Androgen Deficiency Research Articles

Objective – to study the incidence of hypogonadism in men with ankylosing spondylitis (AS) and evaluate its impact on AS and comorbidities. Materials and methods. The one-time continuous study included 124 men with AS who were undergoing inpatient treatment at the V.A. Nasonova Research Institute of Rheumatology. Patients were assessed for total testosterone levels and subsequently divided into subgroups with normal (≥12.0 nmol/l) and reduced levels. An intergroup comparison was carried out on the main indicators used in clinical rheumatological practice to assess the stage, activity and other medical and demographic characteristics of AS, as well as on concomitant diseases. A correlation analysis was performed between the level of total testosterone and some clinical and laboratory parameters. Results. The frequency of detected testosterone deficiency in the study group was 25.0%. With testosterone deficiency, a more frequent incidence of uveitis (45.2% vs 23.6%; p=0.022), as well as arterial hypertension (51.6% vs 30.1%; p=0.030) and type 2 diabetes mellitus (16.1% vs 4.3%; p=0.028). Testosterone deficiency was accompanied by higher levels of C-reactive protein (16.7 [3.2; 43.4] vs 5.0 [1.3; 17.4] mg/l; p=0.020), as well as higher frequency of increased ESR (45.2% vs 25.8%; p=0.043). There was a higher glucose level (5.75±1.19 vs 5.36±0.71 mmol/l; p=0.027) and more frequent impaired fasting glucose (25.8% vs 4.3%; p<0.001). A more frequent occurrence of hypercholesterolemia was revealed (43.3% vs 16.3%; p=0.010). Testosterone deficiency was accompanied by higher levels of uric acid (377.0±105.3 vs 324.0±67.7 µmol/l; p=0.002) and the incidence of hyperuricemia (67.9% vs 41.2%; p=0.014). Conclusion. A high incidence of hypogonadism in patients with AS has been revealed. Testosterone levels and the presence of hypogonadism were not associated with the stage and activity of AS, but testosterone deficiency was accompanied by a higher incidence of uveitis, higher laboratory indicators of AS activity, and the incidence of concomitant metabolic disorders.

Cholesterol metabolism as a key target in triphenyl phosphate-induced testosterone biosynthesis disorder: Implications for male reproductive health.

Association between testosterone replacement therapy and cardiovascular events in men: a retrospective propensity-weighted analysis.

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.

To evaluate the association between sperm DNA fragmentation index (DFI), which quantifies the proportion of sperm with damaged DNA (sperm DNA fragmentation), and sexual dysfunction (SD) using the Sexual Health Inventory for Men (SHIM), a validated 5-item tool assessing erectile dysfunction severity, and the Androgen Deficiency in Aging Male (ADAM) questionnaire, a 10-item screening instrument for symptoms of testosterone deficiency. A retrospective cohort study was conducted at a university-affiliated male infertility clinic. A total of 703 infertile men (mean age 37.4 ± 5.6 years) who completed SHIM and ADAM questionnaires and underwent semen analysis and DFI testing between 2000 and 2020 were included. DFI was categorized as normal (< 30%) or abnormal (≥ 30%). Primary outcomes were intercourse frequency (IF), SHIM scores (erectile dysfunction severity), and ADAM scores (androgen deficiency symptoms). Multivariable regression models evaluated predictors of sexual function, with emphasis on DFI. Abnormal DFI was observed in 39% of men. Average IF was 7.2 ± 4.4 times/month, with no difference by DFI status. A positive ADAM score was reported in 41.1%, while moderate/severe ED (SHIM) was reported in 3%. Multivariable analysis showed that BMI above 30 (kg/m²) alone was associated with reduced IF. Abnormal SHIM scores were predictive of positive ADAM score. Worse SHIM scores were associated with smoking and a positive ADAM score. Men with abnormal DFI had significantly lower SHIM scores (p = 0.02): 65% had normal scores versus 73% in the normal DFI group. Mild and mild-moderate ED were reported in 25% and 9% of the abnormal DFI group versus 19% and 5% in the normal group, respectively. Abnormal DFI was significantly associated with erectile dysfunction. These findings support incorporating sexual health assessments into male infertility evaluations.

Introduction 17α-hydroxylase/17,20-lyase deficiency (17-OHD) typically presents with sexual infantilism, hypertension, and hypokalemia. However, phenotypic variability, particularly breast development, may obscure diagnosis. This study aims to characterize an atypical presentation of 17-OHD with preserved breast development and breast nodules, and to evaluate clinical and hormonal features associated with breast development through a systematic literature review. Methods A 38-year-old woman with bilateral breast nodules and ductal ectasia was diagnosed with 17-OHD, confirmed by CYP17A1 variants. A literature review of 17-OHD cases with near-complete breast development (Tanner stage 4–5) was conducted to analyze clinical, hormonal, and genotypic features. Results The patient exhibited classic signs of 17-OHD including hypertension, hypokalemia, adrenal hyperplasia, and hypogonadism, but also presented with atypical bilateral breast nodules and mammary duct ectasia. Hormone therapy resulted in clinical improvement and regression of the breast findings. Literature analysis of 43 patients with breast development showed that patients with 46,XX were diagnosed later than 46,XY (29.5 ± 11.5 vs. 19.8 ± 6.9 years, P = 0.0095). Estradiol was more often subnormal in 46,XX, while both groups showed progesterone excess and androgen deficiency. Pubic hair development differed by karyotype ( P = 0.027), which was more advanced in the 46,XY group. Genetic data revealed that breast development was associated with non-null CYP17A1 variants, and most variants clustered in exons 5–8, with exon 8 as a hotspot. Conclusion This case broadens the phenotypic spectrum of 17-OHD, highlighting that preserved breast development and benign breast lesions may delay diagnosis. Literature review suggests partial loss-of-function variants contribute to this phenotype. Greater awareness is essential to prevent misdiagnosis and unnecessary interventions.

Background: Male infertility remains a significant reproductive health challenge globally, with increasing evidence implicating hormonal and inflammatory imbalances in its pathophysiology. Objective: This study evaluated serum testosterone and selected inflammatory biomarkers in infertile men (oligospermic and azoospermic) attending fertility clinics across Imo State, Nigeria. Methodology: A total of 204 participants were recruited, comprising 68 oligospermic men, 34 azoospermic men, and 102 apparently healthy, age-matched fertile controls. Serum testosterone, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were quantified using Enzyme linked immunosorbent assay (ELISA) methods. Data were analyzed using SPSS version 21.0 and expressed as mean ± standard deviation (SD); Group comparism were made using independent t-test and one way ANOVA. Statistical significance was set at P ≤ 0.05. Results: Results showed that total testosterone levels were significantly reduced in oligospermic and azoospermic men compared to controls (8.26 ± 1.90 ng/dL) (P &lt; 0.001). Conversely, inflammatory markers were markedly elevated among infertile subjects; CRP levels were significantly higher in azoospermic (10.59 ± 3.11 mg/L) and oligospermic (8.13 ± 2.13 mg/L) men compared to controls (2.63 ± 0.73 mg/L) (P &lt; 0.001). Similarly, IL-6 and TNF-α levels were significantly elevated in azoospermic (respectively) and oligospermic (8.70 ± 1.84 pg/mL and 9.47 ± 1.94 pg/mL, respectively) groups versus controls (P &lt; 0.001). Age and body mass index (BMI) exerted no significant influence on either testosterone or inflammatory markers (P &gt; 0.05). Pearsons Correlation analyses revealed weak and statistically non-significant associations between testosterone and inflammatory (CRP, IL-6, TNF-α) in both oligospermic and azoospermic men. Conclusion: In conclusion, the study demonstrated a clear pattern of systemic inflammation among infertile men in Imo State, who also presented with hypogonadism given their levels of testosterone. There was more pronounced inflammatory derangements in azoospermic subjects, when compared with the oligospermic subjects. These findings suggest that chronic subclinical inflammation may contribute to impaired spermatogenesis and androgen deficiency, highlighting the need for integrative therapeutic interventions targeting both endocrine and inflammatory pathways in male infertility management.

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

Abstract Disclosure: J. Walravens: None. N. Narinx: None. T. Reyns: None. D.M. Vanderschueren: None. F.C. Wu: None. T. Fiers: None. L. Antonio: None. J. Kaufman: None. B. Lapauw: None. Introduction: Guidelines suggest determination of serum free testosterone (FT) for diagnosis of male hypogonadism, especially in men with borderline low total T or with altered sex hormone-binding globulin. While mathematical approximations of FT (cFT) are most used, direct measurement of FT (mFT) using equilibrium dialysis followed by mass spectrometry (ED LC-MS/MS) is considered the gold standard. It is unclear if mFT can provide additional value over cFT in confirming androgen deficiency. Objective: To evaluate whether low mFT and cFT are differentially associated with sexual symptoms of androgen deficiency. Methods: Total T and SHBG levels were determined using LC-MS/MS and immunoassay, respectively, on serum samples of 525 community-dwelling men aged 55 to 85 years participating in the EMAS study1. FT levels were calculated using the Vermeulen formula and measured directly using ED LC-MS/MS. Sexual symptoms of hypogonadism were assessed using the EMAS Sexual Function Questionnaire. Participants were grouped by low or normal mFT and cFT levels. The cFT threshold was 220 pmol/L2. The mFT threshold was 190 pmol/L, the lower reference limit for mFT in healthy men aged 18-39 years in the SIBLOS study3. Logistic regression was used to determine if men with low FT had increased risk of sexual symptoms compared to those with normal FT. Results: Participants were divided in four groups: normal mFT/normal cFT (n = 258; mean age: 67.4 ± 7.6; mean BMI: 26.8 ± 3.2), normal mFT/low cFT (n = 15; mean age: 63.4 ± 8.6; mean BMI: 27.6 ± 2.5), low mFT/normal cFT (n = 112; mean age: 73.3 ± 8.03; mean BMI 27.2 ± 3.6) and low mFT/low cFT (n = 140; mean age: 74.6 ± 7.8; mean BMI: 28.3 ± 3.2). The low mFT/normal cFT and low mFT/low cFT groups had an increased risk of insufficient spontaneous erections (OR: 2.4 (CI: 1.5-4.0) and 2.8 (1.8-4.6)), less frequent sexual thoughts (OR: 1.9 (1.2-3.1) and 2.5 (1.6-4.0)) and lower sexual desire (OR: 1.8 (1.1-3.0) and 2.0 (1.3-3.1)). The normal mFT/low cFT group had no significantly increased risks of sexual symptoms. Conclusion: Men with low mFT had higher risks of lower sexual function, even with normal cFT. As such, mFT may be more accurate to assess androgen deficiency than cFT. However, given challenges in measuring FT, it is now not easily available for clinicians. Future efforts of academy and industry should focus on harmonizing methods and developing validated diagnostic thresholds for mFT. 1.Lee, D. M. et al. The European Male Ageing Study (EMAS): design, methods and recruitment. Int J Androl32, 11-24 (2009). 2.Wu, F. C. W. et al. Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. New England Journal of Medicine363, 123-135 (2010). 3.Lapauw, B. M. et al. Serum Estradiol Is Associated With Volumetric BMD and Modulates the Impact of Physical Activity on Bone Size at the Age of Peak Bone Mass: A Study in Healthy Male Siblings. Journal of Bone and Mineral Research24, (2009). Presentation: Saturday, July 12, 2025

Disclosure: A.K. Clift: 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.Existing randomised trials of testosterone replacement therapy (TRT) for adult men with testosterone deficiency (TD) used topical testosterone. In real-world practice, clinicians also utilise injectable forms of TRT, and/or agents such as clomiphene. The effects of these agents over time on safety (i.e. raised hematocrit [Hct]) and patient-reported quality of life measures in real-world practice are not well characterized. We performed a retrospective service evaluation (cohort study) of men treated for TD at private healthcare providers in the UK between Feb 2019 and Oct 2024. Baseline and follow-up values for QADAM quality of life scores and Hct levels were extracted, with up to 12 months of follow-up. Mixed effects approaches were used to model trends in QADAM and Kaplan-Meier methods used to calculate the incidence of high Hct (>0.54). Patients may be treated on the basis of biochemical and symptomatic profiles at individual experts’ discretion: secondary analyses stratified by level of baseline T (Group 1 = free T<0.226 or total T<12.2; Group 2 = free T 0.226-0.3, but total T>14.9; Group 3 = total T 12-15 but free T in reference range, Group 4 = prevalent TRT users transferred from other providers). Of a total of 6,376 men, 4,414 were in Group 1 (69.23%), 105 were in Group 2 (1.65%), 1,455 were in Group 3 (22.82%), and 402 were in Group 4 (6.30%). 210 (3.29%) were prescribed testosterone creams or gels, 216 (3.39%) were prescribed clomiphene, 5,043 (79.09%) were prescribed cypionate, 1,046 (16.41%) were prescribed enanthate and 545 (8.55%) were prescribed Sustanon during the course of their treatment (some men switched treatments). The average QADAM score at baseline was 27.14 (95% CI: 26.98 to 27.30), at 12months this was 43.58 (95% CI: 43.11 to 44.06). Absolute increases in QADAM scores at 12months ranged between +10.46 to +11.71 by sub-group, with overlapping CIs across groups. 328 men (3.24%) had follow-up Hct> 0.54 (range: 0.99% in Group 2 to 3.34% in Group 4). No significant difference was observed between groups for the incidence of Hct>0.54 (log rank test, p=0.31). The use of TRT was associated with statistically and clinically significant increases in QADAM scores, a patient-reported measure of quality of life in men with TD. The incidence of Hct>0.54 was rare, with no significant difference across baseline T-defined sub-groups. The incidence of cardiovascular events in different sub-groups of men undergoing TRT should be prospectively studied.Presentation: Saturday, July 12, 2025

Disclosure: J. Hubska: None. M. Bobrowicz: None. U. Ambroziak: None.Case report: A 32-year-old female (46XX) with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), salt-wasting classical form, was admitted for evaluation of severe muscle pain, muscle weekness, and depression. Diagnosed in the neonatal period, she had been treated with glucocorticoids (GCS) and mineralocorticoids since that time. Her current regimen included prednisolone 10mg/day and fludrocortisone 100 µg/day. For chronic insomnia, she had taken zolpidem 7.5 mg/day for several years. Muscle pain led to regular use of metamizole and paracetamol, with increased intake and reported dependency over the last three years. Physical examination revealed signs of glucocorticoid (GC) excess; weight gain, plethora, and easy bruising. There were no signs of hyperandrogenism, and menstruation remained regular. Three years earlier, reducing prednisolone to 7.5 mg/day worsened her condition, necessitating a return to 10 mg/day. Current biochemical studies showed complete suppression of ACTH (<1 pg/ml; N: 10-50), DHEAS (1.7 µg/dl; N: 98-340), and testosterone (<0.09 nmol/l; N: 0.29-1.67). Similar results were recorded three years earlier. CK, LDH, ALT, and AST levels were normal. Electromyography, electroneurography, a lactate curve test, brain MRI, and metabolic and rheumatologic diagnostics revealed no abnormalities. Due to anxiety and poor tolerance of lower prednisolone doses, attempts to reduce the dose were avoided. Symptoms were attributed to GC excess, androgen deficiency, and somatization. With complete androgen suppression and GC reduction impractical, testosterone prolongatum 50 mg i.m. every 4-8 weeks was initiated. Three months later, the patient reported significant improvement in overall well-being, including the resolution of muscle pain. Examination revealed arm muscle growth with no other signs of virilization. Menstruation remained regular. Testosterone and prednisolone were continued. Discussion: This case describes an unusual presentation of muscle pain and weakness in a 46XX patient with CAH due to 21OHD, likely resulting from complete androgen suppression caused by excessive glucocorticoid dosing during infancy. While essential for CAH management, excessive GC use can lead to complications like Cushingoid features and androgen suppression. Androgens are crucial for muscle mass and physical function, even in females, and their prolonged deficiency contributed to the patient’s symptoms, which resolved with testosterone therapy. Although rarely used in female CAH patients due to concerns about virilization, this case highlights the safe and effective use of testosterone to treat androgen deficiency. It underscores the importance of individualized treatment and further research on androgen replacement to improve outcomes and quality of life in CAH.Presentation: Monday, July 14, 2025

Abstract Disclosure: M.G. Meirelles: None. R.D. Scalco: None. J.M. Moreira: None. S. Domenice: None. R.L. Batista: None. J. Mesia: None. N. Scalissi: None. J.P. Batatinha: None. J.V. Junior: None. C.B. Bueno: None. A. Narciso: None. A. Reis: None. A. Latronico: None. I.J. Arnhold: None. B.B. Mendonca: None. The luteinizing hormone/choriogonadotropin receptor (LHCGR) is essential for gonadal steroidogenesis and sexual differentiation. Loss-of-function variants in LHCGR lead to a spectrum of 46,XY disorders of sex development (DSD), with phenotypic variability depending on chromosomal sex and mutation type. We report two 46,XY sisters, from a consanguineous family, presenting with primary amenorrhea and absent secondary sexual characteristics. Both, aged 31 and 27, showed tall stature (184 cm and 188 cm; target height: 173 cm), and the elder sister also had obesity and metabolic comorbidities. Hormonal evaluation showed elevated gonadotropins (LH: 49–60 IU/L; FSH: 46–50.7 IU/L), low testosterone (&amp;lt;10 ng/dL), and undetectable estradiol (&amp;lt;17 pg/mL). Pelvic ultrasound and MRI confirmed absence of uterus and presence of bilateral intra-abdominal testes (3.5–4.0 cm AP). Histopathological analysis revealed Leydig cell hypoplasia and severe seminiferous tubule hyalinization. Genetic testing identified a novel homozygous LHCGR splice-site variant (c.384-2A&amp;gt;G; NM_000233.4), classified as pathogenic by ACMG guidelines (PM2, PVS1, PP4). In silico prediction tools indicated complete loss of the canonical AG acceptor site at intron 4. SpliceAI showed high probability of splice site loss (Δ score: 0.99), and MaxEntScan indicated a collapse in splice strength, suggesting exon skipping or intron retention. RNA secondary structure modeling (ViennaRNA Fold) revealed reduced thermodynamic stability (ΔG: –30.05 vs. –32.62 kcal/mol), lower frequency of the minimum free energy structure (0.60% vs. 1.96%), and increased structural diversity (35.3 vs. 23), supporting impaired splicing efficiency. This variant likely disrupts LHCGR expression through aberrant splicing and RNA instability, leading to Leydig cell hypoplasia and testosterone deficiency. The disproportionately high FSH in subject with LHCGR loss-of-function longstanding Sertoli cell damage due to undescended testes. These findings expand the mutational and phenotypic spectrum of LHCGR-related DSD and emphasize the relevance of considering LHCGR defects in 46,XY individuals with hypergonadotropic hypogonadism and female phenotype. Keywords:LHCGR variant, Leydig cell hypoplasia, 46,XY DSD, hypergonadotropic hypogonadism, LH resistance. Presentation: Sunday, July 13, 2025

Disclosure: R. Nadeem: None. D. Tahir: None. M. Herrera: None. F. Pooja: None. P.B. Frechie: None.Introduction:Increased public awareness of androgen deficiency along with the beneficial outcomes of testosterone therapy has raised concerns for androgen overprescription, abuse and adverse effects. Although limited published evidence supports an elevated risk of blood clots, especially in younger adults, we report a case of a 38-year-old male with acute-onset cerebrovascular accident, myocardial infarction, extensive renal infarct and acute limb ischemia secondary to testosterone induced erythrocytosis.Case Presentation:The patient was a 38-year-old male with past medical history of type 2 diabetes, hypertension, and hypogonadism on intramuscular testosterone for one month, who presented with acute-onset confusion and right sided weakness. His blood work was remarkable for hemoglobin of 20 g/dL, previously 14g/dl a month ago, and hematocrit of 54%. CT head without contrast showed left sided middle cerebral artery infarct, requiring mechanical thrombectomy, complicated by intracranial hemorrhage while on dual antiplatelet therapy (DAPT). Following DAPT interruption, he developed an acute ST elevation myocardial infarction with multivessel occlusion requiring stenting. Echo revealed ischemic cardiomyopathy and a newly formed left ventricular thrombus. DAPT therapy was resumed, along with heparin. The patient’s medical history lacked constitutional symptoms suggesting any primary hematologic cause for erythrocytosis. He was a non-smoker and had no personal or family history for vascular, cardiac or lung disease. Further blood work showed normal erythropoietin levels, negative JAK2 mutation, with no concern of steroid or anabolic drug abuse - except for the testosterone replacement therapy. His hospital stay was complicated by gastrointestinal bleeding, acute left renal artery occlusion and extensive right external iliac infarction threatening ipsilateral limb ischemia. His hematocrit and hemoglobin normalized following the gastrointestinal bleeding and remained normal thereafter, with no further clotting seen.Discussion:This case demonstrates the potential for severe and rapid-onset complications with testosterone use, even in young individuals over a short period. It emphasizes the importance of careful monitoring during therapy and consideration of risk regardless of age. Current studies do indicate a potential link between blood hyper viscosity and thromboembolic complications, but the evidence stays inconclusive with lack of evidence-based guidelines on the management of testosterone induced erythrocytosis and expert consensus varying. The case also highlights the need for larger well designed clinical trials, as existing studies are limited by smaller sample size and lack of direct correlation between testosterone therapy-induced erythrocytosis and thromboembolic events.Presentation: Sunday, July 13, 2025

Introduction Testosterone Deficiency (TD) is common in men living with HIV (MLWHIV) and is associated with worse clinical outcomes. This study aimed to evaluate the frequency of TD in MLWHIV and factors potentially associated with this condition. Methodology This observational cross-sectional study included MLWHIV aged &gt; 18 years receiving Antiretroviral Therapy (ART). Clinical and laboratory data were collected, and body composition, Bone Mass (BM), Lean Mass (LM), and Fat Mass (FM), were assessed using Dual-energy X-ray Absorptiometry (DXA). TD was defined as Total Testosterone (TT) &lt;300 ng/dL and/or calculated Free Testosterone (cFT) &lt;6.4 ng/dL (Vermeulen’s formula). Data are presented as median (interquartile range, IQR) and n (%). Results Eighty-four participants were included from May 2014 to August 2015. Median TT was 396.5 ng/dL (IQR 314.8–490.2), Sex Hormone-Binding Globulin (SHBG) 45.4 nmol/L (IQR 35.1–60.2), and cFT 6.6 ng/dL (IQR 5.3–7.4). TD prevalence was 22.6% by TT and 44% by cFT (p&lt;0.001). Using the cFT criterion, participants with TD were older (50 vs 45 years, p&lt;0.01), had higher prevalence of metabolic syndrome (27% vs 4.3%, p&lt;0.01), increased waist circumference (21.6% vs 4.3%, p&lt;0.05), and lower frequency of normal BM (37.5% vs 67.5%, p&lt;0.05). No differences were observed in CD4 count, ART duration or type, LM, FM, or lipodystrophy. Conclusion In MLWHIV, the cFT criterion identified more cases of TD than TT alone. TD in this population is associated with altered bone mass, increased waist circumference, and a higher prevalence of metabolic syndrome, highlighting the importance of systematic evaluation using cFT.

Relative energy deficiency in sport (REDs) is a syndrome describing dysfunction in normal physiology related to the term "negative energy availability" because of a mismatch between energy consumption and expenditure in sport. A disruption of the hypothalamic-pituitary-testes axis, resulting in testosterone deficiency, seems like the dominant feature in males. REDs-associated testosterone deficiency is functional, and treatment should aim towards reducing training and increasing energy consumption, as argued in this review. Testosterone treatment should not be initiated.

BackgroundErectile dysfunction (ED) is a prevalent and multifactorial condition affecting men worldwide, with potential hormonal underpinnings such as testosterone deficiency playing a critical role. Understanding the strength of the association between serum testosterone and ED severity in Pakistani men is essential to inform targeted diagnostic and therapeutic strategies.ObjectiveThis study aims to evaluate the correlation between serum total testosterone levels and the severity of ED (measured by the International Index of Erectile Function-5 (IIEF-5)) among Pakistani men aged 40-65 years attending a tertiary care outpatient clinic.Materials and methodsIn this cross-sectional analytical study, we enrolled 110 men aged 40-65 years presenting with ED at the Institute of Kidney Diseases of Medical Teaching Institution (MTI) - Hayatabad Medical Complex, Peshawar, between 1 January and 30 June 2025. ED severity was assessed using the validated IIEF-5. In the morning (8-10 AM), fasting blood samples were collected for the measurement of serum total testosterone using a chemiluminescent immunoassay. Spearman’s rank correlation was used to assess the relationship between testosterone levels and IIEF-5 scores. ANOVA (and the complementary Kruskal-Wallis test) were used to evaluate differences in testosterone across ED severity categories.ResultsThe mean age was 54.2 ± 6.7 years, and the mean serum testosterone level was 365.4 ± 102.7 ng/dL. Patients with mild, moderate, and severe ED (32.7%, 38.2%, and 29.1% of the sample, respectively) had mean IIEF-5 scores of 20.4, 13.5, and 7.2, and corresponding testosterone levels of 432.8, 362.1, and 278.6 ng/dL, respectively (all p < 0.0001). A strong positive correlation between testosterone and IIEF-5 score was found (Spearman’s ρ = 0.615, p < 0.0001).ConclusionsSerum total testosterone shows a strong and significant positive correlation with ED severity in this outpatient Pakistani male cohort. These findings support the inclusion of hormonal evaluation in ED workups, particularly when clinical suspicion of hypogonadism exists.

SummaryOrchiectomy induces atrophy of epithelial cells in the prostate gland, stimulated by androgen deprivation. The objective of the current study was to assess the changes arising from tissue remodeling during short periods of androgen deprivation in the ventral prostate of Mongolian gerbils. Adult male gerbils were divided into groups: control and castrated, euthanized on the 3rd (Ca3d), 7th (Ca7d), and 14th (Ca14d) days post-orchiectomy (n = 7/group). The ventral lobe of the prostate was submitted for histological, stereological, morphometric, serological, and immunohistochemical analyses. Castration promoted a reduction in the weight of the ventral prostate. It altered the relative proportion of prostate tissue compartments, such as a decrease in the epithelium and non-muscular stroma and an increase in the muscular stroma. In addition, we observed that the number of Cd-68 positive cells increased in the Ca3d group, which represents a period of androgen deprivation not previously reported in the literature for Mongolian gerbils. Matrix metalloproteinase-9 quantification revealed a decrease in the Ca7d group compared to the Ca3d. In addition, the frequency of Tumor Necrosis Factor alpha increased in the Ca14d group, influenced by the duration of testosterone deficiency. The findings contribute to the understanding of prostate tissue remodeling after castration, as well as highlighting the rapid alterations in the prostate microenvironment in a short period following castration.

Testosterone deficiency (TD) affects a notable portion of the aging male population, leading to muscle loss and reduced bone density. Most men with TD do not receive testosterone replacement therapy (TRT). However, the association of untreated TD on surgical outcomes after total joint arthroplasty (TJA), including total hip arthroplasty (THA) and total knee arthroplasty (TKA), remains unexplored. This study aims to assess whether untreated TD is associated with poorer surgical outcomes in TJA patients without prior TRT. This retrospective cohort study used data from the TriNetX US Research Network, a large claims database including over 95 healthcare organizations and 130 million patients. Male patients undergoing THA or TKA were divided into two groups based on testosterone levels (TD: <300 ng/dL; eugonadal/non-TD: ≥300 ng/dL). Those with TRT before or within 2 years after TJA were excluded. Propensity score matching balanced demographics and comorbidities. Outcomes, including thromboembolic events, infections, prosthetic complications, revision, resection, readmission, and mortality, were assessed at 90 days, 1, and 2 years post-TJA. A total of 133,696 male patients without hormone replacement therapy who underwent THA were analyzed, with 5,400 patients in both TD and eugonadal cohorts after matching. TD patients had a higher risk of deep vein thrombosis and pulmonary embolism at 90 days, 1, and 2 years post-THA compared with their eugonadal counterparts. In the TKA population of 147,203 male patients, 6,658 patients per cohort were matched. TD patients had an increased risk of deep vein thrombosis, aseptic loosening, manipulation, readmission, and revision surgery within two years but lower risk of prosthetic joint infection than eugonadal men. TD is associated with poorer postoperative outcomes in TJA, with distinct patterns observed in THA and TKA. These findings suggest that hypogonadal status should be considered in the perioperative management of patients undergoing TJA.

BackgroundEmerging evidence suggests that insulin sensitivity plays a role in testosterone regulation. The estimated glucose disposal rate (eGDR) is a validated metabolic marker reflecting insulin resistance (IR). However, the relationship between eGDR and testosterone levels in adult men remains unclear.AimThis study aimed to examine the association between eGDR, total testosterone (TT) levels, and testosterone deficiency (TD) risk.MethodsData from the 2013-2016 National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted multivariable linear and logistic regression models were used to evaluate the association between eGDR, TT levels, and TD risk (TT <300 ng/dL). A smoothing spline curve fitting approach was applied to assess the shape of the relationship. Subgroup analyses and interaction tests were conducted to explore potential effect modifications. Receiver operating characteristic (ROC) analysis was performed to assess the predictive ability of eGDR for TD.OutcomeseGDR was calculated using waist circumference (WC), hypertension (HTN), and glycated hemoglobin (HbA1c).ResultsA total of 4087 male participants were included in the final analysis. After adjusting for all covariates, higher eGDR was significantly associated with increased TT levels (β = 31.83, 95% CI, 22.13-41.54, P < .001) and a lower risk of TD (OR = 0.68, 95% CI, 0.58-0.80, P = .002). Quartile analysis showed that participants in the highest eGDR quartile (Q4) had significantly higher TT levels than those in Q1 (β = 147.27, 95% CI, 66.99-227.55, P = .02) and a markedly reduced TD risk (OR = 0.20, 95% CI, 0.06-0.70, P = .03). Smoothing spline curve fitting approach confirmed a linear relationship between eGDR and TT levels, as well as an inverse association with TD risk. A significant interaction was observed for diabetes status (P for interaction = .001), indicating a potential modifying effect. ROC analysis demonstrated that eGDR had moderate predictive ability for TD (AUC = 0.6839, 95% CI, 0.6659-0.7019).Clinical ImplicationseGDR may serve as a useful metabolic marker for identifying individuals at risk of TD.Strengths and LimitationsGDR may serve as a valuable metabolic marker for identifying individuals at risk of TD; due to its cross-sectional design, we cannot establish causality between eGDR and testosterone levels.ConclusionThese findings suggest that eGDR is associated with testosterone levels and TD risk in adult men, highlighting the potential metabolic link between insulin sensitivity and testosterone regulation.

Testosterone deficiency is increasingly recognized as a significant public health challenge, strongly correlated with obesity. The link between the body roundness index (BRI) and the prevalence of testosterone deficiency is unclear. This research aims to examine these relationships.To investigate the relationship between BRI and the risk of testosterone deficiency, data from the National Health and Nutrition Examination Survey (NHANES) 2013 to 2016 were examined. This study employed multiple logistic regression and smoothed curve fitting to investigate the relationship between BRI and testosterone deficiency. The stability of the associations was also explored through subgroup analyses, interaction tests, and assessment of threshold effects. The study included 3663 participants, with 25.82% exhibiting testosterone deficiency. Upon adjustment for confounding variables, a positive association was detected between BRI and the prevalence of testosterone deficiency (OR = 1.29, 95% CI: 1.23–1.35, P < .0001). The smooth curve fitting indicated a nonlinear positive correlation between BRI and the prevalence of testosterone deficiency. The turning point of the smooth curve fit between BRI and testosterone deficiency was 4.04. When the BRI value was above 4.04, the association between BRI and testosterone deficiency was OR = 1.32, 95% CI: 1.25, 1.39, P < .0001. The independent positive associations between BRI and the prevalence of testosterone deficiency remained consistent across all subgroups (P for interaction >.05). Higher BRI was associated with a higher risk of testosterone deficiency in American adult men.