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WOMEN'S MEDICAL ISSUES, WOMEN'S HEALTH

HORMONE REPLACEMENT THERAPY REVIEWED--WOMEN--JK

ADVICE ON HRT (hormone replacement therapy for women)

SUMMARY BY JK

Even in well designed studies there are limits of entailment, and these limits are often shoved aside by a press more concerned with ratings than the truth.  For example both New Week and Time Magazines--two of the best sources in the popular press for medical news published articles advising the discontinuation of HRT (hormone replacement therapy) for women based on a 5 year study that showed a surprising increase in cardiac events and increased incidents of breast cancer the risk factor for breast cancer had been known for over 2 decades.  By giving only part of a complex picture, the conclusions reached by these magazines were incorrect.

In an effort to right the record Dr Robert Langer, UCSD Professor of Medicine, spoke in November before an audience of medical students about the WHI study, which he was involved in.  In the broadcast of his lecture, December of 2002, he used for both his introduction and summation the articles in Time and Newsweek about WHI, especially the conclusions they drew.  It provided an avenue for him discuss over studies and their impact on the issue of HRT and also the limits of conclusions which could be drawn from the WHI, limits violated by these two magazines.  Times article The Truth about Hormones, 7/22/02, was short on truth.  They failed to note, for example that one portion of the study was stopped not because of an issue of HRT being unsafe, but that MPA used in this portion was shown to have significantly less health benefits than alternative, alternative which are continued to be tested in the WHI.  Doctor Langer discussed these alternatives, among other things. 

Time's article failed for 3 major reasons and numerous minor ones.  First they didnt rely on the adjusted figures.  When the incident rates were adjusted for contravening variables, the overall risk factors for 5 major health issues (cancer, osteoporosis, blood clot, coronary events, and Alzheimer's) balanced out.  Second, the results for MPA (the hormone combination used in the study of estrogen and medroxyprogesterone) cannot be generalized to other HRTs, namely estrogen alone and estrogen with a different prostaglandin.  And third, since the study was of menopausal women, it could not be applied to postmenopausal women or the effects of such women using long-term HRT.  These limits and more were brought before the audience by Doctor Langer.

There is a large body of research on HRT, which help put the WHI in proper perspective.  For all HRTs there is a modest increase of breast cancer in the first three years.  This is because estrogen stimulates the growth of existing cancer, thus the rate approaches over time that of the control group.  For all HRTs there is an increase in  blood clots.  And for all HRTs there is a decrease in the rate of colon cancer, osteoporosis, and Alzheimer’s disease.  With MPA there wasn't a significant reduction in cardiac events; however, for Estrogen and Estrogen with a different prostaglandin, there is a significant reduction.  These other two HRT therapies both were shown to significantly slow the rate of plaque formation in arties (see study below) and also the constriction of the arties as a stress response.  Instead of a neutral, overall result, these other HRT therapies conferred moderate coronary benefits.

Of particular importance was a study that compared statins to either estrogen or estrogen and prostaglandin.  Statins are given to women with high levels of both cholesterol and low-density lipoproteins.  These women had done just as well if given either estrogen or estrogen and prostaglandin instead of a statin.  Since statins have some serious medical consequences and none of the additional benefits of estrogen, estrogens should be the treatment of choice.  Unfortunately, the MPA therapy does not confer this benefit. 

Finally, one must look to the study itself, in addition to the selection of MPA, for another in the media’s generalization of the results of WHI.  The study was limited to menopausal women.  Four of the 5 medial problems tracked (cancer, coronary events, Alzheimer's and osteoporosis) by the study do not become major health issues until several years past menopause and thus beyond the study.  The extraction of the results of WHI unto these older women is flawed.   

There are 3 immediate reasons for HRT therapy.  One is the control of hot flashes.  Second are cosmetic and psychological reasons:  the skin remains suppler, breasts firmer, and memory improved. All these effect self-esteme and thus quality of life.  Third is sexual performance:  the control of vaginal dryness and the wall of the vagina is thicker.  Medical intervention for social and psychological benefits is common in our society. 

When one considers the long-term benefits (well beyond the scope of the WHI) of very significant reduction of Alzheimer’s, of atherosclerosis, and of osteoporosis, the choice for usage of HRT other than MPA is clear.  When one adds to this the cosmetic and sexual advantages plus the managing of hot flashes, the choice is crystal clear.  And there is no overall increased cancer risk, for the reduction in colorectal and ovarian cancers offset the gain in breast cancers, which is mainly in the first 3 years.  Moreover the increase in the incidents of blood clots does not occur with esterfied estrogen (see article here published).  There is enough data available to put to rest any of the earlier uncertainties over HRT treatment. 

Because of the complexities of issues and the limited time that health professional have to review studies and keep abreast of new studies entails that physicans are under informed.  One solution would be to have panels of INDEPENDENT experts sort out such important health issues and publish their results.  And its the summation of their finding that ought to be reported in the press in articles aimed to guide people in their medical decisions.  Hundreds  of thousands of women will die early because they have discontinued (or not started) HRT due to incorrect coverage in the popular press.  Errors which unfortunate their physican will likely confirm.  The best non-technical publication is the Harvard Medical News Letter.  It should be in every public library.  Something better ought to be done about the generation of health information.--BY JK

 

 

SCIENTIFIC AMERICAN ARTICLE CRITICAL OF MEDIA CONFUSION 

RESEARCH STATES:  "I think that it borders on a tragedy that Premarin and Provera were chosen as the only HRT treatments."   {AS JK STATED ABOVE IT IS THE PROSTOGLANDIN in Provera & Premarin that caused the serious side effects   Another researcher finds that hat Provera--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's. This immune response wears away at brain cells and causes them to leak neurotransmitters such as glutamate, which overloads and kills neurons. "It's basically as if someone were to open your mouth and shove down gallons" of soft drink, Brinton explains. "It's caustic, and you can't metabolize it enough."

After the usual journalistic waffling, the Scientific American articles gets to the issue:

For many scientists, a critical question yet remains: To what extent do the results of the initiative study apply to other forms of hormone replacement? "We cannot be sure whether other hormone combinations will have the same effects," Rossouw cautions, "but in my opinion we should assume they do until proven otherwise." But neuroendocrinologist Bruce S. McEwen of the Rockefeller University is unequivocally critical of the study: "I think that it borders on a tragedy that Premarin and Provera were chosen as the only HRT treatments."

A growing number of researchers believe that Provera is a poor substitute for progesterone. For example, medroxyprogesterone will bind in the breasts to progesterone receptors, which causes breast cells to divide after puberty and during the menstrual cycle, and also to glucocorticoid receptors, which causes cell division during pregnancy. This double-barreled assault on breast cells, explains C. Dominique Toran-Allerand, a developmental neurobiologist at Columbia University, probably led to the high rates of breast cancer in the study. "With Provera you are activating two receptors involved with cell division in the breast," she says, "and that's the culprit, not estrogen."

Hormone Hysteria?

In addition, recent research shows that Provera interferes with estrogen's ability to prevent memory loss and dementia. "Estrogen is able to protect neurons against toxic assaults that are associated with Alzheimer's disease," notes Roberta Diaz Brinton, a neuroscientist at the University of Southern California. Using in vitro studies of several types of progestin, she found that Provera--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's. This immune response wears away at brain cells and causes them to leak neurotransmitters such as glutamate, which overloads and kills neurons. "It's basically as if someone were to open your mouth and shove down gallons" of soft drink, Brinton explains. "It's caustic, and you can't metabolize it enough."

 Scientific News

In this section, The North American Menopause Society features the latest research news, along with expert commentary that places the news into perspective.

The North American Menopause Society requests commentary from experts in the clinical practice and research communities on subjects of interest to its constituents.  Unless specifically stated otherwise, the comments contained on this Web site are opinions or information of the authors and not necessarily the opinions or information of The North American Menopause Society, its officers, agents, or trustees.

 

 

Past estrogen use decreases Alzheimers disease in older women

December 2002 report of NAMS

Zandi PP, Carlson MC, Plassman BL, et al, for the Cache County Memory Study Investigators. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County study. JAMA 2002;288:2123-2129.

Use of hormone therapy is associated with a reduced risk of Alzheimers disease (AD), especially use for longer than 10 years, according to results from this prospective observation al study conducted in Cache County (Logan, Utah). A total of 1,889 women (mean age, 74.5 years) were enrolled. A similarly aged group of men (n = 1,357) served as controls. History of hormone therapy use (either estrogen alone or estrogen plus a progestogen), as well as intakes of calcium and multivitamin supplements, were assessed at baseline. After 3 years of follow-up, 88 women (4.7%) and 35 men (2.6%) had developed AD. Women aged 80 and older had more than twice the rate of AD as men of that age (hazard ratio [HR], 2.11; 95% CI, 1.22-3.86). Overall, hormone therapy significantly reduced the risk of AD by 41% compared with nonusers (95% CI, 0.36-0.96). Hormone use for at least 10 years resulted in a 69% reduction in risk (95% CI, 0.17-0.86), which was statistically the same as the risk for matched males. When the results were assessed by current and former hormone use, current use (72% unopposed estrogen) was not associated with decreased AD risk unless the duration of treatment exceeded 10 years. For former users, 3 or more years of use significantly reduced the AD risk, with more than 10 years use reducing the risk by 83% (95% CI, 0.01-0.80). No similar effects were seen with either calcium or multivitamin use.

Hormone therapys effect on atherosclerosis associated with presence of apolipeprotein A gene.November 2002 report of NAMS

Lehtimaki T, Dastidar P, Jokela H, et al. Effects of long-term hormone replacement therapy on atherosclerosis progression in postmenopausal women relates to functional apolipoprotein E genotype. J Clin Endocrinol Metab 2002;87:4147-4153.

Postmenopausal hormone therapy appears to have a beneficial effect on atherosclerosis progression in women who do not have the apolipoprotein E (apoE) genotype, based on results from this prospective, cohort study conducted in Finland. The study enrolled 141 postmenopausal women aged 45 to 71 with no clinically evident cardiovascular disease or hypertension. Women were classified into three groups: estrogen plus progestogen, estrogen alone, and no hormone use (control). Estradiol valerate (2 mg/day) was used, with either levonorgestrel (0.25 mg/day) or medroxyprogesterone acetate (10 mg/day) administered cyclically to women with a uterus. In all, 93 women completed the 5-year follow-up study. Sonography was used to determine atherosclerosis severity. In apoE-negative women, hormone therapy significantly slowed the progression of atherosclerosis when compared with the control group. In apoE-positive women, no significant between-group differences were seen.

In the commentary it was pointed out that compared with apoE-positive women. Since apoE genetic polymorphism may affect plasma lipids and the severity of atherogenesis, it is possible that the hormone-related adverse effects in the WHI and HERS studies manifested themselves specifically in apoE-positive women, therefore reflecting a biased study population.

  NAMS, North American Menopause Society.

In Patient Care June 15, 1999, p. 144:

 at patientcareonline.com

"Numerous studies have demonstrated an inverse relationship between estrogen replacement therapy and the relative risk of developing A.D.  In a recent meta-analysis of postmenopausal etrogen therapy and risk of dementia, cumulative data from 10 studies suggested that there was a 29% risk reduction with estrogen replacement.  [Yaffe K., Sawaya G, Lieberg I, et a.  Estrogen therapy in postmenoopausal women, effects in cognitive function and dementia. l JAMA 1998; 279:688-695.]

Kristine Yaffe, MD; George Sawaya, MD; Ivan Lieberburg, PhD, MD; Deborah Grady, MD, MPH

JAMA. 1998;279:688-695.

Context.— Several studies have suggested that estrogen replacement therapy in postmenopausal women improves cognition, prevents development of dementia, and improves the severity of dementia, while other studies have not found a benefit of estrogen use.

Objective.— To determine whether postmenopausal estrogen therapy improves cognition, prevents development of dementia, or improves dementia severity.

Data Sources.— We performed a literature search of studies published from January 1966 through June 1997, using MEDLINE, manually searched bibliographies of articles identified, and consulted experts.

Study Selection.— Studies that evaluated biological mechanisms of estrogen's effect on the central nervous system and studies that addressed the effect of estrogen on cognitive function or on dementia.

Data Extraction.— We reviewed studies for methods, sources of bias, and outcomes and performed a meta-analysis of the 10 studies of postmenopausal estrogen use and risk of dementia using standard meta-analytic methods.

Data Synthesis.— Biochemical and neurophysiologic studies suggest several mechanisms by which estrogen may affect cognition: promotion of cholinergic and serotonergic activity in specific brain regions, maintenance of neural circuitry, favorable lipoprotein alterations, and prevention of cerebral ischemia. Five observational studies and 8 trials have addressed the effect of estrogen on cognitive function in nondemented postmenopausal women. Cognition seems to improve in perimenopausal women, possibly because menopausal symptoms improve, but there is no clear benefit in asymptomatic women. Ten observational studies have measured the effect of postmenopausal estrogen use on risk of developing dementia. Meta-analysis of these studies suggests a 29% decreased risk of developing dementia among estrogen users, but the findings of the studies are heterogeneous. Four trials of estrogen therapy in women with Alzheimer disease have been conducted and have had primarily positive results, but most have been small, of short duration, nonrandomized, and uncontrolled.

Conclusions.— There are plausible biological mechanisms by which estrogen might lead to improved cognition, reduced risk for dementia, or improvement in the severity of dementia. Studies conducted in women, however, have substantial methodologic problems and have produced conflicting results. Large placebo-controlled trials are required to address estrogen's role in prevention and treatment of Alzheimer disease and other dementias. Given the known risks of estrogen therapy, we do not recommend estrogen for the prevention or treatment of Alzheimer disease or other dementias until adequate trials have been completed.


From the Departments of Psychiatry (Dr Yaffe), Medicine (Drs Lieberburg and Grady), Epidemiology and Biostatistics (Drs Sawaya and Grady), and Obstetrics and Gynecology (Dr Sawaya), University of California, San Francisco, and Athena Neurosciences, South San Francisco, Calif (Dr Lieberburg).


Endocrinology, doi:10.1210/en.2006-0495, Endocrinology Vol 147, No. 11 5303-5313, 2006 copyright by the Endocrine Society

 

Dose and Temporal Pattern of Estrogen Exposure Determines Neuroprotective Outcome in Hippocampal Neurons: Therapeutic Implications

 

To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17ß-estradiol (E2) exposure were developed and used to assess the neuroprotective efficacy of E2 against ß-amyloid-1–42 (Aß1–42)-induced neurodegeneration in rat primary hippocampal neurons. Low E2 (10 ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous, and intermittent. In contrast, high E2 (200 ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. Although high E2 alone was not toxic, neurons treated with high-dose E2 resulted in greater Aß1–42-induced neurodegeneration. In prevention vs. treatment simulations, E2 was most effective when present before and during Aß1–42 insult. In contrast, E2 treatment after Aß1–42 exposure was ineffective in reversing Aß-induced degeneration, and exacerbated Aß1–42-induced cell death when administered after Aß1–42 insult. We sought to determine the mechanism by which high E2 exacerbated Aß1–42-induced neurodegeneration by investigating the impact of low vs. high E2 on Aß1–42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E2 significantly prevented Aß1–42-induced rise in intracellular calcium, whereas high E2 significantly increased intracellular calcium and did not prevent Aß1–42-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E2 exposure before, but not after, Aß1–42-induced neurodegeneration. These data are relevant to impact of perimenopausal E2 exposure on protection against neurodegenerative insults and the use of estrogen therapy to prevent vs. treat Alzheimer’s disease. Furthermore, these data are consistent with a healthy cell bias of estrogen benefit.

 

Unfortunately the literature does not present easy clear answers.  For examples some studies found that women with dementia did worse with HRT, while those without benefited.  Other studies using the same formulation as the combination with medroxyprogesterone (Provera & Premarin) faired worse, while those using a different formulation benefited.  The Scientific American study zeroes in on this error—while most others mist this important distinction--jk. 

 

 

 


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