The role of vitamin D in male fertility: A focus on the testis

In the last decade, vitamin D has emerged as a pleiotropic molecule with a multitude of autocrine, paracrine and endocrine functions, mediated by classical genomic as well as non-classical non-genomic actions, on multiple target organs and systems. The expression of vitamin D receptor and vitamin D metabolizing enzymes in male reproductive system, particularly in the testis, suggests the occurrence of vitamin D synthesis and regulation as well as function in the testis. The role of vitamin D in the modulation of testis functions, including hormone production and spermatogenesis, has been investigated in animals and humans. Experimental studies support a beneficial effect of vitamin D on male fertility, by modulating hormone production through genomic and non-genomic actions, and, particularly, by improving semen quality essentially through non-genomic actions. However, clinical studies in humans are controversial. Indeed, vitamin D seems to contribute to the modulation of the bioavailable rather than total testosterone. Moreover, although an increased prevalence or risk for testosterone deficiency was reported in men with vitamin D deficiency in observational studies, the majority of interventional studies demonstrated the lack of effect of vitamin D supplementation on circulating levels of testosterone. The most consistent effect of vitamin D was reported on semen quality. Indeed, vitamin D was shown to be positively associated to sperm motility, and to exert direct actions on spermatozoa, including non-genomic driven modulation of intracellular calcium homeostasis and activation of molecular pathways involved in sperm motility, capacitation and acrosome reaction. The current review provides a summary of current knowledge on the role of vitamin D in male fertility, by reporting clinical and experimental studies in humans and animals addressing the relationship between vitamin D and testis function

Metabolic disorders and male hypogonadotropic hypogonadism

Several studies highlight that testosterone deficiency is associated with, and predicts, an increased risk of developing metabolic disorders, and, on the other hand, is highly prevalent in obesity, metabolic syndrome and type-2 diabetes mellitus. Models of gonadotropin releasing hormone deficiency, and androgen deprivation therapy in patients with prostate cancer, suggest that hypogonadotropic hypogonadism might contribute to the onset or worsening of metabolic conditions, by increasing visceral adiposity and insulin resistance. Nevertheless, in functional hypogonadism, as well as in late onset hypogonadism, the relationship between hypogonadotropic hypogonadism and metabolic disorders is bidirectional, and a vicious circle between the two components has been documented. The mechanisms underlying the crosstalk between testosterone deficiency and metabolic disorders include increased visceral adipose tissue and insulin resistance, leading to development of metabolic disorders, which in turn contribute to a further reduction of testosterone levels. The decrease in testosterone levels might be determined by insulin resistance-mediated and, possibly, pro-inflammatory cytokine-mediated decrease of sex hormone binding globulin, resulting in a temporary increased free testosterone available for aromatization to estradiol in visceral adipose tissue, followed by a subsequent decrease in free testosterone levels, due to the excess of visceral adipose tissue and aromatization; by a direct inhibitory effect of increased leptin levels on Leydig cells; and by a reduced gonadotropin secretion induced by estradiol, inflammatory mediators, leptin resistance, and insulin resistance, with the ultimate determination of a substantial hypogonadotropic hypogonadism. The majority of studies focusing on the effects of testosterone replacement therapy on metabolic profile reported a beneficial effect of testosterone on body weight, waist circumference, body mass index, body composition, cholesterol levels, and glycemic control. Consistently, several interventional studies demonstrated that correction of metabolic disorders, in particular with compounds displaying a greater impact on body weight and insulin resistance, improved testosterone levels. The aim of the current review is to provide a comprehensive overview on the relationship between hypogonadotropic hypogonadism and metabolism, by clarifying the independent role of testosterone deficiency in the pathogenesis of metabolic disorders, and by describing the relative role of testosterone deficiency and metabolic impairment, in the context of the bidirectional relationship between hypogonadism and metabolic diseases documented in functional hypogonadotropic hypogonadism. These aspects will be assessed by describing metabolic profile in men with hypogonadotropic hypogonadism, and androgenic status in men with metabolic disorders; afterwards, the reciprocal effects of testosterone replacement therapy and corrective interventions on metabolic derangements will be reported

Smoke, alcohol and drug addiction and female fertility

Background: Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking, alcohol and addictive drugs consumption represent a major concern, given the broad range of diseases which might be favored or exacerbated by these dependable attitudes. Despite the well-characterized effects of prenatal exposure on pregnancy outcomes and fetus health, a substantial proportion of women of reproductive age is still concerned with these habits. At present, the impact of smoke, alcohol and addictive drugs on women fertility, and, particularly, the specific targets and underlying mechanisms, are still poorly understood or debated, mainly due to the scarcity of well-designed studies, and to numerous biases. Objective: The current review will provide a comprehensive overview of clinical and experimental studies in humans and animals addressing the impact of smoke, alcohol and addictive drugs on female fertility, by also embracing effects on ovary, oviduct, and uterus, with particular reference to primary endpoints such as ovarian reserve, steroidogenesis, ovulation and menstrual cycle, oviduct function and uterus receptivity and implantation. A brief focus on polycystic ovary syndrome and endometriosis will be also included. Methods: A Pubmed literature search was performed with selected keywords; articles were individually retrieved by each author. No limitation was set for publication date. Articles in languages other than English were excluded. Additional articles were retrieved from references list of selected manuscripts. Results and conclusions: Currently, the most consistent evidences of a detrimental effect of smoke, alcohol and addictive drugs on specific domains of the female reproductive function are provided by experimental studies in animals. Overall, clinical studies suggest that smoking is associated to decreased fertility, although causal inference should be further demonstrated. Studies addressing the effect of alcohol consumption on female fertility provide conflicting results, although the majority reported lack of a correlation. Extremely scarce studies investigated the effects of addictive drugs on female fertility, and the specific actions of selected drugs have been difficult to address, due to multidrug consumption

Bisphenol A: An emerging threat to female fertility

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies

Long-term high-dose l-arginine supplementation in patients with vasculogenic erectile dysfunction: a multicentre, double-blind, randomized, placebo-controlled clinical trial

Purpose: The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED. Methods: The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). Results: l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p < 0.0001) and in subgroups of patients with mild–moderate (p < 0.0001) and severe (p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p < 0.0001) and in patients with mild–moderate (p < 0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild–moderate vasculogenic ED, reached PSV values compatible with absence of ED. Conclusion: The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds

Fertility in Acromegaly: a single center experience on female patients during active disease and after disease remission

Context: Fertility represents a major concern in patients with acromegaly. Objective: Investigation of gonadal function and fertility rate in acromegalic women. Design: Retrospective study. Anthropometric, metabolic, hormonal parameters, and gynaecological ultrasound were evaluated at diagnosis and after disease control. Data about menstrual disturbances, pregnancy, and PCO-morphology (PCOM) were investigated at disease onset, diagnosis and after disease control. Setting: Referral center. Patients: 50 acromegalic women with disease onset within the reproductive age. Intervention: None. Main outcome measures: Prevalence of gonadal dysfunction and infertility. Results: At presumed disease onset, menstrual disturbances were reported in 32% of patients. Uterine leiomyoma, ovarian cysts and PCOM were diagnosed in 18%, 12% and 8%, respectively; 36.8% of patients were infertile. At diagnosis, menstrual disturbances were found in 58.1% (p = 0.02), being significantly more prevalent in patients with higher IGF-I quartiles (Q) (p = 0.03, Q1 vs Q4). Gynaecological ultrasound revealed uterine leiomyoma, ovarian cysts and PCOM in 39.1% (p = 0.04), 28.2% (p = 0.09), and 13% (p = 0.55), respectively. The infertility rate was 100% (p = 0.02). At disease control, menstrual disturbances (p = 0.05), particularly amenorrhea (p = 0.03), significantly persisted in patients with disease duration above than in those with disease duration below 5 years (median). Among patients with pregnancy desire, 73.3% conceived at least once, resulting infertility significantly decreased compared to diagnosis (26.7%, p = 0.01). At-term, pre-term deliveries and spontaneous abortions were recorded in 86.7%, 3.3% and 10%, respectively. No neonatal malformations and/or abnormalities were recorded. Conclusions: Gonadal dysfunction and infertility are common in acromegalic women within the reproductive age, being directly influenced by the disease status and/or duration