A theory of eu-estrogenemia: a unifying concept

Abstract

Objective: The aim of the study was to propose a unifying theory for the role of estrogen in postmenopausal women through examples in basic science, randomized controlled trials, observational studies, and clinical practice.

Methods: Review and evaluation of the literature relating to estrogen.

Discussion: The role of hormone therapy and ubiquitous estrogen receptors after reproductive senescence gains insight from basic science models. Observational studies and individualized patient care in clinical practice may show outcomes that are not reproduced in randomized clinical trials. The understanding gained from the timing hypothesis for atherosclerosis, the critical window theory in neurosciences, randomized controlled trials, and numerous genomic and nongenomic actions of estrogen discovered in basic science provides new explanations to clinical challenges that practitioners face. Consequences of a hypo-estrogenemic duration in women's lives are poorly understood. The Study of Women Across the Nation suggests its magnitude is greater than was previously acknowledged. We propose that the healthy user bias was the result of surgical treatment (hysterectomy with oophorectomy) for many gynecological maladies followed by pharmacological and physiological doses of estrogen to optimize patient quality of life. The past decade of research has begun to demonstrate the role of estrogen in homeostasis.

Conclusions: The theory of eu-estrogenemia provides a robust framework to unify the timing hypothesis, critical window theory, randomized controlled trials, the basic science of estrogen receptors, and clinical observations of patients over the past five decades.

FIG. 1

The abscissa (x axis) shows the woman's age in years. The ordinate (y axis) shows [E], the concentration of estrogen in cell and the bloodstream. The dotted line represents the concept of eu-estrogenemia, that is, the concentration of estrogen in cells and the blood stream at which all estrogen receptors function optimally. P, pregnancies; M, menopause; R = re-estrogenization; G, geripause. Reprinted from Turner and Kerber with permission of the publisher. Copyright © 2008, International Urogynecological Association.

FIG. 2

The abscissa (x axis) shows the woman's age in years. The ordinate (y axis) shows [E], the concentration of estrogen in the cell and the bloodstream. The dotted line represents the concept of “eu-estrogenemia,” that is, the concentration of estrogen in cells and the blood stream at which all estrogen receptors functions optimally. The inset shows ovulatory dysfunction in the menopausal transition. P = pregnancies. Reprinted from Turner and Kerber with permission of the publisher. Copyright © 2011, North American Menopause Society.

FIG. 3

Estimated discrete annual hazard of Alzheimer's disease (AD) for men and women by age, and by duration of hormone therapy (HT) use for women. Both figures indicate risks estimated for an individual with the mean value of 13 years of education and no ∊4 alleles at apolipoprotein E. (A) The curves depict the annual hazards predicted by fitting the base model including an age-by-sex interaction term. The annual hazard for AD appears similar for men and women before 80 years of age, but diverges rapidly afterward with an excess risk found in women. (B) The curves depict the annual hazards predicted for the women with available HT exposure information, and, in filled circles, the corresponding annual hazards for men after omitting the terms for HT. There were 35 instances of incident AD among 1,357 men. Ordinate values for women differ slightly from those in panel A due to omission of women lacking HT exposure information, several of whom experienced incident dementia. Reprinted from Zandi et al with permission of the publisher. Copyright © 2002, American Medical Association.

FIG. 4

Hazard ratios of renal stones with 95% confidence intervals by age groups. Reprinted from Turner and Kerber with permission of the publisher. Copyright © 2011, North American Menopause Society.

FIG. 5

Hazard ratios of renal stones with 95% confidence intervals by time since menopause at study entry. Reprinted from Turner and Kerber with permission of the publisher. Copyright © 2011, North American Menopause Society.

FIG. 6

Serum estradiol (E₂) by log relative hazard of death was calculated by using restricted cubic splines with five knots with 95% confidence intervals (dashed curves). To convert serum E₂ to pmol/L, multiply by 3.671. Reprinted from Jankowska et al with permission of the publisher. Copyright © 2009, American Medical Association.