Treating Hypothalamic Amenorrhea with Leptin

Hypothalamic amenorrhea (HA) is a one of the main causes of functional reproductive disorder in females. The condition involves the cessation of menstrual cycles in pre-menopausal women in the absence of any specific organic failures (no ovarian cancer, pituitary tumors, etc.). HA can be caused by many environmental factors, but the three leaders are: stress, strenuous exercise, and chronically reduced food intake (individuals with anorexia nervosa often have HA). To a certain extent, these environmental triggers do have some utility – it’s probably not a great bargain to devote energy to maintaining the reproductive system when times are tough and food is apparently scarce. That is, at least, the usual evolutionary view of things.

Lately I’ve been looking at HA and how its development and course may be altered by psychological stress, but I’ve already written about that in a term paper, so instead I’m going to write a bit about HA and energy deficiency. As suggested, the menstrual cycle often stops in the face of severe energy deficit, or as a result of strenuous exercise. Not surprisingly, the condition is seen from time to time in female athletes. Many, but not all cases of HA have hypoestrogenemia as a symptom. Estrogen is produced by the ovaries in a cyclic manner under stimulation by gonadotropic hormones arising from the pituitary gland. When this stimulation ceases, estrogen production drops off. This is an undesirable state of affairs for a number of reasons, among them osteopenia and osteoporosis, not to mention the inability to conceive.

So if HA is caused by nutritional deficit, we might guess that some of the hormonal signals that the body uses to communicate energy balance might also be used by the reproductive system for the same reason. It turns out that this is a very good guess. In the paper I am covering today, the authors took women suffering from HA and assigned them to receive either recombinant leptin or a placebo. After the treatment period elapsed, 7 out of 10 women had seen their menstruation return, compared to just 2 out of 9 for the placebo group. There was also an increase is estrogen and progesterone among leptin treated women. There was not, on the other hand, any chance in bone mineral density did not improve significantly over the treatment period, though perhaps the 36 week observation period was not long enough to detect these differences.

This treatment offers an interesting proof of concept for the use of metabolic hormones in the treatment of female reproductive dysfunction. Leptin treatment is not the perfect therapy. To begin with, it has to be injected (peptide hormones like leptin and insulin are destroyed by digestion, precluding oral administration). It also carries the risk of causing weight loss and loss of fat mass. It also doesn’t seem to help bone restoration, which is a notoriously tricky thing for any treatment to do (it’s enough, perhaps, to simply halt decay). Under normal conditions, leptin is interpreted by the brain as a signal of adequate fat stores, leading to a decrease in food intake. Applying exogenous leptin may also trigger these mechanisms, leading to unnecessary and potentially unhealthy weight loss (remember, women with HA are often underweight to begin with). Likely the optimal treatment for HA will comprise psychological interventions to deal with the stress related problems and maladaptive coping that may give rise to HA. Similarly, replacement of estrogen with oral contraceptives may also form a useful adjunct. But these more complicated therapies would likely require more sensitive and larger-scale study, and papers like this are a necessary prerequisite.

Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, & Mantzoros CS (2011). Leptin is an effective treatment for hypothalamic amenorrhea. Proceedings of the National Academy of Sciences of the United States of America, 108 (16), 6585-90 PMID: 21464293