS was explained by HOMA2%S; in T-KS by BMI and SHBG; and in controls by hip circumference and estradiol. We found no multivariable models explaining variation in PP in U-KS; in T-KS, PP was explained by BMI and LDL cholesterol, and in controls by total cholesterol. Using principal component analysis U-KS was positively associated to D1 (an obese profile, which also included ALAT) and controls negatively associated with D1 (non-obese profile)., Conclusion: KS males have mild liver dysfunction reflected by a significant increase in the main liver markers and decrease in albumin. The presented data underscore a primary role of metabolic conditions including obesity, insulin resistance and unfavourable lipid profile, in the elevated liver function markers seen in males with KS. Whether TRT can improve liver function in KS warrants further studies. Our findings, highlight that an evaluation of the liver function should be part of the clinical care in males with KS., (© 2024. The Author(s).)

Introduction: With thirty percent of the world's population not getting enough exercise, Worldwide, physical inactivity ranks as one of the most common causes of premature mortality. Rapid drops in physical activity, decreased mobility, and early morbidity are aging characteristics. As the population over 80 continues to rise, aging raises the danger of age-related illnesses and changes in hormone release., Aim: Understanding the aging process is useful in developing pharmacological therapies and identifying therapeutic targets for age-related testosterone deficiency. Therefore, this study's purpose is to present a thorough evaluation of the effects of anti-aging strategies on testosterone levels in older, inactive men., Methods: A literature search was completed for clinical and preclinical studies published in English between 2014 and 2024 related to age, sedentary life, testosterone, and anti-aging strategies., Results: A sedentary lifestyle and low testosterone are linked to a vicious cycle. A sedentary lifestyle lowers testosterone levels, which leads to depression, exhaustion, low energy, and weakened bone and muscle strength. These effects exacerbate the detrimental consequences of aging and physical inactivity. Anti-aging techniques can prevent and treat age-related diseases, including calorie restriction, a balanced diet, regular exercise, weight control, diabetes management, and quitting smoking. Regular exercise raises total testosterone, free testosterone, and muscle steroidogenesis. In older men, testosterone replacement treatment increases bone density, cholesterol, protein synthesis, strength, erectile function, sexual desire, and general cognitive performance. However, some studies suggest dehydroepiandrosterone supplementation may provide health improvements without negative effects, potentially reversing arterial aging and reducing cardiovascular disease risk., Conclusion: This article evaluates the prospects for anti-aging procedures to assist in reducing the adverse effects of aging and physical inactivity in men., Competing Interests: The author declares 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 © 2024 Abdel-Sater.)

Background and Objective: Studies examining ambulatory blood pressure (BP) response to testosterone replacement therapy are needed owing to inconsistent prior findings across formulations. This study assessed testosterone gel 1.62% and 24-h ambulatory BP., Materials and Methods: Single-arm non-inferiority trial (NCT04274894) conducted at 36 US sites enrolled 246 men with hypogonadism (mean age, 57.6 years; mean office systolic/diastolic BP [SBP/DBP], 129.8/79.5 mm Hg) who were treated for 16 weeks with once-daily testosterone gel treatment (starting dose, 40.5 mg/day; min, max dose, 20.25, 81.0 mg/day) to achieve testosterone concentration of 350-750 ng/dL. Main outcome measures included mean change in 24-h average SBP (primary endpoint) and DBP from baseline to week 16. The non-inferiority threshold was a two-sided 95% confidence interval (CI) upper limit <3.0 mm Hg for 24-h average SBP., Results: Increase in mean ± SD serum testosterone concentration to a physiologic level (baseline, 244.4 ± 93.9 ng/dL; week 16, 502.5 ± 394.4 ng/dL) was associated with a 1.9-mm Hg mean change in 24-h average SBP observed in the primary analysis (baseline, 123.5 mm Hg; week 16, 125.4 mm Hg; 95% CI, 0.63-3.13 mm Hg; n = 169). As the upper CI limit modestly exceeded the non-inferiority margin (3 mm Hg), study drug effect on SBP could not be ruled out. Non-inferiority was observed in subgroups without hypertension or diabetes (95% CI, upper limit <3.0 mm Hg) and was not observed in those with hypertension or diabetes. Daytime SBP and DBP changes were larger compared with nighttime. No clear cardiovascular adverse events or new safety signals were identified., Discussion and Conclusions: While the effect of testosterone gel 1.62% on 24-h average SBP could not be ruled out based on the study's non-inferiority margin, the clinical relevance of the small-magnitude mean increase of 1.9 mm Hg is anticipated to be minimal considering the results of the TRAVERSE study of testosterone gel 1.62% and major adverse cardiac events., Clinical Trial Information: ClinicalTrials.gov identifier: NCT04274894 (registered February 17, 2020)., (© 2024 American Society of Andrology and European Academy of Andrology.)

Objective: The objective of this study was to evaluate major adverse cardiovascular events in erectile dysfunction (ED) patients who received testosterone replacement therapy (TRT) compared with those who did not., Materials and Methods: From January 2012 to October 2021, we collected the retrospective data of patients with ED at Ramathibodi Hospital. We divided the patients into two groups: those who received TRT (TRT group) and those with normal testosterone levels and therefore not requiring TRT (non-TRT group). The patients' baseline clinicodemographic data were collected. Major adverse cardiovascular events, including cardiovascular death, ST- and non-ST-elevation myocardial infarction, hospitalization from congestive heart failure, transient ischemic attack, and ischemic stroke, were collected and analyzed within 2 years after treatment in all groups., Results: Of the 221 patients, 111 were in the TRT group and 110 were in the non-TRT group. In the non-TRT group, one event each of the following occurred: myocardial infarction, transient ischemic attack, and stroke. In the TRT group, no major cardiovascular event occurred during the 2-year follow-up period. However, no significant difference in major cardiovascular events was noted between the two groups (p = 0.314)., Conclusion: TRT in ED patients with testosterone deficiency does not increase adverse cardiovascular events when compared with ED patients with normal testosterone level., Competing Interests: The authors declare no conflicts of interest., (© 2024 Poopuangpairoj et al.)

Objective: In this study, we aimed to perform a network meta-analysis (NMA) to investigate the effects of different testosterone replacement therapy (TRT) administration routes on lower urinary tract symptoms (LUTS) in aging men with late-onset hypogonadism (LOH)., Methods: A systematic search of PubMed, Embase, The Cochrane Library, CNKI, WanFang Data, and VIP was conducted to identify randomized controlled trials (RCTs) reporting data on International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) level, or prostate volume. NMA was performed, and subgroup analysis was conducted to assess the impact of TRT duration on outcomes., Results: A total of 21 RCTs involving 2453 participants were included. For pairwise meta-analysis, p values for TRT delivered by transdermal, intramuscular, and oral routes were as follows: IPSS: 0.93, 0.20, and 0.76; PSA level: 0.20, 0.27, and 0.98; prostate volume: 0.18, 0.04, and 0.16. There were no significant differences in IPSS, PSA level, or prostate volume between TRT routes. In subgroup analysis, long-term intramuscular TRT significantly decreased IPSS (p = 0.03), short-term transdermal TRT increased PSA levels (p < 0.001), and short-term intramuscular TRT increased the prostate volume (p = 0.04). Other forms of TRT showed no significant change in IPSS, PSA level, and prostate volume compared with the placebo. Indirect comparison of the three administration routes demonstrated no significant differences in IPSS, PSA level, and prostate volume. Nevertheless, surface under the cumulative ranking curve analysis indicated that intramuscular TRT had an 83% probability of being the best method for decreasing IPSS., Conclusions: The results demonstrate that TRT does not worsen LUTS regardless of the administration route. Intramuscular TRT may be the preferred treatment for aging men with LOH and LUTS. Intramuscular TRT may be the preferred treatment for men with LOH and LUTS. Further research is warranted to validate these findings and optimize TRT management strategies., (© 2024 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

Objective: Studies are needed to examine the effects of testosterone replacement therapy on ambulatory blood pressure (BP) parameters. This study assessed a testosterone transdermal system (TTS) using 24-hour ambulatory BP monitoring., Methods: In a single-arm, noninferiority trial conducted at 41 US sites, 168 men (mean age: 56.2 years) with hypogonadism not receiving testosterone replacement therapy in the past 6 months were enrolled and received ≥1 study drug dose. Nightly TTS treatment was administered for 16 weeks (starting dose: 4 mg/d; min, max dose: 2, 6 mg/d) to achieve testosterone concentration of 400-930 ng/dL. The primary endpoint was mean change from baseline to week 16 in 24-hour systolic BP (SBP). Noninferiority was determined based on the upper bound of the 2-sided 95% CI <3.0 mmHg., Results: Sixty-two men had ≥85% study drug compliance and a valid week 16 ambulatory BP monitoring session. Mean change from baseline to week 16 in 24-hour average SBP was 3.5 mmHg (95% CI, 1.2-5.8 mmHg; n = 62). Since the upper limit of the CI was >3 mmHg, an effect of TTS could not be ruled out. Mean changes were larger at daytime vs nighttime and in subgroups of men with vs without hypertension. Cardiovascular adverse events were rare (<2%) and nonserious; no major cardiovascular adverse events were reported., Conclusion: A meaningful effect of 16-week TTS treatment on 24-hour average SBP among men with hypogonadism could not be ruled out based on the study's noninferiority criterion. The magnitude of mean changes observed may not be clinically meaningful regarding cardiovascular events., Competing Interests: Disclosure Financial support for the study was provided by AbbVie, Inc (North Chicago, IL). AbbVie, Inc, participated in study design, research, data collection, analysis, and interpretation of data, and writing, reviewing, and approving the publication. All authors contributed to the development of the manuscript and maintained control over the final content. No authors received payment or other compensation related to the development of the manuscript. Anna Chan and James W. Thomas are employees of AbbVie, Inc, and own AbbVie, Inc stock or stock options. Mitchell D. Efros, Jed C. Kaminetsky, and Neil D. Sherman have no relevant disclosures., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

49,XXXYY is an extremely rare sex chromosomal aneuploidy (SCA), with only seven cases reported worldwide to date. Among these cases, only three have been documented into adulthood. Moreover, no cases of 49,XXXYY have been reported in Japan. This SCA has been identified in two scenarios: in vitro fertilization and abortion. Similar to 47,XXY, this aneuploidy is a type of Klinefelter syndrome. Aneuploidy of the X chromosome can lead to various progressive complications due to excess X chromosomes. Herein, we present the case of a Japanese man with 49,XXXYY. He exhibited developmental delays and external genitalia abnormalities since early infancy but was not closely monitored for these symptoms until the age of 3 years old. At that time, a chromosome test revealed his karyotype to be 49,XXXYY. Subsequent examinations were conducted due to various symptoms, including delayed motor development, intellectual disability, facial dysmorphisms, forearm deformities, hip dysplasia, cryptorchidism, micropenis, primary hypogonadism, and essential tremor. Since reaching puberty, he has undergone testosterone replacement therapy for primary hypogonadism, experiencing no complications related to androgen deficiency to date. He has maintained normal lipid and glucose metabolism, as well as bone density, for a prolonged period. There are no other reports on the long-term effects of testosterone treatment for the SCA. Appropriate testosterone replacement therapy is recommended for individuals with 49,XXXYY to prevent complications. This report will contribute to an enhanced understanding of the 49,XXXYY phenotype, aiding in the diagnosis, treatment, and genetic counseling of future cases.

Previous research has shown a decrease in serum testosterone levels in male patients with depression. In recent years, the results of testosterone replacement therapy (TRT) to improve depression have been mixed. Using the classic CUMS model, we induced depressive-like behaviors in rats and observed a decrease in their serum testosterone levels along with an increase in androgen receptor expression in the hippocampus. We then performed castration and sham surgery on male rats and found that testosterone deprivation led to the manifestation of depressive-like behavior that could be ameliorated by TRT. Through a repeated measures experiment consisting of five blocks over a period of 25 days, we discovered that the reduction in depressive-like behavior in testosterone-deprived rats began 22 days after drug administration (0.5 and 0.25 mg/rat). Furthermore, rats in 0.5mgT group showed the most significant improvements. Subsequently, this dose was used in CUMS rats and reduced the occurrence of depressive-like behaviors. Our study has demonstrated the complex interplay between depression and testosterone, as well as the intricate dose-response relationship between TRT and reduction in depression. Our research supports the use of TRT to alleviate depression, but dosage and duration of treatment are critical factors in determining efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Patients with long-term chronic illnesses frequently present with hypogonadism, which is primarily managed through exogenous testosterone. These same patients also experience a high degree of cachexia, a loss of skeletal muscle and adipose tissue., Objective: To perform a contemporary review of the literature to assess the effectiveness of testosterone replacement therapy (TRT) for managing chronic disease-associated cachexia., Methods: We performed a PubMed literature search using MeSH terms to identify studies from 2000 to 2022 on TRT and the following cachexia-related chronic medical diseases: cancer, COPD, HIV/AIDS, and liver cirrhosis., Results: From the literature, 11 primary studies and 1 meta-analysis were selected. Among these studies, 3 evaluated TRT on cancer-associated cachexia, 3 on chronic obstructive pulmonary disease, 4 on HIV and AIDS, and 2 on liver cirrhosis. TRT showed mixed results favoring clinical improvement on each disease., Conclusions: Cachexia is commonly observed in chronic disease states. Its occurrence with hypogonadism, alongside the shared symptoms of these 2 conditions, points toward the management of cachexia through the administration of exogenous testosterone. Robust data in the literature support the use of testosterone in increasing lean body mass, improving energy levels, and enhancing the quality of life for patients with chronic disease. However, the data are variable, and further studies are warranted on the long-term efficacy of TRT in patients with cachexia., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE ( via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Childhood cancer survivors are at risk of various endocrine late effects affecting their quality of life. The aim of this study was to assess the prevalence and predictors of endocrine and reproductive outcomes in young adult survivors. A secondary aim was to assess possible associations between testosterone replacement therapy (TRT) and other endocrine, cardiovascular and psychosocial late effects. This nationwide study comprised 1212 male childhood cancer survivors aged 19-40 years, identified through the National Quality Registry for Childhood Cancer in Sweden. Median age at diagnosis during 1981-2017 was 7 (range 0-17) and at study 29 (19-40) years. The study combined self-report survey data with cancer treatment data from the national registry. Hormone-induced puberty was self-reported by 3.8% of the survivors and ongoing TRT by 6.0%. In separate logistic regression analyses, these treatments were associated with hematopoietic stem cell transplantation and cranial radiotherapy. Hormone-induced puberty was additionally associated with younger age at diagnosis. Men with TRT had a higher prevalence of other endocrine deficiencies, cholesterol medication, depressive symptoms and fatigue as well as a lower probability of living with a partner, having a biological child or current occupation. In the total male cohort, 28.2% reported having a biological child. Reassuring reproductive outcomes after less intensive therapies and low frequency of TRT were observed in young adult male childhood cancer survivors treated in the most recent treatment era. However, men with TRT suffered from several other endocrine, cardiovascular and psychosocial late effects, indicating a need for long-term monitoring of this high-risk group., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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., (© 2024 American Society of Andrology and European Academy of Andrology.)

Introduction: Previous work has demonstrated a deficiency in urology resident education when it comes to andrology and male infertility. We analyzed the top 100 most frequently cited and influential articles published on testosterone deficiency and its associated therapy, allowing trainees and clinicians to review and understand the characteristics of impactful literature for self-directed learning purposes., Methods: The ISI Web of Knowledge database was used to find articles on testosterone deficiency, hypogonadism, and replacement therapies. Relevant, peer-reviewed, English articles were included. Article details, including title, citation count, publication year, and more, were gathered. Articles were classified based on content (e.g. clinical outcomes, anatomy, and trends) using defined criteria., Results: The top 300 most cited were reviewed with 100 included. The most cited article had 774 citations, averaging 234 in the top 100. Publication years had peaks in 2003-2004 and 2006-2007. The US led in publications (56), followed by England (16), Germany (14), and Italy (13). Common affiliations included US Department of Veteran Affairs, Veterans Health Administration, RIC Research Education Clinical Center, and University of California System. Articles were categorized as LOE 2 (47), LOE 1 (22), and LOE 5 (21). Articles focused on clinical outcomes (71.7%), anatomy/biomechanics/physiology (14.1%), clinical guidelines (8.1%), and screening (4%). The " Journal of Clinical Endocrinology & Metabolism " published 26 of the top 100 cited articles., Conclusions: This analysis highlights influential articles regarding testosterone deficiency and management. The discussed articles have significant clinical and therapeutic implications for the practicing urologist which may bolster deficits in current resident education., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The cardiovascular (CV) safety of testosterone (T) replacement therapy (TRT) is still conflicting. Recent data suggested a TRT-related increased risk of atrial fibrillation (AF). The aim of this study was to systematic review and meta-analyze CV risk related to TRT as derived from placebo controlled randomized trials (RCTs)., Areas Covered: An extensive Medline, Embase, and Cochrane search was performed. All placebo-controlled RCTs reporting data on TRT-related CV safety were considered. To better analyze the role of T on AF, population-based studies investigating the relationship between endogenous circulating T levels and AF incidence were also included and analyzed., Expert Opinion: Out of 3.615, 106 studies were considered, including 8.126 subjects treated with TRT and 7.310 patients allocated to placebo. No difference between TRT and placebo was observed when major adverse CV events were considered. Whereas the incidence of non-fatal arrhythmias and AF was increased in the only trial considering CV safety as the primary endpoint, this was not confirmed when all other studies were considered (MH-OR 1.61[0.84;3.08] and 1.44[0.46;4.46]). Similarly, no relationship between endogenous T levels and AF incidence was observed after the adjustment for confounders Available data confirm that TRT is safe and it is not related to an increased CV risk.

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices.

Context: Few long-term randomized trials have evaluated the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with hypogonadism and whether effects are sustained beyond 12 months., Objective: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. The Sexual Function Study, nested within the parent trial, determined testosterone's efficacy in improving sexual activity, hypogonadal symptoms, libido, and erectile function among men reporting low libido., Methods: Among 5204 men, 45-80 years, with 2 testosterone concentrations <300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk enrolled in the TRAVERSE trial, 1161 with low libido were enrolled in the Sexual Function Study (587 randomized to receive 1.62% testosterone gel and 574 to placebo gel for the duration of their participation in the study). Primary outcome was change from baseline in sexual activity score. Secondary outcomes included hypogonadal symptoms, erectile function, and sexual desire., Results: TRT was associated with significantly greater improvement in sexual activity than placebo (estimated mean [95% CI] between-group difference 0.49 [0.19,0.79] and 0.47 [0.11, 0.83] acts per day at 6 and 12 months, respectively; omnibus test P = .011); treatment effect was maintained at 24 months. TRT improved hypogonadal symptoms and sexual desire, but not erectile function, compared with placebo., Conclusion: In middle-aged and older men with hypogonadism and low libido, TRT for 2 years improved sexual activity, hypogonadal symptoms, and sexual desire, but not erectile function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: As an increasingly popular therapeutic option, testosterone replacement therapy (TRT) has gained significant notoriety for its health benefits in indicated populations, such as those suffering from hypogonadism., Areas Covered: Benefits such as improved libido, muscle mass, cognition, and quality of life have led to widened public interest in testosterone as a health supplement. No therapy exists without side effects; testosterone replacement therapy has been associated with side effects such as an increased risk of polycythemia, benign prostate hypertrophy (BPH), prostate cancer, gynecomastia, testicular atrophy, and infertility. Testosterone replacement therapy is often accompanied by several prophylactic co-therapies aimed at reducing the prevalence of these side effects. Literature searches for sections on the clinical benefits and risks associated with TRT were performed to include clinical trials, meta-analyses, and systematic reviews from the last 10 years., Expert Opinion: Data from clinical studies over the last decade suggest that the benefits of this therapy outweigh the risks and result in overall increased quality of life and remission of symptoms related to hypogonadism. With this in mind, the authors of this review suggest that carefully designed clinical trials are warranted for the investigation of TRT in symptomatic age-related hypogonadism.

The area of geriatrics and the study of the aged are gaining prominence all over the world. In the US, the population of people over 65 years old is expected to reach 71 million in 10 years. Men are projected to account for approximately 43% of the population. Owing to their more complex physiological and pathological state, elderly men face many challenges. Erectile function may diminish in elderly and vulnerable people owing to ageing, physical conditions, psychological stress, or a combination of these factors. This propensity is more common in elderly men. This article reviews the literature on frailty syndrome and erectile dysfunction (ED) to better understand them. Complete MEDLINE/PubMed review of non-systematic literature from 1990 to May 2023 was included. This topic is thoroughly researched using "frailty", "low muscle mass", "erectile dysfunction", and "elderly". Individuals with frailty tend to experience more pronounced instances of ED compared with those who are in good health primarily owing to the anomalies present in their physiological composition. This poses challenges for individuals with physical vulnerabilities to engage in intimate relationships. ED may potentially exert a substantial influence on the mental well-being of older individuals or those who are otherwise vulnerable. Research demonstrates that implementing testosterone replacement therapy (TRT) can effectively enhance erectile function among elderly individuals. This phenomenon persists despite the knowledge that TRT is not devoid of potential adverse effects. The present investigation has revealed a significant association of frailty, exacerbated by advancing age, with the occurrence of ED. Our findings lead to the conclusion that the condition of frailty becomes more pronounced as individuals advance in age., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Over the last 3 decades, there has been an increased interest in testosterone replacement therapy. This trend is a result of an aging population, endocrine disruptors in our foods and environment and rising obesity rates. In addition, there has been a surge in Men's Health clinics and online direct-to-consumer Web sites, making testosterone replacement therapy much more readily accessible. As more men seek to increase their testosterone levels, more long-term random control studies are needed to gain better insight into testosterone optimization to support the anecdotal observation commonly experienced in the practice setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use., Materials and Methods: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland., Results: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses., Conclusion: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

Purpose: Hypogonadism is associated with a wide range of physical and psychological symptoms that can affect the overall health of men. However, in a developing country, there are several imposing challenges in the diagnosis and treatment of hypogonadism, including a lack of awareness and understanding of the condition among healthcare providers and patients, limited resources and the high cost of treatment. This review aimed to examine the potential benefits and risks of testosterone replacement therapy (TRT) and provides a perspective of a developing country on the topic., Materials and Methods: A comprehensive literature review was conducted to gather relevant information on the impact of testosterone deficiency on ageing males and the effectiveness of TRT for treating hypogonadism. Published peer-reviewed articles were analyzed to evaluate the benefits and risks of TRT. Additionally, the unique challenges faced in the diagnosis and treatment of hypogonadism in a developing country were considered., Results: Testosterone replacement therapy has been shown to be an effective treatment for hypogonadism, particularly in symptomatic men with low testosterone levels. It offers potential benefits such as improvements in symptoms and overall quality of life. However, there are associated risks and side effects that need to be considered. In a developing country, challenges such as limited awareness and understanding of hypogonadism, resource constraints, and high treatment costs pose additional barriers to accessing TRT and comprehensive care., Conclusion: In conclusion, TRT holds promise as a treatment for hypogonadism, but its implementation and accessibility face significant challenges in a developing country. Addressing these challenges, including raising awareness, allocating resources, and finding cost-effective solutions, is crucial for ensuring that men with hypogonadism in such settings receive appropriate diagnosis and treatment. Further research and efforts are needed to improve the management of hypogonadism in developing countries and optimize the potential benefits of TRT for affected individuals.

Purpose: To describe the effects of consistent levels of testosterone in a pellet form and it's potential to reverse osteoporosis., Methods: This is a descriptive case report of a 54 year male with a spontaneous fracture and osteoporosis in the presence of what many consider a normal male testosterone level., Results: After discovering and documenting osteoporosis by DXA scan, the patient was shown to reverse the diagnosis of osteoporosis in a year on pelleted testosterone therapy. Consistent levels of 943 ng/dL were achieved; the patient also experienced improvements in quality of life and sleep apnea., Conclusion: Testosterone deficiency (TD) is a clinical syndrome and osteoporosis can be found in levels above standard "criteria" of 300. This patient did not realize a benefit on injections both physical and clinically and both improved on pelleted testosterone. This should be further studied and considered for TD in men.

Obstructive sleep apnoea syndrome (OSAS) is an under-recognized medical disease. The main risk factors for OSAS are male sex, older age, obesity, and metabolic syndrome, that are also associated with male hypogonadism (MH). Therefore, obesity has been classically identified as the most evident link between OSAS and MH. However, OSAS is per se linked to the development of MH by a combined effect of hypoxia, increased night-time awakenings, reduced sleep efficiency and fragmented sleep. Similarly, MH might represent a risk factor for OSAS, mainly related to sleep disturbances that are frequently associated with low testosterone. Data on testosterone replacement therapy (TRT) in patients with OSAS are limited. Nevertheless, TRT is generally contraindicated by guidelines in the presence of untreated or severe OSAS. TRT might in fact worse OSAS symptoms in different ways. Furthermore, OSAS has been proposed to be a risk factor for secondary polycythaemia and TRT might exacerbate polycythaemia. Therefore, TRT in hypogonadal men affected by untreated OSAS or severe OSAS should be considered with caution and in a personalised way. Nevertheless, the type and dosage of TRT should be considered, as short-term high-dose TRT might worsen OSAS, whereas long-term lower doses could eventually determine a clinical improvement of symptoms of OSAS. Here we reviewed the data on the association between OSAS, MH and TRT, including the opportunity of assessment of patients who develop signs and symptoms of OSAS during TRT by polysomnography., 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., (© 2023 Graziani, Grande and Ferlin.)

PURPOSE OF REVIEW: The purpose of this review is to analyze the link between testosterone replacement therapy (TRT) and adverse cardiovascular (CV) events. RECENT FINDINGS: A few published studies suggest a link between TRT and CV events. These studies contained flaws, and many other studies reveal a reduction in CV events. Hypogonadism is associated with increased mortality in men with CVD. TRT in hypogonadal men can improve many CVD risk factors, reduce QT interval prolongation, lead to better outcomes in heart failure patients, and slow the progression of atherosclerosis. The use of TRT to achieve physiologic testosterone concentrations in men does not pose a threat to CV health and has demonstrated a cardioprotective effect., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023 American Society of Andrology and European Academy of Andrology.)

Introduction: The specific role of testosterone (T) replacement therapy in patients with late onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T levels (primary hypogonadism)., Areas Covered: Advantages and limitations related to available new treatments will be discussed in detail. In addition, possible news related to preparations in the pipeline will be discussed., Expert Opinion: The selection of a specific T preparation should be adequately discussed with each subject. Transdermal T preparations are those that can preserve, after a unique morning administration, the circadian rhythmicity of T secretion. Conversely, short-acting preparations (such as oral or intranasal) need two- or three-times daily administration, potentially reducing patient compliance. Long acting T preparations, such as injectable T undecanoate have the advantage of bimestrial or trimestral administration, reducing the required number of administrations. The use of non-steroidal selective androgen receptor modulators (SARM), a heterogeneous class of compounds selectively acting on androgen receptor targets, remains investigational due to the lack of the full spectrum of T's action and the possible risk of side effects, despite their potential use in the treatment of muscle wasting and osteoporosis.

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.)

Introduction: Testosterone replacement therapy is a promising and growing field in modern healthcare. Several novel testosterone preparations aiming at providing an efficient drug without side effects have been developed in recent years. Several oral, nasal, gel, and self-injection preparations are now available, providing a wide variety of options customized to each individual's needs., Areas Covered: We searched Google Scholar for keywords related to the different types of testosterone replacement therapy. This review provides information about the benefits and side effects of the newest testosterone preparations, aiming at giving a summary of the options with regard to testosterone replacement therapy to healthcare professionals., Expert Opinion: As testosterone replacement therapy is increasing in popularity, the development of novel ways of administration minimizing side effects associated with testosterone replacement therapy is growing. Nowadays, hypogonadal patients have several options to treat their conditions and can choose the most beneficial method for their individual condition.

Late-onset hypogonadism (LOH) is generally treated with testosterone replacement therapy. Intramuscular injection of testosterone enanthate is used for LOH in Japan but requires regular painful injections administered every 2-3 weeks at a clinic. Testosterone 2% (AndroForte 2 ® [AF2]) is available for treating LOH but is expensive because it is imported. We developed a new 2% testosterone gel (NTG) and hypothesized that in patients with LOH, NTG would improve serum testosterone concentrations and Aging Males' Symptoms (AMS) scores compared with AF2. We enrolled men with low levels of serum free testosterone (<11.8 pg/mL) and androgen deficiency symptoms (AMS score >27). The primary endpoint was equivalent change in serum testosterone concentrations with NTG compared to AF2. Secondary endpoints were equivalent change in AMS scores for each question with NTG compared to AF2. Each of AF2 or NTG was administered to the study subjects (23 men aged 42-71 years) for 4 weeks separated by a washout period of 2 weeks. The subjects were randomly divided into men who first received NTG and those who first received AF2. No subject experienced any adverse events throughout the study. Compared with the baseline values of serum testosterone, those following NTG and AF2 treatment were significantly higher and were also significantly higher in the subjects taking NTG versus AF2. NTG administration significantly improved the AMS score, whereas AF2 did not. This initial study has shown that this new NTG formulation may be effective in improving serum testosterone concentrations and also LOH-related symptoms.

Testosterone replacement therapy (TRT) has been used to treat hypogonadal males with type 2 diabetes mellitus (T2DM) for a long time, despite variable results. This meta-analysis examines TRT's role in hypogonadal males with T2DM. The databases PubMed, Embase, and Google Scholar were searched for relevant RCTs and observational studies. Estimated pooled mean differences (MDs) and relative risks with 95% confidence intervals were used to measure the effects of TRT (CIs). When compared to the placebo, TRT improves glycemic management by significantly reducing glycated hemoglobin (HBA1c) levels (WMD = -0.29 [-0.57, -0.02] p = 0.04; I2 = 89.8%). Additionally, it reduces the homeostatic model assessment levels of insulin resistance (WMD = -1.47 [-3.14, 0.19]; p = 0.08; I2 = 56.3%), fasting glucose (WMD = -0.30 [-0.75, 0.15]; p = 0.19; I2 = 84.4%), and fasting insulin (WMD = -2.95 [-8.64, 2.74]; however, these results are non-significant. On the other hand, HBA1c levels are significantly reduced with TRT; in addition, total testosterone levels significantly increase with testosterone replacement therapy (WMD = 4.51 [2.40, 6.61] p = 0.0001; I2 = 96.3%). Based on our results, we hypothesize that TRT can improve glycemic control and hormone levels, as well as lower total cholesterol, triglyceride, and LDL cholesterol levels while raising HDL cholesterol in hypogonadal type 2 diabetes patients. To this end, we recommend TRT for these patients in addition to standard diabetes care.

Background: Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old, and testosterone therapy (TTh) can improve the quality of life in these patients., Aim: To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively., Methods: This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75 mg) and E100 (8 pellets of 100 mg)., Outcomes: We evaluated adverse events after implantation and followed men at 2, 4, and 6 months for morning laboratory levels (prior to 10 am): serum testosterone, estradiol, hematocrit, and prostate-specific antigen., Results: After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6 months, with most men (82%) dropping to <300 ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300 ng/dL, with similar rates between the groups in the study., Clinical Implications: Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD., Strengths and Limitations: Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort., Conclusion: E100 compounded testosterone pellets are a noninferior option of TTh as compared with Testopel for men presenting with TD., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Objective: This study aimed to investigate the frequency of sexual dysfunction and the effect of short-term testosterone replacement therapy on sexual functions in congenital hypogonadism patients. Furthermore, we sought to reveal the consistency of the self-report scales used for the diagnosis of sexual dysfunction and the relationship between biochemical parameters., Materials and Methods: The study was conducted on 47 young male patients aged above 18 years who were diagnosed with hypogonadotropic hypogonadism. Short (IIEF-5) and long (IIEF-15) forms of the International Index of Erectile Function and Arizona Sexual Experiences Scale (ASEX) were applied before treatment under the supervision of a physician. The patients' blood pressure, height, and weight were measured, and their luteinizing hormone (LH), FSH, and total testosterone levels were recorded. Patients who started their treatments were called for a follow-up checkup after 6 months. Their blood pressure, height, and weight were measured by reapplying the ASEX, IIEF-5, and IIEF-15. In addition, their LH, FSH, and total testosterone levels in the biochemical tests were rerecorded., Results: In this study, the sexual dysfunction status of patients diagnosed with hypogonadotropic hypogonadism before and after treatment was evaluated using the ASEX, IIEF-15, and IIEF-5 scales. A decrease in sexual dysfunction was observed in all three scales after treatment compared with that before treatment. The IIEF-5 and IIEF-15 scales were found to be uncorrelated in terms of the pretreatment values but were correlated in terms of the post-treatment values. Although a correlation was observed between ASEX and IIEF- 5 before treatment, no correlation was detected between ASEX and IIEF-15. After the treatment, ASEX was found to be correlated with both IIEF-5 and IIEF-15. The results of the scales indicated the correlation in all categories, except the pretreatment results of the IIEF-15 scale., Conclusion: The results of the current study demonstrated a significant improvement in the sexual function of hypogonadism patients undergoing short-term testosterone therapy. The ASEX, IIEF-5, and IIEF-15 scales used in the diagnosis and follow-up of sexual dysfunction were useful for evaluating sexual functions in hypogonadotropic hypogonadism patients.

Background: Type 2 diabetes mellitus and pre-diabetes are associated with reduced circulating testosterone levels. However, the role of testosterone replacement therapy in these patients is still conflicting., Objectives: To summarize and critically analyze available data on the possible effect of testosterone administration in men with glucose abnormalities., Materials and Methods: A comprehensive systematic review was performed. When available, meta-analytic data were preferred. To better analyze the relationship between testosterone and the pre-diabetes condition, a systematic analysis was performed and the data obtained with the latter search were used for a meta-analytic approach. Finally, clinical data derived from a consecutive series of 4682 patients seeking medical care for sexual dysfunction at the University of Florence were also considered., Results: Patients with impaired fasting glucose were characterized by a 3 nmol/L lower level of total testosterone when compared to controls. Similarly, impaired fasting glucose was associated with a 1.8-fold increased risk of hypogonadism, when compared to subjects with normal glucose levels. Waist circumference and body mass index resulted as being the best predictors of reduced total testosterone levels. Secondary hypogonadism was two times higher in subjects with impaired fasting glucose when compared to rates observed in the general population. Testosterone replacement therapy was able to improve body composition, insulin resistance, and glucose profile both in impaired fasting glucose and type 2 diabetes mellitus whereas its role on body weight, lipid profile, and sexual function was less evident., Discussion and Conclusion: Weight loss and physical activities are able to improve both metabolic profile and testosterone levels. The combined approach of testosterone replacement therapy and lifestyle modifications could be suggested in symptomatic hypogonadal men to better motivate patients to perform physical activity which can eventually result in weight loss as well as metabolic profile and sexual function improvement. Whether or not these approaches can prevent the development of type 2 diabetes mellitus from pre-clinical conditions requires more studies., (© 2022 American Society of Andrology and European Academy of Andrology.)

Obesity is currently one of the most serious public health problems which affects up to 30-40% of the population, and its prevalence is higher in men than in women. Complications of obesity include atherosclerosis, cardiovascular diseases, and type 2 diabetes mellitus, but it also has a negative impact on the hormonal system and fertility. The hormonal consequences of excess body fat in men are functional hypogonadism, which not only causes clinical symptoms of testosterone deficiency, but is also a risk factor for obesity (a vicious circle mechanism). Reduced fertility in obese men may be a consequence of functional hypogonadotropic hypogonadism (decreased gonadotropins and testosterone secretion, reduced libido, and erectile dysfunction), but other mechanisms associated with excess adipose tissue, like hyperinsulinaemia, hyperleptinaemia, chronic inflammation, and oxidative stress also play an important role. Therefore, in obese men deterioration of semen parameters (sperm concentration, motility, and morphology) and reduced fertility are observed, also concerning the effectiveness of assisted reproductive techniques. Reducing the mass of adipose tissue causes an increase in testosterone concentrations and has a beneficial effect on semen parameters. Functional hypogonadism in obese men should be diagnosed only after exclusion of organic causes of hypogonadism. Lifestyle changes, including physical exercise and low-caloric diet, and optimization of comorbidities, are still first line of treatment. In some patients, if such treatment is ineffective, pharmacotherapy or bariatric surgery may be considered. Testosterone replacement therapy is contraindicated in obese men with functional hypogonadism, especially in those who desire fertility. Selective oestrogen receptor modulators and aromatase inhibitors improve sperm quality but are not recommended for the treatment of hypogonadism in obese men. GLP-1 analogues appear to be effective and safe in the treatment of low testosterone and infertility in obese men and may be the main method of pharmacotherapy in the future.

Background: Male hypogonadism may be associated with micropenis and cryptorchidism in newborn, absent or incomplete pubertal development when it occurs during childhood. During puberty, androgen replacement therapy plays a pivotal role in subjects with hypogonadism to induce sexual maturation, growth acceleration, anabolic effects on fat-free mass growth increasing muscle strength, directly and indirectly on the attainment of peak bone mass in young men. Moreover, in newborns with congenital hypogonadism, androgen therapy could be effective to increase genital size., Summary: Testosterone replacement therapy (TRT) represents the cornerstone of the management of hypogonadism in boys. During puberty, replacement therapy needs to be modulated with gradual dosing increase to better mimic the physiologic pubertal development. Currently, intramuscular testosterone (T) esters (in particular testosterone enanthate) and subcutaneous T pellets are the only formulations approved by the US Food and Drug Administration for delayed puberty, while no preparation is approved for long-term use in the adolescent age. Several new T formulations (as transdermal, nasal, subcutaneous, and oral formulation) are recently developed to improve the pharmacokinetic profile and to ease the administration route increasing patient compliance in adult males with hypogonadism. All these formulations are not approved for pediatric age, although some of them are used as "off-label" regimens. This special issue is aimed to illustrate new T formulations and their potential role as replacement therapy in the pediatric population, as well as to highlight investigational areas to contribute to health care improvement in these patients., Key Messages: Despite the lack of evidence-based guidelines regarding the choice of T formulation in the pediatric population, new formulations appear to have a potential role for TRT in adolescent age. They have been designed for adult age with a little flexibility of dosage, although a few formulations may be attractive for pubertal induction and penile enlargement thanks to their greater flexibility and easing of administration. On the other hand, long-acting and stable formulations could meet post-pubertal needs, increasing TRT compliance in a critical phase as the adolescent age. Further controlled, long-term safety, and efficacy studies for all these new T formulations within the pediatric population are needed., (© 2021 S. Karger AG, Basel.)

Background/aim: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib., Patients and Methods: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation., Results: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment., Conclusion: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Late-Onset Hypogonadism (LOH) is defined as a clinical and biochemical syndrome associated with advancing age. It is characterized by specific symptoms and less specific manifestations due to deficiency of serum testosterone (T) levels., Objective: This review aims to summarize the evidence related to LOH definition, diagnostic approach, and treatment to answer a clinical question: "Is Testosterone the fountain of youth for aging men?"., Methodology: MEDLINE/PubMed and institutional websites were searched for original papers, guidelines, and position statements published in the last ten years., Results: Observational and randomized controlled studies on T replacement therapy in older men have been reported., Discussion and Conclusion: Despite some heterogeneities regarding diagnostic definition, therapeutic target, and testosterone prescription, all guidelines agreed that male hypogonadism should be diagnosed and managed in aged men as in adulthood. However, trials assessing the efficacy of T therapy conducted for male rejuvenating are lacking; thus, T prescription for this purpose is not recommended., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Sexual function, and testosterone (T) levels, progressively decline in aging men. Associated morbidities and metabolic disorders can accelerate the phenomenon. The specific contribution of low T to sexual function impairment in aging men has still not been completely clarified. Similarly, the role of T replacement therapy (TRT), as well as the combination of TRT with phosphodiesterase type 5 inhibitors (PDE5i) for patients with erectile dysfunction (ED), is still conflicting. Here we aim to summarize and critically discuss all available data supporting the contribution of low T to sexual impairment observed with aging as well as the possible role of TRT. Available data on men with sexual dysfunction show that reduced sexual desire is the most important correlate of male hypogonadism. Conversely, aging and associated morbidities substantially attenuate the relationship between ED and T. TRT is effective in improving sexual function in middle-aged and older subjects but its role is small and extremely variable. Lifestyle interventions can result in similar outcomes to those of TRT. In conclusion, it is our opinion that PDE5i along with lifestyle measures should be considered the first approach for treating ED even in subjects with milder T deficiency. When these interventions fail or are difficult to apply, TRT should be considered., (© 2022. The Author(s).)

Osteoporosis does not only affect postmenopausal women, but also ageing men. The burden of disease is projected to increase with higher life expectancy both in females and males. Importantly, osteoporotic men remain more often undiagnosed and untreated compared to women. Sex steroid deficiency is associated with bone loss and increased fracture risk, and circulating sex steroid levels have been shown to be associated both with bone mineral density and fracture risk in elderly men. However, in contrast to postmenopausal osteoporosis, the contribution of relatively small decrease of circulating sex steroid concentrations in the ageing male to the development of osteoporosis and related fractures, is probably only minor. In this review we provide several clinical and preclinical arguments in favor of a 'bone threshold' for occurrence of hypogonadal osteoporosis, corresponding to a grade of sex steroid deficiency that in general will not occur in many elderly men. Testosterone replacement therapy has been shown to increase bone mineral density in men, however data in osteoporotic ageing males are scarce, and evidence on fracture risk reduction is lacking. We conclude that testosterone replacement therapy should not be used as a sole bone-specific treatment in osteoporotic elderly men., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Due to late onset hypogonadism (LOH), there is an increased usage of testosterone replacement therapy (TRT) in the aging male population. Since prostate is a target organ for androgens and anti-androgenic strategies are used to treat and palliate benign prostate hyperplasia (BPH) and prostate cancer (PC), the prevalence of both increases with age, the possible influence of TRT on prostate health becomes highly relevant. The present review summarizes existing data on the associations between endogenous hormone concentrations and prostate growth and concludes that circulating concentrations of androgens do not appear to be associated with the risks of development of BPH or initiation or progression of PC. The explanation for these findings relates to an apparent insensitivity of prostatic tissue to changes of testosterone concentrations within the physiological range., (© 2022. The Author(s).)

Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcome. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. Important considerations going forward are that major depressive disorder is a heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Male hypogonadism affects 10-30% of the male population and is often under-recognized and under-treated. Different replacement formulations exist, each with specific benefits and limitations. These replacements include gels, patches and short- and long-acting injectables. JATENZO® (oral testosterone undecanoate; Clarus Therapeutics Inc., Northbrook, IL, US) is the first oral formulation of testosterone approved by the US Food and Drug Administration. TLANDO® (oral testosterone undecanoate; Lipocine Inc., Salt Lake City, UT, US), another oral testosterone formulation, has also recently been approved by the US Food and Drug Administration. Based on unique chemistry using a self-emulsifying drug delivery system and lymphatic absorption, JATENZO and TLANDO address some of the limitations of other dosing routes while providing a safe option without evidence of liver dysfunction. This review discusses various testosterone treatment options, focusing on the role and pharmacokinetics of the new oral formulations., Competing Interests: Disclosure: Salman Z Bhat and Adrian S Dobs have no financial or non-financial relationships or activities to declare in relation to this article., (© Touch Medical Media 2022.)

Aims: To study the effect of testosterone undecanoate on sexual functions, glycaemic parameters, and cardiovascular (CV) risk factors in hypogonadal men with type 2 diabetes mellitus (T2DM)., Methods: It was an open label, single-arm interventional study where testosterone undecanoate (TU) was used in 105 T2DM males aged 30-60 years with hypogonadism. The effect of TU on sexual functions was assessed using the Aging Male Symptoms (AMS) Scale and the International Index of Erectile Function-5 (IIEF-5) Questionnaire. The effect on glycaemic parameters, cardiovascular risk factors (lipids, high-sensitivity C-reactive protein [hsCRP] and carotid intima media thickness [CIMT]) were assessed over a period of 54 weeks of TU therapy., Results: Prevalence of hypogonadism in T2DM patients was 19.1%, of which 74.1% had functional hypogonadism. AMS and IIEF-5 scores showed negative and positive correlation, respectively, with baseline serum testosterone levels. The AMS score showed a significant reduction of 5.8% and IIEF-5 score improved by 31.5% at 54 weeks of TU therapy. Glycosylated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), and lipids such as total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) were significantly reduced by 0.6%, 10.9%, 6.28%, 9.04%, and 6.77%, respectively, at 54 weeks. CIMT was significantly reduced by 2.57% at 54 weeks, whereas no significant change observed with hsCRP., Conclusions: TU is an effective treatment modality for hypogonadal men with T2DM, and it has beneficial effects on sexual functions, glycaemic parameters, and CV risk factors., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Endocrinology and Metabolism.)

Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic-hypophysis-gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.

Background: Testosterone is an important hormone for the physical and mental health of men; however testosterone administration has also been suggested to adversely affect the cardiovascular system., Aim: To investigate the effects of excessive testosterone administration on vascular endothelial and erectile function in rats., Methods: A total of seventy-five 12-week-old rats were divided into the following groups: Sham, castrated (Cast), castrated with subcutaneous administration of 100 mg/kg/month testosterone (Cast + T1), and castrated with subcutaneous administration of 100 mg/kg/week testosterone (Cast + T4). To observe the changes in testosterone level after the administration, rats were further divided into the following groups: control; T(6.25), wherein the rats were subcutaneously injected with 6.25 mg/kg testosterone; T(25) per week, wherein the rats were subcutaneously injected with 25 mg/kg testosterone per week; and T(100), wherein the rats were subcutaneously injected with 100 mg/kg testosterone per week. The relaxation responses of aorta were measured in these rats using standardized methods, and their erectile function was also evaluated. Statistical analysis of the obtained data was performed using two-way analysis of variance (ANOVA), Tukey-Kramer's multiple comparison test, or Student's t-test., Outcomes: At the end of the study period, endothelial function was evaluated through measurement of isometric tension, while erectile function was assessed using intracavernosal pressure (ICP), mean arterial pressure (MAP), and the expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), sirtuin 1 (Sirt1) and vascular endothelial growth factor A., Results: The ICP/MAP ratio in the Cast group (0.42 ± 0.04) was significantly lower than that in the Sham group (0.79 ± 0.07). The ICP/MAP ratio in the Cast + T1 group (0.73 ± 0.06) was significantly higher than that in the Cast group (P < .01) and that of the Cast + T4 (0.38 ± 0.01) group was unchanged (P > .05). The T(25) and T(100) groups exhibited significantly lower responses to ACh than the control group at 4 weeks (P < .01). Meanwhile, the ICP/MAP ratios in the T(25) group (0.44 ± 0.07) and T(100) group (0.47 ± 0.03) were significantly lower than that in the control group (0.67 ± 0.05) at stimulation frequencies of 16 Hz (P < .05). The expression of androgen receptor, Sirt1, and eNOS were significantly lower while that of iNOS was higher in the T(25) group compared with the control group (P < .05)., Clinical Translation: The results based on this animal model indicate that extremely high testosterone levels may affect endothelial and erectile function., Strengths and Limitations: We found that high-dose testosterone administration decreased endothelial function in aorta and erectile function in rats. A major limitation of this study is that the blood concentration may not be representative of that in humans, and further research is needed., Conclusion: The findings suggest that high doses of testosterone may cause endothelial dysfunction in the aorta and erectile dysfunction in rats and that the blood concentration should be monitored after testosterone administration. Kataoka T, Fukamoto A, Hotta Y, et al. Effect of High Testosterone Levels on Endothelial Function in Aorta and Erectile Function in Rats. Sex Med 2022;10:100550., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)