Treating Amenorrhea with Recombinant Leptin

Leptin was originally identified as an anti-obesity hormone, but it is increasingly being seen as a hormonal mediator of the adaptation to energy deprivation. Studies in experimentally starved mice and lean humans suggest that low leptin levels are probably responsible for changes in reproductive, thyroid, and growth hormone axes.

Hypothalamic amenorrhea

Hypothalamic amenorrhea is characterized by the absence of menstrual cycles, low estrogen levels, and low or low-normal levels of gonadotropins. It causes more than 30% of cases of amenorrhea in women of reproductive age, and can lead to infertility and bone loss. Functional hypothalamic amenorrhea is the result of a relative energy deficit, from weight loss, excessive exercise, or an eating disorder. It can disrupt secretion of hypothalamic gonadotropin-releasing hormone (GnRh).

Administration of recombinant leptin, a hormone secreted by adipocytes that regulates energy balance and circulates in the bloodstream at levels corresponding to fat mass and acute nutritional changes, may improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea, according to Corrine K. Welt, MD, and her colleagues at Harvard Medical School (N Engl J Med 2004; 351:987).

The researchers studied 8 women with hypothalamic amenorrhea caused by strenuous exercise or low weight for one month before they were given recombinant human leptin and then while the women were treated for up to 3 months. They were studied from 2002 to 2003, and none had active eating disorders. Six control subjects with hypothalamic amenorrhea received no treatment and were studied for a mean of 8.5 months. Women in the active treatment group received r-met-HuLeptin, an investigative form of recombinant human leptin.

Leptin levels rose in treated subjects

In the control subjects, leptin levels increased slightly between the initial and follow-up studies, but weight did not change significantly. In contrast, among treated subjects, leptin levels stayed stable during the one-month observation period at the beginning of the study and increased appropriately with r-met-HuLeptin treatment. Mean body weight decreased slightly among the women treated with leptin, primarily during the third month of treatment, when higher doses of leptin were given, probably due to a small but significant decrease in body fat with no change in lean body mass (measured with x-ray absorptiometry). Two treated subjects completed the study at two months after meeting the primary end-point of ovulation, and 5 subjects continued to month 3. One withdrew after a month, for reasons not related to treatment.

Reproductive function returned rapidly

Three of the 8 treated subjects had an ovulatory menstrual cycle, and ovulation occurred 28, 35, and 58 days after the start of treatment in subjects who had had hypothalamic amenorrhea for 14 years, 6 years, and 9 months, respectively. The authors found that treatment with leptin improved reproductive function after only a few months, even though 7 of the women had had amenorrhea for several years. The time of recovery was much shorter than that expected with the use of lifestyle modifications.

A role in puberty?

The authors also theorized that r-met-HuLeptin treatment appears to repeat a pubertal pattern, and this suggests that leptin may have a role in the initiation of puberty. The estrogen and IGF-1 deficiency and possibly the hyper-cortisolemia associated with hypothalamic amenorrhea contribute to bone loss, which increases the risk of stress fractures and osteoporosis. In this short-term study, r-met-HuLeptin increased markers of bone formation but not markers of bone resorption.