The prevalence of obesity has increased substantially among current generations in Western countries, and the burden of obesity-related complications has been growing steadily, reaching epidemic proportions. Globally, an estimated 2.1 billion adults are classified as overweight or obese and it is likely that changes in lifestyle factors and caloric habits are largely responsible for this course of events. Obesity is a significant risk factor for increased mortality, mainly because of its association with diabetes, cardiovascular disease, cancer, metabolic syndrome, hyperlipidaemia, a proinflammatory state and cancer arising from the severe metabolic alterations caused by excess weight.
Since the 1970s the rates of overweight and obesity in reproductive-age men have nearly tripled, such that in westernised countries between 65% and 70% of adult men are now overweight or obese. There is an increasing awareness that male overweight/obesity reduces sperm quality, and in particular alters the physical and molecular structure of sperm, which is coincident with a growing number of couples requiring intra-cytoplasmic sperm injection (ICSI) for the treatment of male factor sperm defects. This occurs because obesity is associated with significant disturbance in the hormonal milieu that can affect the reproductive system.
Reduced semen quality has been found to be a universal trend in the last few decades due to dramatic changes in the lifestyle of civilised communities around the world. According to the chemical calorie theory, endocrine disruptors are, at least in part, responsible for the pandemic of obesity in the last few decades. Sub-fertile men have a significantly higher body mass index (BMI) than the general population and both low and high BMIs (less than 19 kg/m2 or more than 30 kg/m2 respectively) have been associated with reduced testicular volume and reduced semen quality, suggesting impairment of spermatogenesis. In fact, the odds of infertility increase by 10% for every 9 kg (20 pounds) a man is overweight.
MECHANISMS ASSOCIATED WITH OBESITY
Obesity in men is associated with an increase in the aromatase enzyme activity of adipocytes, which results in a higher peripheral conversion of testosterone to estradiol and, traditionally, it has been thought that the consequent rise in serum estradiol exerts negative feedback on the secretion of LH from the pituitary gland, due to the presence of oestrogen receptors in the hypothalamus–pituitary–gonadal axis, thereby suppressing the axis and leading to a reduction in testosterone levels. Reduced plasma testosterone worsens obesity since it promotes changes in body composition, stimulating an increase in adipose tissue, mainly in the abdomen.
Obesity-associated hypogonadism is characterised by normal or low levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH) and decreased plasma testosterone. The gonadal axis is regulated by a set of hypothalamic neurons that respond to stimulation by the kisspeptin peptide hormones. These neurons produce gonadotropin-releasing hormone (GnRH), which is released in pulses every 60 to 90 min, stimulating the pulsatile secretion of the pituitary gonadotropins, LH and FSH, into the bloodstream.
LH stimulates Leydig cells to produce testosterone, while FSH, in conjunction with intratesticular testosterone, acts on Sertoli cells and seminiferous tubules to stimulate spermatogenesis. In turn, the hormone inhibin is produced in Sertoli cells, which provides negative feedback on the production of FSH in the pituitary gland. Testosterone acts directly through androgen receptors and by its conversion into two active metabolites, dihydrotestosterone, by the enzyme 5-α reductase, and estradiol, by the enzyme aromatase.
EFFECT ON TESTOSTERONE
Several studies document that increased male BMI is associated with reduced plasma concentrations of sex hormone binding globulin (SHBG) and testosterone with a concomitant rise in plasma concentrations of oestrogen. Decreased testosterone and increased oestrogen have long been associated with subfertility and reduced sperm counts by disrupting the negative feedback loop of the hypothalamic pituitary gonadal (HPG) axis. Other hormones involved in the regulation of Sertoli cell function and spermatogenesis, such as FSH/LH ratios, inhibin B and SHBG levels have all been observed to be decreased in males with increased BMI.
The endocrine abnormalities observed in obese men may both derive from global impairment in metabolism and contribute to the increase and worsening of obesity. Since obesity has a direct impact on testosterone levels, contributing to reduced testosterone and increased adipose tissue, male obesity creates a negative cycle called the hypogonadism-obesity cycle. The extension of this theory is based on the fact that adipose tissue is an endocrine organ that secretes various factors that influence the pathogenesis of obesity and affect testosterone production, contributing to the onset of hypogonadism. This is known as the hypogonadism-obesity-adipokine hypothesis.
Leptin, the obese gene product secreted from adipocytes, circulates in plasma at concentrations that parallel the amount of fat reserves and controls adiposity by modulating food intake and energy metabolism in the rodent. Recent research has shown that leptin also plays an important role in human reproduction. It has been demonstrated that leptin receptors are present in ovarian granulosa cells and that leptin treatment of granulosa cell cultures inhibits hormonal-stimulated estradiol production. Leptin receptors are also present in testicular tissue.
Leptin concentrations have been found to inversely correlate with testosterone concentrations, even after controlling for SHBG and estradiol, and leptin concentrations were the best hormonal predictor of low androgen concentrations in obesity. It has been proposed that this resistance to leptin also exists at the central level, favouring hypogonadism. In addition, elevated leptin levels may directly inhibit the production of testosterone in Leydig cells, further decreasing it. Both TNF-α and IL-6 are also expressed in adipose tissue. An elevation in their levels creates a pro-inflammatory state involved in the pathophysiology of obesity and insulin resistance and also negatively influences the secretion of gonadotropins.
Several studies have demonstrated that leptin levels are inversely correlated with testosterone levels and it has been recently proposed that testosterone may regulate obese gene expression. All the above raise the possibility that leptin may directly regulate testicular steroidogenesis in humans. A large human cohort has also determined the negative impact of dyslipidaemia on sperm function, assessing systematic lipid regulation in 501 men over two semen samples.
The study authors found that higher levels of serum total cholesterol, free cholesterol and phospholipids were associated with a significantly lower percentage of sperm with an intact acrosome and smaller sperm heads after adjusting for BMI. These changes to sperm are proposed to occur in the epididymis, where high levels of circulating cholesterols cause degradation in the proximal epididymis leading to sperm morphological abnormalities, decreased motility and premature acrosome reaction.
EFFECT ON OFFSPRING
Alarmingly, there is now evidence that paternal obesity increases the susceptibility to obesity and diabetes in offspring, suggesting a possible mechanism for the amplification of these chronic diseases. Epidemiological evidence has determined that the offspring of obese fathers are at a higher risk of developing metabolic disorders and newborn males of obese fathers exhibit a significant increase in birth weight as well as a change in several anatomical parameters, including head circumference, abdominal diameter, and abdominal circumference. Furthermore, a child born to an obese father and normal weight mother showed an increased risk of becoming obese whereas an obese mother and normal weight father could not predict whether the child would be overweight or obese.
Paternal effects were additionally reported to have transgenerational influences where an increase in nutritional abundance was significantly associated with increased rates of diabetes and cardiovascular problems in the children and grandchildren. Environmental factors, such as nutritional abundance, that do not change the DNA sequence, can instead alter the epigenome causing increased risk for chronic diseases, including metabolic disorders and obesity. In humans, recent reports have shown that paternal obesity and aging can epigenetically reprogramme the gametes and that these epigenetic alterations might be subsequently transmitted to the children. For instance, weight loss after bariatric surgery was shown to remodel sperm DNA methylation patterns particularly in regions/genes that play a role in appetite control.
A recent study identified subtle methylation alterations correlating with donor’s BMI in male sperm at the paternally imprinted MEG3-IG DMR locus. A gender-specific correlation between the DNA methylation of MEG3-IG DMR, HIF3A, and IGF2 DMR0 in the cord blood of the offspring and paternal BMI was observed, indicating that obesity in males can influence DNA methylation programming in sperm and also directly affect the epigenome of the next generation. Epigenetic inheritance might partly help to explain the escalating incidence of obesity among men worldwide, which cannot be attributed to genetic factors alone.
The central role of obesity on male fertility/gonadal dysfunction is indicated by multiple studies of males who have undergone bariatric surgery. Male obesity-associated secondary hypogonadism (MOSH) is present in approximately 60% of men applying for bariatric surgical procedures. Significantly, the marked weight loss that occurs after bariatric surgery results in remission of the hormonal derangements present in MOSH in almost all patients. In fact, the correlation between the two conditions is such that MOSH has recently been proposed as an indication for bariatric surgery.
TESTOSTERONE AND INSULIN RESISTANCE
Many studies have linked hypogonadism with insulin levels, especially in men with prostate cancer receiving antiandrogen hormone therapy. These patients present an increase in visceral fat, which is related to an increase in insulin resistance, aggravated by a concomitant decrease in muscle mass. Increased abdominal fat causes higher concentrations of free fatty acids to be delivered to the liver. With more free fatty acids, there is a higher production of hepatic glucose and a decrease in insulin uptake.
This results in hyperinsulinaemia and increased insulin resistance in peripheral tissues, which also leads to further release of insulin by β-cells. Some studies have found higher prevalence of insulin resistance among patients with hypogonadism compared to those without it and negative correlations between insulin resistance and testosterone levels. The current evidence is therefore consistent with a bidirectional relationship between visceral fat and testosterone levels, creating a self-perpetuated cycle that promotes insulin resistance.
RISK OF PROSTATE CANCER
Recent studies suggest that obesity is consistently related to aggressive prostate cancer. The risk of prostate cancer is almost two times higher in the case of obese men and obese men have an almost six-fold higher risk of developing prostate cancer as compared to non-obese men. Obesity increases the odds that prostate cancer will spread beyond the gland, and it also makes relapse after treatment more likely. In addition, obesity boosts a man’s chance of developing urinary incontinence after a radical prostatectomy operation. It is hypothesised that the increased risk of prostate cancer among obese men is due to the alteration of sex hormones caused by obesity and increased production of growth factors that increase rates of cell multiplication.
Changes in lifestyle should be the first measure proposed in patients with obesity-associated hypogonadism. It should be kept in mind, however, that few randomised clinical trials have specifically assessed the impact of diet and physical activity on testosterone levels in obese men, and those available have obtained contradictory results. Some show an increase in testosterone, while others find no change or even a decrease. In a meta-analysis of these studies, it was found that the increase in testosterone induced by lifestyle interventions was modest. This likely reflects the relatively limited results of diet and physical activity on body weight loss generally observed in the scientific literature.
Testosterone therapy is effective in achieving sustained weight loss in obese hypogonadal men, irrespective of the severity of obesity, but the long-term cardiovascular adverse effects have to be balanced against these benefits. Furthermore, uncertainties about how long testosterone therapy might be needed remain unsolved. Relatively long periods of time are often required to observe their metabolic effects and the temporal course of these effects differs depending on the dose or formulation chosen, among other variables.
Another possible avenue of treatment is aimed at the increased aromatase activity in adipose tissue. The use of letrozole, an aromatase inhibitor, has been investigated in this regard and the results have generally indicated a significant decrease in estradiol levels as well as a significant increase in LH and total testosterone levels, with stable levels of SHBG over the course of a six-week treatment regime. However, it is important to note that aromatase inhibitors have been associated with increased osteoporosis risk, and should be used with caution in patients at high risk for bone fractures.
While bariatric surgery is exceptionally effective, it is mostly recommended for patients who can be classified as morbidly obese (BMIs above 40) and for whom no other avenues of treatment are likely to be effective. In addition to sustained weight loss, surgical treatment provides additional benefits to people with obesity-related comorbidities and reduces relative risk of death due to significant weight loss. Among major surgeries, bariatric procedures have some of the lowest mortality rates, although complication rates range from 10% to 17%, with reoperation rates approximately 7%. Finally, as with most surgical procedures, many patients may find the costs prohibitive.
Pharmacological therapy and the use of appetite suppressants, particularly phentermine, is recommended in many cases in which bariatric surgery is judged to be too extreme an intervention or lifestyle changes alone won’t be sufficient. Pharmacological therapy has been proposed as a necessary adjunct to lifestyle changes to improve weight loss in people with obesity and overweight individuals with metabolic complications. Phentermine, the most often-prescribed weight loss drug in the US, is thought to cause weight loss through a reduction in hunger, which it achieves by stimulating the release of norepinephrine in the hypothalamus.
In a 12-week randomised, double-blind, placebo-controlled clinical trial, 77 adults with obesity received either phentermine or placebo and were enrolled in a weight-loss programme. The phentermine group lost 12.1% of baseline body weight compared with 8.8% in the placebo group. Cravings for all food groups decreased in both groups; however, there was a greater reduction in cravings for fats and sweets in the phentermine group compared with the placebo group. The study authors concluded that both phentermine combined with a meal replacement program and meal replacements alone significantly reduced body weight and food cravings; however, the addition of phentermine enhanced these effects.