ESTROGEN REPLACEMENT THERAPY

Thomas Higgins, MD
7/29/2002

Postmenopausal women who do not use estrogen replacement therapy (HRT) can expect to be estrogen hormone deficient for at least 1/3 of their lives. The decision whether or not to begin ERT is based on multiple factors and is perhaps one of the most important therapeutic decisions women face. Because of the uncertainties involved in making the decision to use HRT, it is estimated that compliance with it is only 20 to 30%.

Recently, the Women's Health Initiative (WHI) has added controversy to an already difficult subject. The Women's Health Initiative was started by the National Institutes of Health in 1991 to address the most common causes of death, disability and impaired quality of life in postmenopausal women. Recruitment for the WHI began in September 1993. Part of this initiative is a study of HRT and involves over 27,000 women. This study was divided into two arms. There was a Prempro (estrogen & progesterone) group vs. placebo (no drug) arm in women with a uterus & a Premarin (estrogen only) vs. placebo arm in women without a uterus. The Prempro arm was stopped after 5.2 years because the incidence of bad outcomes including heart attack, stroke, blood clots & breast cancer outweighed the incidence of good outcomes including less colon cancer & osteoporosis. The Estrogen only arm is still continuing without any obvious increased risk over benefit to date. While the results are disturbing, I believe that it is important to look at the absolute numbers involved. There were 37-heart attacks/10,000 women-years in the Prempro group vs. 30 in the placebo group. There were 29-strokes/10,000 women-years in the Prempro group vs. 21 in the placebo group. There were 38 invasive breast cancers/10,000 women-years in the Prempro group vs. 30 in the placebo group. I also believe that it is important to note that there are significant criticisms of the study which may call the results into question, that the estrogen alone arm is not showing the same disturbing results, that different forms of HRT may react differently, although there was a trend, the breast cancer results did not reach clinical significance & that short term HRT (3 years) for control of menopausal symptoms has not been shown to be harmful.

I will attempt to give you my perspective and some of the factors that I use in deciding where I should and should not recommend HRT.

Pros of Estrogen Replacement:

Feeling of well-being: Menopause is often associated with many adverse symptoms and while estrogen replacement will not alleviate them all, many are improved. Sleep disturbance and vaginal dryness with menopause are examples that are often improved. Hot flushes are often improved but may not be completely eliminated. Hormone replacement is the only effective therapy here.
Osteoporosis: Bone loss occurs rapidly in most women for several years after menopause and can be prevented or repaired in most cases with estrogen. It should be pointed out that there are alternatives to hormone replacement including drugs like Fosamax to prevent & repair bone loss.
Reduction of endometrial cancer risk: In women with a uterus, progesterone must be taken with estrogen to prevent an abnormal buildup of the uterine lining. It is felt that endometrial cancers are found earlier and are of lower grade in women taking estrogen and progesterone.
Reduction of colon cancer: A new finding in the Women's Health Initiative was a reduction of colon cancer risk by 6 women/10,000/year.
Reduction of Alzheimer's: There is early evidence that hormone replacement may reduce the risk of dementia.

Cons of Estrogen Replacement:

Taking medication: There is a psychological hurdle to overcome in HRT. It is one thing to take a medication to treat an illness but another to take medication when you are healthy and are taking it to prevent illness in the future.
Breast tenderness and "bloating": HRT can cause these symptoms in some women but the symptoms are usually mild and controllable with careful attention to medication dosage.
Return of menses: If a women still has a uterus, return of menses (but not fertility) usually occurs with HRT. After several years of therapy, the menses become light and dosage adjustments can be made which result in cessation of menses.
Gallbladder disease: Studies have suggested that the risk of having to undergo gallbladder surgery is approximately two-fold higher in women on long term HRT.
Blood Clots: In some people, estrogen taken orally can predispose to blood clots in veins. This risk was again demonstrated in the Women's Health Initiative with 34 clots/10,000/year in women on Prempro vs. 16 in the placebo arm. The estrogen patch can be substituted for oral estrogen with a reduction in risk of blood clots.
Risk in breast cancer: If you are taking HRT and have a breast cancer which is estrogen receptor positive, the estrogen can speed the cancer's growth. It has been suggested that estrogen can be used safely in breast cancer survivors free of their disease for at least five years. It should be pointed out that the survival in patients found to have breast cancer while taking estrogens is better than those not taking estrogens. This may be because of better follow-up & surveillance with earlier detection in the estrogen treated group.
Risk of new breast cancer: Here we are talking only of the risk of developing a new breast cancer solely because of HRT. There have now been at least 20 separate studies trying to evaluate this risk with the Women's Health Initiative being the most recent. Individually these studies fall on both sides of the line. Analysis of all the studies taken together suggest there is a small but disturbing increase in risk. Interestingly, until the Women's Health Initiative, there has never been a study showing to be an increase in the risk of new breast cancer when HRT is given for less than 5 years. This is a criticism of the Women's Health Initiative and may indicate that they were looking at patients with preexisting tumors.

Unknowns:

Heart disease & stroke risk: Women live longer than men on average probably because of the effect of their estrogen on HDL and LDL cholesterol. HDL is the "good" cholesterol and decreases after menopause, LDL is the "bad" cholesterol and increases through life. Estrogen replacement improves both HDL and LDL levels. A favorable affect on cardiovascular disease (heart attack & stroke) had been listed as a pro to hormone replacement therapy based on numerous observational studies. The Prempro portion of the HRT study in the Women's Health Initiative has called the prior observational data into question. The mechanism of an adverse effect of Prempro on heart attack & stroke may be related to an effect of hormone replacement on triglycerides. Triglycerides can increase with standard hormone replacement. High triglycerides can in turn adversely affect HDL & LDL. Another possible mechanism for heart attack & stroke risk seen in the Women's Health Initiative is the increase risk of clotting which occurs with oral estrogens. The SERM's (Selective Estrogen Receptor Modulators) described below do not increase triglycerides and other forms of HRT may also have a different effect than seen with Prempro. SERM's do have the same effect on blood clots as do oral estrogens. The key here is that all hormone replacement may not have the same effect on lipids or on blood clots. We will need to wait for further studies here.

Making a Decision:

In weighing the pros and cons of HRT for an individual, I find several pieces of information helpful at the present time:

Are there any symptoms related to menopause that may be alleviated?
Is there any personal or family history of breast cancer, blood clots or colon cancer?
Is there any physical exam evidence of breast, gallbladder or pelvic disease? · What are the mammogram results?
Measurement of bone density & the patient's ability to take alternative medications to reduce the osteoporosis risk.
Measurement of lipids and the patient's ability to take alternative medications to reduce cholesterol & triglyceride risk.
Are there other heart disease & stroke risk factors present? For example hypertension, diabetes, smoking & untreated hypothyroidism.
Do you need just estrogens or estrogen & progesterone? Essentially this translates into if you have had a hysterectomy or still have a uterus.

It is also important to define the goals of HRT prior to any decision to begin or to continue taking it. If the goal is only to relieve menopausal symptoms, short-term therapy for up to three years may be all that is needed. As was noted earlier, short term HRT has not been associated with excessive risk over benefit. If the goal is to reduce the risk of osteoporosis or possibly dementia & colon cancer, long-term therapy is required.

Because of the Women's Health Initiative, I consider the risk of heart disease & stroke with HRT to be an unknown at this time. I also think that HRT should not be started or continued for the sole reason of a reduction in these events. An occasional patient does not want to take Premarin because of the alleged mistreatment of pregnant mares used in the production of this compound. In investigating this with the drug companies, I can find no evidence to support mistreatment of the mares or their foals.

Selective Estrogen Receptor Modulators (SERM's) are a group of compounds currently under development that have estrogen like effect on bone and lipids but no estrogen effect on the breast or uterus. Raloxifen (Evista) is such a drug that is currently available. Unfortunately these drugs will not relieve menopausal symptoms and can still increase the risk of venous blood clots in susceptible people. With the availability of raloxifen I am now recommending that women consider changing from standard ERT to a SERM after 3 to 5 years of standard HRT. This change to a SERM may reduce the risk of both breast cancer & cardiovascular disease. By waiting 3 to 5 years after menopause the patients are less likely to have menopausal symptoms like hot flushes with the SERM. There is also no need to use progesterone along with raloxifen or other future SERMs in women with a uterus.

In summary, a decision to use HRT is complex. I believe that the pros of HRT outweigh the cons for many women those needing relief from menopausal symptoms or in those who can't take alternative treatment to manage the risk of osteoporosis. The availability of SERM's may also reduce the worry over the potential for breast cancer, heart disease & stroke in long term ERT users.

See Also: Women's Health Initiative (http://www.nhlbi.nih.gov/whi/index.html)