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Abstract Context Androgen abuse impairs male reproductive and cardiac function, but the rate, extent, and determinants of recovery are not understood. Objective To investigate recovery of male reproductive and cardiac function after ceasing androgen intake in current and past androgen abusers compared with healthy non-users. Methods Cross-sectional, observational study recruited via social media 41 current and 31 past users (≥3 months since last use, median 300 days since last use) with 21 healthy, eugonadal non-users. Each provided a history, examination, and serum and semen sample and underwent testicular ultrasound, body composition analysis, and cardiac function evaluation. Results Current abusers had suppressed reproductive function and impaired cardiac systolic function and lipoprotein parameters compared with non- or past users. Past users did not differ from non-users, suggesting full recovery of suppressed reproductive and cardiac functions after ceasing androgen abuse, other than residual reduced testicular volume. Mean time to recovery was faster for reproductive hormones (anti-Mullerian hormone [AMH], 7.3 months; luteinizing hormone [LH], 10.7 months) than for sperm variables (output, 14.1 months) whereas spermatogenesis (serum follicle-stimulating hormone [FSH], inhibin B, inhibin) took longer. The duration of androgen abuse was the only other variable associated with slower recovery of sperm output (but not hormones). Conclusion Suppressed testicular and cardiac function due to androgen abuse is effectively fully reversible (apart from testis volume and serum sex hormone binding globulin) with recovery taking between 6 to 18 months after ceasing androgen intake with possible cumulative effects on spermatogenesis. Suppressed serum AMH, LH, and FSH represent convenient, useful, and underutilized markers of recovery from androgen abuse.

Abstract Context Endogenous and exogenous androgens increase circulating erythrocytes and hemoglobin but their effects on erythrocyte lifespan is not known. Objective To investigate androgen effects on immature and mature erythrocyte lifespan in humans and mice using novel nonradioactive minimally invasive methods. Design Human erythrocyte lifespan was estimated using alveolar carbon monoxide concentration and blood hemoglobin in Levitt's formula in hypogonadal or transgender men before and up to 18 weeks after commencing testosterone (T) treatment. Erythrocyte lifespan was estimated in androgen receptor knockout and wild-type mice after T or DHT treatment of intact females or orchidectomized males using in vivo biotin labelling of erythrocyte surface epitopes for reticulocytes (Ter119+CD71+) and 2 markers of erythrocytes (CD45–, Ter119+CD71–) monitoring their blood disappearance rate by flow cytometry. Results Before treatment, hypogonadal and transgender men had marked reduction in erythrocyte lifespan compared with controls. T treatment increased erythrocyte lifespan at 6 weeks but returned to pretreatment levels at 18 weeks, whereas serum T and blood hemoglobin were increased by T treatment remaining elevated at 18 weeks. In mice, T and DHT treatment had higher erythrocyte (but not reticulocyte) lifespan but neither orchidectomy nor androgen receptor inactivation significantly influenced erythrocyte or reticulocyte lifespan. Conclusion We conclude that hypogonadal men have reduced erythrocyte lifespan and acute androgen-induced increase in circulating erythrocyte lifespan may contribute to the well-known erythropoietic effects of androgens, but longer term effects require further investigation to determine how much they contribute to androgen-induced increases in circulating hemoglobin.

Abstract Background The impact of testosterone (T) treatment on antidoping detection tests in female-to-male (F2M) transgender men is unknown. We investigated urine and serum sex steroid and luteinizing hormone (LH) profiles in T-treated F2M men to determine whether and, if so, how they differed from hypogonadal and healthy control men. Method Healthy transgender (n = 23) and hypogonadal (n = 24) men aged 18 to 50 years treated with 1000 mg injectable T undecanoate provided trough urine and blood samples and an additional earlier postinjection sample (n = 21). Healthy control men (n = 20) provided a single blood and urine sample. Steroids were measured by mass spectrometry-based methods in urine and serum, LH by immunoassay, and uridine 5′-diphospho-glucuronosyltransferase 2B17 genotype by polymerase chain reaction. Results Urine LH, human chorionic gonadotropin, T, epitestosterone (EpiT), androsterone (A), etiocholanolone (Etio), A/Etio ratio, dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and 5α,3α- and 5β,3α-androstanediols did not differ between groups or by time since last T injection. Urine T/EpiT ratio was <4 in all controls and 12/68 (18%) samples from T-treated men, but there was no difference between T-treated groups. Serum estradiol, estrone, and DHEA were higher in transgender men, and serum T and DHT were higher in earlier compared with trough blood samples, but serum LH, follicle-stimulating hormone, and 3α- and 3β,5α-diols did not differ between groups. Conclusion Urine antidoping detection tests in T-treated transgender men can be interpreted like those of T-treated hypogonadal men and are unaffected by time since last T dose. Serum steroids are more sensitive to detect exogenous T administration early but not later after the last T dose. We studied T-treated F2M transgender and hypogonadal men and found they had serum and urine sex steroid profiles similar to those of hypogonadal men, varying mainly on time since injection.

Abstract Disclosure: J.V. Gialouris: None. A.J. Conway: None. A. Idan: None. S. Savkovic: None. R. Hermosilla: None. C.A. Muir: None. F. Bacha: None. T. Zhang: None. V. Jayadev: None. D.J. Handelsman: None. Introduction: Gonadotropin treatment to induce spermatogenesis and fertility for gonadotropin-deficient men is the only treatable cause of male infertility, excluding IVF bypass. Methods: Using a standardized protocol, 99 consecutive infertile men with congenital or acquired gonadotropin deficiency due to pathologic disorders of the hypothalamus or pituitary were treated using urinary or recombinant hCG and FSH to induce spermatogenesis and fertility. Results: Men aged 35 ± 1 years with female partners 30 ± 1 years had mostly prepubertal onset (73%) of gonadotropin deficiency, with few having cryptorchidism (3% unilateral, 10% bilateral) or other testis pathology (7%). Gonadotropin deficiency was due to congenital hypogonadotropic hypogonadism in 64 men, acquired (pituitary or cerebral tumors or hypothalamic disorders) in 30 men and other/mixed etiology (5). Univariate and multivariate Cox regression and Kaplan-Meier plots of outcomes in 161 treatment cycles (58 with one, 22 two, 17 three, 2 four) with a median duration of 15 (IQR 10, 30) months assessed (a) time to pre-specified sperm density thresholds, (b) time to partner pregnancy and (c) efficacy of urinary vs recombinant gonadotropins. Potential covariables for time to outcome comprised age, female partner’s age, cause of gonadotropin deficiency, onset age, anthropometry, pre-treatment testis volume, cryptorchidism, treatment cycle number and adverse female factors. The proportion (%) and median time (months) to achieve sperm thresholds of >0, >2, >5, >10 and >20 million sperm/mL was 82% (4 months), 59% (10 months), 51% (12 months), 39% (22 months), and 27% (37 months) respectively. The major determinant of time to pregnancy was absence of adverse female fertility factors (75 vs 33%, 15 vs 43 months, HR 0.24 95% CI 0.12-0.48; p<0.001). Other significant predictors of time to attainment of sperm thresholds or time to pregnancy (eg pre-treatment testis volume, bilateral cryptorchidism, 2nd or later cycle) varied between thresholds but were generally consistent with better prognosis for acquired (post-pubertal onset) gonadotropin deficiency. The median sperm concentration and sperm output associated with partner pregnancy was 4.0 (0.4, 16.9) M/mL and 12.8 (0.7, 50.4) M/ejaculate, respectively. Time to >0 and >2 million sperm per mL thresholds was significantly faster for recombinant vs urinary hCG, but not significantly different for higher sperm thresholds or pregnancy, nor was there significant differences in time to sperm threshold for urinary vs recombinant FSH. Conclusion: This analysis of time-dependent spermatogenesis and pregnancy outcomes in 99 men undergoing hCG/FSH treatment for pathologic gonadotropin deficiency confirms that most men will achieve sperm output and fertility within a year, with greatest impact on fertility being detrimental female fertility factors. Presentation: Saturday, July 12, 2025

Abstract Ovarian hyperthecosis (OHT), severe hyperandrogenism after menopause in the absence of ovarian or adrenal tumors, is usually treated by surgical excision. We report a 58-year-old woman presenting with severe hyperandrogenism (serum testosterone 15.7-31.0 nmol/L, normal female <1.8 nmol/L) with menopausal gonadotropins and virilization but no adrenal or ovarian lesions. Multisteroid profiling by liquid chromatography mass spectrometry (LCMS) of adrenal and ovarian vein samples identified strong gradients in the left ovarian vein (10- to 30-fold vs peripheral blood in 17OHP4, 17 hydroxyprogesterone, 17 hydroxypregnenolone, androstenedione, testosterone, dehydroepiandrosterone) but the right ovarian vein could not be cannulated with the same findings in a second ovarian vein cannulation. OHT diagnosis was confirmed by an injection of a depot pure gonadotropin-releasing hormone (GnRH) antagonist (80 mg Degarelix, Ferring) producing a rapid (<24 hour) and complete suppression of ovarian steroidogenesis as well as serum luteinizing hormone and follicle-stimulating hormone lasting at least 8 weeks, with reduction in virilization but injection site reaction and flushing and vaginal spotting ameliorated by an estradiol patch. Serum testosterone remained suppressed at 313 days after the first dose despite recovery of menopausal gonadotropins by day 278 days. This illustrates use of multisteroid LCMS profiling for confirmation of the OHT diagnosis by ovarian and adrenal vein sampling and monitoring of treatment by peripheral blood sampling. Injection of a depot pure GnRH antagonist produced rapid and long-term complete suppression of ovarian steroidogenesis maintained over 10 months. Hence a depot pure GnRH antagonist can not only rapidly confirm the OHT diagnosis but also induce long-term remission of severe hyperandrogenism without surgery.

ContextCan injectable testosterone undecanoate (TU) be administered effectively and acceptably by the subcutaneous (SC) route?ObjectiveTo investigate the acceptability and pharmacokinetics (PK) of SC injection of TU.DesignRandomized sequence, crossover clinical study of SC vs IM TU injections.SettingAmbulatory clinic of an academic andrology center.ParticipantsTwenty men (11 hypogonadal, 9 transgender men) who were long-term users of TU. injections. Intervention: Injection of 1000 mg TU (in 4 mL castor oil vehicle) by SC or IM route. Main Outcome Measures: Patient-reported pain, acceptability, and preference scales. PK by measurement of serum testosterone, dihydrotestosterone (DHT), and estradiol (E2) concentrations with application of population PK methods and dried blood spot (DBS) sampling.ResultsPain was greater after SC compared with IM injection 24 hours (but not immediately) after injection but both routes were equally acceptable. Ultimately 11 preferred IM, 6 preferred SC, and 3 had no preference. The DBS-based PK analysis of serum testosterone revealed a later time of peak testosterone concentration after SC vs IM injection (8.0 vs 3.3 days) but no significant route differences in model-predicted peak testosterone concentration (8.4 vs 9.6 ng/mL) or mean resident time (183 vs 110 days). The PK of venous serum testosterone, DHT, and E2 did not differ according to route of injection.ConclusionsWe conclude that SC TU injection is acceptable but produces greater pain 24 hours after injection that may contribute to the overall majority preference for the IM injection. The PK of testosterone, DHT, or E2 did not differ substantially between SC and IM routes. Hence whereas further studies are required, the SC route represents an alternative to IM injections without a need to change dose for men for whom IM injection is not desired or recommended.

Supraphysiological androgen administration suppresses testicular functions causing reduced sperm output and testosterone secretion. The rate and extent of testicular function recovery after cessation is not known beyond anecdotal reports. As an illicit activity, androgen abuse is difficult to study prospectively so we undertook a cross-sectional, observational study of current and past androgen abusers together with healthy, eugonadal non-users to determine the rate and extent of recovery of sperm output and reproductive hormones after cessation of androgen intake. We recruited (via social media) age-matched (mean 34 years), regularly exercising volunteers comprising 41 current and 31 past users (≥3 months since last use) with 21 healthy, eugonadal non-users. Each underwent physical examination and provided serum (reproductive hormones, steroids by LC-MS; LH, FSH, SHBG, hematology and biochemistry by routine methods) and semen sample (WHO). Current users, compared with past and non-users, had significant suppression of mean orchidometric testicular volume (TV, 14.3, 18.6, 23.2 ml), sperm output (excluding 6 vasectomized men, median 104, 173, 189 million/ejaculate) and mean serum LH (0.5, 5.5,5.2 IU/L), FSH (0.5, 4.7, 4.9 IU/L), SHBG (17.2,33.9,42.0 IU/L) and HDL cholesterol (0.64, 1.10,1.21 mM) with significant increases in serum T (38.5, 6.2,8.6 ng/ml), DHT (1.5, 0.5, 0.7 ng/ml), E2 (146,41,48 pg/ml), E1 (65,32,38 pg/ml), 3α-androstanediol (2.2, 0.4, 0.6 ng/ml), hemoglobin (164, 154,151 g/l) and triglycerides (1.32,1.02,0.91 mM). All but TV and SHBG were not significantly different between past (median 300 days since last use) and non-users consistent with full recovery. Rate of recovery for androgen-suppressed variables, estimated as the time to reach the mean for non-users, was 9 months for serum LH, 14.2 months for sperm output and 18.7 months for serum FSH. We conclude that suppressed testicular function due to androgen abuse is mostly reversible (apart from persistent TV reduction) with recovery taking between 9 to 18 months or longer after ceasing androgen intake. Suppressed serum LH and FSH represent convenient, useful and underutilized markers of androgen abuse and recovery. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.