Suffering the stress of others (termed empathic stress or stress contagion) may affect an individual's health and well-being. To understand the underlying hormonal processes of empathic stress, N = 108 opposite-sex dyads were tested, with one dyad partner passively observing the other undergoing a standardized psychosocial laboratory stressor. A positive link between oxytocin release and empathic stress response was hypothesized, while a negative relationship was expected for testosterone release. Associations of observer oxytocin and testosterone levels with two components of empathic stress were examined: stress resonance (i.e. synchronized observer-target responses) and vicarious stress (observer responses independent of target stress). During the passive observation of a stressed target, salivary oxytocin and testosterone levels increased by 16.64% and 23.00%, respectively, followed by a drop back to baseline levels. Supporting our hypotheses, increased observer oxytocin reactivity was linked to greater stress resonance in HF-HRV reactivity. This association was reversed in low oxytocin responders. Further, testosterone reactivity was negatively associated with stress resonance in heart rate activity. However, testosterone also showed a positive association with vicarious cortisol activity, which resembles the response pattern seen in first-hand stress exposure. We conclude that stress resonance may be the more empathy-dependent component of the empathic stress construct, aligning with previous work on the involvement of oxytocin and testosterone in empathy. To draw further conclusions about the role of oxytocin and testosterone in empathic stress response, future studies including a control group and hormone stimulation are needed.

Pain is felt and expressed through a complex interaction of biological, psychological, and social factors. While hormonal factors have been linked with pain in humans, these factors are underexplored. In this study, daily-diary data from the publicly available Texas Longitudinal Study of Adolescent Stress Resilience and Health dataset was used to examine the longitudinal relationship between a series of stress and sex hormones with self-reported headache, backache, stomachache. Latent growth modeling within a generalized structural equation modelling framework was used. A total of 735 students from 9th grade high school contributed self-reported daily diary on their mental and physical health alongside saliva samples up to 10 days. Analyses included available diary observations with complete data for each model with analytic sample size ranging from 440 to 530 participants. The hormones cortisol, testosterone, estradiol, progesterone, and DHEA-S were all examined as independent variables. In the adjusted models that did not control for sex, higher testosterone was associated with a decrease in the likelihood of having backache (β = -.24, p < .001), headaches β = -.20, p < .001) and stomachache (β = -.19, p < .001). Cortisol was positively associated with a higher likelihood of backache (β =.16, p = .034). In a stratified analysis based on pubertal status, testosterone remained negatively associated with the likelihood of having a headache, backache, and stomachache for participants in late/post puberty. The current study provides evidence that variations in hormonal levels depend on pubertal status when impacting pain.

Adolescence begins with puberty and involves dynamic hormonal, neural, and social changes. The early-pubertal testosterone surge, particularly in boys, may shape the amygdala, which regulates emotion and behavior. However, it remains unclear how testosterone- and amygdala-related correlates of psychobehavioral problems differ across early adolescence. Using data from the Tokyo Teen Cohort and its neuroscience extension, we examined associations among salivary testosterone, amygdala volumes, and parent-rated Child Behavior Checklist (CBCL) scores at approximately ages 10-11 and 12-13. Participants were 106 boys in wave 1 and 98 boys in wave 2, with 69 contributing complete biological measures at both waves. Wave-specific Poisson models of CBCL internalizing and externalizing scores were adjusted for age, Tanner stage, and intracranial volume. In wave 1, higher testosterone was associated with lower internalizing and externalizing scores (exp(β)= 0.64 and 0.66, both adjusted P < 0.001). In wave 2, testosterone was not significantly related to CBCL scores, whereas smaller right amygdala volume was associated with higher internalizing problems (exp(β)= 0.71, adjusted P < 0.001). Exploratory analyses suggested that testosterone moderated the wave-2 right amygdala-internalizing association, and that smaller right amygdala volume and lower testosterone at wave 1 were both prospectively associated with higher wave-2 internalizing problems (n = 104), associations that persisted after adjustment for wave-1 Internalizing score. These findings suggest age-dependent differences in endocrine and neural correlates of psychobehavioral problems and highlight the importance of developmental timing and hormone-brain interplay.

Differentiated Leydig cells (LCs) produce testosterone and INSL3, two hormones essential for male sex differentiation and fertility. In mice, the developmental origin of adult Leydig cells (ALCs) and the presence of stem Leydig cells (SLCs) in adulthood remain unresolved. To investigate this, we used the Leydig cell-specific Insl3iCre line combined with Rosa26lox-STOP-lox-iDTR/lox-STOP-lox-TdTomato to genetically ablate the committed LC lineage in adult mice. These mice displayed a normal phenotype without diphtheria toxin (DT). Following DT administration, TdTomato-positive and CYP17A1-positive LCs were eliminated within 4-7 days, leading to marked reductions in testosterone levels and androgen-dependent organ weights. Activated Caspase 3 confirmed apoptosis of targeted Leydig cells during the acute ablation phase. This was accompanied by transient macrophage recruitment as shown by F4-80 immunofluorescence, consistent with their involvement in clearing apoptotic Leydig cells. Importantly, COUP-TFII-positive/αSMA-negative/CYP17A1-negative/TdTomato-negative cells persisted adjacent to peritubular and perivascular myoid cells, identifying a candidate Insl3-negative precursor population. Newly emerging TdTomato-positive cells subsequently appeared predominantly around seminiferous tubules and, to a lesser extent, blood vessels, marking the onset of Leydig cell regeneration. Testosterone levels progressively recovered as these cells acquired CYP17A1 expression and populated the interstitial compartment. By 65 days post-DT, the ALC population and endocrine function were fully restored. These findings provide strong functional evidence for adult SLCs capable of repopulating the LC lineage after complete ablation and identify the peritubular compartment as a major regenerative niche. This inducible LC-depletion mouse model provides a powerful tool to investigate SLC biology and the mechanisms governing LC differentiation and testicular endocrine homeostasis.

Conditioned sexual arousal (CSA) can develop when initially neutral social cues acquire sexual incentive value through associative learning. In male rats, pairing the D2-type receptor agonist quinpirole (QNP) with cohabitation with an almond-scented juvenile male induces a conditioned sexual response toward that stimulus. Here, we examined how this response changes following repeated nonreinforced exposure to the conditioned social cue. Adult male rats underwent three conditioning trials followed, in the extinction-training groups, by three additional drug-free exposures to the almond-scented juvenile male. Conditioned responding was subsequently assessed toward both a receptive female and the juvenile male. QNP-Paired males showed robust juvenile-directed non-contact erections (NCEs), whereas QNP-Extinction males showed markedly reduced NCE responding. Genital investigation also showed a significant Partner × Treatment interaction, while the remaining behavioral measures did not survive correction for multiple comparisons. Free testosterone did not differ significantly among treatments. Exploratory Fos-immunoreactivity (Fos-IR) analyses revealed treatment-related differences in several brain regions; however, no direct QNP-Paired versus QNP-Extinction regional comparison remained significant after correction for multiple testing. Thus, repeated nonreinforced exposure to the conditioned social cue was associated with a marked reduction in conditioned sexual responding. Because the Paired and Extinction conditions differed in elapsed time and additional experience, this reduction is compatible with extinction but cannot be attributed uniquely to extinction learning. The endocrine and Fos-IR findings should be considered exploratory.

Despite limited evidence supporting its efficacy, the use of post-cycle therapy (PCT) is widespread amongst men following cessation of androgen abuse. The proposed rationale for PCT is to accelerate recovery of hypothalamic-pituitary-gonadal (HPG) axis function following androgen-induced suppression. In this commentary, we consider the distinction between pharmacological response and sustained recovery of endogenous HPG axis function, the relationship between biochemical and symptomatic recovery, and the potential role of PCT as a harm-reduction strategy.

According to the limited soma hypothesis, androgens drive the development of male reproductive traits, including morphological masculinization, but may also impose costs on somatic maintenance and accelerate biological aging. However, the relationship between androgens and biological age remains unclear, with evidence suggesting rather beneficial effects of testosterone in aging men. The study included 176 healthy men (Mage = 53.8 ± 2.99 years). Biological age was assessed using high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α, soluble α-klotho, growth hormone, insulin-like growth factor-1, dehydroepiandrosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and luteinizing hormone. Morphological masculinity was evaluated using sexually dimorphic traits dependent on androgen levels (facial width-to-height ratio, shoulder-to-hip ratio, waist-to-hip ratio, fat-free mass, second-to-fourth digit ratio, handgrip strength, and torso strength). Analyses controlled for socioeconomic status, lifestyle, body adiposity, height, and cortisol levels. In unadjusted analyses, greater fat-free mass was associated with lower inflammatory marker levels and higher growth hormone concentrations, whereas a higher waist-to-chest ratio was associated with higher inflammation. However, these associations disappeared after adjustment for adiposity. The findings do not support the hypothesis that greater morphological masculinization reflecting higher androgen exposure is associated with accelerated biological aging. Instead, body composition and adiposity appear to play a more prominent role. The relationship between testosterone and biological age remains complex and may reflect both beneficial and context-dependent effects.

Persistent Müllerian duct syndrome (PMDS) is a rare difference/disorder of sex development and maturation characterized by the retention of Müllerian structures during fetal development in individuals with a 46,XY karyotype. It is typically due to mutations in anti-Müllerian hormone (AMH) or its receptor, anti-Müllerian hormone receptor type 2 (AMHR2). Here, we report a novel de novo heterozygous loss-of-function frameshift variant in protein phosphatase 1 regulatory subunit 12A (PPP1R12A; p.Lys197IlefsTer13) identified in a 46,XY neonate presenting with bilateral cryptorchidism and a Müllerian remnant detected on pelvic ultrasound. Hormonal evaluation during the first days of life and minipuberty revealed the expected activation of the hypothalamic-pituitary-gonadal axis and preserved gonadal function: serum inhibin B, 108 pg/mL; AMH, 174.4 pmol/L; and testosterone, 1.4 nmol/L at birth; and inhibin B, 259 pg/mL; AMH, 342 pmol/L; testosterone, 9.2 nmol/L; LH, 19.1 IU/L; and FSH, 10.4 IU/L, respectively. At 10 months, AMH (149.8 pmol/L) and inhibin B (76 pg/mL) concentrations were below the reported age-specific reference intervals, raising the possibility of evolving Sertoli cell dysfunction. In silico analyses predict a truncated protein and/or nonsense-mediated mRNA decay. The endocrine profile supports the hypothesis that the PPP1R12A variant may contribute to PMDS through abnormal duct development rather than primary gonadal failure. These findings broaden the endocrine phenotype associated with this syndrome and suggest a role for PPP1R12A in Müllerian duct regression and differentiation rather than in gonadal development.

Klinefelter syndrome (KS) is a common but frequently underdiagnosed sex chromosome aneuploidy that confers a markedly elevated risk of venous thromboembolism (VTE), yet it remains absent from major anticoagulation guidelines. We present a 41-year-old man with known KS on testosterone replacement who developed massive bilateral pulmonary embolism with concurrent deep vein thrombosis, presenting with syncope, dyspnea, and right heart strain on imaging. Hematocrit was 48.8% at admission, below the erythrocytosis threshold despite ongoing testosterone therapy. Serial laboratory data over 13 months consistently showed normal hematocrit values, implicating KS-intrinsic hypercoagulability rather than testosterone-induced erythrocytosis as the primary thrombotic driver. Thrombophilia testing was negative for factor V Leiden, prothrombin G20210A, and JAK2 mutations. The patient was managed with heparin bridged to apixaban and discharged on lifelong anticoagulation. This case highlights KS as a high-risk thrombophilic condition in which the underlying genetic syndrome, not testosterone therapy, is the primary driver of thrombosis. Early recognition and formal inclusion of KS in VTE management guidelines are needed to standardize care for this commonly underdiagnosed population.