Primary amenorrhea may be the first clinical presentation of an underlying 46,XY disorder of sex development (DSD). We report 2 siblings assigned female at birth; the index case presented with primary amenorrhea and the younger sibling was identified through family screening. Both had female external genitalia with minimal virilization, absent Mullerian structures, and testes located in the inguinal/labioscrotal region on imaging. Hormonal evaluation showed impaired androgen synthesis with very low testosterone and markedly elevated 17-hydroxyprogesterone:androstenedione ratios, suggestive of isolated 17,20-lyase deficiency. Whole-exome sequencing identified a novel homozygous missense variant in exon 2 of the CYB5A gene (c.140G>T; p.Gly47Val) in both siblings, and segregation analysis confirmed the same variant in both parents as heterozygous carriers. Subsequently, methemoglobin levels were found to be above the normal reference range in both siblings despite the absence of clinical symptoms. Multidisciplinary evaluation confirmed female gender identity in both siblings without any gender incongruence and advised continuation of the assigned female gender role. Gonadectomy and vaginoplasty were planned after 18 years of age. These cases highlight cytochrome b5 deficiency due to a novel variant as a rare cause of 46,XY DSD and the importance of recognizing methemoglobinemia in a DSD.

Congenital hypogonadotropic hypogonadism (CHH) in boys and adolescents requires age- and developmentally appropriate treatment to address androgen deficiency, testicular maturation, pubertal development, and ultimately fertility. The dynamic physiology of the hypothalamic-pituitary-testicular axis necessitates therapeutic strategies that differ substantially between infancy and adolescence.

Testosterone deficiency (TD) has been closely associated with systemic inflammation and metabolic disturbances. The C-reactive protein-albumin-lymphocyte (CALLY) index is a composite biomarker integrating inflammatory, nutritional, and immune parameters. However, its association with TD remains unclear. This study aimed to investigate the relationship between the CALLY index and TD in adult men.

Background: The demographic crisis observed in industrialized countries has been accompanied by a decline in the reproductive potential of human populations. One of the causes for the global deterioration in men's reproductive health is adiposity and sedentary lifestyle, leading to reduced fertility and a decrease in androgen status. The aim of the study was to assess the association between abdominal obesity and semen parameters, including sperm DNA fragmentation, as well as key indicators of hormonal and metabolic status in young men from the general population. Methods: Our cross-sectional study was conducted among Russian and Belarusian men living in six cities. The examination of men (n = 1283, median age 23 years) included questionnaires, anthropometry, and the collection of peripheral blood and semen samples. Semen analysis was conducted according to WHO guidelines. Sperm DNA fragmentation index (DFI) was evaluated using the SCSA method. The serum and seminal zinc concentration was determined using spectrophotometry and direct calorimetry. Hormonal and metabolic levels were measured using commercial kits. Waist circumference (WC) was used as a surrogate marker of abdominal adiposity. Participants were allocated to three phenotypes: non-obese (control, WC < 94 cm), excess abdominal fat (94 ≤ WC < 102 cm) and abdominal obesity (WC ≥ 102 cm). Results: In our study population, 85.8% of participants were young (under 30 years of age), 8.6% had excess abdominal fat, 5.7% had abdominal obesity (AO), and 65.2% had normozoospermia. Men with AO were characterized by a decrease in semen volume, total sperm count, sperm concentration and progressive motility compared to the non-obese control. DFI was significantly higher in obese compared to non-obese men. Obese participants had significantly lower testosterone and inhibin B levels, but higher FSH and leptin levels compared to non-obese men. Men with AO had elevated serum zinc levels but reduced seminal zinc content. Abdominal obesity was also associated with significant metabolic changes, in particular, with increased levels of triglycerides, total cholesterol, low-density lipoproteins, fasting glucose and uric acid. AO-related testosterone deficiency (serum testosterone level ≤ 12.1 nmol/L) was detected in 38.7% of obese men and was accompanied by elevated DFI, levels of FSH, and zinc, as well as unfavorable changes in metabolic indicators. Physically active AO men (who engaged in recreational sports or physical labor) demonstrated reduced anthropometric indicators of AO and leptin levels, increased LH and testosterone levels, and improved carbohydrate and lipid metabolism compared to sedentary AO men. Conclusions: AO is accompanied by a decrease in the activity of Leydig and Sertoli cells, as well as an imbalance of the hypothalamic-pituitary-testicular axis and metabolic status. AO, associated with testosterone deficiency or a sedentary lifestyle, is a potential risk factor for the weakening of male reproductive health. However, physically active stout men showed more favorable anthropometric, hormonal, and metabolic indicators compared with sedentary stout men. In the long term, obese men who ignore a correction of sedentary lifestyle are not protected from a decline in reproductive health.

Iron deficiency (ID) represents one of the most prevalent nutritional disorders worldwide, affecting approximately 1.2 billion individuals. Beyond its well-established hematological consequences, emerging evidence demonstrates that ID profoundly impacts endocrine function across multiple organ systems. Iron serves as an essential cofactor for numerous enzymes involved in hormone synthesis, metabolism, and signaling pathways. This comprehensive review examines the bidirectional relationships between iron deficiency and endocrine pathologies, including thyroid disorders (hypothyroidism, Hashimoto's thyroiditis, thyroid peroxidase impairment), diabetes mellitus (types 1 and 2), obesity, Polyendocrine Metabolic Ovarian Syndrome (PMOS), male hypogonadism, adrenal insufficiency, growth hormone deficiency, pituitary dysfunction, and parathyroid disorders. We systematically analyze the molecular mechanisms linking iron metabolism to endocrine dysfunction, with particular emphasis on thyroid peroxidase activity, insulin secretion and sensitivity, hepcidin regulation, testosterone synthesis, and cortisol production. Furthermore, we critically evaluate the therapeutic potential of liposomal iron supplementation, a novel delivery system that offers superior bioavailability and gastrointestinal tolerability compared to conventional oral iron formulations. Randomized controlled trials demonstrate that liposomal iron achieves comparable efficacy to intravenous iron while significantly reducing adverse events. This review synthesizes current evidence to provide clinicians with a comprehensive understanding of iron-endocrine interactions and evidence-based recommendations for iron supplementation in endocrine disorders. Recognition of these complex relationships is essential for optimizing diagnostic and therapeutic approaches in patients with concurrent iron deficiency and endocrine dysfunction.

The cardiovascular actions of testosterone remain controversial, particularly regarding the safety of testosterone replacement therapy (TTh) in hypogonadal men. We investigated the effects of sustained supraphysiological testosterone exposure on aortic atherogenesis and cardiac remodelling in the testicular feminised (Tfm) mouse, a model of functional androgen receptor (AR) deficiency. Male Tfm mice and AR-intact XY littermate controls were fed a cholesterol-enriched diet for 28 weeks and received fortnightly intramuscular injections of saline or supraphysiological testosterone, alone or in combination with fulvestrant (oestrogen receptor antagonist) or anastrozole (aromatase inhibitor). Aortic lipid deposition was quantified by Oil Red O staining, while cardiac remodelling was assessed by heart weight, cardiomyocyte cross-sectional area and myocardial gene expression. Supraphysiological testosterone significantly reduced aortic fatty streak formation in Tfm mice compared with saline-treated controls (1.25 ± 0.36% vs. 2.85 ± 0.37%, p < 0.01), an effect preserved following fulvestrant or anastrozole treatment, consistent with mechanisms that do not require classical AR or oestrogen receptor signalling. No additional reduction in aortic lipid deposition was observed in AR-intact XY littermates. In contrast, supraphysiological testosterone increased heart weight, cardiomyocyte size and expression of hypertrophic markers exclusively in XY mice, with no evidence of cardiac remodelling in Tfm mice. Collectively, these findings demonstrate divergent tissue-specific cardiovascular actions of testosterone, whereby supraphysiological exposure promotes AR-dependent cardiac remodelling without conferring additional vascular benefit, supporting maintenance of physiological testosterone concentrations during TTh.

Monitoring children with 21-hydroxylase deficiency (21-OHD) requires suppression of adrenal androgen excess while avoiding glucocorticoid overtreatment. However, the clinical value of serum 11-oxygenated androgens beyond established biomarkers remains uncertain. We evaluated whether serum 11-ketotestosterone (11KT) is associated with overall disease-control status and whether it provides incremental information beyond androstenedione (A4).

Hallmarks of aging are highly variable among individuals, and sexual dimorphism may contribute to these differences. However, the details are unclear.The gut-metabolism axisin naturally aging wild-type and Nrf2 knockout (KO) mouse models was investigated. In this study, intraperitoneal glucose tolerance tests were performed on 12- and 48-week-old wild-type and Nrf2 KO mice to assess glucose tolerance. Serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein levels were measured using biochemicaltest kits. The estradiol and testosterone levels in the serum were detected using enzyme-linked immunosorbent assays. Liver and adipose tissue morphology were examined using hematoxylin and eosin staining, and gut microbiota composition was analyzed using 16S rDNA sequencing of fecal samples.The results showed that glucose tolerance was significantly impaired in aging male Nrf2KO mice, and lipid accumulation in hepatic and adipose tissues increased in aging wild-type (WT) miceandaging Nrf2KO mice of both sexescompared with that in their young counterparts.Aged miceand Nrf2 KO mice exhibited divergent responses in their serum lipid profiles.Notably, female Nrf2 KO mice showed a significantly lowerα-diversity in gut bacterial composition, compared with both male Nrf2 KO mice and female WT controls.In conclusion, the resultsindicatethat aging and Nrf2 deficiency promoted weight gain and tissue lipid accumulation in both sexes but elicited sex-dimorphic differences in blood glucose stability, microbiota composition, and the magnitude of adiposity. Therefore, sex is an important factor contributing to age-related variations in gut microbiota and metabolism.

Objective: Polycystic ovary syndrome (PCOS) and nonclassic congenital adrenal hyperplasia (NCAH) overlap clinically, but direct comparative data specifically addressing non-National Institutes of Health (non-NIH) Rotterdam phenotypes of polycystic ovary syndrome are limited. We compared women with polycystic ovary syndrome, of whom 66.7% were classified as having non-NIH Rotterdam phenotypes, with women with nonclassic congenital adrenal hyperplasia and healthy controls to characterize the extent of phenotypic overlap and evaluate the discriminatory performance of individual androgen measures. Methods: This single-center, prospective, exploratory cross-sectional study evaluated 58 women divided into three groups: PCOS (n = 24, Rotterdam criteria), NCAH due to 21-hydroxylase deficiency (n = 16, previously confirmed by adrenocorticotropic hormone (ACTH)-stimulated 17-hydroxyprogesterone (17-OHP)), and healthy controls (n = 18). Demographic, clinical, metabolic, and hormonal parameters were compared using analysis of variance (ANOVA), Kruskal-Wallis with Dunn's post hoc test (Bonferroni-adjusted), and chi-square or Fisher's exact tests. A sensitivity analysis was performed after excluding 12 participants receiving oral contraceptives (n = 8) or glucocorticoids (n = 4). Results: Within the PCOS group, 66.7% had non-NIH Rotterdam phenotypes. Hirsutism, defined as a modified Ferriman-Gallwey (mFG) score ≥ 8, was more frequent in both patient groups than in controls (p = 0.003) but did not differ between PCOS and NCAH. Total testosterone levels were 0.40 [0.20-0.60], 0.59 [0.45-0.94], and 0.20 [0.15-0.20] ng/mL in the PCOS, NCAH, and control groups, respectively, and androstenedione levels were 1.40 [1.20-2.20], 2.55 [1.64-4.07], and 0.87 [0.56-1.00] ng/mL, respectively; both were higher in the patient groups than in controls (both p < 0.001), without differing between PCOS and NCAH. Basal 17-OHP was the only parameter distinguishing NCAH from both PCOS and controls (p < 0.001). Dehydroepiandrosterone sulfate (DHEAS) levels were 356.5 [217-422], 292 [156-448], and 219 [146-240] µg/dL, respectively (p = 0.020), with a significant difference only between PCOS and controls. Anti-Müllerian hormone (AMH) levels were 3.27 [3.02-4.13], 3.13 [2.87-3.54], and 3.34 [2.93-5.37] ng/mL, respectively, with no between-group difference (p = 0.600). Other metabolic parameters, gonadotropins, estradiol, and prolactin showed no between-group differences. The principal hormonal findings remained unchanged after excluding women receiving oral contraceptives or glucocorticoids. Conclusions: In this PCOS cohort, in which 66.7% of women were classified as having non-NIH Rotterdam phenotypes, PCOS and NCAH showed substantial clinical, metabolic, and hormonal overlap, whereas basal early-follicular 17-OHP was the only parameter that consistently distinguished NCAH from both PCOS and healthy controls. These findings support the inclusion of basal 17-OHP in the evaluation of women presenting with hyperandrogenism.

Secondary hypogonadism is a clinically significant consequence of hypothalamic-pituitary-gonadal (HPG) axis suppression and may result from multiple exposures, including chronic opioid and anabolic steroid use. Long-term treatment strategies for persistent secondary hypogonadism, particularly testosterone replacement therapy (TRT) and its complications, remain incompletely characterized. This case describes a male patient with a history of both opioid and anabolic steroid exposure who developed persistent acquired secondary hypogonadism, with potential contributions from both opioid-induced androgen deficiency (OPIAD) and anabolic steroid-induced hypogonadism (ASIH). The patient subsequently underwent approximately 13 years of TRT, with sustained symptomatic benefit but clinically significant complications including erythrocytosis and late-onset gynecomastia. At the time gynecomastia was documented, serum estradiol testing and breast imaging were not available in the records reviewed, and the diagnosis was based primarily on patient-reported symptoms. This case highlights the challenges of determining the etiology of persistent HPG axis suppression following multiple suppressive exposures and emphasizes the importance of longitudinal monitoring for complications associated with prolonged TRT.