Search Results (308)

Several reproductive issues in both men and women are caused by changes in the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). For males to sustain spermatogenesis and Leydig cell function, and for females to ensure orderly folliculogenesis, ovulation, and ovarian steroidogenesis, precise coordination of LH and FSH secretion is necessary. Pituitary responsiveness, the frequency or amplitude of gonadotropin-releasing hormone pulses, or the dysregulation of feedback signals mediated by sex steroids and inhibins all disrupt the balance between LH and FSH secretion. Oligozoospermia, luteal-phase abnormalities, anovulation, or complete spermatogenic failure are possible clinical signs of these alterations. In addition to functional neuroendocrine disturbances, emerging genetic and epigenetic evidence, including pathogenic variants in genes such as gonadotropin-releasing hormone receptor, kisspeptin, kisspeptin receptor, luteinizing hormone beta subunit, follicle-stimulating hormone beta subunit, follicle-stimulating hormone receptor, and luteinizing hormone/choriogonadotropin receptor, has highlighted the role of inherited and acquired molecular defects in disrupting gonadotropin regulation. This narrative review synthesizes contemporary mechanistic, clinical, translational, and genetic evidence elucidating how dysregulated secretion of LH and FSH contributes to reproductive dysfunction. The molecular processes that regulate gonadotropin synthesis and release, as well as neuroendocrine regulation, gene-level determinants of hypothalamic–pituitary–gonadal (HPG) axis dysfunction, and the clinical phenotypes that result from their disruption, are all given special attention. We conclude with a discussion of new treatment strategies that target local intragonadal regulators to enhance gametogenic capacity, modulate gonadotropin signaling, or restore physiological gonadotropin-releasing hormone (GnRH) pulsatility, with consideration of how genetic insights may inform personalized therapeutic approaches. Full article

In idiopathic azoospermia caused by non-obstructive infertility with AZFc deletion, the testicle usually contains an increased number of mast cells (MCs)—which are responsible for collagen synthesis in the testes—as well as Leydig cell hyperplasia. However, the relationship between MCs and telocytes in this pathology remains unexplored. The aim of this study was to examine ultrastructural changes in the interstitial tissue microenvironment of the convoluted seminiferous tubules in the testis, using clinical specimens from men with genetically determined non-obstructive infertility with AZFc deletion. Histological, immunohistochemical, and electron microscopic (EM) studies were performed on surgical materials from 14 patients with AZFc deletion. The IHC study was performed using a panel of antibodies: tryptase, chymase, carboxypeptidase A3, and αSMA. The EM study was performed on ultrathin sections with a thickness of 100–120 nm. MCs were found to be in a functionally active state and characterized by a variety of secretory activities. For the first time, telocytes and their colocalization with MCs and Leydig cells were visualized. It is possibly the telocytes—interacting with MCs—that synchronize the functional activity of the entire MC population of the testis. The interaction of MCs with telocytes, as well as individual secretory granules associated with loci of tropocollagen and collagen microfibril accumulation, leads to the accumulation of collagen fibrils in the interstitium, as observed in idiopathic infertility with AZFc deletion. Even with a small number of MCs in the interstitium of the convoluted seminiferous tubules in the testis, the telocytes are able to synchronize MCs’ activation and secretory activity, supporting the development of a profibrotic phenotype of the tissue microenvironment. The obtained results advance our understanding of idiopathic infertility with AZFc deletion by delineating the ultrastructural landscape of the testicular interstitium and establishing telocytes as key regulators of cellular crosstalk. Telocytes use complex mechanisms for the spatial integration of MCs and fibroblasts in the profibrotic phenotype formation of the convoluted seminiferous tubule tissue microenvironment. Potentially, telocytes can directly be involved in synchronizing such processes by activating the biogenesis and secretion of collagen monomers by fibroblasts; the MC secretome directly affects the polymerization of collagen monomers and dimers into microfibrils in the extracellular matrix, stimulating excessive collagen fiber formation and the development of fibrotic changes. Full article

Paediatric ovarian neoplasms are rare and histologically diverse tumours with distinct clinical behaviour and prognosis compared to their adult counterparts. This review synthesises current knowledge from an anatomical pathology perspective, emphasising diagnostic and therapeutic strategies. Paediatric ovarian tumours are classified into three main categories: germ cell tumours, sex cord-stromal tumours, and epithelial neoplasms. Germ cell tumours, the most frequent in children, include dysgerminoma, mature and immature teratoma, yolk sac tumour, and choriocarcinoma. Sex cord-stromal tumours encompass Sertoli-Leydig cell tumours, juvenile granulosa cell tumours, and adrenal-like stromal tumours, while epithelial tumours, rare in paediatric patients, include serous and mucinous adenocarcinomas or cystadenomas. Clinical presentation is often nonspecific, with abdominal pain, pelvic mass, or endocrine abnormalities. Diagnosis integrates imaging, serum tumour markers, and histopathology supported by immunohistochemistry. Treatment prioritises fertility-sparing surgery, with selective adjuvant chemotherapy based on histotype and stage. Despite generally favourable outcomes, the rarity of these tumours limits high-quality evidence, highlighting the need for referral centres and multicenter studies. Standardised diagnostic protocols and personalised therapeutic approaches are essential to optimising clinical outcomes and preserve long-term reproductive function. Full article

In Italy, the breeding of alpacas (Vicugna pacos) is on the rise, driven by the value of their precious wool and their docile temperament. This growth is, however, severely limited by the species’ reproductive inefficiency. This study aimed to investigate the specific role of the neuropeptide orexin A (OxA) and its receptor OX1R in modulating testicular steroidogenesis in the alpaca, testing the hypothesis that the OxA/OX1R pathway stimulates testosterone production. Using testicular tissue from two groups of adult male alpacas (five- and seven-year-olds, n = 6 per group), we combined immunohistochemistry with ex vivo functional assays. Immunohistochemical analysis confirmed the expression of both OxA and OX1R in Leydig cells. Functional studies on testicular fragments demonstrated that OxA enhanced testosterone synthesis via OX1R activation. Furthermore, OxA reduced estradiol levels by suppressing aromatase activity and counteracted the inhibitory effect of Müllerian inhibiting substance (MIS) on testosterone secretion. These results provide the first evidence that the peripheral OX1R pathway is functionally involved in promoting a testosterone-dominant steroidogenic milieu in alpaca testes. This preliminary study identifies the orexin system as a potential target for developing strategies to improve reproductive management in this species. Full article

Sickle cell disease (SCD) is an inherited hemoglobinopathy in which hemoglobin S polymerization drives hemolysis and vaso-occlusion with progressive organ morbidity. Male reproductive impairment is increasingly recognized but remains underreported. This narrative review summarizes mechanistic pathways, clinical manifestations, and fertility preservation options relevant to men with SCD. PubMed, the Cochrane Library, and Medscape were searched through 31 December 2025 for human studies addressing endocrine changes, semen quality, priapism and erectile dysfunction, oxidative stress, and treatment-related gonadotoxicity. Evidence supports converging mechanisms: recurrent vaso-occlusion and chronic hypoxia may injure the seminiferous epithelium and impair Leydig cell steroidogenesis; oxidative stress and inflammation contribute to sperm DNA and membrane damage; and disease-modifying or curative therapies such as hydroxyurea and hematopoietic stem cell transplantation can further compromise spermatogenesis. Clinically, men with SCD may present with oligozoospermia, azoospermia, hypogonadism, and sexual dysfunction, particularly after recurrent ischemic priapism. Fertility preservation should be discussed early, ideally before prolonged hydroxyurea exposure or transplantation, and may include semen cryopreservation and testicular sperm extraction (TESE) with assisted reproduction when needed. Prospective longitudinal studies are required to define reproductive trajectories and optimize counseling and management. Full article

Psychological stress is increasingly investigated as a potentially modifiable factor in male infertility, in part through oxidative stress. This narrative review synthesizes mechanistic and translational evidence linking stress-related neuroendocrine activation and coping behaviors with redox imbalance in the male reproductive tract. Chronic activation of the hypothalamic–pituitary–adrenal axis and sympathetic outflow elevates glucocorticoids and catecholamines. In controlled animal stress paradigms, this is accompanied by suppression of the hypothalamic–pituitary–gonadal axis and by immune and metabolic changes that favor reactive oxygen species generation. The resulting oxidative stress may reduce Leydig cell steroidogenesis, impair testicular and epididymal function, and induce lipid peroxidation, mitochondrial dysfunction, and sperm DNA fragmentation. In such models, these lesions, together with apoptosis of germ and supporting cells, are associated with lower sperm concentration, reduced motility, compromised viability, and diminished fertilizing potential. Overall, preclinical animal studies using defined stress paradigms provide experimental evidence consistent with causal effects of stress on oxidative injury and reproductive impairment in preclinical settings. Human studies linking perceived stress, anxiety/depression, and disturbed sleep to adverse semen parameters and oxidative biomarkers are summarized. However, the human evidence is predominantly associative, and the available studies are cross sectional and remain vulnerable to residual confounding and reverse causality. Potential effect modifiers, including smoking, alcohol use, and circadian disruption, are also discussed as contributors to heterogeneity across clinical studies. Standardized assessment of stress biology and redox status, longitudinal designs aligned with spermatogenic timing, and well-powered intervention trials are needed to define dose–response relationships and support individualized prevention and care. Full article

Zearalenone (ZEA) is a mycotoxin commonly found in animal feed and is associated with pronounced reproductive toxicity. However, most studies on ZEA’s reproductive effects have focused on female monogastric animals, while research on male ruminants remains limited. This study aimed to investigate the cytotoxic and metabolic mechanisms underlying ZEA-induced damage in goat Leydig cells (LCs). The CCK8 assay was first used to determine the effective ZEA concentration (IC₅₀ ≈ 20 μM), and a cytotoxicity model was subsequently established. The model’s validity was confirmed using qRT-PCR, transmission electron microscopy, flow cytometry, and JC-1 staining. Results showed that ZEA significantly reduced LCs viability in a dose-dependent manner, decreased mitochondrial membrane potential, induced cell cycle arrest, and triggered apoptosis. Targeted and untargeted metabolomics analyses revealed that ZEA disrupts steroidogenic pathways and alters steroid hormone secretion, resulting in elevated levels of progesterone, corticosterone, and androstenedione, and reduced dihydrotestosterone levels. Furthermore, 52 significantly altered metabolites were identified, predominantly enriched in glycerophospholipid metabolism, choline metabolism, and neurotransmitter vesicle pathways, with corresponding changes in gene expression. Collectively, this study has confirmed that ZEA causes harm to the reproductive cells of male goats in multiple aspects, underscoring the link between metabolic dysregulation and reproductive impairment, and offering a foundation for evaluating ZEA’s impact on goat reproductive performance. Full article

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity. Full article

During the COVID-19 pandemic, the prevalence of death in men was higher than in women. Using transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2), we demonstrated that SARS-CoV-2 infects Leydig cells and uses its steroidogenic machinery for replication. This study investigates the impact of SARS-CoV-2 in the seminiferous epithelium of K18-hACE2 mice, focusing on the immune response, junctional proteins, and spermatogenesis. The seminiferous tubules (STs) and epithelial (EA) areas were measured. The number of Sertoli cells (SCs), spermatocytes, and damaged ST was quantified. Ultrastructural analysis was performed under transmission electron microscopy. Angiotensin II levels and immunolocalization of hACE2, spike, and nucleocapsid were evaluated. TUNEL and immunoreactions for Ki-67, TNF-α, INF-γ, iNOS, NF-κB, and Conexin-43 were performed and correlated with Jam-α, Stat1, Stat3, and iNOS expressions. hACE2, spike, and nucleocapsid immunolabeling were detected in the epithelium along with high angiotensin II levels in the infected mice. The infection caused a significant reduction in ST, EA, spermatocytes, SCs, Ki-67+ cells, Cx43 immunoexpression, and Jam-a expression. In the epithelium, TNF-α, IFN-γ, iNOS, and nuclear NF-κB immunolabeling increased along with Stat1 upregulation. These findings, combined with the increased epithelial hACE2 and high angiotensin II levels, confirm epithelial responsiveness to the infection and explain the spermatogenic failure and impaired junctional proteins. The presence of viral particles, increased TNF-α immunolabeling, and apoptotic features in Sertoli cells suggests that these sustentacular cells are targets for viral infection in the epithelium, and, due to their extensive projections and ability to phagocytize dying infected germ cells, they may disseminate the viruses throughout the epithelium. Full article

Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T < 10.4 nmol/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 ± 0.38 ng/mL vs. 1.83 ± 0.37 ng/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone. Full article

Background/Objectives: Testicular dysfunction is a side effect of radiotherapy due to off-target damage. Germ cells are highly vulnerable. Although Sertoli and Leydig cells are more resistant, they are still affected, impairing spermatogenesis and steroidogenesis. With rising youth cancer rates, strategies to preserve fertility are crucial. Losartan (LOS) has potential to mitigate this damage. This work aimed to determine acute and late effects of radiotherapy in testicular metabolism and if LOS mitigates those effects. Methods: Male Wistar rats (n = 47, 12 weeks old) received 2.5 Gy of ionizing radiation to the scrotum (1.05 Gy/min). LOS-treated rats received 34 mg/kg twice daily before, during and after irradiation. Animals were euthanized at 2 and 60 days post-exposure, to represent acute and late effects, respectively. Reproductive organs were weighed, serum hormones assessed (ELISA), testicular mRNA expression quantified (qPCR) and oxidative stress markers, such as lipid peroxidation, protein carbonylation, and protein nitration measured (slot-blot). Metabolomic profiles were obtained via ¹H-NMR. Results: Acute irradiation reduced seminal vesicle weight, increased FSH, and decreased sperm concentration. Late effects included reduced testicular and epididymal weight, impaired sperm quality, increased protein carbonylation, and altered metabolic profiles. LOS mitigated acute weight loss but not sperm decline. Long-term, LOS improved sperm quality, reduced oxidative stress, and promoted adaptive metabolic responses. Conclusions: Irradiation-based cancer therapy causes structural and functional testicular damage and changes the testicular metabolome of rats, while LOS has the potential to be used as a radioprotector to mitigate the adverse acute and late effects of radiation on male fertility. Full article

Background: The senescence of testicular Leydig cells (LCs) is a key cause of age-related testosterone deficiency, in which oxidative stress (OS) and mitochondrial dysfunction are critical driving mechanisms. We explore whether the bioactive peptide C248 of PRDX4, an intracellular antioxidant, exerts mitochondrial protection to ameliorate LCs’ function. Methods: Based on the antioxidant domains of the PRDX4 protein, small molecular peptides were designed, and bioactive peptide C248 stood out from the crowd. An OS-induced senescence model of LCs was constructed by treating the MLTC-1 cell line with hydrogen peroxide (H₂O₂). C248 peptide or nicotinamide mononucleotide (NMN), as the positive control, was administered in the culture medium. The cellular function-related indicators, including DPPH free radical scavenging rate, cell viability, testosterone level, hydrogen peroxide (H₂O₂) content, senescence-associated β-galactosidase (SA-β-gal) activity, 8-hydroxy-2′-deoxyguanosine (8-OHDG) level, and 4-hydroxynonenal (4-HNE) level, were evaluated. The mitochondrial function and structural indicators, such as mitochondrial membrane potential, ATP production, mitochondrial morphology, and mitochondrial DNA (mtDNA) copy number, were subsequently tested. Results: In vitro experiments confirmed that C248 could scavenge DPPH free radicals in a dose-dependent manner, reduce the levels of reactive oxygen species, and increase antioxidant enzyme activity in LCs (p < 0.01). Both C248 and NMN increased testosterone secretion and improved cell viability (p < 0.01). Both C248 and NMN increased mitochondrial morphology and quantity, mitochondrial membrane potential (p < 0.01), ATP production (p < 0.01), and mitochondrial DNA (mtDNA) copy number (p < 0.01). Conclusion: This study reveals that the small molecular C248, a bioactive peptide of PRDX4, is a new candidate molecule for intervening in LC senescence and confirms that mitochondrial protection is a key strategy for improving age-related testicular dysfunction. Full article

Postnatal testicular maturation in domestic cats remains poorly quantified despite its relevance for reproductive biology, veterinary practice, and the management of threatened felid species. This study aimed to characterize age-related changes in testicular structure from six to thirty-six months of age. Testes were collected from clinically healthy cats undergoing routine orchiectomy, and design-based stereology was used to estimate the volumes and densities of the main testicular components, including the seminiferous epithelium, interstitial tissue, Sertoli cells, and Leydig cells. Immunohistochemical detection of Desert Hedgehog, a developmental signaling molecule, was performed to assess interstitial maturation. Testicular volume and the absolute volumes of the seminiferous epithelium, Sertoli cells, and Leydig cells increased significantly with age, while the numerical density of Leydig cells remained stable, indicating hypertrophy rather than proliferation. Desert Hedgehog immunoreactivity declined progressively across age groups, consistent with the transition from immature to mature interstitial cells. Principal component analysis revealed a clear separation between immature and mature testes based on volumetric and density variables. These results demonstrate that feline testicular maturation follows a coordinated pattern of tubular and interstitial growth and provide quantitative reference values useful for reproductive assessment, comparative studies, and conservation programs in domestic and wild felids. Full article

Bone health might be closely associated with male fertility, yet the molecular pathways remain poorly characterized. We demonstrate that undercarboxylated osteocalcin (ucOCN), a bone-derived hormone, initiates a signaling cascade that stimulates testosterone biosynthesis in porcine Leydig cells. Mechanistically, ucOCN binding to membrane receptor GPRC6A elevates intracellular cAMP levels and sequentially activates PKA, MEK, and ERK. ERK translocates to the nucleus and phosphorylates the transcription factor CREB. Activated CREB binds directly to promoter regions of the key steroidogenic genes and boosts testosterone production. The genetic or pharmacological inhibition of GPRC6A, PKA, MEK, or ERK signaling disrupts CREB activation and abolishes both steroidogenic gene expression and testosterone synthesis. Crucially, the phospho-switch S298 as a previously unrecognized phosphorylation site through which MEK regulates osteocalcin (OCN) signaling was identified. Collectively, our results indicate that ucOCN interacts with GPRC6A to promote testosterone synthesis in Leydig cells via the PKA-MAPK/ERK-CREB pathway. The above findings elucidate a fundamental endocrine axis between bone and the male reproductive system, offering novel mechanistic insights and potential therapeutic strategies for improving male fertility. Full article

Micro-/nanoplastics (MNPs) and their associated endocrine-disrupting chemicals (EDCs) have emerged as pervasive environmental pollutants, with growing concern for their impact on male reproductive health. In this review, we synthesize the findings from twenty-one peer-reviewed studies published between January 2019 and March 2025, selected through a structured literature search conducted in accordance with the SANRA guidelines. Emphasis was placed on studies examining the cellular effects of MNPs and EDCs on Germ, Leydig, and Sertoli cells. The literature indicates multiple mechanisms of testicular toxicity, including degradation of the blood testis barrier, disruption of signaling pathways critical for spermatogenesis and hormone synthesis, induction of oxidative stress and inflammation, and structural and genetic damage to testicular tissues. These data, primarily derived from in vitro and animal models, not only highlight significant biological disruptions but also underscore the limitations in extrapolating results to human physiology. Differences in exposure routes, dosages, and species-specific responses present challenges to direct translation to humans. This review concludes that further human-centric research that mimics real-life exposure and impacts is essential to assess chronic, low-dose exposures and bridge the gap between experimental data and real-world reproductive outcomes, ultimately informing public health strategies and guiding future investigations into the reproductive risks posed by MNPs and EDCs. Full article