Male Infertility
Figure 2: Various Treatment Modalities Can Be Explored to Treat Obesity-linked Male Infertility
Treatment modalities to mutations in the leptin gene or leptin receptor gene.53 Recently, it
was also shown that the absence of the histone demethylase JHDM2A gene (essential for spermatogenesis and critical for sperm nuclear condensation) gives rise to male obesity and infertility.54
Lifestyle changes:
• Diet
• Exercise • Behavioural therapy
Pharmacological interventions:
• Appetite suppressants
• Weight-loss drugs • Aromatase inhibitors
ART = assisted reproductive technologies.
hormone (LH). Subsequently, testicular function and testosterone production are reduced. As a result, the reproductive hormonal profiles of these men differ from normal as they present with hypogonadotrophic hyper-oestrogenic hypoandrogenaemia and even hypogonadotrophic hypogonadism.6,39,40
Interestingly enough,
inhibin B (secreted by Sertoli cells and a marker of their function and spermatogenic activity) secretion is decreased in obese men41 without the accompanying increase in FSH levels.42
These hormone changes yet again confirm the dysregulation of the HPG axis. •
Adipokines (e.g. interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are also secreted in higher concentrations in the presence of increased white adipose tissue. This can lead to inflammation with resulting production and release of reactive oxygen species (ROS). These free radicals are highly reactive, can lead to oxidative stress, and are known to have toxic effects on spermatozoa.43–45
Obese men also may experience some physical changes that can act as mechanisms for infertility. These include sleep apnoea, which disrupts the nocturnal rise in testosterone and thus affects the HPG axis.46,47
Surgical options:
• ART
• Scrotal lipectomy • Bariatric surgery
Obesity Management – Is There Hope? Apart from genetic mutations and predispositions to obesity, it is believed that, in the general population, obesity is a preventable and/or reversible condition. Due to the fact that psychosocial influences also play a role in the manifestation of obesity, prevention is not necessarily the only treatment option, but alternative treatment modalities must be employed and explored to relieve obese patients from the burden of this pathology and its co-morbidities, including infertility.
When a urologist or fertility expert is faced with the obese patient, several approaches can be followed to induce weight loss and/or treat the specific resultant problems related to obesity (see Figure 2). Weight loss can be achieved via lifestyle changes, pharmacological treatments or surgical interventions, and it is advised that the specific order from least to most invasive should be followed. Lifestyle changes include dietary modifications such as choosing healthy foods and eating smaller portions, as well as exercising more. The goal is initially to lose weight and ultimately to attain a normal energy balance and metabolism. Reducing weight via lifestyle changes has been shown to normalise androgen, sex-hormone-binding globulin, leptin and insulin levels and reduce inflammatory cytokine levels to a point where semen parameters improve in obese men.13,55–60
Pharmacological interventions are the next step in the treatment of weight loss in the obese. There are only a few prescription medications currently approved by the US Food and Drug Administration (FDA) for weight loss: Xenical, which reduces intestinal fat absorption (Alli is a reduced-strength version that is sold over the counter [OTC]) and Phentermine, which acts as an appetite suppressant are two, while another appetite suppressant, Meridia, is currently under review by the FDA. However, these medications are not effective at inducing substantial long-term weight loss.61
Scrotal lipomatosis (increased scrotal fat) and a sedentary lifestyle can lead to increased scrotal temperature and genital heat stress, which are associated with impaired spermatogenesis.48 Another physical factor is ED. Obesity may lead to ED by increasing the number of pro-inflammatory cytokines circulating in the bloodstream, which in turn causes endothelial dysfunction and release of nitric oxide, which is responsible for vasodilation. Dysregulation of the HPG axis and decreased testosterone can also have an effect on ED.28,49,50
As initially stated, the human genotype can predispose people to obesity, which in turn can cause infertility. It is therefore not unrealistic to believe that a genetic link(s) may exist between these two pathologies.9
The final resort is bariatric surgery. With this type of surgery, the stomach size is reduced, either with a medical device (e.g. gastric banding) or by removing a portion of the stomach (e.g. sleeve gastrectomy) or portions of the stomach or small intestine are bypassed (i.e. gastric bypass surgery), which decreases the amount of nutrients that can be absorbed. Treatment of this nature is only advisable and justifiable in severely obese patients (BMI >40kg/m2) and only after all other treatments have failed.62
loss, bariatric surgery is extremely effective, but very few studies have looked at whether it restores male fertility. In one study, hormone and adipokine levels returned to normal levels,63
Currently, the only evidence of such a link exists in conditions characterised by rare and severe genetic mutations (e.g. Prader Willi). However, other, less severe genetic mutations might exist that can shed light on chromosomal abnormalities that are typified by both obesity and infertility.51
Alstrom syndrome, for
example, is a condition where a mutation in the ALMS1 gene is responsible for childhood-onset obesity as well as infertility.52
and delayed puberty, as well as hypogonadism, have also been characterised in humans with leptin deficiency or leptin resistance due
62 Obesity
With regard to weight whereas a
It is evident that bariatric surgery as a treatment of obesity-induced infertility is still very much experimental and further research needs to be performed.
second concluded that the procedure actually induced secondary infertility.64
Pharmacological treatment options can also be applied to address certain specific problems and underlying mechanisms of obesity-induced male infertility. Aromatase inhibitors have been prescribed with great success to those with elevated oestrogen levels, thereby effectively restoring testosterone and
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