How a shrinking belly can help a growing family

Obesity and metabolic syndrome are strongly related to male hypogonadism.

Issue: June 2008

ByRonald Tamler, MD, PhD, MBA

A 38-year-old white man came to see me because he and his wife were thinking of having another child.

The patient had a history of hypogonadism and the couple had their first child four years ago with in vitro fertilization/intracytoplasmic sperm injection. The patient had had a normal puberty. He was not complaining of erectile dysfunction or premature ejaculation. He shaved daily. There were no changes to his voice and he had not had any fractures or loss of height. The patient stated that he had been heavy as a child, but was slim in his 20’s. He had gained 45 kg over the past eight years and was diagnosed with type 2 diabetes half a year before the visit.

After brief treatment with insulin, he was switched to his current regimen of metformin 1,000 mg by mouth twice a day and pioglitazone 15 mg by mouth daily. The patient experienced weight gain with pioglitazone. He initiated lifestyle changes by keeping a diet log and attempting to increase his exercise; however, the weight gain continued over three months. The patient stated that his last HbA1c was 5.5%. He was concerned about his continued weight gain and his low testosterone levels.

His other medical history consisted of type 2 diabetes as mentioned above, nonalcoholic fatty liver disease, which improved with treatment on the TZD, and hypertension.

Ronald Tamler

Medications included lisinopril 10 mg by mouth daily, aspirin 81 mg by mouth daily, metformin and pioglitazone as mentioned above. The patient was a physician. Review of systems was relevant for shortness of breath after climbing two flights of stairs.

Physical examination: obese white male in no acute distress. Height six foot one inch and weight 277 lbs; BMI of 36. Blood pressure 130/80 mmHg and heart rate 90. Notable skin tags and acanthosis. Heart: regular rate and rhythm with no murmurs, rubs or gallops. Lungs were clear to auscultation bilaterally. Genitourinary exam revealed normal-sized testicles of about 20 cc bilaterally. There was a small varicocele present. Waist circumference was 48 in. Labs: normal chem 12 and fasting lipids at goal for a patient with diabetes.

Total testosterone low at 193 ng/dL, on repeat blood draw total T 235, sex hormone-binding globulin 13, free T low-normal at 8 ng/dL, bioavailable T low-normal at 153 ng/dL. Luteinizing hormone 4, follicle-stimulating hormone 2.7 mIU/mL, estradiol 34 pg/mL. Semen analysis was remarkable for a low count of 0.5 mill/mL (normal: 20 mill/mL) and decreased sperm motility.

Which of the following is inappropriate for this patient?

Referral to see a bariatric surgery team to discuss weight loss surgery.

Prescribe sibutramine 10 mg daily, increase lisinopril to 20 mg daily and have the patient monitor his blood pressure for worsening hypertension.

Start transdermal testosterone 1%, 5 g daily.

Prescribe orlistat 60 mg with meals and a multiple vitamin injection and warn the patient of loose stools.

Discontinue pioglitazone and start exenatide 5 mcg twice a day with meals.

CASE DISCUSSION

This patient is fairly typical of what we see in the Mount Sinai Men’s Wellness Program. The patient is obese, has low testosterone and a low sperm count.

Obesity and metabolic syndrome are strongly related to male hypogonadism. Hypogonadism has high positive predictive value of future metabolic syndrome and type 2 diabetes. Conversely, metabolic syndrome, in this case type 2 diabetes, obesity and hypertension, are predictive of hypogonadism.

The pathophysiology in obese men is thought to be related to aromatization of testosterone to estradiol in the adipose tissue. This not only means that less testosterone is available due to the conversion, but it also implies increased suppression of luteinizing hormone by estradiol with subsequently decreased testosterone production. This state is therefore aptly named hyperestrogenic hypogonadotropic hypogonadism. Sex hormone-binding globulin is often suppressed due to increased insulin production in these insulin-resistant patients, thus yielding low-normal free and bioavailable testosterone levels.

Weight loss has not only been shown to decrease aromatization and increase testosterone levels but is also associated with improved fertility (see figure 1). Therefore, any method to decrease weight in this patient will also improve testosterone levels and fertility. It should be noted that a systematic attempt to induce lifestyle changes has failed in this patient.

Figure 1. Abdominal CT scan of bilateral macronodular adrenal hyperplasia. (A) Axial image. (B) Coronal Image. The red arrow indicates the bilateral macronodular adrenal hyperplasia with multiple large hypodense nodules. Green arrow: Kidney. L: Liver.

Source: Ronald Tamler

I therefore initially started him on exenatide. This GLP-1 analogue can be used effectively for glycemic control in patients with diabetes and can lead to significant weight loss in some. However, the patient discontinued the medication after two months, because he was still gaining weight.

There are currently two pharmaceutical agents that are FDA approved for long-term (up to two years) treatment of obesity: orlistat and sibutramine.

I first initiated orlistat, which inhibits pancreatic lipase; this decreases breakdown into absorbable fatty acids in the intestine. Adverse effects include “anal leakage,” and one has to make sure that the patient is getting enough fat-soluble vitamins. The patient was very concerned about the gastrointestinal adverse effects and in fact (this is a real case, you can’t make this thing up) got so excited after taking the first dose that he had constipation for three days. He then returned to my office and felt he would not do well on this medication.

Bariatric surgery is a valid option in obese patients with a BMI >40 or a BMI >35 with obesity-related comorbidities, such as type 2 diabetes. Only 10% to 20% of patients undergoing bariatric surgery are male, and the research on hypogonadism and fertility in these patients is therefore limited. However, the data so far show that testosterone levels and semen analyses improve significantly with weight loss after surgery.

In this particular case, however, I started sibutramine 10 mg daily. Sibutramine is a centrally acting agent that decreases appetite. It should not be used in conjunction with antidepressants. The most notable adverse effect is hypertension. Since the patient’s blood pressure was borderline on lisinopril, I increased the dose of his antihypertensive to 20 mg and asked him to monitor his blood pressure at home. Over the next four months, the patient lost 15 lbs, and when I last saw him, he weighed 243 lbs, which yielded a BMI of 32. Total testosterone was up to 732 (bioavailable T at 545), along with a normal semen analysis. The couple had delayed the second child for personal reasons, but the patient has done so well with his weight loss that he was able to discontinue pioglitazone and keep his HbA1c at 5.5% just with metformin 500 mg by mouth twice a day.

Testosterone supplementation (option C) can indeed lead to increased lean body mass and possibly decreased fat mass, but it would decrease semen production even further. It is therefore the wrong choice in this particular patient.

Ronald Tamler, MD, PhD, MBA, is an Assistant Professor in the Division of Endocrinology at Mount Sinai School of Medicine, N.Y.