Obesity and Male Infertility
Obesity and Male Infertility
The mechanisms leading to altered semen parameters and reduced sexual function have been described in detail in previous publications. It is important to review these factors in brief because they constitute the basis of our proposed workup evaluation and treatment of obese infertile men, described later in this article.
Male obesity is associated with lower total testosterone levels. Tajar et al found that BMI is the most powerful predictor of male hypogonadism after analyzing the data from men recruited for the European Male Aging Study. We recently confirmed that male obesity is also associated with low free testosterone levels. This decrease in androgen levels is proportional to the degree of obesity. The mechanisms accounting for reduced total testosterone levels are various and are defined within a reversible hypogonadotropic hypogonadism pathway.
The reduced pituitary function or hypogonadotropic hypogonadism in obese men is likely multifactorial. It is known that in obese men both estrone and estradiol are increased due to increased peripheral aromatization of androgens. Estrogens have a negative effect on the hypothalamus that alters the gonadotropin-releasing hormone (GnRH) pulses and suppresses gonadotropin (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) secretion. Such a role for estradiol is also confirmed showing an increase in gonadotropins and sex steroid production after the administration of aromatase inhibitors to obese men.
The relation between increasing BMI and elevated serum levels of estradiol was challenged recently in a group of men with type 2 diabetes. In this study, serum estradiol levels were not correlated to BMI but were correlated to the substrate of the aromatase enzyme, serum testosterone. We demonstrated that genetic polymorphisms, such as the TTTA polymorphism of the aromatase enzyme, could modulate the relation between obesity and serum estradiol levels in men. Higher TTTAn repeats were associated with an enhancement of the interaction between weight and estradiol levels. The correlation between weight and estradiol level was statistically significantly seen among men homozygous for higher TTTAn repeat numbers, whereas no such correlation is evident for men homozygous for lower numbers of repeats. Interestingly, after 2 years of follow-up, weight loss was associated with reduced serum estradiol levels only in men with higher TTTAn repeat numbers. This effect of the aromatase polymorphism was also found to influence the relation between weight and abnormal semen parameters. Men with high TTTAn numbers were more likely to show semen alteration in relation to increasing weight.
Other factors, different from hyperestrogenemia, have been proposed to explain the hypogonadotropic hypogonadism seen in obesity. Blank et al showed that GnRH infusion caused a significant increase in LH levels in both obese and normal weight men. After infusion of naloxone, LH levels increased only in obese men and not in normal weight men. In obese men, LH pulse frequency after naloxone increased by 51% from baseline. These results suggest a role for endogenous opioids in the pathophysiology of hypogonadotropic hypoandrogenism in extremely obese males. The effect of type 2 diabetes, frequently associated with obesity, on the hypothalamic-pituitary-gonadal axis is increasingly being appreciated.
The Endocrine Society now recommends that men with type 2 diabetes be screened for low testosterone levels. Besides the mechanism mentioned previously, obese men and men with type 2 diabetes can have secondary hypogonadism because of the peripheral and central insulin resistance and the effect of proinflammatory cytokines (TNFα and IL-6) on the hypothalamic-pituitary-gonadal axis. Sex hormone-binding globulin (SHBG) levels are reduced in obese men as a result of increased circulating insulin levels associated with the insulin resistance of obesity. However, after adjusting for SHBG levels, low testosterone levels have been shown to be correlated with insulin resistance and obesity, denoting an independent effect of insulin resistance on testosterone production.
Sleep apnea, more common among the obese, was also proposed to affect morning serum testosterone levels negatively in men. In a recently published study, our group found that the adjusted means (corrected for age and BMI) of total testosterone is reduced proportionally to the severity of the sleep apnea. After correction for age and BMI, other parameters of sleep apnea including hypopnea index, percentage time below a Spo2 of 90% and 80% were also negatively correlated with total and free testosterone levels. Sleep apnea can affect both testosterone levels (with potentially altered spermatogenesis) as well as, independently, erectile function. The combination of both factors may result in a compounding effect on male fertility.
Male obesity is associated with increased circulating estrogens. Estrogens may have a direct deleterious effect on spermatogenesis. Additionally, a negative effect of environmental toxins and endocrine disruptors possessing estrogenic activities on male fertility have been suggested.
Serum levels of multiple organochlorines were positively correlated to male BMI and to infertility. These toxins are fat soluble and tend to accumulate in the fatty tissue.
Sedentary life, prolonged sitting, and fat deposition in the lower abdomen can reduce male fertility, likely through increased testicular temperature to the level of body core temperature. Obesity was also shown to be associated with high homocysteine and low vitamin D levels. Both are suspected to affect semen parameters.
Pathophysiological Alterations of the Reproductive System in Obese Men
The mechanisms leading to altered semen parameters and reduced sexual function have been described in detail in previous publications. It is important to review these factors in brief because they constitute the basis of our proposed workup evaluation and treatment of obese infertile men, described later in this article.
Hypogonadotropic Hypogonadism
Male obesity is associated with lower total testosterone levels. Tajar et al found that BMI is the most powerful predictor of male hypogonadism after analyzing the data from men recruited for the European Male Aging Study. We recently confirmed that male obesity is also associated with low free testosterone levels. This decrease in androgen levels is proportional to the degree of obesity. The mechanisms accounting for reduced total testosterone levels are various and are defined within a reversible hypogonadotropic hypogonadism pathway.
The reduced pituitary function or hypogonadotropic hypogonadism in obese men is likely multifactorial. It is known that in obese men both estrone and estradiol are increased due to increased peripheral aromatization of androgens. Estrogens have a negative effect on the hypothalamus that alters the gonadotropin-releasing hormone (GnRH) pulses and suppresses gonadotropin (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) secretion. Such a role for estradiol is also confirmed showing an increase in gonadotropins and sex steroid production after the administration of aromatase inhibitors to obese men.
The relation between increasing BMI and elevated serum levels of estradiol was challenged recently in a group of men with type 2 diabetes. In this study, serum estradiol levels were not correlated to BMI but were correlated to the substrate of the aromatase enzyme, serum testosterone. We demonstrated that genetic polymorphisms, such as the TTTA polymorphism of the aromatase enzyme, could modulate the relation between obesity and serum estradiol levels in men. Higher TTTAn repeats were associated with an enhancement of the interaction between weight and estradiol levels. The correlation between weight and estradiol level was statistically significantly seen among men homozygous for higher TTTAn repeat numbers, whereas no such correlation is evident for men homozygous for lower numbers of repeats. Interestingly, after 2 years of follow-up, weight loss was associated with reduced serum estradiol levels only in men with higher TTTAn repeat numbers. This effect of the aromatase polymorphism was also found to influence the relation between weight and abnormal semen parameters. Men with high TTTAn numbers were more likely to show semen alteration in relation to increasing weight.
Other factors, different from hyperestrogenemia, have been proposed to explain the hypogonadotropic hypogonadism seen in obesity. Blank et al showed that GnRH infusion caused a significant increase in LH levels in both obese and normal weight men. After infusion of naloxone, LH levels increased only in obese men and not in normal weight men. In obese men, LH pulse frequency after naloxone increased by 51% from baseline. These results suggest a role for endogenous opioids in the pathophysiology of hypogonadotropic hypoandrogenism in extremely obese males. The effect of type 2 diabetes, frequently associated with obesity, on the hypothalamic-pituitary-gonadal axis is increasingly being appreciated.
The Endocrine Society now recommends that men with type 2 diabetes be screened for low testosterone levels. Besides the mechanism mentioned previously, obese men and men with type 2 diabetes can have secondary hypogonadism because of the peripheral and central insulin resistance and the effect of proinflammatory cytokines (TNFα and IL-6) on the hypothalamic-pituitary-gonadal axis. Sex hormone-binding globulin (SHBG) levels are reduced in obese men as a result of increased circulating insulin levels associated with the insulin resistance of obesity. However, after adjusting for SHBG levels, low testosterone levels have been shown to be correlated with insulin resistance and obesity, denoting an independent effect of insulin resistance on testosterone production.
Sleep apnea, more common among the obese, was also proposed to affect morning serum testosterone levels negatively in men. In a recently published study, our group found that the adjusted means (corrected for age and BMI) of total testosterone is reduced proportionally to the severity of the sleep apnea. After correction for age and BMI, other parameters of sleep apnea including hypopnea index, percentage time below a Spo2 of 90% and 80% were also negatively correlated with total and free testosterone levels. Sleep apnea can affect both testosterone levels (with potentially altered spermatogenesis) as well as, independently, erectile function. The combination of both factors may result in a compounding effect on male fertility.
Direct Effect on Testicular Function
Male obesity is associated with increased circulating estrogens. Estrogens may have a direct deleterious effect on spermatogenesis. Additionally, a negative effect of environmental toxins and endocrine disruptors possessing estrogenic activities on male fertility have been suggested.
Serum levels of multiple organochlorines were positively correlated to male BMI and to infertility. These toxins are fat soluble and tend to accumulate in the fatty tissue.
Sedentary life, prolonged sitting, and fat deposition in the lower abdomen can reduce male fertility, likely through increased testicular temperature to the level of body core temperature. Obesity was also shown to be associated with high homocysteine and low vitamin D levels. Both are suspected to affect semen parameters.
