Estrogen–like drugs may help postmenopausal women

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Scientists may debate whether weight gain is a side effect of menopause, but the numbers are clear: On average, women may experience a gain of approximately 10-15 pounds in the years surrounding menopause.

The Debate Over the Cause of Weight Gain in Menopause
Several theories have been advanced to explain the cause of weight gain at the time of menopause. Some scientists have attributed it to a decrease in thyroid function, with a subsequently decreased metabolic rate. With lowered metabolism, fewer calories are required to maintain current weight, and if caloric intake remains the same, then weight will increase. Another theory is that the weight gain is due to age-related decreases in muscle mass. Because muscle tissue burns more fuel than fat tissue, a disproportionate loss of muscle mass can result in a reduced requirement for calories. Consequently, maintenance of the same caloric intake will again result in increased body weight. However, some scientists believe the weight gain that occurs at menopause may in fact be due to the reduced production of the female sex steroid estrogen that occurs at the time of menopause.

Proponents of the "estrogen argument" point to data from clinical and animal experiments indicating that estrogen is an important modulator of food intake and body weight. Scientists, who commonly study rats that have had their ovaries removed (ovariectomized [OVX] rats) in order to mimic the decline in sex steroids that occurs at menopause, have found that OVX rats eat more and gain weight more rapidly than sham-operated control rats. Estrogen replacement reduces both the increased food intake and the body weight gain of the OVX rats.

The Role of Estrogen Receptors ER_ and ER_
Sex steroids such as estrogen induce actions by binding to a receptor. The two subtypes of estrogen receptor are ER_ and ER_. However, the role of each subtype in the effects of estrogens on and food intake and body weight gain has not been conclusively determined.

Mice with a genetic knockout of the gene for ER_ show an increase in fat tissue accumulation compared to wild-type mice, suggesting a role for ER_ receptor in the attenuating effects of estrogens on body weight gain. In contrast, OVX ER_ knockout mice treated with the estrogen estradiol (E2) gain more weight and accumulate more fat than untreated OVX ER_ knockout mice, suggesting an additional role for ER_ in fat tissue accumulation.

Recently, investigators have been focusing on the promise of selective estrogen receptor modulators (SERMs). These drugs have varying affinities for the two subtypes of the estrogen receptor, and whether they stimulate or inhibit activity depends on the shape of the drug-receptor complex and the tissue composition of molecules that interact with the receptor. One hope is that SERMs can be developed that maintain the desirable positive effects but omit the negative effects of estrogens. Researchers have been working with two SERMs: 4,4’,4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) which selectively activates ER_ and 2,3-bis(4-hyroxyphenyl)-propionitrile (DPN) which selectively activates ER__.

A New Study
Researchers at Georgetown University have conducted studies using these SERMs to determine the roles of the ER_ and ER_ in mediating food intake and body weight gain in OVX rats. In addition to contributing to the understanding of the mechanisms by which estrogens modulate food intake and body weight, these studies help determine the feasibility of using SERMs in the future to prevent postmenopausal weight gain. The results of one study are the topic of a presentation, "Effect of Selective Estrogen Receptor Agonists on Body Weight Gain in Ovariectomized Rats." Darren M. Roesch, Ph.D., Division of Endocrinology and Metabolism & Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, DC will present his findings at the American Physiological Society’s (APS) ( annual scientific conference, Experimental Biology 2004, being held April 17-21, 2004, at the Washington, D.C. Convention Center. Dr. Roesch’s research is funded by grants from the Center for Biological Modulators (Dr. Sung-Eun Yoo, Director), Korea Research Institute of Chemical Technology, and the National Kidney Foundation of the National Capital Area.

Rats were OVX and treated with daily injections of control substance, or E2, or one of a range of doses of the ER_ selective drug PPT or the ER_ selective drug DPN for 21 days. Rats were supplied liquid diet and water throughout the study. Body weights and food intake were measured daily.

Dr. Roesch found the following:

  • Body weight: Over the 21-day treatment period, body weight increased by 33% in OVX rats. In rats treated with E2, body weight only increased by 17%. All doses of the ER_ selective drug PPT studied significantly reduced body weight gain in OVX rats to levels comparable to those observed in rats treated with estradiol. None of the doses of ER_ beta selective drug DPN studied significantly altered the weight gain in OVX rats.

  • Food intake: Food intake was not altered by treatment with E2. The ERa selective drug PPT reduced food intake on some days of the study at high doses, but at lower doses the ERa selective drug PPT had no effect on food intake and still reduced body weight gain. None of the doses of the ERb selective drug studied significantly altered food intake.

    The results of this study indicate that the ER_ receptor is the primary mediator of the attenuating effects of estrogens on body weight gain, and indicate that E2 and the ER_ selective drug reduce body weight gain in rats without reducing food intake. Based on these results, the author speculates that ER_-selective drugs may prove to be useful therapeutically to reduce postmenopausal weight gain in women.

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