Testosterone Replacement Research Articles (Page 1)

Congenital genetic disorders have traditionally considered to be lifelong. An exception to this long-held view is the reversal of congenital hypogonadotropic hypogonadism (CHH). Approximately 10% of males with CHH undergo reversal with sustained hypothalamic-pituitary-gonadal (HPG) axis activation and/or fertility after discontinuing hormonal treatment. We conducted a structured, systematic literature search to identify relevant articles published on reversal of CHH in males (up to 2025). This mini-review provides a concise overview and synthesizes findings to inform clinical management of CHH. We identified 31 articles reporting reversal of CHH in males including cases of severe GnRH deficiency and individuals harboring pathogenic variants in CHH genes. Reversal is distinct from delayed puberty and olfactory phenotype (i.e., anosmia) does not predict HPG axis recovery. In males, reversal universally occurs after achieving normal serum testosterone levels on hormone therapy. Testicular growth on testosterone replacement is a hallmark of HPG axis activation - yet reversal is not always lasting. Cases exist on a continuum from normosmic individuals with severe GnRH deficiency to milder cases with partial spontaneous puberty (Pasqualini syndrome subtype). Pathogenic variants in GNRHR favor reversal while ANOS1 variants virtually exclude HPG axis recovery. The reversal phenomenon in males has expanded our understanding of the regulation of human reproduction - yet precise mechanism(s) have yet to be elucidated. Clinicians can use clinical signs and genetic testing to identify patients who may benefit from close surveillance of reversal. Insights from reversal of CHH reversal have helped shape the first tailored approach managing CHH.

Introduction: Testosterone replacement therapy (TRT) is linked to venous thromboembolism (VTE) and cardiovascular risks, but intracardiac thrombus formation has not been reported. This case highlights rapid left ventricular (LV) thrombus development and thromboembolic events in a patient on TRT, with no traditional hypercoagulable risk factors. Case Presentation: A 48-year-old male with tobacco use and daily alcohol intake presented with progressive dyspnea. Transthoracic echocardiography (TTE) revealed reduced ejection fraction (24%) and left ventricular dilatation (LVIDD 6 cm). There was no thrombus visualized in the left ventricle. Coronary angiography showed no obstructive disease. Guideline-directed medical therapy (GDMT) was initiated. He returned within 24 hours of discharge with dizziness and aphasia. Computed tomography angiography (CTA) identified a partially occluding embolus in the left middle cerebral artery (MCA), confirmed by MRI as an acute left frontoparietal infarct. Repeat TTE (5 days from prior TTE) demonstrated a large, mobile apical septal LV thrombus. CT imaging also revealed pulmonary embolism and splenic infarction. Hypercoagulable workup (prothrombin mutation, Factor V Leiden, cardiolipin antibodies) was negative. The patient disclosed scheduled testosterone injections for hypogonadism, with a total testosterone level of 1,081 ng/dL (reference: 300–1,000 ng/dL). Discussion: This case illustrates rapid LV thrombus formation and thromboembolism temporally linked to TRT. Despite guideline-based heart failure management, thrombus developed within 5 days of prior TTE. Prior studies associate TRT with VTE and stroke, but this is the first report of acute LV thrombus and multi-organ emboli in the absence of traditional hypercoagulable states. Proposed mechanisms include TRT-induced erythrocytosis, platelet activation, and endothelial dysfunction [1–4]. Conclusion: TRT may precipitate intracardiac thrombosis and thromboembolic events even without classical risk factors. Clinicians should consider TRT cessation and anticoagulation in similar cases, emphasizing cautious patient selection and monitoring. Further research is needed to clarify TRT’s role in hypercoagulability and cardiac remodeling.

Description of Case: A 58-year-old male with history of primary hypogonadism on testosterone replacement therapy, coronary artery disease with prior myocardial infarction, type 2 diabetes, hypertension, hyperlipidemia, obesity, and obstructive sleep apnea on home CPAP presented with typical anginal chest pain. EKG was consistent with inferior STEMI. He was taken for emergent coronary angiography, revealing the culprit lesion: 100% occlusion of the left circumflex coronary artery (LCx) with TIMI 1 flow. Percutaneous Coronary Intervention (PCI) was performed with placement of two drug-eluting stents, and he was given loading doses of dual antiplatelet therapy. There was significant thrombus present requiring manual aspiration thrombectomy, with intravascular ultrasound confirming underlying atherosclerosis. Ultimately, TIMI 3 flow was achieved. Post-PCI, the patient had significant anginal chest pain refractory to medical management. EKG demonstrated resolution of ST elevations, and echocardiogram showed moderately reduced ejection fraction without pericardial effusion or structural complications. His initial hemoglobin was 23.1 (hematocrit 65%), and testosterone levels were markedly elevated above 1,500. We suspected coronary thrombosis may have been partially driven by hyper viscosity from polycythemia, so we performed three therapeutic phlebotomy treatments of 500mL each and gave three one-liter intravenous fluid boluses, until hemoglobin levels were below 18. His chest pain improved markedly after phlebotomy, and he was discharged with close cardiology and endocrinology follow-up. JAK2 mutation test was negative, and testosterone supplementation was discontinued for the interim. Discussion: Only observational data exists thus far, but testosterone-induced polycythemia has been noted as a risk factor for major adverse cardiac events (MACE) in men on testosterone therapy with hematocrit>52% compared to those on therapy with hematocrit<52% 1 . Moreover, any degree of polycythemia is associated with increased MACE as early as 3 months after testosterone initiation 2 . Phlebotomy is mainstay treatment for JAK2-positive polycythemia, targeting hematocrit<45% to reduce MACE 3 . This case demonstrates how ACS in the setting of polycythemia may present with a thrombotic phenotype in younger patients. Furthermore, post-PCI chest pain may be alleviated with therapeutic phlebotomy when hematocrit is dangerously high, regardless of JAK2 positivity.

While testosterone replacement therapy (TRT) is generally effective in restoring testosterone levels and improving quality of life, its dermatological adverse effects are underreported compared to cardiovascular and oncologic risks. This review aims to synthesize existing evidence on cutaneous complications associated with TRT to better inform clinical practice. A scoping review was conducted using PubMed, Scopus, and Cochrane databases to identify studies reporting dermatologic adverse events related to TRT in adult men. Inclusion criteria focused on original studies documenting skin-related side effects in TRT recipients. Ten studies met eligibility: eight prospective clinical trials and two retrospective chart reviews published between 2006 and 2025. Data were extracted and summarized narratively. Across all included studies, dermatologic adverse events were consistently reported. Acne was the most frequent, affecting 0.6%-9.1% of participants, with the lowest incidence in oral formulations. Pruritus occurred in up to 10.0%, rashes in up to 5.3%, and abnormal hair growth in up to 5.3%. Injectable formulations were generally associated with higher rates of acne and systemic reactions than topical or oral preparations. Despite the prevalence of these effects, most studies lacked standardized reporting or detailed management strategies. Dermatologic side effects of TRT, though often considered non-severe, can significantly impact patient satisfaction, adherence, and quality of life. Acne and other cutaneous reactions vary by delivery method and patient susceptibility, emphasizing the need for clinician awareness, patient counseling, and better adverse event reporting. Future research should standardize dermatologic outcome measures and explore effective prevention and management strategies to improve the safety and tolerability of TRT.

Constitutional delay of growth and puberty (CDGP) is the most common cause of short stature and delayed puberty in children. Little is known about the changes in sex steroid and insulin like growth factor-1 (IGF-1) concentrations, body mass index (BMI), and growth velocity (GV) after testosterone therapy for CDGP. Retrospective chart review of 16 boys with CDGP treated with six monthly doses of testosterone cypionate 50 mg was carried out. Data on weight, BMI, height, GV, IGF-1, testosterone level and bone age radiographs were collected prior to testosterone treatment, six months and one year after the last testosterone injection. At six months and one year from last dose of testosterone, the mean height, weight, GV, mean IGF-1 and testosterone levels improved from baseline. There was a positive correlation between testosterone and GV (r= 0.74, p-value= 0.008) six months after the last testosterone injection. At six months and one year after the last testosterone injection, the weight, BMI, growth velocity, IGF-1 concentrations and testosterone levels were higher than at baseline, and puberty progressed when compared to baseline. Testosterone levels six months after completion of testosterone cypionate were positively correlated with growth velocity confirming the effect of sex steroids in pubertal growth.

Effects of testosterone deficiency and therapy on the cardiometabolic syndrome in men.

Testosterone deficiency (TD), or male hypogonadism, affects up to 25% of Canadian men aged 40 to 60. Testosterone replacement therapy (TRT) is widely used to manage symptoms of TD. Despite over seven decades of clinical use, the relationship between TRT and major adverse cardiovascular events (MACE) remains unclear. To investigate the association between TRT and MACE using a large population-based database. A propensity-weighted, retrospective cohort study was conducted using provincial health administrative databases. Men were eligible if they had no prior TRT use or MACE and maintained at least one year of provincial health coverage between April 1, 1995, and December 31, 2018. TRT was defined as having at least two prescriptions filled within one year for testosterone products (capsules, gels, patches, or injections). MACE was defined as the first occurrence of myocardial infarction, coronary revascularization, ischemic stroke, or hospitalization for heart failure. A logistic regression model including age, socioeconomic status, index year, diabetes, hypertension, dyslipidemia, and renal disease generated propensity scores. Stabilized inverse propensity treatment weighting was applied. A Cox proportional hazards model was used to assess time to first MACE. Among 6949 men who received TRT and 415 837 controls, TRT was associated with a 27% increased risk of MACE (HR 1.27, 95% CI: 1.16-1.39) in weighted analyses. Among 7306 men diagnosed with TD and 442 602 matched controls, those with TD also showed a 27% increased risk of MACE (HR 1.27, 95% CI: 1.16-1.39). Median time to MACE was 2828days in the TRT group and 2707days in controls. MACE occurred in 9.95% of TRT users versus 5.56% of controls. Clinicians should be aware that both TRT and underlying TD are associated with increased cardiovascular risk. Assessment of comorbidities and patient-specific cardiovascular risk remains essential when initiating TRT. This study leverages a large, real-world, population-based dataset with robust propensity weighting methodology. However, unmeasured confounding such as obesity, smoking, or physical activity levels may influence outcomes. Diagnostic coding limitations may also affect TD case identification. Both TRT use and TD were associated with a significantly increased risk of MACE. Whether TRT independently drives this risk or merely reflects underlying disease requires further investigation. Risk stratification and shared decision-making should guide the initiation of TRT.

Preoperative Testosterone Replacement Therapy Is Associated With Increased Complication Risk After Total Knee Arthroplasty: A Propensity-Matched Analysis of 13,250 Patients.

Type 2 diabetes mellitus (T2DM) is frequently associated with testosterone deficiency, which affects male reproductive function. Currently, exogenous testosterone replacement therapy poses inherent risks, underscoring the need to develop safer and more effective treatment strategies. This study aimed to elucidate the mechanism by which ML221, a potent apelin receptor (APJ) functional antagonist, promotes testosterone secretion, and alleviates reproductive dysfunction. Diabetic mouse models demonstrated reduced testosterone levels, impaired spermatogenesis, and low sperm quality. Elevated APLN expression impaired Leydig cell function and testosterone synthesis. Treatment with ML221 restored testosterone levels and spermatogenesis in diabetic mice. Mechanistically, ML221 regulated Leydig cell metabolism by elevating S-D-lactoylglutathione levels, reducing mitochondrial reactive oxygen species, preserving mitochondrial membrane potential, and enhancing adenosine triphosphate production. At the epigenetic level, ML221 enhanced the binding of nuclear receptor subfamily 2 group F member 2 to the promoters of testosterone-synthesizing genes, thereby facilitating testosterone biosynthesis. These findings advance the understanding of the male reproductive system in the context of diabetes and highlight ML221 as a potential therapeutic approach for T2DM-induced testosterone deficiency.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12964-025-02474-8.

Testosterone replacement therapy (TRT) remains controversial despite its established role in symptomatic hypogonadism. Cardiovascular (CV) safety is debated: while the TRAVERSE trial found no excess of major CV events, observational data remain conflicting. Glycemic outcomes add further complexity: real-world studies suggest HbA1c reductions in men with type 2 diabetes, but evidence is heterogeneous. In obesity-related metabolic hypogonadism, substantial weight loss from GLP-1/GIP receptor agonists such as Tirzepatide has been shown to restore testosterone levels, prompting discussion on whether metabolic therapy should precede TRT. Safety monitoring also remains critical-prostate health surveillance is essential despite no proven increase in cancer risk, and polycythemia continues to be a leading hematologic complication requiring vigilant hematocrit monitoring. Testosterone replacement therapy sits at the intersection of endocrinology and metabolism, cardiology and urology. Recent data support careful, individualized use, but controversies persist, and novel metabolic agents may redefine treatment algorithms. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S22]

Kallmann syndrome (KS) is a rare genetic disorder (1:4,000–10,000, predominantly in males) marked by hypogonadotropic hypogonadism and anosmia due to defective GnRH neuron migration. Mutations in KAL1, FGFR1, and other genes are implicated. A 20-year-old male presented with absent puberty and lifelong anosmia. He had eunuchoid habitus, micropenis, gynecomastia, small bilateral testes, Tanner stage I genitalia, and absent axillary/facial hair. Hormonal profile confirmed hypogonadotropic hypogonadism (testosterone 30.2 ng/dL, LH 0.24 mIU/mL, FSH 1.68 mIU/mL) with normal prolactin and thyroid function. Semen analysis showed azoospermia, and the karyotype was 46, XY. Scrotal USG demonstrated bilateral testicular atrophy (R: 2.2 × 1.0 cm; L: 1.7 × 0.9 cm). Abdominal USG was normal. Brain MRI revealed a normal hypothalamic–pituitary axis with structurally preserved olfactory bulbs. The patient received intramuscular testosterone decanoate (250 mg/mL) every 21 days, gradually increased from half to one ampoule. After four months, testosterone rose to 289 ng/dL, FSH increased slightly (2.03 mIU/mL), and LH remained suppressed (0.40 mIU/mL). This case highlights the diagnostic challenge of KS, with the classic triad present despite normal MRI findings of the olfactory bulbs. Diagnosis was confirmed through clinical, hormonal, cytogenetic, and radiological evaluation, and testosterone therapy promoted endocrine recovery and initiation of secondary sexual characteristics. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S62]

Testosterone is a hormone that plays a crucial role in men, maintaining muscle mass and bone density and regulating sexual function. This hormone is associated with the inhibition of obesity and the prevention of obesity-related diseases, such as type 2 diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary artery disease, and non-alcoholic fatty liver disease. Obesity has a complex effect on testosterone production and metabolism. Chronic inflammation and hormones associated with obesity cause dysfunction of the hypothalamic-pituitary-gonadal axis, leading to reduced testosterone production. Studies have demonstrated that blood testosterone levels decrease in obese men, suggesting a reciprocal interaction between decreased testosterone and obesity. Additionally, decreased testosterone levels are closely associated with aging. The natural decline in testosterone levels with age can lead to visceral obesity, thus increasing the risk of type 2 diabetes and other chronic metabolic diseases. In many countries, the population is aging, and the importance of testosterone replacement therapy (TRT) for aging men with low testosterone is increasing. Recent studies have expanded our understanding of TRT, highlighting its potential benefits in obese individuals, its interaction with gut microbiota, and the influence of racial differences and genetic polymorphisms on treatment efficacy. This review provides a comprehensive overview of the physiological mechanisms linking obesity and testosterone, current therapeutic approaches including TRT, and emerging research directions that may inform personalized treatment strategies.

BackgroundTestosterone therapy can also lead to physiologic changes in structures such as the endometrium and ovaries. Given this, testosterone may alter uterine bleeding patterns. Although ultrasounds are routinely performed for the purposes of uterine bleeding on testosterone, there has been little data to support this practice. The goal of this study was to evaluate differences in pelvic ultrasound findings among transgender and gender-diverse individuals on testosterone and determine whether these findings are useful for monitoring abnormal uterine bleeding in this population.MethodsThis was a retrospective cohort study examining ultrasound findings in transgender and gender-diverse individuals on testosterone who did and did not experience uterine bleeding within 3 months of ultrasound. Demographic and clinical data collected from the EMR included age at testosterone initiation, age at ultrasound, latest body mass index (BMI), latest testosterone and estrogen levels, testosterone dose and route of administration. Additional reproductive history variables included age at menarche, history of menstrual concerns prior to testosterone therapy, and presence of gynecologic comorbidities. Ultrasound findings were reviewed for the indication for imaging, uterine size, endometrial stripe thickness, ovarian size, and any radiology comments regarding the endometrium, uterine body, or ovaries. Chi square analysis was used to test for differences between groups for binary or categorical variables, and one-way analysis of variance (ANOVA) was used to test for differences between groups for continuous variables.ResultsThe final sample included a total of 144 individuals on gender-affirming testosterone, 63 who experienced uterine bleeding within 3 months of ultrasound and 81 who did not experience bleeding. There were no significant difference in endometrial stripe measurements between the two groups (p = 0.901) or in any other measurements taken by ultrasound.ConclusionsOur study found no significant differences in pelvic ultrasound findings between transgender and gender-diverse individuals on testosterone with and without uterine bleeding, suggesting that routine ultrasound has limited diagnostic utility in this population. Given the multifactorial nature of bleeding on testosterone, including hormonal and metabolic influences, a trial of medical management may be preferable before imaging in low-risk individuals - particularly given risk that vaginal ultrasounds could exacerbate gender dysphoria.

Osteoporosis is a chronic, progressive illness characterized by low bone mass and strength of the bone, resulting in increased risk of bone fracture. Testosterone replacement therapy (TRT) is one of the main treatments for male osteoporosis. However, TRT causes side effects, mainly prostate cancer and liver dysfunction. So, an alternative agent is required. This study was conducted to determine the effects of Eurycoma Longifolia (EL) on serum testosterone in orchidectomized rats, the androgen-deficient osteoporosis model. Thirty-two male Sprague Dawley rats were divided into 4 groups, with 8 rats in each group, which followed different treatments for 6 weeks, namely the sham-operated group, orchidectomized-control group, orchidectomized group and treated with EL (15 mg/kg), and orchidectomized group and treated with testosterone (8 mg/kg). Body weights of rats were taken weekly, and blood samples were taken before and after treatment to measure serum testosterone using the Testosterone ELISA technique. The result showed that EL and testosterone therapy have led to an increase in rat body weights. The levels of testosterone in the serum were considerably higher (p < 0.05) for the orchidectomized group treated with testosterone compared to the orchidectomized control and sham group. The orchidectomized group treated with EL also showed a significant increase in serum testosterone (p < 0.05) compared to the same group before treatment, but there was no significant difference between the other groups. In conclusion, EL treatment was successful in raising the level of serum testosterone in orchidectomized rats

Testosterone supplementation is increasingly widespread and has well established beneficial effects on sexual function and metabolic health. However, there remains uncertainty regarding associated cardiovascular risks. Human genetics studies demonstrated that 'Mendelian randomization' (MR) approaches recapitulate the beneficial effects of testosterone therapy, here we apply this to cardiovascular disease. We performed a Mendelian randomisation study to assess the causal effect of higher circulating testosterone on coronary artery disease (CAD). We also tested the phenotypic association between measured circulating testosterone and CAD in the cohort of men aged 40-69. Testosterone genetic instrument data had been derived from 425,097 European ancestry adults from the UK Biobank study; and CAD from SNP-level summary statistics from 1,165,690 individuals in CARDIoGRAMplusC4D. CAD as defined in CARDIoGRAMplusC4D was the main outcome. In longitudinal analyses, CAD was defined according to medical records and self-report. We found that higher genetically-predicted circulating testosterone conferred higher risk of CAD in men (OR: 1.17, 95% CI [1.07-1.27], P=3.32×10-4). There was no evidence of an effect in women (OR: 1.01, 95% CI [0.94-1.10], P=0.73). The genetic association in men appeared to be mediated by higher blood pressure. In longitudinal observational analyses, a directionally-opposite association was observed in men, likely arising due to confounding by Type 2 diabetes and BMI. These data suggest increased testosterone may increase risk of cardiovascular disease and recommend this safety concern should be a focus in future clinical trials for testosterone supplementation.

Approximately 25 million people worldwide do not identify with the sex assigned at birth. Treatment options for gender dysphoria are multidisciplinary and include gender-affirming hormone therapy and surgery. Uterus transplantation in women without a uterus is promising for treating absolute uterine factor infertility, and its efficacy has been demonstrated through successful transplant surgeries and subsequent births via cesarean section following single embryo transfer. Transgender men undergoing gender-affirming hysterectomy to alleviate gender dysphoria symptoms should be considered as potential uterus donors for transplantation. Although transgender men show positive attitudes toward uterus donation to women with infertility, who do not have a uterus, long-term gender-affirming testosterone therapy induces uterine changes that necessitate assessment before donation for transplantation should be considered. This commentary highlights the major challenges associated with uterus donation by transgender men for transplantation.

Disclosure: A.K. Clift: I am an employee of Manual (Menwell Ltd), a healthcare provider that provides testosterone replacement therapy. H. Johnson: I am an employee of Manual (Menwell Ltd), a healthcare provider that provides testosterone replacement therapy. V.N. Liu: I am an employee of Manual (Menwell Ltd), a healthcare provider that provides testosterone replacement therapy. D.R. Huang: I am an employee of Manual (Menwell Ltd), a healthcare provider that provides testosterone replacement therapy. M. Khera: consulting fees from Endo, Inc., serves as a consultant for Halozyme, Marius Pharmaceuticals, Petros Pharma, AbbVie, Inc., Tolmar, and Boston Scientific, and holds stocks of Sprout Pharmaceuticals.The bidirectional interplay between testosterone deficiency (TD) and cardiometabolic health in men is complex. Cross-sectional studies show associations between lower endogenous testosterone and poorer metabolic health, and trials report that testosterone replacement therapy (TRT) benefits metabolic health in men with metabolic syndrome or diabetes but without TD. However, the longitudinal impact of TRT on key cardiometabolic markers in men with TD is poorly understood. This retrospective cohort study utilized routinely collected data from men commencing TRT for TD with UK-based private healthcare providers. We examined trends over 12 months in the following markers: total cholesterol, HDL, LDL, HbA1c, triglycerides and the triglyceride: HDL ratio. Mixed effects methods were used to model marker trajectories during the course of TRT, and relative percentage changes were calculated from 0 to 12 months. Relative changes were estimated overall and in sub-groups (by age group, BMI group, and in men with elevated baseline marker results). The cohort comprised 4,307 men (median age 41 years; baseline BMI 28.4 kg/m²) starting TRT between Nov 2019 and Oct 2024. There were modest changes in total cholesterol (-7.20%, p<0.01), HDL (-11.38%, p<0.01), and HbA1c (-3.38%, p<0.01) over 12 months of TRT. No changes in LDL were observed (0%). Larger differences were observed for triglycerides and triglyceride:HDL ratios. The relative change in triglycerides at the cohort level was -28.37%; for men aged <50 this was -27.23%; for men aged 50+ this was -30.23% (all p<0.01). In men with baseline triglycerides >2.3mmol/L, the relative change at 12 months was -43.42% (p<0.01). The relative change in triglyceride:HDL ratio at 12months was -19.60%; in men aged <50 this was -19.50% and for men aged 50+ this was -25.64% (all p<0.01). Triglyceride:HDL changes across BMI categories ranged between -14.02% (up to 25) to -27.31% (30-39.9) (p<0.01). We observed that men with the highest baseline triglyceride:HDL ratios (>6) had a relative change of -66.49% at 12months (p=0.012). The cardiometabolic effects of TRT were most pronounced on triglyceride levels, with significant reductions observed over 12 months in both total triglycerides and the triglyceride:HDL ratio. The latter is a strong predictor of cardiometabolic risk. These reductions were of larger magnitude in men with elevated baseline values, suggesting potential of TRT to improve longer-term metabolic health in hypogonadal men. Further study is needed to quantify these potential benefits.Presentation: Saturday, July 12, 2025

Disclosure: S.G. Ribeiro: None. K.O. Eskandar: None. A.D. Francisco: None. E.B. Oliveira: None. J.C. Neto: None. K. Woodhams: None.Background: Testosterone therapy is increasingly utilized in postmenopausal women to manage symptoms and enhance quality of life. However, concerns persist regarding its potential association with breast cancer risk. This meta-analysis critically evaluates the incidence of breast cancer in postmenopausal women receiving testosterone therapy compared to population-based controls.Objective: To assess the association between testosterone therapy and breast cancer risk in postmenopausal women compared to population-based controls.Methods: A systematic review and meta-analysis were conducted to assess breast cancer incidence in postmenopausal women using testosterone therapy. A comprehensive search of PubMed, Cochrane, and Embase was conducted to identify randomized, non-randomized, and observational studies.Pooled risk ratios (RRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical significance was assessed via p-values for overall effect. Results: A total of 5,747 postmenopausal women receiving testosterone therapy were analyzed, with a follow-up ranging from 4.4 to 10 years. Breast cancer incidence in testosterone users was consistently lower compared to the population-based cancer incidence data, with individual study risk ratios (RRs) ranging from 0.530 to 0.638. The overall meta-analysis confirmed this reduction, with a pooled RR of 0.592 (95% CI: 0.381-0.920; p = 0.02; I² = 21%), indicating a statistically significant decrease in breast cancer risk among postmenopausal women receiving testosterone therapy. Conclusions: In this meta-analysis of observational studies, testosterone therapy was not associated with an increased risk of breast cancer. Instead, pooled estimates suggest a statistically significant reduction in risk (p = 0.02 for RR, p = 0.04 for OR). The data indicate that testosterone therapy may be protective, but due to the observational nature of the included studies, further randomized controlled trials (RCTs) are necessary for definitive conclusions.Presentation: Saturday, July 12, 2025

Disclosure: A. Al-Thunaibat: None. L.L. Ponce Rosas: None. K. Sanu: None. A. Abualnil: None. J.S. Martins Torrontegui: None. C. Penaherrera: None.Introduction: The use of testosterone has become increasingly prevalent in recent years, both through medical prescriptions and non-medical, unauthorized channels. While testosterone is primarily prescribed for the management of hypogonadism, it is also widely misused by athletes and bodybuilders to enhance muscle mass and physical performance due to its anabolic effects. Herein, we presented a case of PE and DVT secondary to testosterone use in a patient with no other risk factors for venous thromboembolism (VTE). Case Presentation: A 45-year-old male with a medical history of HTN, primary hypogonadism, polycythemia secondary to testosterone supplement, asthma, and OSA on CPAP presented to the ED with progressive shortness of breath. He had been on testosterone replacement therapy (TRT) for over seven years. Due to polycythemia, he was advised to undergo therapeutic phlebotomy twice monthly but had been non-compliant for the past month. On presentation, laboratory results showed Hgb 17.8 g/dL, HCT 55%, RBC 6.6 million/μL, WBC 20,000/μL, and troponin 70 ng/L. ABG values 7.40/27/53/17, and total testosterone level was 1004 ng/dL. CT chest with IV contrast revealed massive bilateral pulmonary emboli with right heart strain. Lower extremity doppler ultrasound demonstrated a DVT in the right posterior tibial vein. The patient underwent catheter-directed thrombolysis via EKOS procedure and was subsequently transitioned to a DOAC. Given the diagnosis of VTE, TRT was discontinued permanently. Discussion: Testosterone has well-documented erythropoietic effects, which can contribute to erythrocytosis (HCT > 54%) and increased blood viscosity, thereby raising the risk of VTE. According to the Endocrine Society guidelines, TRT should be withheld if HCT exceeds 54%, and to be resumed only after HCT returns to the normal range, typically at a lower dose. Additionally, therapeutic phlebotomy—in which one unit of blood (500 mL) is removed at regular intervals—is an effective strategy for managing testosterone-induced erythrocytosis. Per the American Urological Association guidelines, total testosterone and CBC should be measured every 6-12 months during therapy. Conclusion: Erythrocytosis is a well-recognized adverse effect of TRT, requiring regular monitoring of CBC and serum testosterone levels. If HCT exceeds 54%, the TRT dose should be adjusted or temporarily discontinued, and therapeutic phlebotomy may be considered to reduce the risk of VTE.Presentation: Sunday, July 13, 2025

Disclosure: Y. Park: None. S. Sarlos: None. R.I. McLachlan: None. I. Sim: None. R. Upreti: None. C.A. Allan: None.Introduction: Infertility affects one-third of couples, with male factors contributing up to 50%. Spermatogenesis induction (SI) can be an effective treatment for men with hypogonadotropic hypogonadism (HH). However, the impact of pre-SI testosterone replacement therapy, especially its modality, on fertility outcomes remains unclear. Methodology: In a retrospective cohort study, men treated for SI by clinical andrologists from an Australian tertiary centre, either in the public outpatient service (2012-2020) or private clinics (2003-2024), were screened. Human chorionic gonadotropin (hCG) was titrated to achieve normal serum total testosterone. Recombinant follicular stimulating hormone (FSH) was typically added after 6 months for persisting azoospermia. SI was defined as any detectable sperm. Pre-SI testosterone replacement therapy (TRT), if any, was documented. Results: 47 azoospermic men with HH were treated for infertility with a median age of 34 years. Causes were classified as congenital, defined by pre-pubertal onset or absence of spontaneous puberty (n=25) and acquired, defined by post-pubertal onset (n=22). The causes of HH included iatrogenic pituitary pathology (n=16), idiopathic (n=15), congenital HH (CHH) including Kallmann syndrome (n=8), iron overload (n=4), prolactinoma (n=3) and opioids (n=1). 42 men (89.4%) achieved SI. The median (Q1-Q3) time to SI was 19.0 (12.0-33.1) months. Those on pre-SI testosterone replacement therapy (TRT) (n=22) had a comparable time to SI than those without pre-SI TRT (n=17) (19.0 [12.0-28.2] vs. 20.0 [12.4-36.3] months; p=0.79). Pre-SI TRT modality (long-acting [n=14] and short-acting intramuscular [n=2], transdermal [n=5] or oral [n=1]) was not associated with the time to SI (18.8 [16.0-24.0 vs. 18.9 [5.2-32.6] vs. 19.0 [12.0-22.0] vs. 29.0 [29.0-29.0] months; p=0.77). Congenital causes of HH (n=20) required a longer time to SI than acquired causes (n=19) (23.5 [18.0-37.5] vs. 16.0 [7.0-20.3] months; p=0.02). Time to SI was different across HH aetiologies (Table 1, p=0.04), with the longest time in CHH (n=7, 29.0 [22.9-47.0] months) and the shortest from opioids (n=1, 3.5 months). A greater pre-SI testicular volume was associated with a shorter time to SI (n=28, rho=-0.446, p=0.02). Of those who are known to have achieved pregnancy (n=26), assisted reproductive technology was commonly used (65%) compared to natural conception (27%). Conclusions: Neither pre-SI TRT status nor its modality was associated with SI outcomes. Congenital causes of HH and lower pre-SI testicular volume were associated with a longer time to SI compared to acquired causes of HH. There were significant differences in time to SI across HH aetiologies, with the longest in CHH followed by idiopathic HH. Larger studies are warranted to further elucidate the potential clinical importance of TRT modality before SI.Presentation: Saturday, July 12, 2025