Menopause: A New Perspective

Anthony E. Karpas, M.D. FACE

            The world of menopause changed in 2003 with the publication of the Women’s Health Initiative (WHI) study.  Panic ensued and the women of North America were told that estrogen equals heart disease, stroke, and breast cancer, regardless of age or need.  Physicians told patients to discontinue therapy as quickly as possible. Many did, resulting in hot flashes and other discomfort. Women had to choose between ignoring their physician and their quality of life and sanity. What had changed?         

            Forty years of observational data had shown a positive benefit for estrogen used after menopause.  Large studies such as the Nurses Study showed decreased heart disease, dementia, and a large decrease in osteoporosis and fractures. “Estrogen forever” was pushed as the fountain of eternal youth.  Physicians felt bound to start all patients, regardless of risk, on estrogen therapy as the panacea to all bad health in late midlife women. Clearly a study was needed to test this hypothesis.  A large randomized double-blinded study (WHI) was undertaken to prove that estrogen prevented of heart disease.  The study was to last for five years.  Thus, in order to achieve statistically relevant results, a high-risk group was selected.  The patients were randomized without regard to blood pressure, weight, diabetes, smoking, cholesterol, or family history.  This approach had worked well in previous “Statin” trials showing a decrease in cardiac events.  . None had been on estrogen for ten years.  Some had previous hormone therapy.  A history of pregnancy or birth control use was not considered. Average age of the patients was sixty-three years.  Several theoretical weaknesses in this study were already known at the time of the study and many became apparent later. Animal studies in macaque monkeys doing at the University of Virginia showed a protective effect estrogen alone.  The addition of medroxyprogesterone (MPA) reversed this effect.  A study, which was carried out in patients with previous myocardial infarctions (HERS), showed a deleterious effect of CEE and MPA on subsequent coronary events.

            The only drugs studied were conjugated estrogens (CEE) without (Premarin©) or with medroxyprogesterone (MPA) (Prempro©).  WHI-1 studied CEE and MPA and the data was released with great media fanfare in 2003.  WHI-2 studied CEE alone and the data was released in 2004 with limited publicity since the outcome data was not as controversial.  In WHI-2, there were no significant findings other than a reduced risk of fractures.  Risks are summarized in Table I.

Vascular Issues

            It is well known that oral estrogens (i.e. oral contraceptives) increase clotting factors and reduce antithrombin III thus increasing clotting risk. Progestins may have a separate additive effect.  Heart attacks occur because of plaque development in the intima of coronary vessels, followed by inflammation and plaque rupture. Thrombosis of the vessel then completes the pathological event.  The women in WHI were clearly at increased risk because of previous plaque formation.  Estrogen did not reverse this risk. Although the conclusions showed an increase in risk they can be interpreted in the context of this study only. The question that this study did not address was whether early use of estrogen (prior to the onset of coronary damage) may protect women. Following WHI-1, It was widely extrapolated that all estrogen therapy in all women would cause heart disease.  While it is widely accepted that a double-blinded study is the best evidence, the data cannot be used outside of the context of that study. The estrogen only part of this study did not show any added risk. Thus the WHI has been widely used inappropriately to define risk for all women regardless of age and risk factors.

            The lesson learned is that women should have thorough screening for pre-existing heart disease prior to the institution of hormone replacement therapy (HRT).  The following screenings are probably indicated for all women prior to the institution of estrogen therapy: history of smoking, lipid profiles, blood pressure, obesity, family history, diabetes screening, history of metabolic syndrome (polycystic ovaries, trunchal obesity, elevated triglycerides, infertility).  If there is suspicion of heart disease, stress testing has been shown to be a good predictor of myocardial infarction in the face of advanced disease.  A new technique of electron beam scanning (CardioCT scan) is a sensitive predictor of early plaque buildup.  Risks factors such as hypertension and diabetes treatment and smoking cessation, should also be vigorously pursued.  Dietary counseling and weight reduction should be addressed.  Aggressive treatment with Statins and low dose aspirin is mandatory before instituting hormone therapy.

            Unfortunately, there are no research studies on parental or transdermal estrogen.  Since these agents do no pass through the liver (first pass metabolism), there is little effect on clotting and renin substrate production.  Thus, these agents could be safer from a coronary vascular standpoint. The danger of stroke might be diminished, and dementia of vascular origin might lessen. A study called the Kronos study has been initiated to evaluate this proposal.

Breast Cancer

            Most women have been lead to believe that the cause of breast cancer is estrogen treatment.  Most women also fear they are going to die of breast cancer.  Unfortunately, since many women believe that not taking hormones confers immunity from breast cancer, they neglect timely mammography.  The lifetime risk of developing breast cancer is about 1 in 7 for all women.  This does not change much with estrogen treatment. For example, in WHI-2, the risk of developing breast cancer (unheralded by the press) actually dropped.  There are several good studies at this time that show the relative risk of developing breast cancer is about 1.2-1.4 (5/10000) after fourteen years of treatment over age 55.  This risk is approximately doubled with addition of medroxyprogesterone (MPA).  Both WHI-1 and 2 and the Million Women Study confirmed the increased risk from MPA. Other risks include family history, early puberty and obesity (RR=2.0). Annual mammographic screening will increase early detection and decrease the death rate substantially. A recent study in JAMA showed smaller tumor size and stage and better prognosis in mammographically detected tumors. Dense tissue and high risk lesions should also be examined with ultrasound .Women with a family history of BRCA mutation have been shown to benefit from MRI screening. Self-exam is still an important component of prevention and should be encouraged. Screening by a health professional is important as a component of a physical exam.

Osteoporosis

            Improvements in life style and medical care have vastly extended the projected lifespan of women.  For many of these women, quality of life will be seriously diminished by osteoporotic fractures that cause pain, deformity and loss of independence. While hip fractures cause a large mortality, spine fractures are also debilitating and are often the first step in a marked decline in health.  A single spine fracture is usually soon followed by others and hip fracture becomes more likely.   Estrogen replacement remains unequalled to all other therapeutic modalities in the prevention of osteoporotic fractures.  Evista© is 50% as effective as estrogen in spine fracture prevention and has no hip fracture protection data.  Bisphosphanates (Alendrinate and Recindranite) are as effective as estrogen in fracture prevention studies of seriously osteoporotic women.  These agents have not been studied in younger normal populations or premenopausal women with osteopenia as long-term prevention.  No data exists beyond ten years on these therapies.

            Although calcium and Vitamin D are not effective in preventing fractures without the addition of other hormonal and non-hormonal agents, calcium and vitamin D deficiency is common and contribute to the risk factors.  Dietary supplements containing adequate amounts of these should be encouraged.  Weight bearing exercise is important.   In the “Million Women Study”, a rapid decline in bone density and increased frequency of fractures was observed after discontinuing estrogen.  Since many women discontinued hormone therapy following WHI and are not taking measures to prevent fractures, there may be a public health problem in the future.  Recent studies from Holland found no benefit of soy for osteoporosis prevention.  There is no data on other “alternative methods”.

Estrogen therapy is not approved for the treatment of osteoporosis, although it is approved for osteoporosis prevention.  The FDA has recently approved very low dose estrogen therapy (which does not cause endometrial hyperplasia (Minastar©)) for osteoporosis prevention. This therapy has been shown to be effective in women with very low levels of circulating estrogen, increasing bone density by 2%.  Progesterone therapy is not needed, potentially reducing the risk of breast and endometrial cancer.  The addition of low dose androgens, which will be approved soon, may also help prevent osteoporosis. 

Appropriate Dosing

            Hormone replacement therapy (HRT) in women has never been logically pursued.  There are approximately twelve different doses of thyroid medication that are carefully titrated with blood levels.  Insulin therapy is also carefully administered with sugar levels monitored several times daily.   Unfortunately, the philosophy of HRT has often been “one dose fits call and see you next year.”  No attempt has been made to optimize replacement estrogen levels in women.  Premenopausal women, in their mid thirties, have estrogen levels of 70- 150pg/ml.   Menstruation ceases when estrogen levels are approximately 50-60.  The ovary continues to function as a hormone-producing organ for years past menopause even after estrogen levels  drop. Since women post oophorectomy have no means of estrogen production, they are more symptomatic.  They may also suffer from an androgen deficiency. There needs to be an age corrected norm for estrogen.  The optimum levels for osteoporosis prevention are poorly defined.  For example, in the WHI study, there was only one dose of estrogen (0.625mg of CEE) used in post-menopausal subjects aged 50-80 years!  Unfortunately, existing laboratory assays for estrogen levels are virtually useless because of inaccuracy, non availability of free estradiol levels, cross reactivity with other estrogen metabolites, and lack of specificity for estrogens in clinical use.

            The current recommendations for the lowest dose for the shortest period of time does not take age into account . This trend toward lower and lower estrogen will have the effect of under treating many women since the current lowest doses approach placebo-only effects.  Young women post oophorectomy or women with premature ovarian failure or early menopause are currently being inadequately replaced or encouraged to stop treatment with consequences such as hot flashes, sleep disturbances, vaginal atrophy, loss of libido, premature aging of skin and accelerated osteoporosis.  An evidence-based attempt should be made to define normal estrogen level for each age group. Since serum estradiol levels are inaccurate, suppression of FSH levels may be easier to monitor.  In the absence of ovarian function, there is no Inhibin so an FSH levels will be somewhat elevated.  A level of > 30 is probably acceptable.  In younger women, there is no data that estrogen therapy has elevated risks other than those with genetic clotting abnormalities or previously existing breast cancer. Currently only a barely statistical reduction of hot flashes is required for approval of an estrogen, Quality of life assessments are not taken into account. Even a few flashes can be debilating for some patients.

Indications and Alternative Therapies

            At this time the only FDA approved indications for estrogen therapy is hot flashes, vaginal atrophy, and osteoporosis prevention.  About 30% of women go through natural menopause without any symptoms.  30% of women have a few hot flashes for a short period of time.  The other 30% of women, however, are intensely uncomfortable with few treatment options.  Oophorectomised women are 95% likely to have symptoms.  No-estrogen treatments for hot flashes such soy, black cohosh etc. have not been shown to be effective in double blinded studies although there is a significant (40% placebo effect.)  Some advocate the use of SSRI antidepressants although recent studies have raised questions about suicide risk in patients treated with these substances.  The use of such neuroactive agents has not been studied long term and no data exists as to their long-term safety. Other agents that may help to relieve some of the symptoms of vasomotor instability include vasoactive agents such as clonidine (hot flashes) and anticholinergics such as Ditropan© (sweats).

            When William Osler MD revolutioned American Medicine at the onset of the last century by advocating that a single diagnosis be sought to explain a cluster of symptoms, he argued that a single agent should be sought, if possible, to manage this condition.  Regrettably, the management of menopause today is directed to treatment of individual conditions.  Although there have been no studies of morbidity and mortality or cost-benefit analysis, the following medications have been proposed as a recipe for menopause management (Table II).

Table I

Excess Events/10,000 users and Confidence Intervals Associated with Hormone Replacement Therapy (Women’s Health Initiative)

CEE + MPA    0.625mg conjugated estrogens (CEE) with ) 2.5mg medroxyprogesterone (MPA) (Prempro©)

CEE                 0.625mg conjugated estrogens (CEE)  (Premarin©)

* If the CI is either great than or less than 1, it is significant.

Table II--The Modern Woman's Receipt for "The Change"

Psychological Issues              Psychotherapy plus....

Neurophysiological Issues

Aging and Atrophy

OR, FOR ALL OF THE ABOVE.............ESTROGEN!!!!!!

References

1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288:321-333.
2. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA. 2001; 291:1707-1712.
3. Stampfer M, Colditz G. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.  Prev Med. 1991; 20:47-63.
4. Bush TL, Barrett-Connor E, Cowan LD, et al.  Cardiovascular mortality and non-contraceptive use of estrogen in women; results from the Lipid Research Clinics Program follow-up study. Circulation. 1987; 75:1102-1109.
5. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003; 362:419-427.
6. Li Cl, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA. 2003; 289:3254-3263.
7. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000; 343:522-529.
8. Eskin BA, Troen, BR. Geripause: a newly defined postmenopausal phase. Menopause Management. 2004; 13:12-16.
9. Estrogen and Thrombo-Embolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen replacement therapy with venous thromboembolism risk. Lancet. 2003; 362:428-432.
10. Joensuu H, Lehtimaki, T, et al. Risk for distant recurrence of breast cancer detected by mammography screening or other methods. JAMA. 2004; 292:1064-1073.

Dr. Anthony Karpas recently passed away.  If you have any questions about his article please call or write

Andrew B. Dott MD MPH

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