EMBARGOED UNTIL
MONDAY, APRIL 19, 2004
Contact: Donna Krupa
703.967.2751 (cell)
703.527.7357 (office)
djkrupa1@aol.com
APS Newsroom: April 17-21, 2004
Washington, DC Convention Center
East Registration Area/Flex Unit
Telephone: 202.249.4009
Estrogen–Like Drugs May Eventually Help
Postmenopausal Women With Weight Gain
Study
using animal model points to a potential pharmacological strategy to stop
the average 10-15 pound weight gain during menopause
Washington, DC -- 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 ERα and
ERβ
Sex steroids such as estrogen induce actions by binding
to a receptor. The two subtypes of estrogen receptor are ERα and ERβ.
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 ERα show an increase in fat
tissue accumulation compared to wild-type mice, suggesting a role for ERα
receptor in the attenuating effects of estrogens on body weight gain. In
contrast, OVX ERα knockout mice treated with the estrogen estradiol (E2)
gain more weight and accumulate more fat than untreated OVX ERα knockout
mice, suggesting an additional role for ERβ 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 ERα and 2,3-bis(4-hyroxyphenyl)-propionitrile (DPN)
which selectively activates ERβ.
A New Study
Researchers at Georgetown University have conducted
studies using these SERMs to determine the roles of the ERα and ERβ 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) (www.the-aps.org)
annual scientific conference, Experimental Biology 2003, 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.
Methodology
Rats were OVX and treated with daily injections of
control substance, or E2, or one of a range of doses of the ERα
selective drug PPT or the ERβ selective drug DPN for 21 days. Rats were
supplied liquid diet and water throughout the study. Body weights and food
intake were measured daily.
Results
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 ERα 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 ERβ 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.
Conclusions
The results of this study indicate that the ERα
receptor is the primary mediator of the attenuating effects of estrogens on
body weight gain, and indicate that E2 and the ERα selective drug
reduce body weight gain in rats without reducing food intake. Based on
these results, the author speculates that ERα-selective drugs may prove to
be useful therapeutically to reduce postmenopausal weight gain in women.
- end -
The
American Physiological Society (APS) was founded in 1887 to foster basic and
applied science, much of it relating to human health. The Bethesda, MD-based
Society has more than 11,000 members and publishes 3,800 articles in its 14
peer-reviewed journals every year.
***
Editor’s
Note: For further information or to schedule an interview with a member of
the research team, please contact Donna Krupa at 703.967.2751 (cell),
703.527.7357 (office) or at
djkrupa1@aol.com. Or contact the APS newsroom at 202.249.4009 between
9:00 AM and 6:00 PM EDT April 17-21, 2004.
|
