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Context:The effectiveness of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with congenital combined pituitary hormone deficiency (CCPHD) has not been investigated because of the limited number of patients, as well as these patients’ presumed pituitary hypoplasia, poor gonadotrophic cell reserve, and impaired gonadotrophic response to GnRH.Objective:To assess the pituitary response to pulsatile GnRH therapy in men with CCPHD.Design:Prospective, self-controlled, 3-month clinical trial.Settings:University endocrine clinic.Patients:Men with hypogonadotropic hypogonadism caused by CCPHD.Intervention:Pulsatile GnRH was administered subcutaneously for 3 months.Main outcome measures:Primary endpoints were total serum testosterone, testicular volume, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Secondary endpoints included occurrence of spermatogenesis.Results:A total of 40 men with CCPHD completed the study. Of these, 60% (24 of 40) showed a good response to pulsatile GnRH treatment (response group). At 3 months, their LH and FSH levels increased to within the normal range and their testosterone levels increased to 8.67 ± 4.83 nmol/L. Of the patients in the response group, 33.3% (8 of 24) of them achieved spermatogenesis. The remaining 40% (16 of 40) of patients had a poor response to pulsatile GnRH treatment. Magnetic resonance imaging (MRI) did not reveal any correlation between pituitary response and pituitary height and/or integrity of the pituitary stalk.Conclusions:This study suggests that gonadotrophs in patients with CCPHD can exist and be functional—even with MRI evidence of pituitary hypoplasia or dysplasia. Pulsatile GnRH therapy restored pituitary–testis axis function in 60% of patients with CCPHD. These results may directly guide the clinical therapeutic choice.This study found pulsatile gonadotropin-releasing hormone therapy restored pituitary-testis axis function in 60% of male patients with congenital combined pituitary hormone deficiency.

The gut microbiota operates at the interface of host–environment interactions to influence human homoeostasis and metabolic networks 1 – 4 . Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues 5 – 9 . However, the systemic impact of the gut microbiome on the germline—and consequently on the F 1 offspring it gives rise to—is unexplored 10 . Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory ‘gut–germline axis’ in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function. Disturbances in the gut microbiota of male mice manifest as fitness defects in their offspring by affecting plancenta function, revealing a paternal gut–germline axis.

Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system. The testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB). The testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

Purpose The two most common procedures for open tension-free groin hernia repair with prosthetic mesh are the Lichtenstein operation and the mesh plug (Rutkow–Robbins) technique. Our study evaluated these two techniques on testicular blood flow and volume, and sperm function in young adults. Methods We randomized operation types with a systematic sampling method, and handled consecutive patients of age 20–30 years having unilateral inguinal hernia repair at our institution from March to August 2008. The study subjects were divided into the Lichtenstein group (LG) and the mesh plug group (MPG). All subjects received color Doppler ultrasonography to determine testicular volume and resistive index (RI) the day before surgery and 3 months postoperatively by a physician blinded for the type of planned or performed operation. Spermiograms done preoperatively and at 3 months postoperatively measured sperm concentration and the rate of progressive motility. Results Sixty-four patients met the study criteria, with 32 patients each in the LG and MPG. RI levels were elevated postoperatively in both the LG ( P  = 0.027) and MPG ( P  = 0.012); there was no significant alteration in terms of testicular volume and spermiogram in the LG and MPG. Conclusion The Lichtenstein and mesh plug techniques in unilateral inguinal hernia increase the RI level significantly in the early postoperative period, but do not have a significant effect on sperm concentration and the rate of progressive motility.

To facilitate temperature adjustments, the testicles are located outside the body cavity. In most mammals, the temperature of the testes is lower than the body temperature to ensure the normal progression of spermatogenesis. Rising temperatures affect spermatogenesis and eventually lead to a decline in male fertility or even infertility. However, the testes are composed of different cell types, including spermatogonial stem cells (SSCs), spermatocytes, spermatozoa, Leydig cells, and Sertoli cells, which have different cellular responses to heat stress. Recent studies have shown that using different drugs can relieve heat stress-induced reproductive damage by regulating different signaling pathways. Here, we review the mechanisms by which heat stress damages different cells in testes and possible treatments.

Background To investigate the correlation between testicular fat content (TFC) and sex hormone levels in patients with cryptorchidism and its value in assessing postsurgical testicular function. Methods Pelvic MRI with the mDIXON Quant sequence was performed on 23 cryptorchidism patients and 15 normal controls. The TFC before and after surgery was measured and compared. The correlations between cryptorchid TFC and testosterone (TSTO), follicle-stimulating hormone (FSH), and estradiol (E2) levels were analyzed, as was the specificity of TFC and each hormone for assessing testicular function after surgery. Results The preoperative cryptorchid TFC (3.06% ± 0.74) was higher than that of the normal controls (1.36% ± 0.49). TSTO was negatively correlated with the cryptorchid TFC (r = −0.698), while FSH and E2 were positively associated with the cryptorchid TFC (r = 0.658, 0.676). Cryptorchid TFC after surgery (2.01% ± 0.55) was lower than the preoperative TFC, but hormone levels were not significantly different. The TFC after surgery (0.864) had a larger AUC value than did TSTO (0.639), FSH (0.597), and E2 (0.586). Conclusion Noninvasive quantification of cryptorchid TFC using the mDIXON Quant sequence is more specific than hormone levels for assessing postsurgical changes in testicular function. Impact The cryptorchid testicular fat content is significantly higher than the normal testicular fat content. Cryptorchid testicular fat content is negatively correlated with presurgical serum TSTO levels and positively correlated with presurgical FSH and E2 levels. Pre- and postoperative changes in cryptorchid testicular fat content change are more sensitive than changes in TSTO, FSH, or E2 levels. Noninvasive cryptorchid testicular fat content quantified by the mDIXON Quant sequence is more specific than serum TSTO, FSH, and E2 levels for assessing changes in testicular function after cryptorchidism surgery.

The increasing concern for the reproductive toxicity of abundantly used phthalates requires reliable tools for exposure risk assessment to mixtures of chemicals, based on real life human exposure and disorder-associated epidemiological evidence. We herein used a mixture of four phthalate monoesters (33% mono-butyl phthalate, 16% mono-benzyl phthalate, 21% mono-ethyl hexyl phthalate, and 30% mono-isononyl phthalate), detected in 1 st trimester urine of 194 pregnant women and identified as bad actors for a shorter anogenital distance (AGD) in their baby boys. Mice were treated with 0, 0.26, 2.6 and 13 mg/kg/d of the mixture, corresponding to 0x, 10x, 100x, 500x levels detected in the pregnant women. Adverse outcomes detected in the reproductive system of the offspring in pre-puberty and adulthood included reduced AGD index and gonadal weight, changes in gonadal histology and altered expression of key regulators of gonadal growth and steroidogenesis. Most aberrations were apparent in both sexes, though more pronounced in males, and exhibited a non-monotonic pattern. The phthalate mixture directly affected expression of steroidogenesis as demonstrated in a relevant in vitro model. The detected adversities at exposures close to the levels detected in pregnant women, raise concern on the existing safety limits for early-life human exposures and emphasizes the need for re-evaluation of the exposure risk.

Diabetes mellitus is a global epidemic contributing to the rising male infertility rates. Addressing testicular dysfunction in diabetic patients requires a multimodal strategy encompassing medication, lifestyle changes, early diagnosis, and innovative treatments targeting specific biochemical pathways. This review explores the mechanisms of diabetes-induced testicular dysfunction and potential intervention targets. A comprehensive literature search was conducted using PubMed, Science Direct, Google Scholar, and Web of Science with keywords related to diabetes and testicular dysfunction. Diabetes leads to reduced testosterone synthesis, decreased spermatogenesis, increased germ cell apoptosis, and damage to Leydig and Sertoli cells. Mechanisms involved in the pathogenesis of diabetes-induced testicular dysfunction include: hyperglycaemia oxidative stress, inflammation, apoptosis and disrupted hormone levels among others. Targeting biomolecular regulators involved in the pathogenic pathways offers a promising therapeutic avenue. Additionally, exploring plant-based therapies as alternative treatments shows potential in alleviating testicular dysfunction in diabetes. Implementing a comprehensive approach combining diagnostics, pharmacological interventions, and lifestyle modifications is crucial in managing testicular dysfunction in diabetic individuals. Future research directions suggest the need for large-scale clinical trials, personalized medicine strategies, and innovative technologies to address and mitigate testicular dysfunction in diabetic populations effectively.

Glutathione synthetase (GSS) catalyzes the final step in the synthesis of glutathione (GSH), a well-established antioxidant. Research on the specific roles of the Gss gene during spermatogenesis remains limited due to the intricate structure of testis. In this study, we identified pachytene spermatocytes as the primary site of GSS expression and generated a mouse model with postnatal deletion of Gss using Stra8-Cre (S8) to investigate the role of GSS in germ cells. The impact of Gss knockout on reducing male fertility is age-dependent and caused by ferroptosis in the testis. The 2-month-old S8/ Gss −/− male mice exhibited normal fertility, due to a compensatory increase in GPX4, which prevented the accumulation of ROS. With aging, there was a decline in GPX4 and an increase in ALOX15 levels observed in 8-month-old S8/ Gss −/− mice, resulting in the accumulation of ROS, lipid peroxidation, and ultimately testicular ferroptosis. We found that testicular ferroptosis did not affect spermatogonia, but caused meiosis disruption and acrosome heterotopia. Then the resulting aberrant sperm showed lower concentration and abnormal morphology, leading to reduced fertility. Furthermore, these injuries could be functionally rescued by inhibiting ferroptosis through intraperitoneal injection of GSH or Fer-1. In summary, Gss in germ cells play a crucial role in the resistance to oxidative stress injury in aged mice. Our findings deepen the understanding of ferroptosis during spermatogenesis and suggest that inhibiting ferroptosis may be a potential strategy for the treatment of male infertility. Facts and questions Conditional deletion of Gss decreases the fertility of 8-month-old male mice Disrupted meiosis and ectopic acrosome are observed in 8-month-old S8/ Gss −/− mice Gss knockout in germ cells causes testis ferroptosis in older mice Both GSH and Fer-1 improve the fertility of 8-month-old S8/ Gss −/− male mice

Although many studies have focused on SARS-CoV-2 infection in the lungs, comparatively little is known about the potential effects of the virus on male fertility. SARS-CoV-2 infection of target cells requires the presence of furin, angiotensin-converting enzyme 2 (ACE2) receptors, and transmembrane protease serine 2 (TMPRSS2). Thus, cells in the body that express these proteins might be highly susceptible to viral entry and downstream effects. Currently, reports regarding the expression of the viral entry proteins in the testes are conflicting; however, other members of the SARS-CoV family of viruses — such as SARS-CoV — have been suspected to cause testicular dysfunction and/or orchitis. SARS-CoV-2, which displays many similarities to SARS-CoV, could potentially cause similar adverse effects. Commonalities between SARS family members, taken in combination with sparse reports of testicular discomfort and altered hormone levels in patients with SARS-CoV-2, might indicate possible testicular dysfunction. Thus, SARS-CoV-2 infection has the potential for effects on testis somatic and germline cells and experimental approaches might be required to help identify potential short-term and long-term effects of SARS-CoV-2 on male fertility.Early studies in patients and animal models have suggested that SARS-CoV-2 can access the reproductive system and could have effects on fertility. In this Perspective, Edenfield and Easley present the evidence for mechanisms of infection of reproductive cells by SARS-CoV-2 and consider the potential for testicular dysfunction in patients who have had COVID-19.