Amenorrhea

LISBON -- Recombinant human leptin appears to normalize many of the hormonal defects associated with hypothalamic amenorrhea, Dr. Christos S. Mantzoros reported at the 12th International Congress of Endocrinology.

The results of this landmark "proof of concept" study of eight women with hypothalamic amenorrhea and six controls suggest that leptin--a hormone secreted by adipocytes that regulates energy homeostasis--might represent a potential novel treatment for a range of neuroendocrine disorders, such as anorexia nervosa, infertility, and exercise-induced bone loss, said Dr. Mantzoros, director of the Human Nutrition Research Unit at Beth Israel Deaconess Medical Center, Boston.

If replicated by a placebo-controlled interventional study now underway in 80 subjects, the use of human recombinant leptin may prove preferable to current infertility treatment using pulsatile gonadotropin-releasing hormone therapy. Leptin is less expensive and better tolerated. It also improves bone density, which gonadotropin-releasing hormone does not.

"We are not at the stage of recommending treatment at this point, but I think that leptin could offer several therapeutic advantages," said Dr. Mantzoros, who is also with Harvard University.

In an open-label, prospective study that was funded by both the National Institutes of Health and Amgen, recombinant methionyl human leptin (r-metHuLeptin) was self-administered subcutaneously by eight otherwise healthy women aged 19-33 years who had secondary amenorrhea for a mean of 5.1 years due to increased exercise or low weight. None had eating disorders. The findings were published during the endocrinology congress (N. Engl. J. Med. 351[10]:987-97, 2004).

The recombinant leptin dosage was 0.08 mg/kg daily, with 40% of the total dose given at 8:00 a.m. and 60% given at 8:00 p.m. to mimic normal diurnal variation. If the patient ovulated, the study was concluded at 2 months. If not, the dose was increased to 0.2 mg/kg daily and continued for another month. Six similar women received no treatment.

During a 1-month observation period before treatment, there were no changes in treated subjects or controls in luteinizing hormone, pulsatility, body weight, ovarian variables, or hormone levels. In contrast, mean LH levels and LH pulse frequency increased in the treated subjects after 2 weeks, while maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels increased over 3 months.

Three patients experienced an ovulatory menstrual cycle, and two others had preovulatory follicular development and withdrawal bleeding during treatment, Dr. Mantzoros reported.

Among other changes in the leptin-treated subjects but not the controls were increases in free triiodothyronine, free thyroxine, and insulin-like growth factor-I. Markers of bone formation (bone alkaline phosphatase and osteocalcin) increased during leptin treatment, while urinary N-telopeptides, a marker of bone resorption, did not.

Total bone density did not change during this short study, he noted.

Body weight decreased slightly in the treated subjects, due mostly to a decrease in body fat. There were no significant changes in cortisol or corticotropin levels during treatment, similar to previous findings. Subjects reported decreased appetite during the third month, but otherwise reported no adverse effects.

In an accompanying editorial, Dr. Rexford S. Ahima said that the decrease in leptin levels during fasting--which mediates the suppression of reproductive, growth, and thyroid hormones, increases glucocorticoids, and stimulates food intake--may have evolved as a defense against starvation, which hypothalamic amenorrhea closely resembles.

According to Dr. Ahima of the University of Pennsylvania, Philadelphia. "Patients with hypothalamic amenorrhea, a disease that was first described in the 1940s and was poorly understood for decades, may finally benefit from a rebirth of investigation leading to rational therapy."

BY MIRIAM E. TUCKER

Senior Writer

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