Ralph J. Turner

Renal stones, timing hypothesis, and eu-estrogenemia.

ObjectiveThe aim of this study was to apply the theory of the timing hypothesis to the data presented on the incidence of renal stones in the Women’s Health Initiative and the theory of eu-estrogenemia. MethodsThe study is a review of the literature on the theory of renal stone formation and postmenopausal women, including data from the Nurses’ Health Study and the Women’s Health Initiative. ResultsThe analysis of the hazard ratios and CIs of renal stones in the Women’s Health Initiative shows that specific subgroups are affected. The CIs of the hazard ratios did not overlap 1.0 in the 60- to 64-year-old age group and in women whose time since menopause at study entry was 6 to 10 years. The CIs of all other age groups and years from menopause overlapped 1.0. Hormone therapy use by women described as “current users” at time of entry into the study in the treatment had a hazard ratio of 0.99. ConclusionsThe timing hypothesis of Clarkson (Menopause 14:373-384; 2007) seems to explain the hazard ratio and CI of renal stones in the Women’s Health Initiative. A closer analysis of the subgroups of women who had a higher incidence of renal stones suggests that the timing hypothesis may explain the results from the Women’s Health Initiative versus previous studies such as the Nurses’ Health Study. The CIs of the hazard ratios of the subgroups that did not overlap 1.0 included women 6 to 10 years beyond menopause, those who were aged from 60 to 64 years, and “never users” of hormone therapy. The hazard ratio for renal stones among “current users” in the Women’s Health Initiative was 0.99. This analysis suggests that the timing hypothesis may affect estrogen receptor-&agr;–mediated processes in the kidney. Furthermore, Clarkson’s work may support the vascular etiology of renal stones.

Eu-estrogenemia, WHI, timing and the “geripause”

The premature termination of the Women’s Health Initiative (WHI) in 2002 has dominated the debates in health care for menopausal women for the past 6 years. Each new release of the findings in a particular subset of patients has prompted a re-analysis of the basic question—“to take estrogen or not to take estrogen”. Three decades of observational large-cohort studies have been re-evaluated in the light of WHI findings. In his Personal Perspective published in Menopause entitled, “NIH and WHI—time for a mea culpa and steps beyond”, Wulf Utian, the executive director of the North American Menopause Society (NAMS), chastised the investigators for their interpretations of the WHI data [1]. In the last half of the twentieth century, practicing gynecologists prescribed hormones, known as hormone replacement therapy (HRT) and estrogen replacement therapy (ERT or ET), in order to maintain a “eu-estrogenemic” state [2]. The manifestation of “eu-estrogenemia” on a cellular level was to achieve the optimal concentration of estrogen at which all estrogen receptors, ubiquitously distributed throughout the body, functioned optimally. Basic science research in receptors and intracellular function has begun to suggest this life-long role of estrogen in a woman’s health and well-being. The classic research by Thomas B. Clarkson, in cynomolgus monkeys evaluated the atherosclerotic changes that occur in hypothalamically and emotionally stressed, non-dominant pre-menopausal female monkeys. The chronic hypo-estrogenicity in the stressed monkeys resulted in vasoconstriction and more rapid progression in atheromatous coronary arterial disease [3]. Clarkson also showed that early estrogen replacement markedly decreased the progression of atheromatous disease in ovariectomized females, whereas late replacement did not decrease the progression. Phyllis M. Wise evaluated the neuro-protective aspects of continuous estrogen replacement in ovariectomized mice [4, 5]. Her research showed that “pharmacological levels of estrogen protect the brain through mechanisms that do not require estrogen receptors (ERs), while physiological levels of estradiol protect the brain through mechanisms that depend upon ERs” [4]. In an article entitled “Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and anti-inflammatory actions” [5], the rats with continuous “eu-estrogenemia” were reported to have less inflammation and a smaller area of infarction than those rats which were “hypo-estrogenic” for a long period of time prior to the ischemic insult. The longitudinal observational “Cache County Study” demonstrated that the women with the lowest rates of Alzheimer’s disease (AD) were those who had 10+ years of post-menopausal estrogen therapy [6]. The authors state “[a] new finding in this study is an apparent limited window of time during which sustained HRT exposure seems to reduce the risk of AD.” Our review of the WHI’s data also suggests the trend towards a “timing factor” in replacing estrogen to prevent Int Urogynecol J (2008) 19:1461–1463 DOI 10.1007/s00192-008-0708-6

A theory of eu-estrogenemia: A unifying concept

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 womens 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.

Euestrogenemia and healthy mitochondria

the review “Pleiotropic actions of estrogen: a mitochondrial matter” by Velarde ([10][1]) gives us physiological insight to the clinical responses we have observed in hormone replacement menopausal patients for many years. The improved quality of life and other benefits seen in the observational

Eu-estrogenemia and contemporary knowledge versus Rossouw's cohort and recommendations for HRT

Thank you, Dr Langer, for the lucid, coherent discussion of the last four decades of menopausal hormone replacement therapy (HRT) in the recent issue of Climacteric. You beautifully contrasted the deficiencies of the Women’s Health Initiative (WHI), which was essentially a ‘new drug trial’ for cardiovascular disease in ‘vasomotorly’ asymptomatic, older, menopausal women, and the wealth of clinical data derived from cohorts such as the Nurses’ Health Study, which studied ‘vasomotorly’ symptomatic, younger women. For practical application, the cohort studies compared the quality-of-life improvements in women who used various HRT regimens and doses to achieve clinical goals through the stages of menopause. Clinicians now try to understand the complexity of HRT, with the actions of different estrogen and progestogen ligands, the different hormone receptors, co-regulators and the endogenous and exogenous agonists/antagonists (e.g. selective estrogen receptor modulators). Despite the complexity, it appears that there may be an ideal level in the serum, cell cytoplasm and nucleus at which estrogen receptors function optimally, a ‘eu-estrogenemia’ if you will. The graph in Figure 1 depicts the milieux to which Langer alludes and illustrates the concept of ‘euestrogenemia’. In the figure, one sees the pre-estrogenic milieu prior to menarche, the eu-estrogenemic milieu of the reproductive years, the hyper-estrogenemic milieu of pregnancy, and the hypo-estrogenemic milieu of menopause. The WHI was an attempt to reactivate or re-estrogenize this complex system which, apparently illustrated by the results in older patients, is not possible and indeed may be deleterious (the geripause). The dotted line is a theoretical eu-estrogenemia achieved by HRT. Those in clinical medicine, who continue to care for menopausal women, daily see confused, frustrated, ‘vasomotorly’ unstable women who abruptly terminated their HRT upon the recommendation of the principal investigator of the WHI, Jacques Rossouw. We call these women ‘Rossouw’s Cohort’. One should look forward with great trepidation to see the clinical outcomes in these chronically hypo-estrogenic women. Syed Islam’s study, illustrating the increased fracture rates, may be just the beginning of the adverse clinical outcomes in Rossouw’s Cohort.

Euestrogenemia and metabolic dysfunction: A clinician's perspective

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 functionI’’ (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-betaestradiol 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.

Translational Physiology: Understanding the WHI gap

“impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation” by Pechenino et al. ([7][1]) is an exciting addition to the literature that helps explain the discrepancy between the observational studies and the randomized clinical trials with regard to

When will the WHI investigators acknowledge what they are saying

and who may be at an increased risk for development of all of the medical conditions alleged to result from the loss of estrogen in the menopause 7 . For the benefi t of millions of women now transitioning into menopause, WHI investigators must recognize that age and time since menopause do matter, as we recently showed with renal stones 8 . For many women, living one-third of their lives in a hypoestrogenic state may be deleterious 7 .

Eu-estrogenemia and retinal blood flow

of a detailed description of Figure 1. As to the research itself, the authors used an infrared eyetracking system with an accuracy of no better than 0.5°, and that varies with gaze angle. Yet, they reported a single mean amplitude of nystagmus of 0.22° across all gaze angles. In any case, a measuring system should be at least twice as sensitive as the effect that one intends to measure. Consequently, one can have no confidence in any reported nystagmus with amplitude of 1° or less. In addition, the authors provide no information about the parameters of the targets that the subjects fixated. With regard to data analysis, reporting of means and standard deviations implies that the data are normally distributed. The reported mean amplitude of nystagmus is an absolute value, and a negative amplitude has no meaning. Consequently, the SD 0.33° gives a 2-SD range (that should include approximately 95% of the sample) of 0.88° to 0.44°. Thus, the data are not normally distributed. Finally, and most important, is the issue of the authors’ conclusion that their findings somehow relate to the HGN test conducted by police officers. The authors state that they did not visually observe the nystagmus that was being recorded. Yet the HGN test is one of visual observation. Even the most experienced clinician under ideal conditions can recognize an eye movement of no less than approximately 2 prism diopters, or approximately 1.1°. The only conclusion that the authors can make is that they measured small-amplitude physiologic nystagmus using a non–visually observed method. This method has nothing to do with the HGN test. Karl Citek