Sexual Health in HIV-Positive Men Under Stable Antiretroviral Therapy During a 12-Month Period.

BACKGROUND: Sexual health is becoming increasingly important for many HIV-positive men undergoing highly effective antiretroviral therapy (ART) but remains frequently unaddressed in routine clinical consultation. AIM: To comprehensively evaluate sexual health in male patients with HIV on stable ART over a 12-month period. METHODS: The prospectively registered cohort study comprising 87 HIV-positive men on stable ART (median age: 43 years) was conducted between 2011 and 2015 at a university hospital. Patients were enrolled from the outpatient infectious disease unit and underwent an extensive andrological workup to assess parameters of sexual health (questionnaires, sex hormones, ultrasound, 2-glass urine test including semen analysis with microbiological and viral diagnostics). The study period per patient lasted 12 months. OUTCOME: The primary endpoint was the impact of chronic HIV infection on sexual health. RESULTS: Although, on average, sexual health was fine at baseline, 56% of the patients reported erectile dysfunction, 28% experienced reduced libido, 5% had hypogonadism, 36% showed at least 1 atrophic testicle with a volume of <10 ml, 8% suffered bacterial sexually transmitted infections, 35% had seminal inflammation, and up to 47% showed reduced sperm quality. Sexual satisfaction was linked to mental health (12-Item Short Form Health Survey questionnaire) and International Index of Erectile Function scores. During the study period, the collected parameters on sexual health were generally stable. However, 35% of patients had new sex partners (median: 5 partners), 7% had fathered a child or were planning procreation, 47% reported changed libido, 17% suffered bacterial sexually transmitted infections in the urogenital tract, 16% revealed a positive HIV viral load in blood, 11% had a positive HIV viral load in semen, and 28% were treated for andrological disorders. CLINICAL IMPLICATIONS: Sexual ill-health exists in about one third of patients. This manifests itself in sexual dysfunction, sexually transmitted infections, urogenital tract inflammation, and abnormal sperm parameters, all of which require adequate counseling and therapy. STRENGTH AND LIMITATIONS: The strength of this study is its comprehensive analysis of male sexual health over a 12-month period of stable ART treatment. Limitations are a heterogeneous patient cohort and a rather small percentage of patients with a positive HIV viral load in blood or semen, which prevented multivariate risk analysis. CONCLUSION: Our study provides evidence that sexual health should be actively taken into account in the routine consultation by infectious disease specialists, and an interdisciplinary approach is desirable in the case of symptoms or signs of sexual ill-health. Pilatz A, Maresch CC, Discher T, et al. Sexual Health in HIV-Positive Men Under Stable Antiretroviral Therapy During a 12-Month Period. J Sex Med 2021;18:284-294.

Elevated CCL2 causes Leydig cell malfunction in metabolic syndrome.

Metabolic syndrome (MetS), which is associated with chronic inflammation, predisposes males to hypogonadism and subfertility. The underlying mechanism of these pathologies remains poorly understood. Homozygous leptin-resistant obese db/db mice are characterized by small testes, low testicular testosterone, and a reduced number of Leydig cells. Here we report that IL-1ß, CCL2 (also known as MCP-1), and corticosterone concentrations were increased in the testes of db/db mice relative to those in WT controls. Cultured murine and human Leydig cells responded to cytokine stress with increased CCL2 release and apoptotic signals. Chemical inhibition of CCL2 rescued Leydig cell function in vitro and in db/db mice. Consistently, we found that Ccl2-deficient mice fed with a high-energy diet were protected from testicular dysfunction compared with similarly fed WT mice. Finally, a cohort of infertile men with a history of MetS showed that reduction of CCL2 plasma levels could be achieved by weight loss and was clearly associated with recovery from hypogonadism. Taken together, we conclude that CCL2-mediated chronic inflammation is, to a large extent, responsible for the subfertility in MetS by causing damage to Leydig cells.

Hyperglycemia induces spermatogenic disruption via major pathways of diabetes pathogenesis.

Diabetes-induced hyperglycemia has previously been shown to impact on male sub-/infertility, however, still little is known about the underlying mechanisms. In the present study we have addressed three major biochemical pathways implicated in the pathogenesis of hyperglycemia induced organ damage (the advanced glycation end product (AGE) formation pathway, the diacylglycerol-protein kinase C pathway (PKC), and the polyol pathway) in both testis and epididymis of the Ins2Akita mouse model of Type 1 diabetes (T1DM). Hyperglycemia activated both the PKC and the polyol pathway in a significant and progressive manner within the testis, but not within the epididymis. While the AGE receptor was ubiquitiously expressed in the testis, concentrations of precursor methylglyoxal and AGE carboxymethyllysine were increased in both epididymis and testis in diabetic mice. However, AGEs did not activate intracellular pathways of ERK1, ERK2, Rela, Nrf-2, IkBkB, NFkB except CDC42, Akt1. In conclusion, two of the major pathways of hyperglycemia-induced organ damage were clearly activated within the testis of T1DM mice. This provides therapeutical opportunities in the treatment of diabetic male reproductive dysfunction.

Diabetes-induced hyperglycemia impairs male reproductive function: a systematic review.

BACKGROUND: Hyperglycemia can result from a loss of pancreatic beta-cells or a decline in their function leading to decreased insulin secretion or may arise from insulin resistance and variable degrees of inadequate insulin secretion resulting in diabetes and related comorbidities. To date several reviews have addressed the issue of diabetes-related male infertility but most have focused on how metabolic syndrome causes the decline in male fertility. However, a comprehensive overview as to how diabetes-induced hyperglycemia impairs male fertility is missing. Impaired regulation of glucose and the resultant hyperglycemia are major threats to the health of individuals in modern societies especially given the rapidly rising prevalence affecting an increasing number of men in their reproductive years. Consequently, diabetes-induced hyperglycemia is likely to contribute to a decline in global birth rates especially in those societies with a high diabetic prevalence. OBJECTIVE AND RATIONALE: This systematic review addresses and summarizes the impact of hyperglycemia on male reproductive health with a particular emphasis on the molecular mechanisms that influence the testis and other parts of the male reproductive tract. SEARCH METHODS: A systematic search of the literature published in the MEDLINE-Pubmed database (http://www.ncbi.nlm.nih.gov/pubmed) and Cochrane Library (http://www.cochranelibrary.com) was performed, as well as hand searching reference lists, from the earliest available online indexing year until May 2017, using diabetes- and male fertility-related keywords in combination with other search phrases relevant to the topic of hyperglycemia. Inclusion criteria were: clinical studies on type 1 diabetic (T1D) men and studies on T1D animal models with a focus on reproductive parameters. Case reports/series, observational studies and clinical trials were included. Studies on patients with type 2 diabetes (T2D) or animal models of T2D were excluded to distinguish hyperglycemia from other metabolic effects. OUTCOMES: A total of 890 articles were identified of which 197 (32 clinical, 165 animal studies) were selected for qualitative analysis. While the clinical data from men with hyperglycemia-induced reproductive dysfunction were reported in most studies on T1D, the study designs were variable and lacked complete information on patients. Moreover, only a few studies (and mostly animal studies) addressed the underlying mechanisms of how hyperglycemia induces infertility. Potential causes included impaired function of the hypothalamic-pituitary-gonadal axis, increased DNA damage, perturbations in the system of advanced glycation endproducts and their receptor, oxidative stress, increased endoplasmatic reticulum stress, modulation of cellular pathways, impaired mitochondrial function and disrupted sympathetic innervation. However, intervention studies to identify and confirm the pathological mechanisms were missing: data that are essential in understanding these interactions. WIDER IMPLICATIONS: While the effects of regulating the hyperglycemia by the use of insulin and other modulators of glucose metabolism have been reported, more clinical trials providing high quality evidence and specifically addressing the beneficial effects on male reproduction are required. We conclude that interventions using insulin to restore normoglycemia should be a feasible approach to assess the proposed underlying mechanisms of infertility.

Hyperglycemia is associated with reduced testicular function and activin dysregulation in the Ins2Akita+/- mouse model of type 1 diabetes.

Type 1 diabetes (T1D) is associated with subfertility in men. We hypothesised that this results from inhibitory effects of chronic hyperglycemia on testicular function and used the Ins2Akita+/- mouse model to investigate this. Diabetic mice exhibited progressive testicular dysfunction, with a 30% reduction in testis weight at 24 weeks of age. Diabetic mice showed significantly reduced seminiferous tubule diameters and increased spermatogenic disruption, although testes morphology appeared grossly normal. Unexpectedly, serum LH and intra-testicular testosterone were similar in all groups. Ins2Akita+/- mice displayed elevation of the testicular inflammatory cytokines activin A and IL-6. Intratesticular activin B was downregulated, while the activin regulatory proteins, follistatin and inhibin, were unchanged. Activin signalling, measured by pSmad3 and Smad4 production, was enhanced in diabetic mice only. These results suggest that prolonged exposure to hyperglycemia in the Ins2Akita+/- mice leads to progressive testicular disruption mediated by testicular activin activity, rather than hormonal dysregulation.