*10.4.1 Pathophysiology of obese male factor infertility*

*Lifestyle and Epidemiology - The Double Burden of Poverty and Cardiovascular Diseases...*

with irregular menses, ovulatory dysfunction and ovarian aging [77].

**10.4 Metabolic syndrome and male reproductive health**

defined as an underlying feature associated with MetS [89].

Obesity, as a cardinal feature of MetS, has been associated with an increased incidence of male factor infertility. Although the effect of excess body fat on reproduction has been more extensively studied in females, there has been a recent increase in literature assessing the relationship between obesity and semen characteristics, male endocrine changes, male sexual function and male factor infertility. Over the past decade, numerous studies have found an inverse correlation between increased obesity and semen quality that negatively affects male fertility, with an increased chance of subfertility among couples in which the male partner is obese. Various mechanisms for this relationship have been proposed and can be broadly divided into direct negative effects on spermatogenesis and sperm function (lower sperm counts, poorer sperm quality), hormonal factors and, and increased rates of erectile dysfunction [89, 90]. In males, a state of primary hypogonadism is also well

*10.3.2 PCOS and obesity*

Interference with the hypothalamic – pituitary – gonadal axis function may affect follicular recruitment and impact subsequent oocyte quality and affecting overall subfertility in obese women. Studies of women undergoing assisted reproductive technologies (ART) have demonstrated that obesity also has direct effects on the quality oocytes and embryos and on the status of the endometrium. Audit data from retrospective studies demonstrated obesity to be associated with increased risk for miscarriage in spontaneous conceptions [82] as well in pregnancy achieved through donor oocytes after IVF [83]. The pathophysiology underlying this association is complex and likely multifactorial, involving the oocyte, embryonic development, and the endometrium. Apart from fertility and pregnancy problems, female adiposity may influence the timing of onset of puberty, associated

Polycystic ovary syndrome (PCOS) is a hormonal disorder common, among women of reproductive age affecting 5 to 10 percent, often complicated by chronic anovulatory infertility and hyperandrogenism with the clinical manifestations of oligomenorrhoea, hirsutism and acne [84, 85]. The link between PCOS and obesity is complicated. Signs and symptoms of polycystic ovarian syndrome begin for some females soon after menarche. Women with PCOS have insulin resistance (IR) [86]. This insulin resistance is one reason why women with PCOS tend to gain weight or experiences challenges in losing weight. In some females, PCOS develops later on, following substantial weight gain. Women affected by obesity are also more likely to face reproductive problems like polycystic ovarian syndrome (PCOS) and women with PCOS have a greater risk for obesity. Obesity and PCOS share some common features, anovulation and hyperandrogenism although simple or non-syndromic obesity is much more prevalent than PCOS and seems to have a different pathophysiology with respect to the obesity-related reproductive impairment [87]. The difference in the two is that PCOS is characterized by increased serum LH whereas obese women typically have in general lower serum LH. Obesity may modify some aspects hypothalamic – pituitary – gonadal axis function [88]. Although obesity can affect many facet of PCOS, it is a cause of this syndrome and without doubt have an effect on reproduction regardless of PCOS symptomatology [87]. In this review, we will focus on how obesity in the absence of PCOS affects the

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HPO axis.

Obesity in men contribute to the poor reproductive function through numerous postulated mechanisms. First, hormonal perturbations that involves peripheral conversion of testosterone to estrogen in excess peripheral adipose tissue may lead to secondary hypogonadism through HPG axis inhibition. Second, elevated levels of inflammatory mediators and reactive oxygen species (ROS), generating oxidative stress at the level of the testicular micro environment may result in decreased spermatogenesis and sperm DNA fragmentation. Lastly, the accumulation of supra pubic and inner thigh fat may result in increased testicular heat, which cumulatively can have substantial, detrimental effects on spermatogenesis [74, 90–92].

Men with obesity, the metabolic syndrome and type 2 diabetes have low total and free testosterone and low sex hormone-binding globulin SHBG. On the other hand, the presence of low testosterone and/or SHBG predicts the future development of metabolic syndrome and T2DM [93]. Thus, the observed decrease in testosterone levels in obese males is likely due to several factors, including decreased synthesis of testosterone, inhibition of SHBG synthesis, and decreased gonadotropin secretion [93]. In summary, total testosterone, free testosterone and SHBG are all commonly decreased in obese males. Obesity is also characterized by higher insulin levels and insulin resistance this is suggested to impair steroidogenesis at the Leydig cells which may negatively impact the male reproductive function in the case of obesity [94, 95]. Derby et al. [96] conducted a longitudinal trial of 942 men ages 40–70 years enrolled in the Massachusetts Male Aging Study, demonstrated that BMI was negatively associated with total testosterone, free testosterone, and SHBG, as well as that these levels decline more rapidly with age in obese men.

Adipose tissue behaves like an endocrine gland, it produces hormonally active proteins involved in satiety and metabolism as well as HPG axis regulation [97]. The white adipose tissue produces leptin [74, 97] which has been found to stimulate gonadotropin-releasing hormone secretion in the hypothalamus and FSH and LH secretion in the anterior pituitary in the rat animal studies [98, 99]. Leptin is also believed to have a direct effect on regulation of testosterone production in the testicle taking into account the presence of leptin receptors in Leydig cells [100]. Obesity generates a leptin resistant state, given that high circulating leptin levels are linked with increased adiposity and lower testosterone levels [101].

Obesity creates a proinflammatory state with production of adipokines and cytokines by adiopocytes that result in an increase in systemic inflammation [102] Any form of Inflammation of the reproductive tract has been shown to be associated with infertility in male patients. The cytokines tumor necrosis factor (TNF-a) and interleukin-1(IL-1) have been implicated as the main mediators of the inflammatory process [103]. Inflammation increases levels of reactive oxygen species generating oxidative stress at the level of the testicular that can negatively impact normal reproductive pathways [104]. Elevated oxidative stress leads to increased DNA damage of spermatozoa and is negatively correlated with normal sperm morphology [105–107]. Tunc et al. [108] compared reactive oxygen levels in semen samples from both overweight/obese men and men of normal BMI and found that there was a weak but statistically significant positive correlation between increasing BMI and reactive oxygen species levels.

Spermatogenesis is also adversely effected by elevated testicular temperature. Increased adiposity in the legs and pannus overlying the scrotum may lead to increased testicular temperatures. Shafik and Olfat [109] performed lipectomy to remove the excess scrotal lipoma from a series of infertile men and later observed improvements in their semen parameters in 64.7% of study participants and

pregnancies in 19.6% [109]. Prolonged inactivity in obese men has also been associated with increased scrotal temperatures [110].
