Abnormal HPG Regulation

Although several mechanisms that parallel obesity to infertility have been proposed, many remain ambiguous and relatively undefined. Studies indicate that the central factor linking the mechanisms associated with obesity and infertility is an abnormal regulation of the HPG axis, as well as the previously discussed OS. The HPG axis responds to fluctuations in hormones causing a range of widespread and local effects on the body and aspects of reproduction. Excess fat accumulation can impair the feedback regulation of the HPG axis and be a contributing factor to abnormal semen quality. Since sex steroids and glucocorticoids control the interaction between the hypothalamic-pituitary-adrenal (HPA) and the HPG axes, any imbalance may in turn affect spermatogenesis and male reproductive function. The abnormal endocrine changes observed in obese, infertile men are not similar to men with either obesity or infertility alone. Therefore, simultaneous irregular hormonal profile and adipose-derived hormone levels, such as with aromatase, leptin, resistin, inhibin B, cytokines, as well as many genetic factors and physical manifestations may further explain the connection between the escalating frequency of global obesity and subfertility. Aromatase

White adipose tissue exhibits elevated aromatase activity and secretion of adipose-derived hormones in abdominal and visceral fat. Aromatase is an important cyto-chrome P450 enzyme involved in sexual development and is vital in the biosynthesis of estrogens from its precursor androgens, such as testosterone and dehydropi-androsterone. Ironically, obese men show signs of elevated estrogen levels as well as low levels of testosterone and follicle-stimulating hormone (FSH) [10]. Depleted levels of free and total testosterone are interrelated to aromatase overactivity in both intra-abdominal and subcutaneous fat. This condition of hypotestosteronemia—low levels of testosterone—and deregulated levels of sex hormones are related to a reduction in spermatogenesis and subsequent lowered sperm concentrations [68] . Therefore, both may potentially hinder additional aspects of male reproductive function causing suboptimal fertility in obese males.

In an in vitro study involving male mice, it was demonstrated that estrogen is required for fertility and that a mutation in the estrogen receptor gene leads to reduced mating frequency, lowered sperm numbers, and defective sperm function [69] . Nevertheless, since estrogen is more biologically active than testosterone, overproduction of estrogen from elevated expression levels of aromatase activity in obese men may elicit significant abnormal downstream effects in the testes. A report notes signs of both overexpressed levels and the absence of estrogen to elicit adverse effects on spermatogenesis, simultaneously affecting normal male reproductive potential [70] .

The endocrine system, which is responsible for the regulation of metabolic activities, growth and development, as well as guiding reproduction, has estrogen receptors in the male hypothalamus involved in a negative feedback mechanism with gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and FSH from the anterior pituitary gland. As estrogen agonist levels are elevated, an inhibitory effect on androgen biosynthesis is observed, pointing to a regulatory role of the HPG axis to cause detrimental effects on spermatogenesis and, in turn, further increasing the likelihood of subfertility in obese men. Leptin

Leptin is an adipose-derived peptide hormone secreted from white adipocytes vital in the regulation of energy intake and expenditure. Human leptin is a protein made up of 167 amino acids. The level of secreted and circulating leptin is directly proportional to the total amount of body fat. It acts on hypothalamic neurons responsible for the secretion of GnRH. This tropic hormone stimulates the synthesis and secretion of gonadotropins, FSH and LH from the anterior pituitary.

Normally, elevated leptin levels are associated with an increase in weight gain and respond through a feedback mechanism in the hypothalamus to reduce food intake and to increase both energy expenditure and sympathetic activity. On the other hand, leptin deficiency from mutations in the Ob(Lep) gene located on chromosome 7 has also indicated relations to obesity [1], A majority of obese males presented elevated serum concentrations of leptin with no mutation in their leptin receptors. This indicates that the development of an insensitivity and resistance to the action of endogenous leptin is one of the fundamental mechanisms of obesity [71],

2n addition, the aromatase overactivity expressed in obese men that causes a higher conversion of testosterone to estrogen will induce a negative feedback signal on the hypothalamus and anterior pituitary to inhibit GnRH, FSH and LH secretion. The combination of effects from both the insensitivity to endogenous leptin and stimulation of the negative feedback pathway may have profound effects on male reproductive function via abnormal hormonal regulation. Furthermore, an excess secretion of leptin from adipose tissue in obese males illustrated deleterious effects on both spermatogenesis and the production of androgens from inhibitory receptors mediated by Leydig cells [72] . It has been speculated that the presence of leptin plasma membrane receptors in testicular tissue and semen samples may be the link between leptin and male reproductive function [73]. The findings reinforce a direct effect on sperm quality via abnormal HPG regulation and further suggest a plausible link between obesity and male infertility. Resistin

Resistin is an endocrine secreted adipose-tissue specific factor. It is a cysteine-rich protein that serves in endocrine function and regulation. Resistin causes tissues, particularly the liver, to become insulin resistant. As a result, blood glucose levels rise from increased glycogenolysis and gluconeogenesis processes in the liver.

Glycogenolysis, glycolysis and the tricarboxylic acid cycle act to conserve energy as ATP from the catabolism of carbohydrates. If ATP supplies are sufficient, these pathways and cycles are allosterically inhibited. Although under conditions of excess ATP production, the liver will attempt to convert the excess mixture of molecules into glucose and/or glycogen. In general, during glycogenolysis, glycogen stored in the liver and muscle cells is converted to glucose-6-phosphate—the first byproduct of the glycolytic pathway.

In gluconeogenesis, glucose molecules are synthesized from non-carbohydrate sources, such as lactic acid, amino acids and glycerol. This process is constantly occurring in the liver in order to maintain glucose homeostasis. Gluconeogenesis proceeds in times of low acetyl CoA concentrations and high levels of ATP production.

Although both glycogenolysis and gluconeogenesis processes require ATP to take place, there is very little, if any, deficiency in ATP production reported that will hamper the motility of sperm. Although sperm motility is critical at the time of fertilization, as it allows the passage of sperm through the zona pellucida, a lack of ATP production from resistin and its subsequent impact on sperm motility cannot yet be confirmed as credible rationale for the increased incidence rate of male infertility.

Since resistin causes an increase in blood glucose levels from insensitivity to insulin, it is a primary factor associated with Non-Insulin-Dependent Diabetes Mellitus (NIDDM), or Type II diabetes. Over 80% of people with Type II diabetes suffer from obesity. Consequently, this resistance to insulin causes an increase in circulating insulin in the bloodstream—hyperinsulinemia—leading to an inhibitory effect on spermatogenesis and impacting male fertility potential. Interestingly, although diabetic men share normal semen parameters (concentration, morphology, and motility), the amount of impairment to nuclear and mito-chondrial DNA was notably higher, again pointing to a reduction in reproductive capabilities and health.

Although resistin shows a strong association in humans with high levels of glucose, obesity and Type II diabetes, it is actually a major product of macrophages.

Macrophages are a type of white blood cells that ingest foreign material by means of phagocytosis. When the number of macrophages that reside in adipose tissue increases, this may result in elevated levels of ROS. Many studies have associated insulin resistance with elevated OS levels, inferring naturally produced ROS in obese males to maintain normal biological processes as a potential reason [74] . Inhibin B

Inhibin is a glycoprotein, growth-factor like hormone of gonadal origin. It is a dimer consisting of two covalently linked alpha and beta subunits. The beta subunit of inhibin exists in two forms, A and B. Although many studies have been conducted on inhibin, both in vivo and in vitro, they have failed to demonstrate and verify a systemic relationship between serum inhibin levels and spermatogenesis [75, 76],

The site of inhibin B production has been under much scrutiny as some studies indicate that germ cells and possibly Leydig cells can produce inhibin [77, 78] . However, the predominantly believed source of inhibin B originates from Sertoli cells, which play a supportive role in germ cell survival, in the testis into the seminal plasma [79, 80]. This hormone is involved in the HPG axis and displays a proportional decrease in obese males. The consequent decrease in germ cells demonstrates a decrease in sperm count and a reduced likelihood to fertilize.

The mechanistic pathway inhibin B follows to exert its biological effects remains unknown and is a subject of future study [81]. Normally, it acts to inhibit both FSH production and stimulation of testosterone release by Leydig cells. However, many studies have revealed that the expected compensatory increase in FSH levels in response to low levels of inhibin B were not observed in obese men. These low levels of inhibin B observed may have resulted from the suppressive effects of elevated estrogen levels from overly expressed aromatase in obese men.

Since inhibin B levels are directly related to sperm formation, low levels observed in obese males will result in abnormal spermatogenesis. As previously mentioned, the increased estrogen levels contribute to a negative feedback effect on the hypothalamus decreasing gonodoliberin and gonadotropin release, and subsequent lowered testosterone levels. As levels of testosterone fall, sperm function and quality become impaired, resulting in a reduction in male reproductive potential. Nevertheless, inhibin B seems to be an accurate biomarker of testicular damage and could become essential for future diagnosis of spermatogenic disorders in populations exposed to testicular toxicants.

Aside from both ROS and abnormal-induced HPG axis regulation, there continues to be a variety of other factors that have demonstrated evidence of recognized effects of obesity on male infertility. However, there still remain numerous cases of obese men with reproductive function and potential to fertilize. This present unex-plainable link in some instances may be credited to unfavorable inherited genotypes. Although it has been well documented that obese-infertile men show significantly lower testosterone levels than obese-fertile men, genetic mutations may exist to clarify this discrepancy [10]. Cytokines

As excess fat storage accumulates in tissues other than adipose tissue, such as in the liver or striated tissue of the skeletal muscle, local insulin resistance may ensue and cause inflammation. Inflammation is the response to tissue injury and is often characterized by an increase in blood flow to the tissue, consequently increasing temperature in the localized area, as well as redness, swelling and pain.

Changes in morphology and composition of adipose tissue from obesity can cause alterations in protein production and secretion. Many of the secreted proteins may be proinflammatory mediators produced by macrophages residing in the adipose tissue. Proinflammatory cytokines originating from adipose tissue display elevated signs of insulin resistance during inflammatory response. Cytokines have demonstrated to directly interfere with insulin signaling pathways by tumor necrosis factor-alpha (TNF-a), inhibiting tyrosine phosphorylation of insulin receptor substrate-1 [82]. Recent studies initiated and conducted by Hotamisligil have illustrated a positive correlation between an increase in adipose tissue accumulation and proin-flmmatory gene TNF-a expression [82] . It is indicated that the involvement of TNF-a and interleukin-6 cytokines results in a reduction in sperm motility during systemic inflammation response [83]. This decrease in motility may further result in the inability of the spermatozoa to progressively travel to the oocyte, thereby diminishing the likelihood of fertility.

Furthermore, an excess of white adipose tissue has shown to increase the secretion of adipocytokines, causing enhanced inflammation and a toxic effect on spermatozoa through the release of ROS [84]. This subsequent ROS release during periods of inflammation and its impact on sperm quality and function may be a causative aspect to male infertility. Therefore, it is reasonable to believe that excess fat buildup in obese men causing insulin resistance from elevated resistin levels, inflammation response, higher metabolic rates, release of ROS, and elevated temperatures may all be contributing factors to the previously noted nuclear and mitochondrial DNA damaged and, ultimately, decreased reproductive potential in Type II diabetic males.

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