Hypogonadism and Metabolic Syndrome

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Fat produces inflammatory cytokines that lead to impaired testosterone synthesis.
Fat produces inflammatory cytokines that lead to impaired testosterone synthesis.

WASHINGTON, D.C.—Hypogonadism is related to variety of chronic illnesses and conditions, including erectile dysfunction (ED) and metabolic syndrome, and fat may have a crucial role in a process leading to low testosterone levels, a researcher said here.

“Fat is an endocrine organ. It secretes things, it's not something that just sits on someone's hips and doesn't go away. It is metabolically active,” observed Adrian S. Dobs, MD, MHS, Professor of Medicine and Oncology in the Division of Endocrinology and Metabolism at Johns Hopkins University School of Medicine in Baltimore.

Fat produces various proinflammatory factors and hormones, such as cytokines, that inhibit testosterone synthesis in the testes directly by blocking the action of enzymes in the testosterone production pathway, said Dr. Dobs, who participated in a symposium on hypogonadism held in conjunction with the American Urological Association 2011 annual meeting.

Many diseases are associated with increased inflammation, she said. Elevations in inflammatory cytokines will have a direct blunting effect on the hypothalamus and pituitary gland, Dr. Dobs explained. Elevated levels of inflammatory cytokines inhibit release of gonadotropic-releasing hormone from the hypothalamus. This, in turn, results in decreased levels of follicle-stimulating hormone and luteinizing hormone from the pituitary gland, which leads to decreased testosterone production.

Dr. Dobs' presentation focused on the association between hypogonadism and metabolic syndrome, which is a constellation of medical disorders—including obesity, hypertension, dyslipidemia, hyperglycemia, and insulin resistance—that increase the risk of cardiovascular disease and type 2 diabetes. These disorders frequently are observed in the presence of hypogonadism, she said.  Hypogonadism is present is 52% of obese men and 50% and 42% of men with diabetes and hypertension, respectively, Dr. Dobs noted. It is present in only 19% of men of ED.

Low testosterone plays a central role in the pathology of metabolic syndrome, insulin resistance, and type 2 diabetes, she said. Dr. Dobs explained that men with low testosterone will have decreased muscle mass and increased fat mass. This increased fat leads to visceral obesity, which is associated with insulin resistance. In addition, with more fat, there is increased aromatization of testosterone and an increase in estradiol levels.

Study data show that higher testosterone levels are associated with improved insulin sensitivity and that testosterone replacement therapy (TRT) improves glycemic control in hypogonadal men. In a double-blind, placebo-controlled study involving 24 diabetic hypogonadal men (Eur J Endocrinol. 2006:154:899-906), researchers demonstrated that testosterone therapy for three months significant decreased the homeostatic model assessment (HOMA) index (indicating improved fasting insulin sensitivity) and significantly decreased hemoglobin A1c levels compared with placebo. In addition, the investigators reported that testosterone-treated men had a significant reduction in visceral adiposity as assessed by waist circumference and waist/hip ratio, and a reduction in total cholesterol.

In another study (TIMES2), investigators showed that over a six-month period TRT using a transdermal 2% testosterone gel improved insulin resistance, total and LDL-cholesterol, and sexual health in hypogonadal men with type 2 diabetes and/or metabolic syndrome (Diabetes Care. 2011;34:828-837).

The chair of the symposium, Allen D. Seftel, MD, Professor of Urology at the Robert Wood Johnson School of Medicine in Camden, N.J., advised attendees on the use of TRT in hypogonadal patients. Patients placed on TRT must remain on it long-term to benefit from its positive effects, as demonstrated in a study by O'Connell et al (J Clin Endocrinol Metab. 2011;96:454-458).

In a single-center, double-blind, placebo-controlled study, the investigators enrolled 274 intermediate-frail and frail men aged 65-90 years with low testosterone levels to examine the effects of six months of TRT (25-75 mg daily) on muscle strength, body composition, physical function, and quality of life. Six months of TRT improved muscle mass, physical function, and quality of life and increased lean body mass and decreased fat mass compared with placebo. These improvements were not maintained at six months post-treatment, however.

In accordance with Endocrine Society guidelines, he said, TRT should be used only in men who show symptoms of low testosterone. Clinicians should be cautious about prescribing TRT to men with prostate cancer, he noted.

In general, for patients who are identified as hypogonadal and are candidates for testosterone treatment, TRT should be given for at least six months to achieve therapeutic testosterone levels (500-700 ng/dL), Dr. Seftel said. Patients need to be monitored closely during treatment, typically baseline, at three and six months, and then annually thereafter, according to Dr. Seftel, who is head of the Division of Urology at Cooper University Hospital in Camden, N.J. Initial patient assessments should include a digital rectal examination and measurement of PSA and hematocrit levels.

When discussing TRT with patients, clinicians should emphasize the importance of adhering to treatment. Adherence to therapy improves if patients are involved in therapy selection, understand the importance of treatment, and perceive that the treatment regimen is convenient, Dr. Seftel said. Thus, patients need to be involved in treatment choice, with discussions that include convenience of administration, convenience of the regimen, safety profile, minimal adverse effects, and cost, he said.

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