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J Appl Physiol 99: 2471-2472, 2005; doi:10.1152/japplphysiol.00900.2005
8750-7587/05 $8.00
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LETTER TO THE EDITOR

Eu-estrogenemia

To the Editor: Bravo, bravo, bravo. Clinicians on the front lines of women's care applaud your Invited Editorial entitled "Women, hormones, and clinical trials: a beginning, not an end" (1).

Many of us have been wrestling with these hormonal issues since that infamous day in July 2002 when Dr. Jacques Rossouw of the National Institutes of Health released the results of the Women's Health Initiative (WHI) and told the women of this country to call their doctors to interpret the significance of the results. Since that day, we have attempted to understand the differences in the outcomes of this randomized, controlled trial with the results of the previous observational, animal, and basic science studies and our own clinical observations.

Millions of women have become confused, frustrated, angry, and "vasomotorly" unstable. More significantly, as you state in your editorial, many "may endure cardiac events and bone fractures that could have been prevented." We strongly concur with your assessment of the WHI and thank the researchers for leading the Kronos Early Estrogen Prevention Study (KEEPS) trial. Hopefully, the results of KEEPS will return some common sense and better science to the care of our menopausal patients.

In the meantime, it is our hope that you, the thought leaders of our specialty, will also elucidate "the real world" risk of menopausal hormone therapy. Nineteen "net bad outcomes" per 10,000 women years in the WHI is similar to the risk of a 20-year-old pregnant woman delivering a chromosomally abnormal baby. Is this risk sufficient for us to have concluded "the smallest dose, for the shortest period of time" in all menopausal women?

We agree with your assessment that there may be a difference in starting estrogen in newly menopausal women before endothelial damage has occurred. Furthermore, we would like to suggest, that in view of the ubiquitous nature of the estrogen receptors in Homo sapiens, that low levels of estrogen may be necessary not only in females but also in males to maintain normal homeostasis. The medical literature is replete with studies delineating the benefits of estrogen for cognition, vision, acusis, dentition, integumentary well-being, and bone health in women. It appears that in men a low level of estrogen may also be necessary to maintain bone density and cognition. It makes little biological sense for estrogen receptors to lie fallow for one-third of a woman's life. Rather the basic science studies of estradiol receptors suggest the need for a homeostatic level of serum estradiol, a "eu-estrogenemia," for an optimal quality of life in both genders.

Finally, we congratulate your integrating the bench researchers into the team of clinical scientists. Perhaps they can elucidate the optimal serum concentrations of estrogen that provide the quality of life that we sought to provide empirically to our patients in the last century.

REFERENCES

  1. Miller VM, Thomas B, Clarkson TB, Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Naftolin F, and Santoro N. Women, hormones, and clinical trials: a beginning, not an end. J Appl Physiol 99: 381–383, 2005.[Free Full Text]

I. J. Kerber
 University of Texas Southwestern
Dallas, Texas
e-mail: irwin.kerber{at}utsouthwestern.edu


R. J. Turner
 Genesis Physicians Group
Plano, Texas

 

REPLY

We thank Dr. Kerber for the supportive letter and interest in the KEEPS trial. Dr. Kerber raises some interesting points and questions. The first point relates to the "risk" of using hormone therapy (HT) products and recommendations for dose and duration of treatment. At present there are no reliable tests to predict who might be at risk for an adverse event such as myocardial infarction, stroke, or venous thromboembolism while on HT. Although various proinflammatory cytokines are considered "CVD risk markers," their utility as predictors of risk for individuals using HT has not been substantiated. Indeed, recommendations to prescribe the "smallest dose, for the shortest period of time" are conservative and may not be appropriate for each individual woman. This point is emphasized in the Position Statement by the Executive Committee of the International Menopause Society, which presents the conclusion that "there are no new reasons to place mandatory limitations on the length of treatment, including arbitrary cessation of HT in women who started replacement during the menopausal transition and remain symptom-free while on hormones" (2). Clearly more research is needed, and as we learn more about individual variation in estrogen receptors, enzymes that metabolize exogenous hormones, and differences in routes of administration, we hope that dosing and duration recommendations can be improved. Results of the KEEPS trial should provide useful data in regard to these issues.

Dr. Kerber's comment regarding "eu-estrogenemia" for both men and women is well taken. As indicated, there are data supporting a role of estrogen in maintaining bone health in men as in women (3). Furthermore, estrogen may contribute to cardiovascular health in both sexes, because polymorphisms in estrogen receptors are associated with accelerated atherosclerosis in men (4, 5). The issue of what is the optimal serum concentration of hormones is emerging as some evidence indicates that some biological effects of estrogen may occur at concentrations below the typical detection limits of most standard assays (1). In this age of genomics and proteomics, there is much to be learned about contributions of estrogen, testosterone, and other sex steroid hormones on the normal physiology of both men and women. The popular, although still murky, concept of "bio-identical" hormones reflects how interest by consumers may drive these scientific advances.

We also agree that translating discoveries from basic science to clinical application requires expertise from diverse scientific disciplines. The KEEPS designers and investigators include individuals with expertise in endocrinology, public health, internal medicine, obstetrics and gynecology, cardiology, veterinary medicine, and statistics. This diverse group embraces the TEAM (Together, Each can Achieve More) concept ofmultidisciplinary research needed to benefit and improve the health of our long-lived society.

Again, we are grateful to Dr. Kerber for the words of praise for KEEPS and we look forward to sharing its results.

REFERENCES

  1. Khosla S, Melton L, Atkinson EJ, O'Fallon WM, Klee GG, and Riggs BL. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 83: 2266–2274, 1998.[Abstract/Free Full Text]
  2. Naftolin F, Schneider HP, Sturdee DW, Birkhauser M, Brincat MP, Gambacciani M, Genazzani AR, Limpaphayom KK, O'Neill S, Palacios S, Pines A, Siseles N, Tan D, and Burger HG. Guidelines for hormone treatment of women in the menopausal transition and beyond. Climacteric 7: 333–337, 2004.[CrossRef][Web of Science][Medline]
  3. Riggs BL, Khosla S, and Milton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocrin Rev 23: 279–302, 2002.[Abstract/Free Full Text]
  4. Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, and Levy D. Association between estrogen receptor {alpha} gene variation and cardiovascular disease. JAMA 290: 2263–2270, 2003.[Abstract/Free Full Text]
  5. Sudhir K, Chou TM, Messina LM, Hutchison SJ, Korach KS, Chatterjee K, and Rubanyi GM. Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene. Lancet 349: 1146–1147, 1997.[CrossRef][Web of Science][Medline]

Virginia M. Miller
 Mayo Clinic College of Medicine
Surgery and Physiology, and Bioengineering
Rochester, Minnesota
e-mail: miller.virginia{at}mayo.edu


Thomas B. Clarkson
 Wake Forest University School of Medicine
Comparative Medicine Clinical Research Center
Winston-Salem, North Carolina


S. Mitchell Harman
 Kronos Longevity Research Institute
Phoenix, Arizona


Eliot A. Brinton
 University of Utah
Metabolism Section, Cardiovascular Genetics
Salt Lake City, Utah


Marcelle Cedars
 University of California at San Francisco
Obstetrics and Gynecology
San Francisco, California


Rogerio Lobo
 Columbia University College of Physicians and Surgeons
Obstetrics and Gynecology
New York, New York


JoAnn E. Manson
 Brigham and Women's Hospital and Harvard Medical School
Division of Preventive Medicine
Boston, Massachusetts


George R. Merriam
 University of Washington
Veterans Affairs Puget Sound Health Care System
Department of Medicine
Tacoma, Washington


Frederick Naftolin
 Yale University School of Medicine
Obstetrics and Gynecology and Biology
New Haven, Connecticut


Nanette Santoro
 Albert Einstein College of Medicine
Obstetrics, Gynecology and Women's Health
Bronx, New York





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