Obesity and Male Reproduction: Do Sirtuins Play a Role?

Obesity is a major current public health problem of global significance. A progressive sperm quality decline, and a decline in male fertility, have been reported in recent decades. Several studies have reported a strict relationship between obesity and male reproductive dysfunction. Among the many mechanisms by which obesity impairs male gonadal function, sirtuins (SIRTs) have an emerging role. SIRTs are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that play a role in gene regulation, metabolism, aging, and cancer. SIRTs regulate the energy balance, the lipid balance, glucose metabolism, and adipogenesis, but current evidence also indicates a role for SIRTs in male reproduction. However, the majority of the studies have been conducted in animal models and very few have been conducted with humans. This review shows that SIRTs play an important role among the molecular mechanisms by which obesity interferes with male fertility. This highlights the need to deepen this relationship. It will be of particular interest to evaluate whether synthetic and/or natural compounds capable of modifying the activity of SIRTs may also be useful for the treatment of obesity and its effects on gonadal function. Although few studies have explored the role of SIRT activators in obesity-induced male infertility, some molecules, such as resveratrol, appear to be effective in modulating SIRT activity, as well as counteracting the negative effects of obesity on male fertility. The search for strategies to improve male reproductive function in overweight/obese patients is a challenge and understanding the role of SIRTs and their activators may open new interesting scenarios in the coming years.

Aqueous extract of Pedalium murex D. Royen ex L. leafy stem protects against lead induced testicular toxicity in Wistar rats

Objectives Lead exposure seriously impairs male reproductive function. The protective capacity of Pedalium murex leafy stem and fruit aqueous extracts against lead testicular toxicity is evaluated to find herbals drugs able to improve semen quality. Methods Phytochemical screening were performed according to classical methods. Twenty four male rats were divided into four groups of six rats each and received the following treatments via oral route: distilled water; 0.2% lead acetate in drinking water; 0.2% lead acetate in drinking water with 400 mg/kg P. murex aqueous leafy stem extract; 0.2% leaded water with 400 mg/kg P. murex aqueous fruit extract. Treatments were administered for 70 days. Body and reproductive organs weights, sperm parameters and testicular histological sections of each group were examined. Results Flavonoids, tannins, coumarins, alkaloids, and lignans were found in both extracts. Lead intoxication reduced sperm motility and count but increased the percentage of morphologically abnormal sperms. The germinal epithelium of seminiferous tubules histoarchitecture was disorganized by lead. The leafy stem extract was effective in reducing lead induced testicular disruption whereas fruit has not shown any beneficial effect. Conclusions P. murex leafy stem aqueous extract is effective against semen alterations caused by lead.

Dynamic Expression of the Homeobox Factor PBX1 during Mouse Testis Development

Members of the pre-B-cell leukemia transcription factor (PBX) family of homeoproteins are mainly known for their involvement in hematopoietic cell differentiation and in the development of leukemia. The four PBX proteins, PBX1, PBX2, PBX3 and PBX4, belong to the three amino acid loop extension (TALE) superfamily of homeoproteins which are important transcriptional cofactors in several developmental processes involving homeobox (HOX) factors. Mutations in the human PBX1 gene are responsible for cases of gonadal dysgenesis with absence of male sex differentiation while Pbx1 inactivation in the mouse causes a failure in Leydig cell differentiation and function. However, no data is available regarding the expression profile of this transcription factor in the testis. To fill this knowledge gap, we have characterized PBX1 expression during mouse testicular development. Real time PCRs and Western blots confirmed the presence Pbx1 mRNA and PBX1 protein in different Leydig and Sertoli cell lines. The cellular localization of the PBX1 protein was determined by immunohistochemistry and immunofluorescence on mouse testis sections at different embryonic and postnatal developmental stages. PBX1 was detected in interstitial cells and in peritubular myoid cells from embryonic life until puberty. Most interstitial cells expressing PBX1 do not express the Leydig cell marker CYP17A1, indicating that they are not differentiated and steroidogenically active Leydig cells. In adults, PBX1 was mainly detected in Sertoli cells. The presence of PBX1 in different somatic cell populations during testicular development further supports a direct role for this transcription factor in testis cell differentiation and in male reproductive function.

Recovery of Male Reproductive Function After Ceasing Prolonged Testosterone Undecanoate Injections

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known. Objective: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. Methods: Men (n=303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo(P)-controlled randomized clinical trial of TU treatment were recruited for a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after last injection) and 6, 12, 18, 24, 40 and 52 weeks later. Results: In the nested cohort of TU-treated men, serum T was initially higher but declined to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 showed no difference between T and P treated men. Initially fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since last injection. Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Impacts of COVID-19 and SARS-CoV-2 on male reproductive function: a systematic review and meta-analysis protocol

IntroductionCOVID-19 pandemic caused by SARS-CoV-2 has become a global health challenge. SARS-CoV-2 can infect host cells via the ACE2 receptor, which is widely expressed in the corpus cavernosum, testis and male reproductive tract, and participates in erection, spermatogenesis and androgen metabolism. Also, the immune response and persistent fever resulting from COVID-19 may lead to damage of the testicular activity, consequently compromising male fertility.Methods and analysisPubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal database, Chinese Biomedical Databases and Wanfang Data will be systematically searched for observational studies (case–control and cohort) published up to March 2021 in English or in Chinese literature on the impacts of COVID-19 and SARS-CoV-2 on male reproductive function. This protocol will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines and Meta-analysis of Observational Studies in Epidemiology. The primary outcome will be semen parameters, and the additional outcomes will include: (a) detection of SARS-COV-2 in semen, (b) male sexual hormones, (c) sperm DNA fragmentation index, (d) erectile function, (e) evaluation of testis and also the male genital tract. Two reviewers will independently extract data from the included studies based on a predesigned data extraction form. The risk of bias of included studies will be evaluated through the Newcastle-Ottawa Scale for observational studies. Review Manager software V.5.3 will be used for statistical analysis. Q statistic and I² test will be performed to assess the heterogeneity among studies. Sensitivity analysis will be used to explore the robustness of pooled effects. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence.Ethics and disseminationEthical approval is not required and results will be published in a peer-reviewed journal.PROSPERO registration numberCRD42021245161.

Antihypercholesterolemic and Antioxidant Effects of Blumea balsamifera L. Leaf Extracts to Maintain Luteinizing Hormone Secretion in Rats Induced by High-Cholesterol Diets

BACKGROUND: The discovery of herbal ingredients for antihypercholesterolemic and to improve male reproductive function is very necessary due to high-cholesterol diet factors. Blumea balsamifera leaf extract (BBLE) is known to be able to increase the number and diameter of Leydig cells in rats given high-fat feed. This study was to conducted to determine the levels of total cholesterol, body weight, plasma malondialdehyde (MDA), Superoxide Dismutase (SOD), Luteinizing Hormone (LH) in high-cholesterol-fed male rats provided with BBLE.METHODS: This research utilized a randomized post-test only control group. Ethanol was used to extract the BBLE, which was then evaporated. For 21 days, 16 Wistar rats were given a high-cholesterol diet. To determine the effect of BBLE on the high-cholesterol diet, the samples were divided into two groups (control and BBLE group) on day 22. The treatments lasted 30 days. SOD, plasma MDA, LH, and total cholesterol were measured.RESULTS: The results showed that the SOD and LH parameters were significantly higher in the treatment of BBLE compared to the control group (p<0.05). The parameters of total cholesterol levels, bodyweight, and MDA of rats given BBLE were significantly lower than those of the control group (p<0.05).CONCLUSION: Our findings highlight that BBLE has antihypercholesterolemic and antioxidant effects. The BBLE also has potential to be used as a therapy to maintain male reproductive function because it has a positive effect on the hypothalamic-pituitary axis through increasing LH secretion.KEYWORDS: Malondialdehyde, Superoxide dismutase, Luteinizing hormone, Blumea balsamifera extract, High-cholesterol diet

Cadmium Toxicity and Reproductive Function of Males

The purpose of the review of foreign literature was to analyze current research on the effects of cadmium on male reproductive function. Results. According to the researcher data, at least 15–20% of cases of fertility decline in males fall on infertility. The etiology of this phenomenon in 50% of cases remains unknown, however, increasing environmental pollution contributes to a constant increase in male infertility. One of the most toxic pollutants is cadmium. Numerous animal model studies and human epidemiological studies indicate an adverse effect of cadmium on male fertility. Smoking is an important source of cadmium, which is absorbed into the human body. In vitro studies confirm the deleterious effects of cigarette smoke compounds on sperm motility and spermatozoon parameters. Depending on the concentration, nicotine suppresses the progressive motility of the spermatozoon parameters, starting from the lowest concentration used (1 ng/ml). Likewise, it decreases the percentage of viable spermatozoon parameters and increases the amount of spermatozoon parameters in late apoptosis with altered chromatin compactness or DNA fragmentation already after 3 hours of incubation. On average, the daily intake of cadmium in humans is 1.06 μg/kg body weight, the half-life of cadmium is more than 20-40 years, which causes its accumulation in the body. The testicles are the organ in which cadmium is stored in large quantities. Studies have shown that the testicles are extremely sensitive to cadmium because these organs are characterized by intense cellular activity, where vital spermatogenesis processes take place. Exposure to cadmium leads to reproductive tract abnormalities such as cryptorchidism and hypospadias, testicular cancer, subfertility or infertility, called testicular dysgenesis syndrome. In the genesis of the testicles during the embryonic and neonatal periods, Sertoli’s cells play a critical role, the development of which is influenced by cadmium. Exposure to cadmium (1-2 mg/kg, subcutaneously) in pregnant and lactating rats causes vacuolization of Sertoli’s cells and loss of cells in the epithelium of the seminiferous tubules in adult animals. Cadmium inhibits proliferation, induces apoptosis and DNA damage in immature Sertoli’s cells. Perinatal exposure to cadmium affects the development and function of fetal Leydig cells, which are endocrine cells in the testicle. In pregnant rats that received a single dose of cadmium (0.25, 0.5, and 1.0 mg/kg, intraperitoneally), synthesis of testosterone in the fetal tests was significantly reduced, while gene expression in cells was suppressed, and the androgen-dependent formation process was reduced. The mechanism by which cadmium mediates impaired male fertility is also associated with the production of reactive oxygen species in the testicles, which leads to oxidative stress that interferes with the development and functioning of the spermatozoon parameters. Exposure to cadmium, for both environmental and occupational reasons, can contribute to a decrease in the quality of human sperm, which confirms high toxicity of cadmium. Conclusion. Thus, in humans and other mammals, cadmium damages the male reproductive system, disrupts its structure, including the vascular system of the testicles, leads to DNA damage, inhibits functions of germ cells, leads to loss of sperm quality and quantity, sub-fertility or infertility

ZDHHC19 localizes to the cell membrane of spermatids and is involved in spermatogenesis

Sperm is the ultimate executor of male reproductive function. Normal morphology, quantity, and motility of sperm ensure the normal reproductive process. Palmitoylation is a posttranslational modification mediated by palmitoyltransferases whereby palmitoyl is added to proteins. Seven palmitoyltransferases have been identified in Saccharomyces cerevisiae and 23 in humans (including ZDHHC1–9 and ZDHHC11–24), with corresponding homologs in mice. We identified two testis-specific palmitoyltransferases ZDHHC11 and ZDHHC19 in mice. The Zdhhc11 and Zdhhc19-knockout mouse models were constructed, and it was found that the Zdhhc11 knockout males were fertile, while Zdhhc19 knockout males were sterile. ZDHHC19 is located in the cell membrane of step 4–9 spermatids in the mouse testis, and phenotypic analysis showed that the testicular weight ratio in the Zdhhc19−/− mice decreased along with the number and motility of the sperm decreased, while sperm abnormalities increased, mainly due to the “folded” abnormal sperm caused by sperm membrane fusion, suggesting the involvement of ZDHHC19 in maintaining membrane stability in the male reproductive system. In addition, Zdhhc19−/− mice showed abnormal sperm morphologies and apoptosis during spermatogenesis, suggesting that spermatogenesis in the Zdhhc19−/− mice was abnormal. These results indicate that ZDHHC19 promotes membrane stability in male germ cells. Summary sentence: ZDHHC19 is located in the cell membrane of Step4–9 spermatids in mouse testis; Zdhhc19 knockout mice showed male infertility, abnormal spermatogenesis, sperm morphology and motility.

Effectiveness of Exercise Training on Male Factor Infertility: A Systematic Review and Network Meta-analysis

Context: Mounting evidence from the literature suggests that different types of training interventions can be successful at improving several aspects of male reproductive function in both fertile and infertile populations. Objective: The aim of this study was to evaluate the effectiveness of exercise training on male factor infertility and seminal markers of inflammation. Data Sources: We searched PubMed, CISCOM, Springer, Elsevier Science, Cochrane Central Register of Controlled Trials, Scopus, PEDro, Ovid (Medline, EMBASE, PsycINFO), Sport Discus, Orbis, CINAHL, Web of Science, ProQuest, and the ClinicalTrials.gov registry for randomized controlled trials (RCTs) that analyzed the impacts of selected types of exercise interventions on markers of male reproductive function and reproductive performance. Study Selection: A total of 336 records were identified, of which we included 7 trials reporting on 2641 fertile and infertile men in the systematic review and network meta-analysis. Level of Evidence: Level 1 (because this is a systematic review of RCTs). Data Extraction: The data included the study design, participant characteristics, inclusion and exclusion, intervention characteristics, outcome measures, and the main results of the study. Results: The results of network meta-analysis showed that, compared with a nonintervention control group, the top-ranking interventions for pregnancy rate were for combined aerobic and resistance training (CET) (relative risk [RR] = 27.81), moderate-intensity continuous training (MICT) (RR = 26.67), resistance training (RT) (RR = 12.54), high-intensity continuous training (HICT) (RR = 5.55), and high-intensity interval training (HIIT) (RR = 4.63). While the top-ranking interventions for live birth rate were for MICT (RR = 10.05), RT (RR = 4.92), HIIT (RR = 4.38), CET (RR = 2.20), and HICT (RR = 1.55). Also, with the following order of effectiveness, 5 training strategies were significantly better at improving semen quality parameters (CET > MICT > HICT > RT > HIIT), seminal markers of oxidative stress (CET > MICT > HIIT > HICT > RT), seminal markers of inflammation (CET > MICT > HIIT > RT > HICT), as well as measures of body composition and VO2max (CET > HICT > MICT > HIIT > RT). Conclusion: The review recommends that the intervention with the highest probability of being the best approach out of all available options for improving the male factor infertility was for CET.