Sexual dysfunctions affect a large percentage of men and women worldwide. Dietary patterns, such as the Mediterranean diet (MeD), may play a role in the protection of sexual dysfunction. The aim of the present narrative review was to investigate the influence of MeD dietary patterns on male and female sexual dysfunctions. We aimed to evaluate potential mechanisms and clinical implications that could prompt further research and dietary recommendations. An electronic database search was performed to identify and retrieve peer-reviewed articles that examined the association of the MeD with sexual function in adults. Although the included studies were heterogeneous in design and outcome measures, most reported a positive association between increased adherence to a MeD pattern and better sexual function for both sexes. Higher adherence in men results in improved erectile performance and reduced frequency of erectile dysfunction. The results pointed to a possible improvement in all domains of overall sexual satisfaction for women who adhere to the MeD. Potential underlying mechanisms include improvements in vascular health, anti-inflammatory actions, and healthier metabolic profiles, which collectively may exert favorable effects on sexual function. Preliminary evidence supports a beneficial role of the MeD patterns on sexual health in both genders. While the findings are encouraging, confirmation of causality, together with more detailed practical recommendations, will require larger-scale, longitudinal, and interventional studies with standardized measures. Future work should focus on the identification of specific components of the MeD that promote the benefits described and explore personalized interventions to optimize sexual function.

BACKGROUND:Iron overload (IO) disorders, including thalassaemias, hereditary haemochromatosis, and transfusion-dependent anaemias, represent a growing clinical challenge with widespread systemic implications. Reproductive dysfunction remains severely underappreciated despite its high prevalence. Hormonal changes due to iron toxicity are frequently reported, yet are seldom the focus of reproductive medicine, causing fragmented knowledge, inconsistent clinical approaches, and a lack of consensus guidelines. OBJECTIVE AND RATIONALE:This review synthesizes evidence on the impact of IO on male and female reproductive function, including gonadal dysfunction, impaired fertility, sexual dysfunction, and endocrine-metabolic complications. By addressing gaps in study design, diagnostic criteria, and management, we aim to provide the first comprehensive, expert-driven synthesis on the topic, integrating clinical, translational, and mechanistic insights to establish a structured framework for future research and patient care. SEARCH METHODS:A systematic literature search was conducted across PubMed, Scopus, and Web of Science, including studies up to May 2025. Search terms included 'iron overload', 'thalassemia', 'hemochromatosis', 'hypogonadism', 'fertility', 'spermatogenesis', 'ovarian insufficiency', and 'pregnancy'. Quantitative synthesis involved pooling data on prevalence rates of hypogonadism, semen abnormalities, primary and secondary amenorrhoea, age at menarche, and pregnancy outcomes. OUTCOMES:Gonadal dysfunction primarily arises from iron deposition within the hypothalamic-pituitary-gonadal axis, coupled with oxidative damage to Leydig and Sertoli cells in males, disrupting testosterone synthesis and spermatogenesis, and to ovarian follicles and granulosa cells in females, causing reduced ovarian reserve and altered hormonal signalling. Iron-induced hypogonadism is the most frequent endocrine complication, significantly impacting reproductive health and quality of life. Our analysis of 1201 men and 2134 women indicated hypogonadism, reflecting impaired testicular endocrine function, in 47.0% of men; among those specifically assessed for spermatogenesis, over half presented azoospermia (17.6%) or other sperm abnormalities (37.5%). In women, primary amenorrhoea was reported in 45.7%, secondary amenorrhoea in 20.0%, and the weighted mean age at menarche was delayed (14.4 ± 2.1 years). Sexual dysfunction, notably erectile dysfunction, commonly accompanies hypogonadism, further impairing quality of life. Female sexual health has not been investigated at all. Pregnancy is increasingly achievable, but remains clinically challenging. Across 3536 reviewed pregnancies, ART was required in ∼20%, miscarriage occurred in 11.2%, and caesarean section was used in ∼80%. Mean gestational age at delivery was 37.1 ± 3.1 weeks, and mean birth weight was 2.64 ± 0.68 kg. Besides gonadal damage (direct or pituitary-related), systemic iron-related endocrine and metabolic disturbances, including hypothyroidism, growth hormone deficiency, diabetes mellitus, and cardiovascular disease, further aggravate reproductive impairments. Although effective iron chelation therapy reduces the systemic iron burden and is effective in preventing endocrine complications when initiated early, evidence supporting the reversal of established reproductive dysfunction remains limited, highlighting the need to optimize iron control from a young age to preserve reproductive health. WIDER IMPLICATIONS:This review underscores the critical need for standardized gonadal screening to facilitate personalized reproductive care and early intervention in subjects with IO disorders. We propose an integrated clinical framework, combining early endocrine monitoring, fertility preservation protocols, and reproductive counselling. Future multidisciplinary research should prioritize prospective studies with clearly defined reproductive endpoints and explore optimized chelation strategies to safeguard reproductive potential. Addressing these gaps will fundamentally reshape clinical management, bridging haematology, endocrinology, and reproductive medicine.

BACKGROUND:Sarcopenic obesity (SO) is a multifactorial condition characterized by the coexistence of excess adiposity and reduced skeletal muscle mass and function. Its development reflects a complex interaction of metabolic, inflammatory, and endocrine mechanisms that disrupt the balance between anabolic and catabolic processes. MAIN FINDINGS:Endocrine dysfunction is a major driver of the altered adipose-muscle crosstalk characteristic of SO. Hormonal imbalance amplifies mitochondrial dysfunction, oxidative stress, and chronic inflammation, leading to reduced muscle quality and increased visceral and intramuscular fat. Age-related hormonal decline, including reductions in testosterone and estrogens, growth hormone (GH), insulin-like growth factor 1, and thyroid hormones, together with increased catabolic activity of glucocorticoids and the renin-angiotensin-aldosterone system, as well as altered sympathoadrenal signaling, promotes insulin resistance, muscle catabolism, and fat accumulation. Beyond aging, endocrine diseases such as hypogonadism, GH deficiency, hypothyroidism, Cushing syndrome, hyperaldosteronism, and diabetes replicate many features of SO and serve as valuable models for investigating its underlying mechanisms. FUTURE DIRECTIONS:Emerging anabolic or anti-catabolic agents, such as Selective Androgen Receptor Modulators (SARMs), myostatin inhibitors, and ghrelin analogues, show promise but require further validation. Future research should explore endocrine disorders as experimental models of SO, focusing on the shared molecular and hormonal mechanisms that link fat accumulation and muscle loss. Finally, studying endocrine pathways in an integrated manner, rather than focusing on obesity and sarcopenia separately, may identify new hormonal targets for precision therapies aimed at restoring anabolic-catabolic balance and improving metabolic and functional outcomes in individuals with SO.

La sarcopenia è sempre più riconosciuta per i suoi effetti negativi sullo stato funzionale e sulla qualità della vita, spesso associati a disfunzioni metaboliche e ormonali. Queste condizioni possono anche avere un impatto negativo sulla salute sessuale. La letteratura valutata è costituita principalmente da studi trasversali condotti su uomini con età avanzata, ad eccezione di una ricerca che ha riportato una forte associazione tra sarcopenia (o le sue componenti) e disfunzioni sessuali, in particolare la disfunzione erettile. Tuttavia, la significativa eterogeneità dei criteri diagnostici e il numero limitato di studi incentrati sulle donne portano a risultati non conclusivi. Sono necessari ulteriori studi longitudinali con coorti più ampie e criteri di valutazione standardizzati per chiarire i meccanismi sottostanti, stabilire relazioni causali e sviluppare interventi su misura per un trattamento ottimale. Infine, questa rassegna sottolinea la necessità di approfondire tale tematica nelle donne.

BACKGROUND:Fertility preservation in patients with testicular cancer remains a clinical priority, yet the optimal timing for sperm cryopreservation-before or after orchidectomy-remains a matter of debate. OBJECTIVES:The aim of this study was to determine the optimal timing for semen cryopreservation and the best-quality sample for ART. We evaluated various markers, including semen analysis, hormonal profiles, ultrasound analysis and sperm DNA fragmentation (SDF) before and after orchidectomy. MATERIAL AND METHODS:Comprehensive evaluations were conducted, including semen analysis, hormonal profiling, testicular ultrasound, and SDF assessment. RESULTS:Post-orchidectomy samples exhibited a significant decline in total sperm count and progressive motility, as well as an increase in morphological abnormalities. However, a notable and significant reduction in SDF was observed after surgery, suggesting improved chromatin integrity once the tumour had been removed. Elevated preoperative follicle-stimulating hormone (FSH) and higher body mass index (BMI) were identified as risk factors for post-operative oligozoospermia. Hormonal assessment revealed increased levels of FSH and luteinising hormone (LH) post-surgery, with a slight decrease in total testosterone. A significant relationship emerged between testicular volume and changes in SDF: patients with larger contralateral testicular volume experienced a more pronounced improvement in DNA fragmentation, while testicular echotextural heterogeneity was associated with a diminished benefit. DISCUSSION AND CONCLUSION:Although not all participants underwent full diagnostic evaluation, limiting certain analyses, the findings nonetheless underscore the importance of a detailed andrological assessment at the time of diagnosis. This should include semen analysis, hormonal evaluation and ultrasound examination of the contralateral testis to inform personalised fertility preservation strategies. Despite the deterioration in conventional semen parameters, the post-orchidectomy sample demonstrated better DNA integrity and may thus represent the more suitable sample for use in assisted reproductive technologies.

PURPOSE:Klinefelter syndrome (KS), the most common sex chromosome aneuploidy in males, is frequently associated with hypogonadism and metabolic dysfunction during adolescence and adulthood. However, data on the early endocrine and metabolic phenotype of prepubertal individuals with KS remain limited. This study aimed to descriptively characterize reproductive hormone profiles and metabolic parameters in prepubertal boys with 47,XXY KS and to explore early endocrine-metabolic associations across developmental stages. METHODS:A retrospective cross-sectional analysis was conducted on 40 prepubertal boys with confirmed 47,XXY karyotype, aged 0.6-10.0years. Anthropometric, biochemical, and hormonal data were collected. Participants were stratified into three age groups:<2, 2-5, and>5years. Statistical analyses included Kruskal-Wallis and Mann-Whitney U tests, Spearman correlations, and multiple linear regression models adjusted for age and body mass index. RESULTS:Age-related increases in luteinizing hormone, inhibin B, and testosterone suggested early activation of the hypothalamic-pituitary-gonadal axis. Although most metabolic parameters fell within pediatric reference ranges, 27.5% of participants had high-density lipoprotein (HDL) cholesterol<40mg/dL, 17.5% had elevated triglycerides, and 5.0% exhibited insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR]>2.5). HDL levels rose and triglycerides declined with age. Testosterone was positively associated with insulin and HOMA-IR. While the regression model predicting HDL was significant, no single hormone emerged as an independent predictor. CONCLUSIONS:Prepubertal boys with 47,XXY KS may exhibit early hormonal changes and subtle metabolic alterations. These findings support the importance of early endocrine and cardiometabolic surveillance, even before the onset of clinical puberty.

This study aims to quantify bias in self-reported height and weight, assess its impact on body mass index (BMI)-based obesity classification, and identify clinical and demographic predictors of misreporting in a specialist outpatient population. Cross-sectional observational study comparing self-reported and measured anthropometric data, with multivariable regression analyses to investigate factors associated with discrepancies in height, weight, and BMI. A total of 408 adult outpatients were enrolled in a tertiary-level outpatient endocrinology and obesity clinic in Italy. Self-reported height and weight were recorded immediately before standardized measurements. Body mass index was calculated from both data sources. Differences were expressed as Δ height, Δ weight, and Δ BMI. Agreement in WHO BMI categories was evaluated, and sensitivity/specificity for detecting obesity (BMI ≥30 kg/m²) was calculated using measured BMI as reference. Multivariable linear models included sex, age, menopausal status (in women), measured BMI, and waist circumference. Mean (95% confidence intervals) misreporting was +3.13 cm (+2.90 to +3.36) for height, −0.97 kg (−1.29 to −0.65) for weight, and −1.63 kg/m² (−1.80 to −1.47) for BMI. WHO BMI-category misclassification occurred in 20.0% of participants, primarily due to under-classification (19.4%). Sensitivity and specificity for detecting obesity based on self-report were 0.72 and 1.00, respectively. Age predicted height over-reporting; age and measured BMI predicted both weight under-reporting and BMI underestimation. Self-reported anthropometric data systematically underestimate BMI and result in substantial misclassification of obesity. Given the clinical and policy implications of BMI-based criteria for obesity treatment access, objective measurement should be prioritized in all relevant settings.

Background/Objectives: Mammalian sirtuins (SIRTs) are evolutionarily conserved proteins that are epigenetically involved in biological processes such as metabolism and longevity. SIRT1 expression is reduced in metabolic disorders and in complicated diseases such as obesity. However, whether the SIRT1 level in subcutaneous adipose tissue (SAT) matches with its circulating form in obesity is unknown. The aim of our study is to evaluate SIRT1 derived from SAT and plasma of the same subject in individuals with and without obesity to assess whether plasma measurements may provide clinically significant information. Methods: Eleven subjects with obesity (BMI ≥ 30 kg/m2) and six controls without the disease (BMI < 30 kg/m2) were enrolled, and SIRT1 was measured in SAT and plasma by ELISA. Anthropometric parameters, glycemia and transaminases were also assessed. Results: Patients with obesity showed similar levels of SIRT1 in SAT and plasma (1.28 ± 0.45 and 1.9 ± 0.25 ng/mL, respectively, p = 0.243). Patients without obesity showed higher SIRT1 levels in SAT than in plasma (4.19 ± 1.33 and 1.06 ± 0.12 ng/mL, respectively, p = 0.039). An inverse correlation between SAT-derived SIRT1 and BMI was found (r = -0.632, p = 0.007). Conclusions: In this pilot study, our results show that the plasma SIRT1 levels substantially reflect those of SAT in patients with obesity. Given the metabolic role of SIRT1, further comprehensive investigations in larger longitudinal cohorts are needed to support plasma SIRT1 as an eligible diagnostic tool for stratifying metabolic risk associated with fat mass expansion in obesity.

Primary amenorrhoea is defined as the absence of menarche by the expected age, with or without delayed pubertal development in adolescents. It may result from anatomical, genetic, endocrine, and functional causes. Among the latter, we propose the term primary functional hypothalamic amenorrhoea (P-FHA) to describe primary amenorrhoea characterised by hypothalamic-pituitary-ovarian axis suppression in the absence of organic disease. P-FHA is frequently associated with low energy availability (LEA), particularly in individuals with feeding and eating disorders (FEDs) or excessive exercise, often within the spectrum of Relative Energy Deficiency in Sport (REDs). Despite its clinical relevance, P-FHA remains under-recognised, with limited dedicated research. This review aims to synthesise clinical studies addressing P-FHA in the context of FEDs or excessive exercise. A systematic literature search was conducted using PubMed, Web of Science, and Scopus. Studies focusing on P-FHA and its association with FEDs, excessive exercise, and REDs were included. Case reports and aggregated studies combining P-FHA and S-FHA were excluded to ensure specificity. Twenty-four studies addressing patients with P-FHA were identified. Available evidence suggests that the reported frequency of functional hypothalamic causes of primary amenorrhoea may have increased over time, although estimates varied substantially across populations and study designs. In patients with FEDs, the prevalence of PA ranged from 2.4% to 14.8%, while athlete cohorts reported frequencies ranging from 7.3% to 53.8%. FEDs and excessive exercise, including REDs-related conditions, emerged as major clinical settings. Data specifically addressing hormonal profiles or body composition in this context remain limited. P-FHA may represent an early clinical manifestation of chronic LEA occurring during a critical developmental window. Early recognition and multidisciplinary management are essential to minimise potential consequences on growth, skeletal health, reproductive function, body composition, and psychological well-being. Further prospective studies are needed to better define its epidemiology, neuroendocrine mechanisms, and optimal management strategies.

Sarcopenia is increasingly recognised for its detrimental effects on functional status and quality of life. When combined with obesity, in a condition known as sarcopenic obesity, these effects are further exacerbated by metabolic and hormonal dysfunctions. In this scenario, emerging evidence suggests that these conditions may also negatively impact sexual health. To explore this relationship, we conducted a systematic review (PROSPERO registration: CRD42025646427). Out of 943 identified articles, only seven met the eligibility criteria. The majority of studies, mainly cross-sectional studies conducted in older men, except one, reported a strong association between sarcopenia (or its components) and sexual dysfunctions, particularly erectile dysfunction. However, significant heterogeneity in diagnostic criteria and the limited number of studies focusing on women lead to non-conclusive results. Further longitudinal studies with larger, standardised cohorts are needed to clarify the underlying mechanisms, establish causal relationships, and develop tailored interventions for optimised treatment. Finally, this systematic review allows more attention to be paid to a topic that has really been little discussed and lays the groundwork for soliciting new insights, particularly in women.

Objective: Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined. Methods: We employed different Pde5a knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism. Results: Loss of Pde5a resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, Pde5a-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of Pde5a, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations. Conclusions: Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.

Sexually transmitted infections (STIs) are a significant public health issue, especially among adolescents and young adults. Despite improvements in diagnostic tools and treatments, over 1 million new STIs occur daily worldwide, many of which are asymptomatic. These infections can severely affect quality of life and reproductive health, particularly when contracted at a young age. This review provides an overview of STIs’ recent epidemiology data, clinical trends, and diagnostic challenges in Italian adolescents and young adults, focusing on the Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, Thricomonas vaginalis, and Mycoplasma/Ureaplasma species. Worrying new evidence indicates that young women are at a higher risk of contracting STIs than men and multidrug-resistant strains have increased in young heterosexuals. This evidence shows a general change in lifestyle, where a lack of awareness about the risks of STI reflects a significant educational gap. To address the rising STI rates, targeted school educational interventions and innovative multidisciplinary healthcare models, such as the hub-and-spoke approach, are needed.

Background/Objectives: HPV is the most common sexually transmitted infectious agent worldwide and adolescents are at high risk of contracting HPV. The aim of our study was to find out how much adolescents know about the virus and its effects, and to obtain information on attitudes and behaviors regarding HPV vaccination to close these gaps. Methods: As part of the ESPRIT project, 598 lower secondary (11–14 years) and upper secondary (14–19 years) school students from three Italian regions were surveyed between December 2023 and March 2024 using a seven-question online questionnaire on awareness, knowledge, and attitudes about HPV and the HPV vaccine. Count and zero-inflation models were used to determine correlations between sexes, urban/suburban, province of residence, and school type with knowledge. Results: Lower secondary students believed that HPV causes HIV/AIDS (8.9%) or hepatitis C (3.0%) and rarely mentioned anal (21%) and oral sex (9.6%) as ways of transmission. Among upper secondary students, misconceptions were similar, with worrying rates of students stating that HPV only causes cancer in females (18%) or males (2.4%), and low rates of identifying transmission risk through anal (41%) and oral (34%) sex and genital contact (38%). The HPV vaccination rate was quite low (47% in lower secondary students, 61% in upper secondary students). In the regressions, sex, urban/suburban area, and province were the variables associated with higher levels of knowledge for lower secondary students; for upper secondary students, level of knowledge was associated with sex, urban/suburban area, school type, and province of residence. Conclusions: Awareness and knowledge of HPV and the HPV vaccine are low among Italian students in this study and reported vaccination coverage is below the national target. Coordinated efforts at the national level are needed to address this public health issue.

Craniopharyngiomas are frequently diagnosed during childhood and adolescence, crucial periods for physical and psychosocial development. Despite improvements in survival rates, patients with childhood-onset craniopharyngioma face a wide array of lifelong complications, which emerge or worsen during adolescence, complicating the transition to adult care. Nevertheless, the transition age (15–25 years) remains an understudied phase in clinical practice. This narrative review synthesises current literature on the endocrine, neurocognitive, and metabolic consequences of transition-age childhood-onset craniopharyngiomas, providing a practical clinical approach to their diagnosis and management, along with an overview of emerging treatment strategies. Childhood-onset craniopharyngiomas are frequently associated with pituitary hormone deficiencies, which typically worsen post-treatment. While replacement protocols largely mirror those for adult patients, particular emphasis should be placed on patient education and optimal timing of treatment, especially regarding puberty induction and growth hormone replacement. Emerging therapies, such as long-acting growth hormone and modified-release hydrocortisone, should be considered to improve compliance. Hypothalamic dysfunction, both pre- and post-treatment, can lead to obesity, sleep disorders, and cognitive impairment. GLP-1 receptor agonists and melanocortin receptor agonists have recently shown promise in managing hypothalamic obesity. Sleep disturbances and cognitive impairment, often overlooked in clinical practice, should be systematically assessed in patients with hypothalamic involvement. Cardiovascular and bone health complications should be proactively addressed to improve long-term outcomes. Childhood-onset craniopharyngioma survivors require multidisciplinary care, particularly during the transition to adulthood. Timely endocrine management, individualised treatment strategies, and emerging targeted therapies are crucial for optimising quality of life and metabolic and neurocognitive outcomes.

CONTEXT:Medical therapy for Cushing syndrome (CS) typically aims to reduce daily cortisol output without addressing circadian rhythm restoration. No licensed drugs target this goal. OBJECTIVE:We investigated the efficacy and safety of timed, once-daily osilodrostat administration in improving circadian cortisol profiles in CS. METHODS:A prospective, multicenter study evaluated patients with well-controlled CS on a stable twice-daily osilodrostat therapy before and 60 to 90 days after transitioning to a single equivalent daily dose at 19:00 ± 1 hour. Circadian steroid analysis was performed on saliva, serum, and urine using ultra-high performance liquid chromatography-tandem mass spectrometry. Additional assessments included cardio-metabolic markers, quality of life, sleep function, and safety outcomes. RESULTS:Sixteen patients (4 males; 7 pituitary, mean age 53.3 ± 11.8 years) were enrolled. At baseline, CS was well-controlled with a mean osilodrostat dose of 4.2 ± 1.3 mg. After transitioning, salivary cortisol exposure decreased significantly during the afternoon to early morning period (AUC16:00-08:00: -6.1 [-0.15 to -12.1] ng/mL/h, P = .029). Quality of life and sleep improved (CushingQoL: +4.2, P = .029; Pittsburgh Sleep Quality Index: -1.7, P = .049). Serum steroid precursors, including 11-deoxycorticosterone (-3.1 ng/mL/h, P = .008) and 11-deoxycortisol (-17.8 ng/mL/h, P = .005), decreased. Eight patients advancing dosing to 16:00 ± 1 hour showed comparable reductions, with phase shifts in acrophase and nadir. No patients developed adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control. CONCLUSION:Once-daily osilodrostat effectively and safely treats patients with biochemically controlled CS, improving circadian cortisol profiles, quality of life, and sleep. Findings support further exploration of chronotherapy-based approaches in CS management.

Sex steroids are pivotal in skeletal development and maintenance throughout life. Testosterone primarily drives male cortical bone growth and periosteal expansion, particularly during puberty, while estradiol (E2) is essential for trabecular bone formation and inhibiting resorption. The conversion of testosterone to dihydrotestosterone and E2, the transport proteins, the somatotropic axis, and the nonandrogenic functions of the testis underscore the intricate interplay protecting male bone health. Clinical models, including estrogen resistance, aromatase deficiency, and complete androgen insensitivity syndromes, highlight E2's critical role in maintaining male bone integrity. The use of aromatase inhibitors and androgen deprivation therapy reveals the adverse effects of estrogen and androgen blockade, often resulting in substantial bone loss. Gender-affirming hormone therapies provide further insights into testosterone's influence on cortical bone during development and the maintenance role of sex steroids in adulthood. This review digs into the link between male hypogonadism and osteoporosis, emphasizing testosterone replacement therapy (TRT) and findings from major trials, including T-Trial Bone, T4Bone, and TRAVERSE Fracture. While TRT has been shown to improve bone mineral density, its effect on fracture risk remains inconclusive. Unexpected findings from the TRAVERSE Fracture trial highlight the importance of caution and confirm that antiresorptive therapies remain the first-line treatment for male osteoporosis. Investigating the synergistic effects of combining TRT with antiresorptive therapies, the effect of therapeutic timing on peak bone mass accrual, and the role of confounders in fracture risk are promising areas for future research to optimize male skeletal health.