Current Pharmaceutical Design - Volume 27, Issue 24, 2021

Sperm production starts from puberty in the seminiferous tubules providing testosterone production by the Leydig cells that takes place in the interstice of the testicles. Normal spermatogenesis depends on specific signalling from the hypothalamic-pituitary-gonadal axis. GnRH, FSH and LH are the main hormones involved in the production and maturation of spermatozoa. Exogenous administration of androgens influences the hypothalamic- pituitary-gonadal axis with negative feedback that may lead to a partial or complete cessation of spermatogenesis by decreasing FSH and LH. Despite the fact that many trials have confirmed that exogenous testosterone affects male fertility status, evidence regarding the long-term effects of treatment is conflicting. Regarding this aspect, many studies have confirmed a return to baseline sperm concentration after testosterone treatment discontinuation; however, none of them can specify how long recovery will take or whether the sperm count is sufficient for fertility.

Gonadotropin-releasing hormone (GnRH) is the focus of the scientific debate for the treatment of hypogonadotropic hypogonadism. Sexual maturation and reproductive function depend on the pulsatile secretion of GnRH that are mainly congenital and may or may not be associated with other genetic anomalies or syndromes. Clinical manifestations include a wide range of metabolic, endocrine, and psychologic dysfunctions. The following manuscript focuses on the effects of GnRH therapy on fertility and cognitive abilities, aiming to investigate the current level of evidence for this treatment regimen. Current literature has been reviewed with the aim of highlighting the key findings on these two aspects.

Background: Despite the limited evidence about the effect of micronutrient supplementation on the semen quality, many micronutrient supplements have been used to improve male fertility. Approximately, 40%- 50% of male infertility cases in general and up to 80% in men with idiopathic infertility cases are caused by oxidative stress and decreased level of seminal total antioxidant capacity. Objective: To investigate the beneficial effects of micronutrient supplementation on sperm concentration, motility and morphology. Methods: A PubMed, Google Scholar, Embase data, Web of Science and Cochrane Library database extensive research of the randomized controlled studies utilizing micronutrient vitamins and supplements was performed. Results: The existent international literature is rather heterogeneous and a definitive is difficult to be drawn. Several micronutrients have beneficial effects on sperm parameters. Rational use of micronutrients might be helpful for infertile patients. Conclusion: Further randomized, controlled clinical trials are required to elucidate the efficacy and safety of micronutrients and propose proper protocols for their use. A well-rounded, balanced diet is more preferable than the widespread use of micronutrient supplements beyond the recommended doses. Future studies should concern the pregnancy rate as a primary outcome in their designs. Further research should be done to determine the appropriate antioxidant compounds, the duration of the treatment, as well as a certain dose of antioxidants in clinical practices. The pre-treatment evaluation of the seminal oxidative status is also an important parameter to proceed with micronutrient supplementation without the risk of reductive stress. Under these conditions, supplements could support the quality of sperm and help to alleviate male infertility.

The demand for availability of efficient and safe contraceptive methods is strengthened by the predictions made by the United Nations regarding the future growth of the human population. So far, women are not only the main victims of the unsafe procedures related to terminating unwished pregnancies but do also carry the main responsibility for family planning. There is a significant desire among men for sharing this responsibility and a substantial proportion of females are willing to trust their male partners in regard to the use of contraception. Therefore, there is a need for developing new reversible, safe, effective, acceptable, affordable and available methods of male contraception. Thus, hormonal manipulation resulting in the suppression of sperm production seems, so far, to be the most feasible approach to achieve the above-mentioned goal. Several strategies of such hormonal manipulation have been tested. Most of them are based on the administration of more or less supra-physiological doses of exogenous testosterone, alone or in combination with other means of endocrine suppression of gonadotropin secretion. Although, so far, the goal of hormonal male contraception fulfilling the above-mentioned criteria, has not yet been achieved; continuing development of new molecules, gives hope for the near future.

Hypogonadotropic hypogonadism (HH) is caused by a dysfunction in the hypothalamus and/or the pituitary gland and it can be congenital or acquired. This condition is biochemically characterized by low or inappropriately normal gonadotropin levels along with low total testosterone levels. If fertility is not an issue, testosterone therapy is the treatment of choice to induce and maintain secondary sexual characteristics and sexual function. Spermatogenesis is frequently impaired in patients with HH, but usually responsive to hormonal therapy such as gonadotropin therapy or GnRH supplementary/replacement therapy. When gonadotropins are the choice of treatment, conventional therapy includes human chorionic gonadotropin (hCG) along with different FSH formulations: human menopausal gonadotropins (hMG), highly purified urinary FSH preparations (hpFSH) (e.g., urofollitropin) or recombinant FSH (rFSH). The combination of FSH and hCG demonstrated to be associated with better outcomes than single compounds, whereas similar results were obtained with different FSH preparations in male individuals; both regarding the ability to stimulate spermatogenesis and eventually inducing physiology pregnancy. Gonadotropins can be administered either subcutaneously or intramuscularly. The combination therapy with hCG and FSH for a period of 12-24 months was found to promote testicular growth in almost all patients, spermatogenesis in approximately 80% and pregnancy rates in the range of 50%. Gynecomastia is the most common side effect of gonadotropin therapy and is due to hCG stimulation of aromatase causing increased secretion of estradiol. The therapeutic success is higher in patients with post-pubertal HH, in those without previously undescended testes, in patients with higher baseline testicular volume, who underwent repeated cycles of therapy and in patients with higher baseline inhibin B serum concentrations. Reversal of hypogonadism can occur in up to 10% of patients but its physiopathologic mechanism has yet to be elucidated. In conclusion, gonadotropin therapy is effective in promoting puberty and in supporting spermatogenesis onset and preservation in HH patients with either hypothalamic or pituitary conditions.

Male infertility is a global problem and the number of men suffering from this condition has increased dramatically over the last decade. Currently, approximately 10–15% of couples have been affected by this worldwide. Although this is a crucial problem, treatment options are limited and sometimes even ineffective. In order to arrest this worrisome increase, the development of new treatment strategies has become fundamental. Redox regulation driven by NO in reproductive biology represents a novel pathway in male infertility and it plays a crucial role in maintaining normal fertilisation capacity. Compelling evidence states that ROS synthesis and degradation should be in perfect balance and tightly regulated by endogenous and exogenous antioxidant enzymes. NO donor drugs might play a beneficial role in restoring this fragile equilibrium and have shown great potential in ameliorating overall fertilisation capacity.

Background: Medical treatments are used either alone or in combination with assisted reproductive techniques for the treatment of infertile patients with hypergonadotropic hypogonadism. A wide range of treatment options such as gonadotropins, aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs) and their combination are available as options. Objective: The aim of this review was to evaluate treatment options for infertile men with hypergonadotropic hypogonadism. Methods: A literature search of MEDLINE (1980-2019) was conducted using the terms ‘hypogonadism’, ‘male infertility’, ‘gonadotropins’, ‘SERMs’ and ‘AIs’. Pathologies leading to hypergonadotropic hypogonadism and treatment modalities such as gonadotropins, SERMs, AIs and surgical treatment were discussed. Results: FSH increases spontaneous pregnancy rates but the level of evidence was proven to be low for live birth rates. AIs are valid treatment options for patients with low T/E2 ratio as they significantly increase sperm concentrations. SERMs are recommended for infertile males with a sperm concentration between 10-20 million. Varicocele was reported to increase testosterone levels of hypogonadic infertile males. Conclusion: Medical treatment modalities such as gonadotropins, SERMs, AIs and a combination of these therapies has been showed to have some effect in improvement of fertility but is not mainstream of the treatment.

Background & Objective: Significant advances in the field of male infertility have been witnessed during the last years. Given the well-known detrimental effects of reactive oxygen species (ROS), the administration of antioxidants has emerged as a promising solution for oxidative stress (OS)-induced male infertility. Nevertheless, this perception seems largely oversimplified, and the existing literature fails to recognize a notable superiority of the excessive use of these widely available nutritional compounds. Taking into consideration that several trials have shed light on the so-called “antioxidant paradox” phenomenon, we recognize that over-the-counter consumption of such supplements might be harmful. Methods: The relevant studies indexed in PubMed, Google Scholar and Scopus databases, published until September 2019 were identified and reported. Conclusion: In this setting, we acknowledge that there is an urgent need for more elaborate studies in the future that will efficiently elucidate the risks and benefits of antioxidants on semen parameters and their impact on fertility potential.

Background: Hyperglycemia-induced microglia activation can cause a continuous release of proinflammatory cytokines, which gradually damages neurons and contributes to central diabetic neuroinflammation. Objective: This study aimed to illustrate the possible mechanism related to NLRP3 inflammasome and the aggravation of diabetes neuroinflammation. Methods: The targeted proteins from BV2 cells and brain tissues were tested by Western blot or immunohistochemistry. Cytokines from cell supernatant and serum were detected by ELISA. Meanwhile, cytoplasm and mitochondria ROS were determined by DCFHDA and Mito sox Red, respectively. Results: In vitro, BV2 cells were stimulated by different glucose concentrations (5.5 to 65 mM/L) above physiological values and maintained for different periods (12 to 48h). The proinflammatory cytokines IL-1β, IL18, IL6, TNFα and cytoplasm ROS were significantly increased in a dose-dependent manner, while mitochondrial ROS was unaffected. NLRP3 inflammasomes, MAPKs, and NF-ΚB pathways were obviously activated at the concentration of 35 mM/L for 12h. Inhibition assay using specific inhibitors indicated that the treatment of glucose (35 mM/L for 12h) could stimulate NLRP3 inflammasome activation via ROS/JNK MAPKs/NF-ΚB pathway. In STZ induced diabetes mice models, microglia NLRP3, ASC, and caspase-1 proteins were highly expressed, and serum cytokines IL-1β, IL6, IL18, and TNFα were remarkably increased. Conclusion: Microglia NLRP3 inflammasomes activation involves diabetic neuroinflammation in diabetic mice and BV2 cells via ROS/JNK MAPKs/NF-ΚB pathways.

Background: Epigenetic modifications have recently attracted much attention in the study of the biological mechanisms of Acute Myelocytic Leukemia (AML) for therapy and prognosis. However, studies on DNA methylation changes during AML treatment are limited. Objective: The comprehensive DNA methylation-transcriptome profiles association analysis in this study aimed to establish whole-genome DNA methylation profiles and explore DNA methylation-related genes and their potential functions before and after treatment. And more appropriate biomarkers are expected to be identified for therapy strategies in AML. Methods: Illumina 450K and RNA-Seq data were obtained from the Cancer Genome Atlas. We performed comprehensive DNA methylation-transcriptome profiles association analysis, pathway analysis, correlation analysis, and survival analyses. The StarBase database was utilized to predict interactions between lncRNAs, miRNAs and target mRNAs. Results: In total, 1592 distinct CpG sites and 2419 different expression transcripts were identified between pretreatment and post-treatment AML. The significantly enriched functions of methylated genes were stem cell differentiation, cell population maintenance, and cell development. The expression of UGT3A2, MOG, and VSTM1 was correlated with DNA methylation levels (r² >0.5). Lastly, we identified 4 lncRNAs, 9 miRNAs and 142 mRNAs to construct a lncRNA-miRNA-mRNA ceRNA network. Conclusion: Our results revealed that DNA methylation was altered before and after treatment. Alterations in DNA methylation affected target gene expression and participated in the key biological processes of AML. Therefore, ceRNA networks may provide further insight into the study of favorable therapeutic markers in AML.

Background: Type 1 diabetes is a chronic autoimmune disease featured by insulin deprivation caused by pancreatic β-cell loss, followed by hyperglycaemia. Objective: Currently, there is no cure for this disease in clinical treatment, and patients have to accept a lifelong injection of insulin. The exploration of potential diagnosis biomarkers through analysis of mass data by bioinformatics tools and machine learning is important for type 1 diabetes. Methods: We collected two mRNA expression datasets of type 1 diabetes peripheral blood samples from GEO, screened differentially expressed genes (DEGs) by R software, and conducted GO and KEGG pathway enrichment using the DEGs. Moreover, the STRING database and Cytoscape were used to build PPI network and predict hub genes. We constructed a logistic regression model by using the hub genes to assess sample type. Results: Bioinformatic analysis of the GEO dataset revealed 92 and 75 DEGs in GSE50098 and GSE9006 datasets, separately, and 10 overlapping DEGs. PPI network of these 10 DEGs showed 7 hub genes, namely EGR1, LTF, CXCL1, TNFAIP6, PGLYRP1, CHI3L1 and CAMP. We built a logistic regression model based on these hub genes and optimized the model to 3 genes (LTF, CAMP and PGLYRP1) based logistic model. The values of the area under the curve (AUC) of training set GSE50098 and testing set GSE9006 were 0.8452 and 0.8083, indicating the efficacy of this model. Conclusion: Integrated bioinformatic analysis of gene expression in type 1 diabetes and the effective logistic regression model built in our study may provide promising diagnostic methods for type 1 diabetes.