*5.1.1 Hypogonadism and pseudo-gynecomastia*

Insulin resistance may be responsible for obesity-induced hypogonadism in males. Male obesity secondary hypogonadism or MOSH is caused by hyperestrogenism, metabolic endotoxemia, and hyperleptinemia. Hyperestrogenism decreases pituitary secretion of luteinizing hormone through a negative feedback action that impairs the synthesis and production of testosterone from Leydig cells. Hypercaloric diet with excess lipids causes breakdown of the normal leaky gut, facilitating passage of bacterial endotoxin from gut lumen into the blood stream (metabolic endotoxemia). Some animal studies suggest that bacterial endotoxin (Lipopolysaccharides-LPS) reduces testicular function by binding toll-like receptor 4 (TLR4) on Leydig cells, stimulating production of inflammatory cytokines [131–134].

Obesity is associated with elevated levels of leptin and leptin resistance. Leptin prevents the neuropeptide Y (NPY) neurons from inhibiting the release of GnRH. Leptin resistance results in reduced release of GnRH, FSH, and LH and impairs spermatogenesis [135].

Kisspeptin, a hypothalamic peptide encoded by the KiSS1 gene, is an important neuromodulator involved in HPG axis and fertility control. Most kisspeptin cells are localized at the hypothalamic level in humans. Kisspeptin and its G-protein-coupled receptor (KISS 1R or GPR-54) increase the delivery of GnRH into portal circulation, resulting in enhanced secretion of LH and FSH from the anterior pituitary. Decreased endogenous kisspeptin secretion is seen in obesity-related hypogonadotropic hypogonadism (HH) [136–139]. Increased leptin levels are associated with decreased total and free testosterone levels in males.

Hyperinsulinemia results in decreased production of sex hormone binding globulin (SHBG) by the hepatocytes, causing increased availability of free testosterone for reaction by aromatase in the adipose tissue. Aromatase converts testosterone to estradiol [140], further decreasing testosterone level with increase in estrogen level. This may result in pseudo-gynecomastia, with excess adipose deposition in breast area [134]. Sleep apnea associated with obesity disrupts the nocturnal rise in testosterone [134].

High waist circumference is associated with erectile dysfunction due to atherogenic effect on peripheral vasculature [141]. Low ejaculatory volume and oligo-zoospermia have been noted in males with increased BMI and waist circumference [142]. Increased testicular heat, elevated inflammatory mediators, and increased presence of reactive oxygen species in men with obesity affect the quality of sperms [143].

### **5.2 Reproductive problems in females**

Earlier onset of menarche has been reported in adolescent females with overweight or obesity, compared with their normal-weight counterparts. The association of obesity with menstrual disorders, infertility, and recurrent miscarriages was recognized early [144, 145].

Insulin resistance promotes hyperandrogenemia and decreases the level of steroid hormone binding globulin (SHBG) resulting in elevated levels of free testosterone (discussed above). Aromatization of testosterone to estrogens by aromatase in the adipose tissue suppresses the release of gonadotrophin from the pituitary [140]. Elevated levels of leptin impair follicle development, ovulation, and oocyte maturation in women with obesity [146, 147].

### *5.2.1 Polycystic ovarian syndrome (PCOS)*

This hormonal disorder is one of the most common endocrine disorder in premenopausal women, is also associated with obesity, metabolic syndrome, and T2DM. Irregular periods, anovulatory cycles, oligo-amenorrhea, excess androgen, hirsutism, and polycystic ovaries are the main characteristics of PCOS [148, 149]. Most women with PCOS have elevated levels of plasma free fatty acids, are insulin resistant, and have compensatory hyperinsulinemia. High levels of free fatty acids induce mitochondrial dysfunction, inflammation, oxidative stress, and immune disorders [150]. High levels of plasma free fatty acids cause increased synthesis of androgens in the ovary as well as in the zona reticularis of the adrenal gland. Insulin stimulates androgenesis by stimulating P450c17 activity in zona reticularis of the adrenal gland to produce DHEA and androstenedione [151]. Hyperinsulinemia causes decreased expression of SHBG by hepatocytes (see above), thus further increasing free testosterone levels. Aromatase (CYP19A1) in adipocytes as well as in the tissue of endometriosis converts androgens to estradiol, which inhibits the secretion of gonadotropin releasing hormone, resulting in decreased release FSH and LH from the pituitary. This affects maturation of follicles, production of estrogen, ovulation, maintenance of function of corpus luteum.

Women with PCOS may have problems in conceiving and increased risk of gestational diabetes and miscarriage or premature birth. Impairment of the hypothalamuspituitary-gonadal (HPG) axis and follicular environment caused by obesity results in fertility problems, miscarriages, and complications in pregnancy.

### *5.2.2 Anovulation and quality of oocyte*

Ovulation disorders account for at least 30% cases of infertility. Menstrual cycle without the release of ovum is called anovulatory cycle. Women with obesity have higher rates of anovulatory menstrual cycles [152, 153], the exact mechanism of which is not known. Common causes of anovulation include hyperandrogenism (as in PCOS, congenital adrenal hyperplasia, androgen-producing tumors), hyperprolactinemia, anorexia, excessive strenuous exercise, stress, thyroid dysfunction,

*The Multiple Consequences of Obesity DOI: http://dx.doi.org/10.5772/intechopen.104764*

primary pituitary dysfunction, premature ovarian failure, and certain medications. Obesity and strenuous exercise are known to alter profiles of insulin and adiponectin, thus impairing fertility in women. Obese women remain sub-fertile even in the absence of ovulatory dysfunction [154, 155].

Obesity affects the quality of sperm, ovum, embryo, placenta, and the uterine environment. The competence of the oocyte is defined in terms of its ability to become fertilized and support embryo development. Oocyte competence may be influenced by obesity. Machtinger et al. [156] have shown that oocytes from women with obesity are smaller in size, have more abnormal spindles and chromosome misalignment than those from women with normal BMI. Negative outcomes for women undergoing in vitro fertilization (IVF) are more common in women with higher BMI, due to the poor oocyte quality, lower preimplantation rate, and uterine receptivity [157]. Decreased rate of conception, infertility, early pregnancy loss, and reduced success of assisted reproductive technology (ART) have been reported in females with obesity [158].

High serum levels of insulin, insulin resistance, high levels of glucose, lactate, triglycerides, and C-reactive protein in the follicular fluid have a negative impact on oocyte maturation.

Mitochondria of the oocyte must be fully functional, as ATP generated by them are required for oocyte maturation and blastocyst formation. High levels of fuel molecules (glucose, free fatty acids, triglycerides, and cholesterol) in environment increase intracellular lipid accumulation and cause damage to the endoplasmic reticulum and mitochondria. Mice fed on high-fat diet have oocytes with accumulated lipid, increased reactive oxygen species (ROS), and have altered structure of mitochondria [159].

### *5.2.3 Endometrial hyperplasia*

Abnormally thickened lining of the uterus due to disordered proliferation of endometrial glands or endometrial hyperplasia is caused by excess androgen with a relative deficiency of progesterone [160]. Untreated endometrial hyperplasia may develop into endometrial cancer [161]. Endogenous estrogen excess may occur in anovulatory cycles (during perimenopause or PCOS), obesity, and estrogen secreting tumors of the ovary. The most common symptom of endometrial hyperplasia is abnormal uterine bleeding.

### **5.3 Obesity-related complications in pregnancy**

Women with obesity have a higher risk of miscarriage, gestational diabetes, preeclampsia, premature delivery, cesarean section, and post-partum hemorrhage. Maternal obesity with poor glycemic control may result in fetal macrosomia and associated complications. Twenty percent less detection of fetal anomalies has been reported in women with obesity [162].

### *5.3.1 Risk of miscarriage*

A Danish cohort study [163] involving more than 5000 women reported a hazard ratio for miscarriage of 1.23 for women with obesity conceiving spontaneously. Risk of miscarriage is higher in women with obesity who conceive with IVF, even when using donor eggs from women with normal BMI.

### *5.3.2 Gestational diabetes*

Schummers et al. [164] studied 226,000 singleton pregnancies in British Columbia. They have reported an incidence of gestational diabetes of 7.9%. The risk of gestational diabetes was doubled with a BMI > 30, and more than tripled at BMI > 40 kg/m2 .

### *5.3.3 Risk of preeclampsia*

Women with overweight have double the risk of preeclampsia, while women with obesity have triple the risk, compared with women with normal BMI [164, 165]. Increased physical activity during pregnancy may reduce the risk of both gestational diabetes and preeclampsia.

### *5.3.4 Preterm labor*

Obesity has been shown to increase the risk of preterm delivery [165, 166]. This may be due to increased levels of circulating cytokines and inflammatory proteins in women with obesity.

### *5.3.5 Cesarean section*

The rate of Cesarean section increases with increase in maternal BMI [165, 167]. There is also an increased risk of wound infection, dehiscence, post-partum hemorrhage, and deep vein thrombosis. Duration of labor is longer in women with obesity. There is an increased risk of fetal distress, instrumental delivery, and shoulder dystocia in women with obesity.
