It is known that any systemic illness or anything harmful to total body health can negatively affect sperm production. Is there a mechanism that can explain why, with respect to obesity, it affects some men more than others? How does Obesity actually affect male fertility? A study by Dr. Seetharam et al (J Sex Med Volume 19, Issue 4, Supplement 1, April 2022, Pages S27-S28) explores the effects of a peptide involved in fat metabolism , Leptin, on Leydig stem cell differentiation (Leydig cells are the cells that produce testosterone in the testicle).
The HPG axis (Hypothalamic -Pituitary – Gonadal axis) is a major regulatory mechanism for sexual function in the male. It includes and involves both excitatory and inhibitory factors that modulate both fertility and testosterone production. Briefly, the hypothalamus (a part of the brain that sits just above the pituitary gland) releases GnRH (gonadotropin releasing hormone) which causes the pituitary gland to release both LH (luteinizing hormone) and FSH (follicle stimulating hormone). LH acts on Leydig cells in the testis to release testosterone whereas FSH has a role in regulation of Sertoli cells in the testis. Sertoli cells are intimately connected to sperm producing cells.
Increasing testosterone levels inhibit the hypothalamus from releasing more GnRh as well as LH from the pituitary. FSH stimulation of Sertoli cells results in the release of inhibin which negatively affects pituitary release of more FSH.
Obesity can be a profound disruptor of the HPG axis and may reduce spermatogenesis and fertility.
Increased BMI (body mass index, a formula combining height and weight) is associated with both decreased testosterone levels and sperm production. What is the relationship?
Obese men are more likely to have insulin resistance, Sleep apnea, increased estrogen levels and leptin dysregulation. Leptin is a peptide made mainly by adipocytes (fat cells) that has a role in metabolism, immune function, and reproduction. Leptin causes the release of hypothalamic peptides that decrease food intake and increase energy expenditure, ultimately influencing body weight. Since obese men have more fat cells, they are likely to have higher levels of leptin but those higher levels, rather than cause more energy expenditure, can instead result in “leptin resistance” reducing leptin’s normal effects.
Leptin receptors have also been identified on Leydig cells raising the possibility of leptin resistance having a causative role in male infertility. In the study by Dr. Seetharam et al, there is a reference to prior work revealing that leptin is secreted by Sertoli cells and causes differentiation of Leydig cells and subsequent testosterone production.
In a study of 20 men who underwent testicular sperm extraction surgery, testis tissue from lean BMI men were found have correlation between increased leptin levels and increased Leydig stem cell differentiation. This was compared to the obese BMI population where increasing leptin dose actually had the opposite effect.
Weight loss in obese people can be made more difficult in cases of insulin resistance. Intermittent fasting as a means of lowering insulin resistance has been proposed by others as a more effective method to lose weight. Now it turns out that leptin resistance, also related to obesity, can be a co-factor in male infertility and low serum testosterone levels. This will continue to be an exciting area of physiologic research to watch as more information is uncovered.
In my practice, recreational substance use, lack of sleep, lack of exercise as well as obesity and other lifestyle issues are often confronted in an attempt to enhance male reproductive function, raise sperm production, and improve other findings on semen analysis.
