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__.