Search Results (167)

Background/Objectives: Male hypogonadism affects 35–50% of men with type 2 diabetes mellitus (T2DM) and obesity. The relationship between testosterone deficiency and response to incretin-based therapies (GLP-1 and GIP receptor agonists) remains incompletely understood. This systematic literature review, conducted following PRISMA 2020 guidelines, examines whether male hypogonadism represents a risk factor for poor response to incretin therapy or, conversely, whether these agents offer therapeutic benefits for this population. Methods: A comprehensive systematic literature search was conducted on 31 December 2024, across PubMed/MEDLINE, Scopus, and Web of Science using three search domains: (1) hypogonadism and incretin therapy response; (2) testosterone deficiency and GLP-1/GIP receptor agonists; (3) incretin response and testosterone. Eligibility criteria included human studies (randomized controlled trials [RCTs], observational studies, cohort studies, cross-sectional studies, systematic reviews, and meta-analyses) in adult men reporting testosterone levels and/or incretin response. Animal studies, pediatric populations, case reports with n < 5, editorials, and letters without data were excluded. Study selection followed PRISMA 2020 guidelines with independent dual screening. Risk of bias was assessed using the Cochrane Risk-of-Bias 2.0 tool (ROB2) for RCTs, the Newcastle–Ottawa Scale (NOS) for observational studies, and AMSTAR-2 for systematic reviews and meta-analyses. Due to substantial heterogeneity in study designs, populations, interventions, and outcome measures, a meta-analysis was not feasible; therefore, a narrative synthesis was performed. Results: From 326 records identified, 29 studies were included after deduplication and screening (primary studies: 14; systematic reviews/meta-analyses: five; narrative reviews/expert opinion: 10). Risk-of-bias assessment revealed moderate-to-high overall risk: RCTs had small sample sizes (n = 12–42) and short follow-up (12–24 weeks), raising concerns about statistical power; observational studies were of fair-to-good quality (NOS 4–7 stars) but subject to confounding; and systematic reviews were of low-to-moderate confidence (AMSTAR-2). Primary evidence from RCTs and observational studies demonstrates that GLP-1 receptor agonists (GLP-1RAs)—particularly semaglutide and liraglutide—and the dual GIP/GLP-1 receptor agonist tirzepatide significantly increase total testosterone levels in men with obesity-related functional hypogonadism (mean increase 2.5–5.2 nmol/L). This effect is largely mediated by weight loss and improvement of insulin resistance rather than direct androgenic action. Evidence regarding whether baseline hypogonadism impairs glycemic or weight-loss response to incretin therapy is limited and indirect; no adequately powered comparative trials stratified by baseline testosterone status were identified. Conclusions: Incretin-based therapies, particularly GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide, appear to improve testosterone levels in men with obesity-related functional hypogonadism, an effect that is largely mediated by weight loss and improvement of insulin resistance rather than a direct androgenic action. However, direct comparative evidence between hypogonadal and eugonadal men regarding glycemic or weight-loss response to incretin therapy remains insufficient to draw firm conclusions. The hypothesis that male hypogonadism does not impair incretin therapy response is biologically plausible but is currently supported only by indirect evidence. Prospective, adequately powered trials stratified by baseline testosterone status are needed to resolve this question. Full article

Obesity is associated with metabolic dysregulation and impaired male reproductive capacity, where the gut microbiota affects male reproductive function through diverse mechanisms that warrant further elucidation. This study aims to evaluate the effects of ketogenic and vegan dietary interventions in attenuating obesity-associated testicular injury and to examine the extent to which specific gut microbiota profiles mediate their impact. Forty-nine male adult albino rats were assigned to seven groups: control group, obese group (HFD), obese group + modified microbiota, obese group + ketogenic diet, obese group + ketogenic diet + modified microbiota, obese group + vegan diet, and obese group + vegan diet + modified microbiota. Metabolic markers (glucose, insulin, leptin, and HOMA-IR), reproductive hormones (testosterone, FSH, and LH), and testicular gene expression (IL-6, eNOS, and androgen receptor) were analyzed over five months. Gut microbiota composition (qPCR) and testicular histology/immunohistochemistry were assessed. HFD-fed rats exhibited hyperglycemia, insulin resistance, hypogonadism, and testicular degeneration. Both diets improved metabolic and hormonal profiles, restored testicular architecture, and downregulated inflammatory genes. Microbiota modification additively enhanced these effects, increasing the abundance of Lactobacillus and Akkermansia while reducing inflammation. The vegan diet showed superior efficacy in improving metabolic parameters, modulating pituitary–gonadal hormones, and attenuating testicular structural and functional alterations. Our findings demonstrate that ketogenic and vegan diets alleviate obesity-induced testicular dysfunction and that microbiota modulation amplifies these benefits by regulating the gut–testicular axis. Integrating dietary and microbial interventions may provide a basis for a promising approach to managing obesity-related male infertility. Full article

Non-obstructive azoospermia (NOA) is the most severe phenotype of male-factor infertility and reflects impaired spermatogenesis rather than ductal obstruction. Microdissection testicular sperm extraction (micro-TESE) is the primary sperm retrieval method, but sperm retrieval rates remain at approximately 40–60% and vary with etiology, genetics, histopathology, surgical expertise, and endocrine phenotype. This narrative review synthesizes major international and regional guidelines and contemporary evidence on preoperative hormonal optimization, with particular emphasis on endogenous testosterone dynamics. Exogenous testosterone is contraindicated in fertility-seeking men because it suppresses gonadotropins and intratesticular testosterone. By contrast, selective estrogen receptor modulators, aromatase inhibitors, human chorionic gonadotropin, and follicle-stimulating hormone aim to preserve or augment endogenous Leydig- and Sertoli-cell function. Low-certainty, predominantly observational evidence suggests an association between hormonal pretreatment and higher sperm retrieval in selected normogonadotropic or hypogonadal men, but not consistently in hypergonadotropic NOA. A larger testosterone rise during stimulation has been positively associated with retrieval and may reflect residual Leydig-cell reserve, although causality and transferable thresholds remain unproven. Preoperative endocrine therapy should therefore remain individualized, phenotype-guided, off-label, closely monitored, and preferably investigated within clinical trials; the testosterone response is best regarded as a candidate prognostic biomarker rather than a validated therapeutic target or decision rule. Full article

Background/Objectives: Male obesity secondary hypogonadism (MOSH) is a highly prevalent condition characterised by reduced testosterone levels in obese men, driven by increased aromatase activity, reduced SHBG, insulin resistance, and HPG axis suppression. Dietary interventions represent a cornerstone of non-pharmacological management; however, the comparative efficacy of different dietary patterns on testosterone restoration remains unclear. Methods: We conducted a systematic literature review following PRISMA 2020 guidelines. Comprehensive searches were performed in SciSpace, Google Scholar, and PubMed through June 2026. Eligible studies included human adult males with obesity (BMI ≥ 30 kg/m²) undergoing Mediterranean diet (MedDiet), ketogenic diet (KD/VLCKD), or intermittent fasting (IF) interventions, with quantitative assessment of testosterone or androgen status. Results: From 697 initial records, 500 unique papers were identified after deduplication. Following abstract screening (n = 442 excluded) and full-text assessment (n = 6 excluded), 52 studies were included in the final synthesis. VLCKD demonstrated the most consistent evidence for testosterone improvement, with RCTs reporting significant increases in total testosterone (+1.5 to +3.0 nmol/L). Intermittent fasting showed promising but more heterogeneous results. Evidence for Mediterranean diet was limited, focusing primarily on metabolic rather than hormonal outcomes. Weight loss emerged as a critical mediator across all dietary interventions (~3 nmol/L per 10 kg weight loss). Conclusions: Among dietary interventions for MOSH, VLCKD shows the strongest evidence for testosterone restoration in obese men, through rapid weight loss, improved insulin sensitivity, reduced inflammation, and potential direct HPG axis effects. Intermittent fasting represents a viable alternative. Mediterranean diet, while beneficial for cardiovascular health, lacks robust interventional evidence for testosterone improvement in this population. Systematic Review Registration: This review was not prospectively registered. PROSPERO registration is recommended for future updates. Full article

Background: Testosterone deficiency is highly prevalent in men with obesity and type 2 diabetes mellitus and often reflects functional suppression of the hypothalamic–pituitary–gonadal (HPG) axis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in these conditions, but their effects on male reproductive endocrinology remain incompletely defined. Objective: To systematically review the effects of GLP-1 receptor agonists on testosterone, HPG axis hormones, and male reproductive outcomes. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed/MEDLINE, Cochrane, and Google Scholar were searched (January 2021–January 2026) for studies evaluating GLP-1 RA therapy in adult men with reported endocrine or reproductive outcomes. Results: Eight studies met inclusion criteria, including one randomised placebo-controlled crossover trial and six observational or interventional studies. In men with obesity, type 2 diabetes, or functional hypogonadism, GLP-1 RAs were associated with modest increases in testosterone and improvements in erectile function or selected semen parameters. In contrast, a placebo-controlled trial in healthy eugonadal men showed no significant endocrine or reproductive effects. Responses appeared dependent on baseline metabolic status. Conclusions: GLP-1 RAs are associated with improvements in male reproductive endocrinology in metabolically compromised populations with metabolic hypogonadism while remaining neutral in healthy individuals. Larger prospective studies are needed. Full article

Male hypogonadism is associated with metabolic and cardiovascular comorbidities, and emerging evidence implicates testosterone deficiency in immune dysregulation that may elevate cancer risk. To review current evidence on the relationship between male hypogonadism, immune function, and cancer risk, focusing on mechanisms linking testosterone deficiency to immune suppression and oncologic outcomes. PubMed/MEDLINE, Google Scholar, and SciSpace were systematically searched (through April 2026) using predefined search strings. After removal of duplicates (n = 1535 records screened), 156 full-text articles were assessed for eligibility; 20 studies met predefined inclusion criteria (comprising 4 experimental studies, 4 prospective/RCT studies, 7 observational studies, and 5 reviews used as secondary literature) and were included in a narrative synthesis. Testosterone deficiency was consistently associated with elevated IL-6, TNF-α, IL-1β, and CRP, impaired neutrophil maturation, and reduced NK-cell cytotoxicity. Androgen deprivation augmented thymic output and anti-tumor T cell responses in prostate cancer models, yet promoted chronic inflammation in other contexts. Epidemiologically, low testosterone correlated with increased colorectal cancer risk and poorer survival in advanced malignancies; the prostate cancer relationship followed a paradoxical saturation model. The immunological consequences of hypogonadism are context-dependent. Testosterone deficiency drives pro-inflammatory signaling that may promote carcinogenesis, while androgen-mediated immunosuppression can paradoxically impair anti-tumor surveillance. No simple linear relationship exists between hypogonadism and cancer risk via immune suppression. Prospective studies are needed to guide clinical decisions on testosterone replacement therapy in hypogonadal men. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and male hypogonadism (HG) are prevalent disorders that frequently coexist, suggesting a bidirectional “liver–testis axis” as a potential pathophysiological link. This review explores the mechanistic basis and clinical implications of this axis. Molecularly, metabolically stressed hepatocytes release an altered hepatokine signature—marked by reduced sex hormone-binding globulin (SHBG) and elevated fibroblast growth factor 21 (FGF21)—along with pro-inflammatory cytokines (e.g., interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), which enter the systemic circulation. These factors may contribute to the impairment of Leydig cell steroidogenesis, the perturbation of blood–testis barrier integrity, and the disruption of spermatogenesis. Conversely, testicular dysfunction and subsequent testosterone deficiency promote visceral adiposity, worsen insulin resistance and amplify chronic inflammation, thereby accelerating hepatic steatosis and fibrosis. Clinically, these molecular interactions manifest as mutually worsening of MASLD and HG. Thus, the liver–testis axis establishes a framework that reveals the bidirectional crosstalk between hepatic metabolism and gonadal function, providing novel pathophysiological insights into these interconnected conditions. Full article

Background/Objectives: Clomiphene citrate (CC) is widely used off-label for male infertility despite limited evidence and inconsistent guideline recommendations. Although previous studies suggest variability in clinical practice, real-world data on prescribing patterns, patient selection, monitoring, and treatment success definitions remain limited. This study assessed CC prescribing patterns among urologists and identified factors associated with its use. Methods: A national, cross-sectional, web-based survey was conducted among urologists in Türkiye between November and December 2025. Of 1558 invited participants, 421 responded (27.0%), and 402 were included in the final analysis. The questionnaire was based on European Association of Urology and American Urological Association guidelines, refined through expert consensus, and pilot-tested. Multivariable logistic regression identified factors independently associated with CC use. Results: CC was used by 39.3% of respondents and was independently associated with private practice (odds ratio [OR] = 2.90, p < 0.001), greater professional experience (OR = 2.18, p = 0.002), and higher infertility case volume (OR = 2.27, p = 0.001). Substantial heterogeneity was observed in patient selection, dosing, monitoring, and success definitions. Treatment goals and perceived success definitions most frequently focused on laboratory-based endpoints, including semen parameters and testosterone levels, which were more frequently selected than pregnancy-related endpoints. However, spontaneous pregnancy was also commonly reported as a perceived success definition, whereas live birth was not separately assessed. An apparent indication paradox was observed for hypogonadotropic hypogonadism, which may reflect differing interpretations of functional versus irreversible hypogonadotropic states, and 31.6% of clinicians reported not routinely providing risk counseling. Conclusions: CC prescribing for male infertility remains heterogeneous among responding urologists and was associated with clinician experience, practice setting, and infertility case volume rather than standardized protocols. The predominance of laboratory-based endpoints, together with the frequent inclusion of spontaneous pregnancy as a perceived success definition and the absence of separate live-birth assessment, underscores the need for clearer terminology, standardized prescribing frameworks, structured risk counseling, and future studies incorporating clinically meaningful reproductive endpoints. Full article

Background: Vitamin D has traditionally been recognized for its role in calcium homeostasis and skeletal health, but vitamin D receptor expression and vitamin D-metabolizing enzymes have also been identified in extra-skeletal tissues, including components of the male reproductive tract. Observational evidence has suggested associations between vitamin D status and androgen-related markers; however, whether vitamin D supplementation has a measurable effect on androgen bioavailability remains uncertain. Objective: This systematic review and meta-analysis evaluated the effects of vitamin D supplementation on total testosterone (TT) and androgen bioavailability markers in adult men, including sex hormone-binding globulin (SHBG), free androgen index (FAI), calculated free testosterone (calculated FT), and bioactive testosterone (BAT) where methodologically compatible. Methods: The review was registered in PROSPERO (CRD420261365005) and conducted according to PRISMA 2020 and Cochrane methodological guidance. Searches were conducted from database inception to April 2026 in PubMed, Web of Science, Scopus, ClinicalTrials.gov, and the WHO ICTRP. Embase was initially planned but was not searched because institutional access was unavailable; this amendment was made before screening, extraction, risk-of-bias assessment, and synthesis. Records were deduplicated in Zotero, screened in a structured matrix, and converted from report-level records into independent comparison-level datasets where appropriate. Meta-analyses used random-effects REML models with Hartung–Knapp adjustment. Results: The official search set comprised 2854 records, of which 703 duplicates were removed, leaving 2151 records for title and abstract screening. The full-text screening file was reconciled to 162 PRISMA-countable reports/records: 135 reports were assessed, 27 reports could not be assessed because the full text was unavailable or had not been obtained for review, and 27 reports/studies were retained for qualitative synthesis. Eighteen reports were considered candidate sources for quantitative synthesis and were operationalized into 21 comparison-level records. The primary TT model included 11 comparisons and showed no clear effect of vitamin D supplementation on final TT (MD 0.47 nmol/L, 95% CI −0.50 to 1.44; I² = 24.1%). No clear effects were observed for SHBG (MD 0.27 nmol/L, 95% CI −2.14 to 2.68), FAI (MD −0.37, 95% CI −4.28 to 3.55), calculated FT sensitivity evidence (MD −0.0096 nmol/L, 95% CI −0.0525 to 0.0332), or BAT exploratory evidence (MD −0.47 nmol/L, 95% CI −1.77 to 0.83). GRADE certainty was low for TT, SHBG, and FAI, and very low for calculated FT and BAT. Conclusions: Current randomized evidence does not demonstrate a statistically clear or reproducible effect of vitamin D supplementation on total testosterone or androgen bioavailability markers in adult men. GRADE certainty was low for total testosterone, SHBG, and FAI, and very low for calculated free testosterone and bioactive testosterone. Because directly measured and calculated free testosterone are not analytically equivalent, free testosterone was not pooled as a primary outcome; method-compatible calculated FT was handled as sensitivity evidence and BAT as exploratory evidence. Full article

Obesity is a major global health challenge strongly associated with increased cardiometabolic morbidity and mortality. In men, obesity is characterized by a predominance of visceral adiposity, which is metabolically active and closely linked to systemic inflammation, hormonal dysregulation, and adverse cardiovascular outcomes. Despite its clinical relevance, male obesity remains underrecognized as a distinct pathophysiological condition. This study aimed to analyze the inflammatory mechanisms underlying male obesity and their relationship with cardiometabolic risk. A structured narrative review was conducted based on a PICo-guided research question, with literature searches performed in PubMed/MEDLINE, Scopus, Web of Science, Embase, and ScienceDirect, covering publications from 2015 to 2026. Studies focusing on male obesity, inflammatory pathways, and cardiometabolic outcomes were included. Evidence indicates that visceral adipose tissue acts as an active endocrine organ, releasing pro-inflammatory cytokines such as TNF-α and IL-6, contributing to chronic low-grade inflammation. This inflammatory state is associated with insulin resistance (IR), endothelial dysfunction, and oxidative stress, mediated by intracellular pathways including NF-κB and JNK. Additionally, adipokine imbalance, characterized by reduced adiponectin and increased leptin levels, further exacerbates metabolic and vascular impairment. Hormonal alterations, particularly reduced testosterone levels, play a key role in amplifying visceral fat accumulation and inflammation, creating a bidirectional relationship between hypogonadism and metabolic dysfunction. Clinically, these mechanisms highlight the importance of integrating inflammatory biomarkers, body composition assessment, and hormonal evaluation into the management of male obesity. Emerging therapies, including GLP-1 receptor agonists and immunometabolic interventions, offer promising strategies for reducing cardiometabolic risk. In conclusion, male obesity represents a complex, inflammation-driven condition requiring a comprehensive and mechanism-based approach to improve clinical outcomes and guide future therapeutic developments. Full article

Normogonadotropic azoospermia (NOAN) represents a diagnostic and therapeutic challenge in male infertility, affecting men with normal gonadotropin levels but absent sperm in the ejaculate. Emerging evidence has identified 17-hydroxyprogesterone (17OHP) as a potential biomarker for detecting reduced intratesticular testosterone (ITT) levels, and the presence of round spermatids in ejaculate as an indicator of residual spermatogenic activity. This report synthesizes current evidence on a proposed hypothesis-generating diagnostic framework that utilizes these markers to guide hormonal treatment strategies. Specifically, patients with elevated 17OHP levels (>1.18 ng/mL) and detectable round spermatids may benefit from combined human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH) therapy at doses lower than those used for hypogonadotropic hypogonadism. However, this cutoff has not been prospectively validated in NOAN-specific cohorts, and the evidence supporting this approach remains preliminary, derived from small heterogeneous cohorts. Alternative therapeutic strategies, including FSH monotherapy and non-hormonal pharmacological treatments, are also discussed. This framework requires rigorous prospective validation before clinical implementation. Full article

Background/Objectives: This study aimed to evaluate the prevalence of hypogonadism in men with RRMS (relapsing–remitting multiple sclerosis) who are undergoing treatment with disease-modifying therapies (DMTs) and its association with clinical and magnetic resonance imaging (MRI) parameters. Methods: A total of 126 male patients with RRMS, aged 18–67 years, receiving DMTs and a group of 35 age- and BMI-matched healthy individuals were enrolled. Clinical and demographic data were collected, including neurological disability (EDSS, T25FW, 9-HTP, SDMT), and MRI findings. Symptoms of androgen deficiency and depression were assessed using ADAM questionnaire and Beck Depression Inventory, while quality of life was evaluated using MSIS-29. Serum total testosterone (TT), sex hormone-binding globulin (SHBG), and free testosterone (fT) were measured in two stored morning blood samples. Results: A total of 118 (93.6%) MS patients (median age of 38.8 y) had normal TT levels; only 2 (1.6%) MS patients and 2 (5.7%) healthy controls had below-normal levels. Meanwhile, low fT levels were observed in 53 (43.7%) MS patients and 12 (34.3%) controls. However, the fT level was significantly lower in the MS patients under 38 years of age than in control individuals (p = 0.015). Only depression from all concomitant diseases was more prevalent in MS patients with low fT (p = 0.016). There was no correlation between low fT and clinical (EDSS, T25FT, SDMT) and MRI (new T2 and new Gd+ lesions) parameters but a longer disease duration and a higher total number of steroid treatments were associated with below-normal fT levels (p = 0.048 and p = 0.003, respectively). Change of DMT and current and previous DMT type did not correlate with low fT. Patients with low fT levels had a higher median score on the BDI (8.00; IQR: 3.00–12.50 vs. 5.00; IQR: 1.00–10.50) (p = 0.034) and the higher median ADAM questionnaire score (4.00 [IQR: 2.00–7.50] vs. 2.00 [IQR: 0.00–6.00]) (p = 0.034). Only a longer duration of MS (11.83 years) exhibited a significant positive correlation with the risk of a low fT level (OR = 1.19, CI 95%: 1.06–1.35, p = 0.004) in multivariate logistic analysis. Conclusions: Total testosterone level was normal in most male RRMS patients; however, low free testosterone level was observed, in particular in younger MS patients. Depression was more prevalent in patients with low fT but longer duration was a significant risk factor for a low fT level. Full article

Background: Male DSD is a rare disorder in which individuals with an XX chromosomal background present as phenotypic males due to the presence of the SRY gene translocation. We present here cytogenetic and molecular characterization of rare phenotypic male patients with primary infertility involving SRY translocation on the X chromosome, resulting in the absence of Y centromeric sequences. Methods: Routine hormonal analysis, scrotal ultrasonography, karyotype and FISH analysis were performed. Results: Normal male appearing patients presented with a long history of primary infertility. Physical examination revealed bilateral small, soft testes but reportedly normal libido and erectile function. Hormonal analysis revealed hypergonadotropic hypogonadism with very low total testosterone, high FSH and LH. Semen analysis consistently revealed azoospermia, and multiple testicular sperm extraction procedures and bilateral varicocelectomy failed to retrieve sperm. Karyotyping and FISH showed 46,X,der(X)t(X;Y)(p22.1;p11.2), and SRY-positivity on the derivative X chromosome, respectively. Conclusions: These findings expand the spectrum of 46,XX male infertility with SRY-positivity and underscore the necessity of lifelong testosterone replacement therapy for the management of hypogonadism. Future efforts should aim to establish regional registries for DSD to document genetic diversity surveillance in underrepresented populations. Full article

Purpose: Male breast cancer (maleBC) is an orphan disease. Aside from age, risk factors include genetic mutations and conditions like Klinefelter syndrome or other reasons of hypogonadism. Treatment is based on standards in women, but biological differences may exist, with maleBC exhibiting higher rates of hormone-receptor expression. Limiting data exists regarding the rate of low/ultralow HER2 expression, a predictive biomarker for the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in HER2-negative disease in women. Materials and Methods: We conducted a retrospective single-center analysis of clinicopathological features of maleBC at a tertiary cancer center. We identified a cohort of 57 maleBC patients, described demographic, pathological, prognostic and surgical and systemic treatment data and evaluated frequencies of low and ultralow HER2 expression. Results: The mean age was 64.3 (SE ± 1.79) years; 94.7% (n = 54) of patients presented with early/nonmetastatic breast cancer and 40.7% (22 of 54) of patients exhibited nodal involvement. Most patients (92.6%, 50 of 54 patients) had luminal disease and approximately one third of patients received chemotherapy. Endocrine therapy was administered in 87.7% (n = 50/57) of cases. For 52 of the patients included, full receptor status data including HER2 IHC scoring and/or histological specimens were available. IHC slides of tumor specimens from 24 patients with either historically reported “HER2 negative” or “HER2 0” expression were available for reassessment; 79.2% (n = 19 of 24) of these tumors exhibited either HER2-low or -ultralow expression. In the whole cohort, rates of HER2-low and -ultralow expression were 75.0% (39 of 52) and 5.8% (3 of 52 patients), respectively. The median follow-up was 7 years. Six deaths occurred in the total population (n = 57). The median event-free survival (EFS) was 8.39 years (95% CI 7.36–11.35). No statistically significant associations were observed between HER2 expression categories and clinicopathological variables including grade, ER status, nodal status, genetic variant status, age, Ki67 index, or overall survival events. Conclusions: In this cohort of maleBC patients, high rates of combined HER2-low and -ultralow expression were observed upon reassessment of tumors with historically negative HER2 status, shedding light on potential ADC eligibility in male breast cancer. Full article

Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes—such as NR0B1 pathogenic variants in men—can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families. Full article