Obesity: A Doorway to a Molecular Path Leading to Infertility

Abstract

The dramatic rise in obesity has recently made it a global health issue. About 1.9 billion were overweight, and 650 million global populations were obese in 2016. Obese women suffer longer conception time, lowered fertility rates, and greater rates of miscarriage. Obesity alters hormones such as adiponectin and leptin, affecting all levels within the hypothalamic-pituitary-gonadal axis. Advanced glycation end products (AGEs) and monocyte chemotactic protein-1 (MCP-1) are inflammatory cytokines that may play an important role in the pathophysiology of ovarian dysfunction in obesity. In obese males, there are altered sperm parameters, reduced testosterone, increased estradiol, hypogonadism, and epigenetic modifications transmitted to offspring. The focus of this article is on the possible adverse effects on reproductive health resulting from obesity and sheds light on different molecular pathways linking obesity with infertility in both female and male subjects. Electronic databases such as Google Scholar, Embase, Science Direct, PubMed, and Google Search Engine were utilized to find obesity and infertility-related papers. The search strategy is detailed in the method section. Even though multiple research work has shown that obesity impacts fertility in both male and female negatively, it is significant to perform extensive research on the molecular mechanisms that link obesity to infertility. This is to find therapeutics that may be developed aiming at these mechanisms to manage and prevent the negative effects of obesity on the reproductive system.

Keywords: adipokine; cytokines; hypothalamic-pituitary-gonadal axis; infertility; inflammation; insulin resistance; obesity; ovarian dysfunction; sperm parameter.

Figure 1. The complications of obesity in females leading to infertility, including early follicle atresia, follicle apoptosis, reduced receptivity of endometrium, release of inflammatory cytokines, adipokines like leptin, increased androgen and estrogen formation due to adiposity; hyperinsulinemia and insulin resistance; reduced sex hormone binding globulin from the liver; reduced gonadotropin releasing hormone from hypothalamus and decreased gonadotropins from pituitary gland.

SHBG: sex hormone binding globulin. GnRH: gonadotropin-releasing hormone. TNFα: tumor necrosis factor alpha. FFA: free fatty acids. IL6: interleukin 6.  ↓: Decrease. ↑: Increase. Image Credit: Rahnuma Ahmad

Figure 2. Free fatty acid due to adiposity leads to insulin resistance which in turn causes hyperinsulinemia. Raised insulin levels cause a decrease in SHBG and an increased level of GnRH and LH, which causes hyperandrogenism.

SHBG: sex hormone binding globulin. GnRH: gonadotropin-releasing hormone. LH: luteinizing hormone. This figure has been developed using BioRender (https://biorender.com) License number: RU24HIWXUW. Image Credit: Rahnuma Ahmad.

Figure 3. Hormones, cytokines, and adipokines acting at the level of brain and gonads in obesity resulting in decreased levels of testosterone, spermatogenesis, and erectile dysfunction. Obesity causes releases of leptin, increases aromatase activity, and decreases sex hormone binding globulin with decreases in testosterone and increases in estrogen levels; leptin resistance in obesity decreases kisspeptin and, in turn, decreases gonadotropin-releasing hormone from hypothalamus and decreases LH and FSH from pituitary gland; insulin resistance, TNFα, IL in chronic inflammation; hyperthermia, AMPK in Sertoli cells.

SHBG: sex hormone binding globulin. AMPK: AMP-activated protein kinase. LH: luteinizing hormone. FSH: follicle stimulating hormone. TNFα: tumor necrosis factor alpha. ↓: Decrease. ↑: Increase. Image Credit: Rahnuma Ahmad.

Figure 4. The complications of obesity in males leading to infertility, including increased aromatase activity and rise in estrogen level; increase in scrotal temperature; adipokines like leptin, chemerin, resistin, visfatin increase and decrease in adiponectin; leptin resistance; release of inflammatory cytokines and oxidative stress; insulin resistance, hyperinsulinemia and decrease in sex hormone binding globulin; epigenetic modification.

SHBG: sex hormone binding globulin. TNF: tumor necrosis factor. ↓: Decrease. ↑: Increase. Image Credit: Rahnuma Ahmad.

Figure 5. The impact of obesity on sperm DNA, leading to reduced pregnancy rate in partners of obese males and also an increase in obesity risk in the offspring of obese male individuals.

This figure has been developed using BioRender (https://biorender.com/) License number: FR24I07PEF. Image Credit: Rahnuma Ahmad.