As clinical gynecologists, we have pondered the disparate results and conclusions of clinical studies like the Women’s Health Initiative (WHI) (8) with our own clinical observations and basic science studies such as the authors present. The review by Spangenberg et al. (5), “Metabolic Dysfunction Under Reduced Estrogen Levels: Looking to Exercise for Prevention,” and numerous other basic science and animal studies point to the ubiquitous presence of the estrogen receptor (3) and the beneficial effects of estrogen on cell function. The authors stated, “In women, estrogens encourage physiological mechanisms that prevent chronic disease; however, the loss of estrogen function results in the development of pathological function…” (5). Hormone replacement (17-beta estradiol) in OVX and ARKO mice suggests that “estrogens are likely the critical regulator and not another ovarian hormone.” Furthermore, “there is a clear association of lost estrogen function with the onset of metabolic disease.” When estrogen levels are reduced chronically in women, there is an increase in visceral fat mass, putting women at an increased risk for developing metabolic and cardiovascular disease, which can be attenuated by the use of hormone therapy. We question if the adipocyte and visceral fat changes explain the beneficial effect of hormone therapy in reducing the incidence of Type II diabetes mellitus in the WHI treatment cohorts as shown by Margolies et al. (2).
Our question has been why the WHI (8) did not clinically reflect the overall putative beneficial effects that Spangenberg et al. (5) present. There have been numerous suggestions, but the ones that keep surfacing are Clarkson’s Timing Hypothesis (1,7) and the critical window for estrogen administration. Regrettably, this study does not address this important issue of timing and hypoestrogenemic milieus. We hope that a future publication will tell us if there is a critical window to “reestrogenize” adipocytes, as may be true in other tissues of the body. It is our belief that some level of estrogen is necessary for the optimum function of the ubiquitous estrogen receptors (7) (euestrogenemia), but that there is a critical period during which these receptors respond positively (1,6).
To date, clinical trials have failed to tell us why 17-beta-estradiol is beneficial during the reproductive stage of a woman’s life, but other formulations of estrogen with or without a progestogen may be ineffective (4) or deleterious (1,7,8) if administered exogenously in the postreproductive period, especially after a prolonged hypoestrogenemic hiatus. Hopefully, future basic science studies, such as the authors’ adipocyte research, will help us better understand this enigma.
Ralph J. Turner
Department of Surgery
University of Texas Health Science Center at Tyler
Irwin J. Kerber
Department of Obstetrics and Gynecology
University of Texas Southwestern Medical School
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