Thursday, September 02, 2004

The Toe Bone is Connected to the Head Bone

It always interests me to learn of some new medical finding that challenges the way we think about human physiology. Yesterday, there was a report in Medscape News about the role of leptin in the regulation of hypothalamic neurohormones. This advances our understanding of basic physiology, and reveals a treatment strategy for some forms of infertility. It also helps explain the infertility often seen in female patients with Anorexia Nervosa. I suspect the same holds true for men with Anorexia, but this was not studied specifically.

In any introductory physiology course, it is taught that there are nine types of endocrine glands in each person:

endocrine glands
Illustration from AMA website

This may lead one to conclude erroneously that the sources of hormones in the body are discrete, well-localized, and understood. That is not the case; it is an oversimplification. Another oversimplified view would be to say that all parts of the body are in constant communication with all other parts. The truth is somewhere in the middle, but the latter view is closer to the truth. This communication often takes place via the release of hormones, although there are many different kinds of chemical messengers.

Today's article illustrates that not all hormones are produced or released in endocrine glands. Leptin, for example, is produced in fat cells. It is released into the bloodstream, where it circulates and interacts with a variety of tissues, signaling them to alter their function in some way. The Medscape article reports on a study that shows how leptin interacts with the hypothalamus, thereby influencing the release of hormones from the anterior pituitary gland. This, in turns, affects reproductive function.

It has been known for a long time that a very low body fat percentage can impair fertility. Indeed, athletic women, and women with Anorexia, often have great difficulty getting pregnant -- although such women are well-advised not to rely on this as a means of contraception. One theory to account for this finding has been to implicate leptin as a factor in hypothalamic function. The study reported in Medscape (free registration required) is a test of that hypothesis:

Leptin Improves Reproductive, Neuroendocrine Function in Hypothalamic Amenorrhea
Yael Waknine
Medscape Medical News 2004. © 2004 Medscape

Sept. 1, 2004 — Leptin replacement therapy in women with hypothalamic amenorrhea improves reproductive, thyroid, and growth hormone axes and markers of bone formation without causing adverse effects, according to the results of a small, prospective, open-label study published in the Sept. 2 issue of the New England Journal of Medicine.

"Functional hypothalamic amenorrhea occurs when a relative energy deficit...disrupts the secretion of hypothalamic gonadotropin-releasing hormone (GnRH) and other neuroendocrine axes," writes Corrine K. Welt, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues, adding that although the precise signal indicating energy availability remains unknown, leptin is a prime candidate.

According to the authors, the adipocyte-secreted hormone leptin regulates homeostasis and circulates at levels corresponding to fat mass and acute nutritional changes. "As compared with controls matched for weight and body composition, women with hypothalamic amenorrhea have low leptin levels and a striking absence of normal diurnal leptin variation," the authors write. [...]

"In women with hypothalamic amenorrhea, the administration of r-met-HuLeptin in an effort to normalize the relative leptin deficiency results in follicular growth and significantly increases levels of LH, estradiol, IGF-1, thyroid hormone, and bone-formation markers, indicating that low leptin levels may be responsible for reproductive and neuroendocrine abnormalities associated with this disorder," the authors point out.

The authors also note that reproductive function improved after a few months, despite the fact that seven of eight women had a history of several years of amenorrhea, and that the improvement was not related to lifestyle modifications, altered exercise patterns, or weight gain.

"Our findings help elucidate the pathophysiology of hypothalamic amenorrhea and may have therapeutic implications," the authors write, adding that further studies are needed to determine the safety and efficacy of recombinant leptin and the optimal dose and duration of treatment required to restore reproductive function without inducing an undesirable amount of weight loss in already lean patients. [...]

The full article at Medscape includes additional information about the physiological effects of leptin, including effects on thyroid function, bone formation, and body weight. It also includes a quote which illustrates that main point of this post:

"Basic science only occasionally reshapes our understanding of major biologic systems as quickly and profoundly as the discovery of leptin has done," comments Rexford S. Ahima, MD, PhD, from the University of Pennsylvania School of Medicine in Philadelphia.

Note that the results of the study are preliminary, from a clinical standpoint. That means that additional study will be needed to determine if administration of leptin would be a safe and effective means of treating hypothalamic amenorrhea.

In addition to a possible role in the treatment of infertility, it is interesting to speculate about a possible role for leptin in the treatment of Anorexia Nervosa. It is possible that leptin could reverse some of the adverse physiological effects of Anorexia, such as osteoporosis. We already have am effective treatment for Anorexia: eating enough food. But with some patients, this is not acceptable. Weight gain is a side effect. The study reported here indicates that patients treated with leptin do not gain weight, at least in the short term.

This raises an interesting ethical question. At what point would it be ethically permissible to administer leptin to a patient with Anorexia who refuses to eat enough food to gain weight? Would it even be ethical to study this, given that such a study would involve giving an experimental treatment to patients, even though we already have a 100% safe and effective treatment? Ordinarily, the answer would be no. You would not administer an unproven drug if there is an existing treatment that is safe and that always works. The thing is, food does not always work, but the reason for treatment failure is the patient's own behavior. Some patients with Anorexia find the treatment unacceptable, because of the side effect of restoration of normal body weight.

It is ethically permissible to investigate new drugs that may have a lower side effect burden than existing treatments. But if the side effect is actually a restoration of a normal body size and function, does that count?

(Note: The Rest of the Story/Corpus Callosum has moved. Visit the new site here.)
E-mail a link that points to this post:

Comments: Post a Comment