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Testosterone is a familiar villain, a ready explanation for innumerable social ills, from the stock market crash and the overrepresentation of men in prisons to male dominance in business and politics. It's a lot to pin on a simple molecule. Yet your testosterone level doesn't in fact predict your competitive drive or tendency for violence, your appetite for risk or sex, or your strength or athletic prowess. It's neither the biological essence of manliness nor even \"the male sex hormone.\" This unauthorized biography pries T, as it's known, loose from over a century of misconceptions that undermine science even as they make urban legends about this hormone seem scientific. T's story didn't spring from nature: it is a tale that began long before the hormone was even isolated, when nineteenth-century scientists went looking for the chemical essence of masculinity. And so this molecule's outmoded, authorized life story persisted, providing ready cause for countless behaviors--from the boorish and the belligerent to the exemplary and enviable. What we think we know about T has stood in the way of an accurate understanding of its surprising and diverse functions and effects. Rebecca Jordan-Young and Katrina Karkazis focus on what T does in six domains: reproduction, aggression, risk-taking, power, sports, and parenting. At once arresting and deeply informed, Testosterone allows us to see the real T for the first time.-- Provided by publisher

In this subtrial involving middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. Fracture incidence was numerically higher with testosterone.

Abstract Disclosure: S.M. Harman: None. G. Gill: None. G. Ovanessoff: None. G. Andzel: None. J. Marchette: None. Male hypogonadism (mHG) is defined as subnormal testosterone (T) and/or spermatogenesis. T therapy raises plasma T level, but suppresses FSH, LH, and T production. Clomiphene citrate (CC) inhibits estrogen negative feedback on GnRH secretion at the hypothalamus. In patients with central mHG and an intact pituitary, CC can increase LH-mediated endogenous T secretion. We compared T responses to oral CC in 31 male Veterans with central mHG (at least 2 T levels <250 ng/dL, low or low normal LH and FSH, and no pituitary abnormalities on MRI) who were naïve to T (NT, n=15) vs previously T-treated (TT, n=16) with last dose at least 3 months previously. Both groups were started on CC 25 mg/day PO. T was measured at 3 weeks and T and LH at 7 weeks. Those failing to achieve a goal T of ≥450 ng/dL at 3 weeks were up-titrated to 50 mg/day. Continuous values were compared by t-tests and ANOVA and class variables by Chi square tests. In the NT vs. TT groups respectively, baseline (mean ± SD) ages (48.1±13.4 vs 49.6±10.0 years, p=0.73), BMIs (35.6±4.2 vs 37.4±7.3 Kg/m2, p=0.40), and T (221±81 vs 178±70 ng/dL, p=0.13) as well as LH, FSH, SHBG, and prolactin did not differ significantly. At 3 weeks T levels in NT vs. TT were 474±217 vs. 361±148 ng/dL (p=0.11) and 47% vs 31% were at goal (p=0.38). In the NT vs. TT groups the 3-week T levels in those who had reached goal did not differ significantly from one another (641±186 vs. 528±81 ng/dL, p=0.14) nor in those not at goal (328±110 vs 285±100 ng/dL, p=0.47). At 7 weeks T levels were higher in the NT vs. TT group (591±203 vs 388±112 ng/dL, p=0.003) with 80% vs. 37% at goal (p=0.014). Those at goal at 3 weeks in the NT vs TT groups had significantly higher 7-week T levels (697±153 vs. 480±67 ng/dL, p=0.009) but those not at goal at 3 weeks (498±203 vs 346±104 ng/dL, p=0.08) did not. Increasing CC dose in those not at goal in the NT vs the TT groups led to 63% vs 18% achieving goal (p= 0.05). LH levels increased significantly (p<0.001) by 7 weeks in both NT and TT groups, but did not differ significantly between NT and TT groups at baseline (2.85±1.65 vs 3.05±1.65 ng/mL, p=0.75) or at 7 weeks (8.33±4.66 vs 8.94±4.52 ng/mL, p=0.72) with non-significant differences in LH between 7 weeks at goal and not at goal subjects respectively (9.43±5.05 vs 7.51±3.44 ng/mL, p=0.23). Although baseline testosterone in NT and TT subjects were similar, and those naïve to T were not significantly more likely to achieve goal at 3 weeks, NT subjects had higher plasma T levels at 7 weeks, and, if not at goal at 3 weeks, were more likely to reach goal after an increase in CC dose. Thus, previous T treatment impaired or delayed T response to CC, which appeared to be due mainly to Leydig cell dysfunction, since LH responses to CC did not differ between groups. Longer periods of treatment and/or higher doses of CC may be required to optimize T levels in mHG patients previously treated with exogenous T Presentation: Saturday, July 12, 2025

Abstract Disclosure: S. Aizawa: None. M. Otsuka: None. Y. Takeuchi: None. M. Moriyama: None. S. Egoshi: None. S. Takeuchi: None. M. Matsuyama: None. G.E. Bentley: None. The objective of this study was to elucidate the role of endogenous Neuromedin U (NMU), a peptide hormone, in male rats by performing NMU knockout (KO). Although NMU administration is well known to be anorexigenic, our previous study demonstrated that NMU KO rats did not change their feeding amount and body weight. In the present study, we demonstrated that male NMU KO rats exhibited a reduction in wheel-running activity compared to wild-type (WT) rats. However, overall home cage activity remained unaltered. In addition, plasma testosterone levels in male WT rats exhibited a diurnal variation with a peak and a nadir, whereas in male NMU KO rats, these levels remained stable throughout the day. Furthermore, chronic administration of testosterone restored the wheel-running activity amount in male NMU KO rats to the same level as in male WT rats, suggesting that the decrease in wheel-running activity in male NMU KO rats is due to disruption of the daily variation of plasma testosterone concentration. In agreement with the reduction in daily testosterone variation, expression of the gonadotropin subunit LHb mRNA in the pars distalis of the pituitary was significantly reduced in male NMU KO rats as compared to male WT rats. Immunostaining revealed that the size of LH-expressing cells was relatively small in male NMU KO rats compared to male WT rats. In the hypothalamic-pituitary-gonadal axis of male WT rats, the expression levels of Nmu, NMU receptor types 1 (Nmur1) and 2 (Nmur2) were notably low in both the testis and the pars distalis of the pituitary. In the brain, Nmu demonstrated high expression in the pars tuberalis, while Nmur2 exhibited high expression in the ependymal cell layer of the third ventricle in male WT rats. These findings show locations of NMU action and suggest a potential impact of NMU deficiency on the hypothalamic regulatory system.This study reveals a novel function of NMU: that endogenous NMU in rats plays a role in the regulation of motivated activity via the regulation of testosterone. Presentation: Saturday, July 12, 2025

Abstract Disclosure: G.A. Wittert: Sanofi, Besins, Amgen Inc. A. Vincent: None. M.M. Umapathysivam: None. D.R. Jesudason: None. S. Tafari: None. W. Goai: None. Background: Guidelines recommend the diagnosis of androgen deficiency by symptoms and low serum total testosterone concentration (TT). Studies vary as to whether the calculation of free testosterone (cFT) adds diagnostic accuracy when TT is borderline low. Aim: To determine whether cFT provides discriminant ability to infer that insufficient testosterone exposure is causally related to low sexual desire (SD) in men with borderline low TT.Methods: Cross-sectional analysis of a cohort of community-dwelling men (n=1195) aged 35 years and over with TT (LCMS), cFT (Vermeulen equation) and assessment of SD (dyadic scale of the Sexual Desire Inventory (SDI-D)). Borderline low TT and low cFT were defined as 6.1-12nmol/L and <0.2pmol/L respectively, and low SDI <19. Data were analysed by linear regression with and without adjustment for age and fat mass. Exact binomial confidence intervals for positive and negative predictive values (PPV and NPV), and false positive (FP) and negative (FN) estimates were generated. Results: There were 1169 men in the analysis sample (missing TT N=9, and SDI N=11). Mean age 55 years (SD 11.6); BMI 28.6kg/m2 (4.5); TT 17.3nmol/L (6.7); cFT 0.36pmol/L (0.15); SDI-D 34.3 (14.2). TT was borderline low in 207 men and low in 12 men. Men with TT<12nmol/L were older (p=0.02), more obese (p<0.001), with lower SDI scores (p<0.001) compared to men with TT ≥12nmol/L. In men with borderline low TT, a linear association between SDI-D score and cFT was explained by age and fat mass. The prevalence of low SDI was 23.3% (43/207) in men with borderline low TT, 41.9% in men with low cFT and 18.3% in men with normal/high cFT. (PPV = 41.9%, 95%CI=[27.0, 57.9]; NPV=81.7% [74.9, 87.3]; FP=58.1% [42.1, 73.0] & FN = 18.3% [12.7, 25.1]). Conclusion: Borderline low TT is associated with older age, greater adiposity and reduced sexual desire. While a cFT cut-off <0.20pmol/L helps rule out low sexual desire (NPV ≈ 82%), its false-positive rate and confounding by age and fat mass limit clinical applicability. Presentation: Saturday, July 12, 2025

In a randomized trial, men 65 years of age or older who had low serum testosterone levels and limitations in mobility were assigned to either placebo or testosterone gel to be applied daily for 6 months. The primary end point was improvement in leg-press strength, which was greater with testosterone therapy than with placebo. However, the trial was stopped early because of a greater number of cardiac adverse events in the testosterone group. In men 65 years of age or older with low serum testosterone levels and limitations in mobility, improvement in leg-press strength was greater with testosterone therapy than with placebo. However, there were more cardiac adverse events in the testosterone group. Limited mobility is a common geriatric condition that is a predictor of disability, poor quality of life, and death. 1 – 7 In men, an age-related decline in the serum testosterone concentration is associated with reduced muscle mass and lower-extremity strength, limitations in physical function, and poor mobility. 8 – 13 Testosterone supplementation increases muscle mass and strength and leg power, all of which are important determinants of mobility. 14 – 21 Previous trials of testosterone supplementation have been conducted primarily among healthy older men. The safety and efficacy of testosterone treatment in improving muscle performance and physical function in older men with limitations in mobility . . .

Abstract Context A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. Objective Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. Design Randomized, active-controlled, open-label study. Setting and Patients Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. Methods Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). Results 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. Conclusion A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

In a randomized trial involving men with hypogonadism and preexisting or a risk of cardiovascular disease, testosterone therapy was noninferior to placebo with respect to major adverse cardiac events.