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Letter to the Editor-in-Chief

Euestrogenemia and Metabolic Dysfunction: A Clinician’s Perspective

Turner, Ralph J.; Kerber, Irwin J.

Author Information
Exercise and Sport Sciences Reviews: July 2013 - Volume 41 - Issue 3 - p 182
doi: 10.1097/JES.0b013e318292f18f
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Dear Editor-in-Chief

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

Tyler, TX

Irwin J. Kerber

Department of Obstetrics and Gynecology

University of Texas Southwestern Medical School

Dallas, TX


1. Clarkson TB. NAMS endowed lecture — estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause 2007; 14: 373–84.
2. Margolies KL, Bonds DE, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 2004; 47: 1175–87.
3. Nah H, Danko CG, Core L, et al. A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 2011; 145: 622–34.
4. Rizk DEE, Hassan HA, Al-Marzouqi AH, Shafiullah M, Fahim MA. Combined estrogen and ghrelin administration decreases expression of p27kip1 and proportion of isomyosin type I in the striated urethra and anal sphincters and levator ani of old ovariectomized rats. Int. Urogynecol. J. 2008; 19: 1363–9.
5. Spangenberg EE, Wohlers LM, Valencia AP. Metabolic dysfunction under reduced estrogen levels: looking to exercise for prevention. Exerc. Sport Sci. Rev. 2012; 40: 195–203.
6. Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell D, Wise PM. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 6013–9.
7. Turner RJ, Kerber IJ. Renal stones, timing hypothesis, and eu-estrogenemia. Menopause 2012; 19: 104–8.
8. Writing Group for the Women’s Health Initiative Investigators. Risk and benefits of estrogen plus progestin in healthy menopausal women: principal results from the Women’s Health Initiative randomized control trial. JAMA 2002; 288: 321–33.
© 2013 American College of Sports Medicine