Obesity and Male Infertility

A Practical Approach

Ahmad O. Hammoud, M.D., M.P.H.; A. Wayne Meikle, M.D.; Leonardo Oliveira Reis, M.D., MSc, Ph.D.; Mark Gibson, M.D.; C. Matthew Peterson, M.D.; Douglas T. Carrell, Ph.D.

Disclosures

Semin Reprod Med. 2012;30(6):486-495. 

In This Article

A Practical Approach

Evaluation of the Obese Man in an Infertility Clinic

The evaluation of the infertile obese man includes a basic evaluation of male infertility with an special focus on potential obesity-related risk factors ( Table 1 ). The history should ensure that other etiologies for male infertility are not overlooked. Relevant history includes prior fertility, childhood illnesses such as viral orchitis or cryptorchidism, genital trauma or prior pelvic or inguinal surgery, infections such as epididymitis or urethritis, gonadotoxin exposures such as prior radiation therapy/chemotherapy, recent fever or heat exposure, current medications, family history of birth defects, mental retardation, reproductive failure or cystic fibrosis, prior medical problems (in particular severe liver disease), history of smoking, use of alcohol, illegal drug use, and anabolic steroids.

The clinician should look for symptoms of hypogonadism including sexual dysfunction such as reduced libido, ED, diminished penile sensation, difficulty in attaining orgasm as well as reduced ejaculate with orgasm, reduced energy, depressed mood or diminished sense of well-being, increased irritability, difficulty concentrating, and other cognitive problems.[75]

An important part of the evaluation is the assessment of comorbidities such as cardiovascular diseases including coronary artery disease and stroke, sleep apnea, and diabetes. Such comorbidities may aggravate infertility or affect treatment options. The patient's history can suggest the presence of ED. The severity of the ED can be assessed using the five-item version of the International Index of Erectile Function questionnaire.[76]

Physical examination should note the blood pressure, weight, and height for BMI calculation. The examination should also assess the stage of virilization (Tanner stages of pubic hair) and volume (using a Prader Orchidometer) and consistency of testis, consistency of the epididymis, presence of a varicocele, and signs of hypogonadism that include anemia, muscle wasting, absence or regression of secondary sex characteristics including body habitus, hair distribution, and gynecomastia. Of note, the prevalence of varicocele is thought to be lower in obese men. This was attributed in part to a more difficult diagnosis because of the adipose tissue.[77,78]

A hormonal profile consisting of serum estradiol, total and free testosterone, FSH, LH, prolactin, thyroid-stimulating hormone, and SHBG should be obtained. In the absence of adequate techniques to measure free testosterone, free testosterone calculation based on measures of total testosterone and SHBG remains an adequate assessment of the free testosterone levels.[79] This evaluation should also include screening for diabetes (fasting glucose, glycosylated hemoglobin or 2-hour 75-g oral glucose tolerance test) and lipid abnormalities (lipid panel) in men with severe obesity and signs of metabolic syndrome. Furthermore, all obese infertile men would benefit from screening for sleep apnea.

The semen analysis is the cornerstone of the laboratory evaluation of infertile men. At least two properly performed semen analyses after 2 to 7 days of abstinence are necessary to confirm the diagnosis. A semen analysis not only evaluates the number and quality of the sperm ejaculated but the function of the accessory glands as well. Semen analysis includes testing of semen volume, sperm concentration, sperm motility, and sperm morphology.

These composite parameters thought to correlate with fertility can be calculated:

–Total sperm count per ejaculate = semen volume × sperm concentration

–Total motile sperm count = semen volume × sperm concentration × percentage motile sperm

–Total progressive motile sperm count = semen volume × sperm concentration × percentage progressive motile sperm

Although debatable, DNA fragmentation can be evaluated in the presence of unexplained infertility or otherwise unexplained poor embryo quality in IVF.

Therapeutic Suggestions

There is a paucity of studies specifically targeting the outcomes of treatment of infertility in obese men. The therapeutic interventions discussed in the following section are designed to reverse the previously discussed abnormalities associated with obesity. The assignment of cause for poor semen parameters is often difficult. It is reasonable, however, to manage infertile obese men with poor semen parameters and without the causes enumerated here as though their obesity is responsible.

Lifestyle Modifications and Weight Loss Interventions The effect of lifestyle modification and weight loss on the short- and long-term fertility of the obese man is currently not known. A few studies, however, have reported the effect of weight loss programs or bariatric surgery on intermediate outcomes of male fertility such as the hormonal profile, sperm parameters, and sexual function. Obese men showed increases in sex hormone binding globulin and testosterone (free and total) after a very low-energy diet.[80,81] Other studies showed that weight loss through bariatric surgery was associated with correction of the abnormal hormonal profile in obese men with an increase in SHBG and total testosterone levels and reduction in estradiol levels.[29,82,83] In this context, the effect of weight loss on inhibin B levels as surrogate for spermatogenesis is of particular interest. Globerman et al studied inhibin B levels following silastic ring gastroplasty. Of 13 obese men, the 4 men with the largest decrease in BMI showed an increase in inhibin levels. However, mean inhibin B levels before and after gastroplasty were not statistically significant.[83]

In a recent article, Håkonsen et al described the effect of a weight loss program of 14 weeks on the hormonal profile and semen parameters of obese men (BMI: 33 to 61 kg/m2). The median weight loss was 22 kg. After subanalyses of <10 patients presenting the largest weight loss (among 43 men, a third with low baseline sperm concentrations; median/range weight loss: 15%; 3.5 to 25.4), an increase in total sperm count (p = 0.02), semen volume (p = 0.04), testosterone (p = 0.02), SHBG (p = 0.03), and anti-Müllerian hormone (p = 0.02) were found.[25] However, it is likely that, apart from due to chance, the differences in the semen parameters were secondary to the increase in semen volume, related to emission and accessory glands, because sperm concentration had not changed (p = 0.33).[25]

It is worth mentioning reports associating bariatric surgery with male infertility. In a case report, di Frega et al described six severely obese men with at least one previous child who presented with azoospermia after Roux-en-Y gastric bypass operation.[84] Sermondade et al described three male patients who underwent bariatric surgery and subsequently developed oligo-astheno-teratozoospermia. In one case, the alterations of spermatogenesis were reversible 2 years after the surgical procedure. This finding led the authors to suggest preserving sperm before bariatric surgery in men to preserve fertility.[85]

Confronting these alarming reports of nine anecdotal cases, a prospective randomized study presented by Reis et al showed that semen parameters did not change in 20 morbid obese Brazilian men (mean age: 39.3 years ± 11.3; mean weight and BMI: 168.6 ± 28.2 and 55.7 ± 7.8, respectively) followed for 24 months in an intensive weight loss program, of whom 10 underwent bariatric surgery presenting a mean BMI reduction of 24.7 kg/m2. No patient presented semen characteristics below World Health Organization (2010) reference level after bariatric surgery.[86] Although lifestyle modifications impacted merely BMI (mean: 12.6 reduction), bariatric surgery reversed baseline ED and hormonal imbalance, in line with our study that showed an improvement in overall scores of sexual satisfaction after weight loss through Roux-en-Y gastric bypass surgery.[29] In another randomized study, obese men who received detailed advice about how to achieve a loss of ≥10% in their total body weight by reducing caloric intake and increasing their level of physical activity had a higher rate of weight loss and improvement in ED than controls.[87]

In the presence of sleep apnea, patients that lose weight and improve sleep apnea can also increase their testosterone levels.[88] Grunstein et al showed that 3 months of nasal continuous positive airway pressure (CPAP) resulted in an increase in SHBG and total testosterone but not free testosterone.[89] Luboshitzky et al found similar changes 9 months after CPAP.[90] Santamaria et al showed that uvulopalatopharyngoplasty in men with sleep apnea can improve testosterone levels without significant changes in BMI.[91]

In contrast, Bratel et al did not find a difference in testosterone levels after 7 months of nasal CPAP.[92] Meston et al conducted a randomized trial comparing therapeutic nasal CPAP or placebo and showed no improvement in testosterone levels after 4 weeks of follow-up.[93] The lack of benefit in this trial could be attributed to the short follow-up.

Medical TherapyAromatase Inhibitors The finding of increased estradiol and reduced testosterone-to-estradiol ratio in obese men suggests that aromatase inhibitors may be a potential therapy for infertility in this group. The role of aromatase inhibitors in the treatment of idiopathic male infertility remains debatable. In the context of obese men, aromatase inhibitors were found to improve hypogonadism. Treatment with aromatase inhibitors, such as testolactone 1 g daily for 6 weeks,[94] letrozole 2.5 mg daily or 2.5 mg every other day for 6 weeks,[40,95] and Arimidex 1 mg for 6 months,[96] resulted in an increased LH and total testosterone and reduced estradiol levels in obese men.

These studies included a small number of participants (<10) with severe obesity (average BMI ≥40 kg/m2) and did not evaluate fertility, except the study by Roth et al that was a case report of a 29-year-old man with infertility who was able to father a child 6 months after anastrozole therapy.[96]

Two studies investigating the effect of this class of medication on infertile men with reduced testosterone-to-estrogen ratio are worth mentioning because of the similarity of hormonal profile to that found in obese men.

Pavlovich et al treated 45 men (11 obese) with severe male factor infertility and reduced testosterone-to-estradiol values with testolactone 50 to 100 mg twice daily for 5 months (range: 1 to 24). After treatment, there was improvement in the hormonal profile with increased serum testosterone and testosterone-to-estradiol ratio. Semen parameters were tested in a subgroup of 12 oligospermic and 12 azoospermic men before and after testolactone treatment. Sperm concentration, motility, and total sperm count improved in the oligospermic but not in the azoospermic men with a low testosterone-to-estradiol ratio.[97]

Raman and Shlegel evaluated the effect of anastrozole 1 mg on the hormonal and semen profiles of infertile men with decreased baseline testosterone-to-estradiol ratio (testosterone (ng/dL)/estradiol (pg/mL) <10). After an average of 4.7 months of therapy, there was improvement in the serum testosterone and a reduction in the serum estradiol, resulting in an increase in the testosterone-to-estradiol ratio; these results were also confirmed in the subgroup of obese men (defined as BMI >35 kg/m2). A total of 25 oligospermic and 14 azoospermic men had their semen tested before and after at least 3 months of therapy. In the oligospermic men, there was an increase in semen volume, sperm concentration, and motility index after treatment in correlation to a decrease in estradiol concentration and an increase in the testosterone-to-estradiol ratio. There was no change in the azoospermic men.[98] Unfortunately the analysis of semen data was not reported in the obese subgroup, likely because of the small number.

Gonadotropin Therapy In obese men, hypogonadism can be independent of increased estradiol. When this picture occurs in the presence of low or normal levels of gonadotropins, such central hypogonadism is expected to be responsive to gonadotropin stimulation. The efficacy of FSH in the treatment of idiopathic male infertility, and FSH-human chorionic gonadotropin (hCG) treatment for idiopathic hypothalamic hypogonadism is suggested by multiple studies.[99] Little is known about the efficacy of hCG or FSH/hCG in the treatment of the secondary hypogonadotropic hypogonadism related to obesity.

Phosphodiesterase Inhibitors and Androgen Therapy Phosphodiesterase (PDE) inhibitors are considered the first-line medical treatment of ED after lifestyle modification.[76] The major contraindications are concomitant treatment with nitrates or nitric oxide-donating drugs (including amyl nitrite poppers), patients in whom sexual activity is inadvisable (those with unstable angina, severe heart failure, recent infarction), and patients who are allergic or intolerant to the drug. For patients with ED, sildenafil was the first oral PDE inhibitor to become commercially available. Tadalafil and vardenafil are two newer oral agents used for ED. PDE inhibitors do not improve libido.[76]

In hypogonadal men who have low testosterone levels, androgen therapy is typically indicated to treat sexual dysfunction resistant to PDE inhibitors, particularly the decreased libido.[76,100] However, testosterone treatment in infertile men can have a deleterious effect on spermatogenesis and fertility. Testosterone can block gonadotropin secretion through a negative feedback at the hypothalamic-pituitary level. The resulting decrease in gonadotropins results in decreased testicular production of testosterone and presumed lower intratesticular testosterone levels. In fact, androgens are often used in male contraception.

Although the negative impact of androgen therapy on fertility is well known, due to the relative short period since the launching of oral PDE5 inhibitors, more investigations should be performed on a wider scale.

Metformin With the finding of an independent contribution of insulin resistance to hypogonadism, studies explored the effect of metformin on the hormonal profile and semen parameters of obese men.[101,102]

Ozata et al studied the effect of a low-calorie diet (1200 to 1400 Kcal/day) and metformin (850 mg twice daily) for 3 months on the hormonal profile of obese men with and without type 2 diabetes. After intervention, there was a reduction in total and free testosterone in obese men when compared with diabetic men who had a reduction in their total but not their free testosterone. In obese men without diabetes, the reduction in free testosterone can be explained by the increase in sex hormone-binding protein.[101]

In a more recent article, Casulari showed improvement in free and total testosterone in men with metabolic syndrome who were normogonadal or hypogonadal after 4 months of therapy with metformin 850 mg twice daily.[102]

Both studies described previously did not report on semen parameters. Morgante et al described the effect of metformin (850 mg three times daily for 6 months) in 45 overweight and obese men with metabolic syndrome. There was a significant improvement in total and free testosterone, a decrease in estradiol, and an increase in sperm concentration, motility, and normal morphology after treatment, despite an absence of change in BMI and waist circumference.[103] More research focusing on the impact of metformin on male fertility is needed. These studies highlight the role of insulin in the pathophysiology of disordered reproductive function in obese men and suggest important new avenues for treatment.

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