Age-related hearing loss is a progressive bilateral sensorineural loss that increases steeply with age, contributing to communication disabilities and social isolation, impacting healthy aging. Across diverse cohorts, men tend to develop earlier and more severe high-frequency threshold elevations than age-matched women. This male disadvantage is partly explained by gender-related lifetime exposure (e.g., occupational noise, smoking), likely reflecting interactions with biological sex factors, including steroid signaling and mitochondrial susceptibility. Sex differences in cochlear physiology are detectable from infancy, including larger otoacoustic emissions in female newborns, supporting developmental endocrine influences. Adult men usually exhibit earlier and steeper high-frequency declines. Conversely, studies in menopausal women have indicated heterogeneity rather than a uniform female inflection point. Mechanistic studies have demonstrated inner-ear estrogen receptor expression and context-dependent otoprotection. However, human epidemiology does not support uniform auditory benefits from menopausal hormone therapy; rather, long-term oral estrogen or estrogen plus progestogen use may increase the risk of hearing loss. Evidence for androgen pathways is emerging, albeit limited. In older men, higher serum testosterone, but not dehydroepiandrosterone sulfate, is associated with lower odds of high-frequency hearing loss. The precise mechanisms and clinical effects of exogenous hormone therapies on auditory aging remain uncertain. This review synthesizes current evidence using a life-course "multi-hit" framework. Rather than pointing to a single biological driver, we describe how innate susceptibilities such as the aging endocrine axis and mitochondrial variation interact with male-predominant ototoxic exposure and cardiometabolic comorbidities to shape auditory dimorphisms. Addressing current knowledge gaps requires sex-stratified longitudinal research integrating precise endocrine profiling with functional auditory outcomes. Clinically, although endocrine pathways are not yet therapeutic targets, understanding this multidimensional vulnerability highlights the utility of risk-stratified screening. Incorporating proactive hearing assessment into routine evaluations of aging men, particularly those with late-onset hypogonadism, can facilitate early detection, timely rehabilitation, and possible downstream cognitive benefit.

Congenital hypogonadotropic hypogonadism (CHH) is a rare group of disorders of gonadotropin deficiency, either isolated or as a part of multiple pituitary hormone deficiencies (MPHD). We aimed to describe the spectrum of presentation, diagnosis, and management practices of CHH spanning 30 years at an Australian tertiary paediatric centre. This is a retrospective cohort study of patients with CHH seen at the Children's Hospital at Westmead between January 1994 and December 2024 (n = 96, 66% male), categorised by diagnostic subtypes: Kallmann Syndrome (KS), normosmic HH, MPHD and other syndromes (including CHARGE). RESULTS: In patients with KS (n = 31, 87% male), the most common presenting features were micropenis and/or cryptorchidism (45%) or pubertal delay (45%), with two peak ages of presentation: 0.6 [IQR 0.3-0.8] and 14.6 [11.5-15.7] years. Patients with MPHD (n = 23, 52% male) presented with neonatal hypoglycaemia in 52%. Comorbidities stratified by diagnostic subtypes (KS, MPHD, and other syndromes) included hearing impairment (10%, 4%, 100%), visual impairment (7%, 17%, 77%), cardiac anomalies (3%, 9%, 77%), and intellectual disability (13%, 26%, 46%). Genetic testing was performed in 32% in 1995-2009 vs 66% in 2010-2024. Pathogenic gene variants associated with HH were found in 61% of those tested, including CHD7 (n = 10), ANOS1 (n = 4), and FGFR1 (n = 3). Pubertal induction was commenced in males at a mean age of 14.1 ± 1.6 years using testosterone (n = 27 oral; 14 intramuscular; 1 subcutaneous) or gonadotropins (n = 5), and in females, at a mean age of 14.6 ± 1.8 years using oestradiol (n = 21 oral; 8 transdermal) ± progesterone. CONCLUSIONS: CHH is a heterogeneous group of disorders, with varying prevalence of associated comorbidities according to diagnostic subtypes. Our data highlight the paediatric-specific modes of presentation of CHH, and in KS, the bimodal distribution of age at presentation in males and the under-representation and delayed diagnoses in females. Despite advances in genetics in the past three decades, there remain areas for further research in the diagnostics and therapeutics of CHH in the paediatric age group.

Relative energy deficiency in sport (REDs) not only affects female athletes, but male athletes as well. It results from severe and/or prolonged low energy availability, when energy intake no longer meets energy expenditure. In men, REDs may present as decreased performance, persistent fatigue, recurrent infections, mood disturbances, reduced libido, functional hypogonadism, impaired bone health, and an increased risk of stress fractures. Diagnosis is a medical decision based on a comprehensive clinical evaluation, as there are no specific biomarkers, and may be supported by structured tools such as the Relative Energy Deficiency in Sport Clinical Assessment Tool - version 2, developed under the auspices of the International Olympic Committee.

46,XX testicular disorder of sex development (DSD) is a rare condition usually diagnosed during adolescence or adulthood due to infertility or hypogonadism. Early diagnosis in phenotypically normal infants is uncommon. We report a male infant identified following discordant prenatal sex assessment, with noninvasive prenatal testing suggesting a female fetus and prenatal ultrasonography demonstrating male genitalia. Postnatal chromosomal analysis revealed 46,X,add(X) (p22.3) with SRY positivity. Physical examination showed normal male external genitalia with bilaterally descended testes and no genital anomalies. After two years of multidisciplinary follow-up, the patient remained clinically stable without gonadal abnormalities.

Multiple epiphyseal dysplasia (MED) is a genetically diverse skeletal disorder characterized by abnormal and delayed epiphyseal ossification, early-onset osteoarthritis, joint pain and mild short stature. MED is primarily caused by pathogenic variants in genes involved in cartilage and bone development, including COMP, MATN, COL9A1-3, CANT1 and SLC26A2. FGFR1 was suggested as a cause of MED in a study published in 2020, which reported a frameshift variant in the last exon of this gene. We assembled an international cohort of 13 individuals with MED carrying C-terminal frameshift variants in FGFR1 (NM_023110.3: c.2424_2425del, c.2436_2440del, and c.2460dup). In all three families, the frameshift variants are predicted to result in the same 164-amino acid C-terminal elongation tail. The cohort includes two families (three affected individuals in one, nine in the other) and one previously reported individual. All affected individuals presented with MED without vertebral involvement. Age of symptom onset ranged from 3 to 13 years, with complete penetrance. Genu valgum was very frequent, and most affected patients required its surgical correction. Hypogonadotropic hypogonadism was present in approximately half of the cases. Adult height was mildly reduced, with an median of 164.0 cm in males (-1.7 SDS) and 153.1 cm in females (-1.6 SDS). Structural modeling for the novel C-terminal stretch as a result of the variants could acquire secondary structures, including an α-helix and a β-sheet domain, and could bring a potential antimorphic effect. Our findings confirm FGFR1 C-terminal frameshift variants as a cause of MED and provide further clinical characterization of this disorder.

The androgen receptor (AR), beyond its classical roles in male sexual function and muscle maintenance, has emerged as a pivotal regulator of metabolic health. In men, age- or hypogonadism-related androgen decline is strongly associated with an increased risk of type 2 diabetes and impaired glucose tolerance, underscoring the protective role of AR signaling in glucose homeostasis. Conversely, its physiological significance in women remains largely unexplored, as clinical and basic research has predominantly focused on pathological hyperandrogenism, such as polycystic ovary syndrome (PCOS). This review delineates the genomic and non-genomic molecular mechanisms of AR action and synthesizes evidence from male genetically modified mouse models and cellular studies to clarify its role across key metabolic tissues, including skeletal muscle, liver, pancreatic β-cells, adipose tissue, and the central nervous system. Based on these insights, we hypothesize that physiological AR signaling exerts beneficial metabolic effects in women, whereas adverse metabolic outcomes are primarily associated with supraphysiological AR activation. Finally, we highlight key knowledge gaps and propose future directions to validate this hypothesis, with the goal of establishing a novel conceptual framework for understanding female metabolic homeostasis and informing sex-specific therapeutic strategies.

Introduction Hypogonadotropic hypogonadism (HH), or secondary gonadal dysfunction, is a result of gonadal failure due to deficiencies in gonadotropin secretion, caused by hypothalamic or anterior pituitary dysfunction. There are multiple forms of HH, with the syndrome divided into congenital, acquired organic, and functional forms. The relationship between HH and oncological processes is complex and multidirectional, and little is known about the relationship between HH and cancer in female patients. Hormone replacement therapy (HRT) can be important for symptom control in many women with HH. However, exogenous estrogen use is additionally associated with a higher risk of both arterial and venous thromboses. There is little information available regarding the impact of HRT on rates of cancers or thromboses in women with HH. Methods TriNetX's US Collaborative Network was utilized to study rates of development of estrogen-associated cancers in female patients at or above 50 years old diagnosed with HH using ICD-10 codes. Adult female patients diagnosed with HH were identified and stratified according to HRT use and ICD-10 codes. HH patients prescribed HRT were matched with a control group of HH patients without HRT based on age, ethnicity, race, and comorbidities. Patients were followed to assess rates of estrogen-associated cancer development at any time after the index event, defined as HH development with or without HRT prescription, or menopause development. Cancers studied included breast, cervical, uterine, ovarian, endometrial, gastric, and colorectal cancer. Development of venous thromboses, including deep venous thromboses (DVTs) and pulmonary emboli (PEs), was also studied. Patients with outcomes prior to the indexing date were excluded from the study.  Results Following propensity-score matching, we identified 8,293 female patients at or above 50 years old in each cohort, with diagnosed HH, but with and without prescribed HRT. There were no significant differences in rates of breast, cervical, uterine, ovarian, endometrial, or colorectal cancers between HH cohorts. There were no significant differences in rates of DVTs or PEs between HH cohorts. A cohort of female patients at or above 50 years old with HH and no HRT prescription was propensity-score matched with a cohort of post-menopausal women at or above 50 years old without HH or HRT prescription. There were no significant differences in rates of breast, colorectal, cervical, or ovarian cancers. The postmenopausal cohort demonstrated a significantly increased risk of endometrial cancer (HR 0.246, 95% CI 0.220 - 0.275, p<0.001). The HH without HRT cohort demonstrated a significantly increased risk of gastric cancer (HR 3.150, 95% CI 2.549 - 3.892, p=0.001), acute DVT (HR 1.709, 95% CI 1.595 - 1.831, p<0.001), and acute PE (HR 1.612, 95% CI 1.494 - 1.740, p<0.001).  Conclusions Our findings indicate that female patients at or above 50 years old with HH may have an elevated risk of venous thromboses and gastric cancer, but reduced risk of endometrial cancer when compared to a cohort of post-menopausal female patients above 50 years old without HRT prescription. No significant differences existed between cohorts with HH with and without HRT prescription. Further study into this population is warranted.