| INDICATIONS
* Prevention of osteoporosis in early postmenopausal women with low bone density *Treatment of menopausal symptoms |
|---|
| CONTRA-INDICATIONS
* Pregnancy * Breast cancer * History of thrombophlebitis without trauma * Active hepatitis * Severe hypertriglyeridemia |
| USE WITH CAUTION
* Lupus * Endometriosis * May need to adjust doses of thyroid or coumadin * Coronary Artery Disease (don't start estrogen) |
| SIDE EFFECTS | |||
| Negative effects | Positive effects | ||
|---|---|---|---|
| Short-term | Breast tenderness Vaginal bleeding or spotting Enlarge fibroids Migraine headaches Abdominal bloating Nausea Skin rashes Increase triglycerides Coronary artery disease (with progestin) Thrombophlebitis Stroke | Reduce hot flashes
Less gain of abdominal fat Increase HDL cholesterol Decrease LDL cholesterol Helps vaginal atrophy In women 50-59 yrs old: Lower mortality Fewer cases breast cancer Better coronary arteries | |
| Long-term | Gall stones Breast cancer (especially with progestin) Endometrial cancer (if no progestin) | Fewer osteoporotic fractures
Decrease risk of colon cancer Improves pelvic musculature Prevents collagen loss in skin (fewer wrinkles) Questionable effects on Alzheimer's disease | |
June 21 2007 article by Manson in the New England Journal of Medicine showed that women aged 50-59 who took their estrogen (conjugated equine esgrogen 0.6mg/d) for 7 years had significantly fewer coronary calcifications than those who took placebo. The pie chart shows the degree of calcifications seen on CT scans (the higher the score, the higher the risk of coronary artery disease).
Another study looked at the incidence of breast cancer in those women who took the estrogen. There were significantly fewer cases of cancer in these women. It is important to note that they were not taking progestins.
Stefanick ML. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. Jama 2006;295(14):1647-57. Copyright 2006. American Medical Association. All Rights reserved. Used with permission.
This graph demonstrates the major findings of the Women's Health Initiative. There were two parallel studies, one using progestin and estrogen in 16,000 women, the other in 10,000 women who had a hysterectomy, using estrogen alone. The first trial was terminated after 5 years due to increased risk of breast cancer. The second was terminated after 7 years due to increased risk of stroke. From the graph you can see that in both studies the death rate was the same in estrogen users and placebo users, the rate of fractures was lower in the estrogen groups, and the number of strokes and blood clots was higher in the estrogen groups. The women who took estrogen and progestin had higher risks of heart disease and breast cancer than placebo, but this was not seen when women took estrogen alone.
The above graph shows the results from the estrogen-only study in a subset of the women who were age 50-59. The incidence of total fractures were not given, and only 5 of these younger women (of about 3,000) had a hip fracture. None of the differences between placebo and estrogen were considered statistically significant overall, but in women who actually took their medications the mortality and breast cancer rates were better in the estrogen group. In the estrogen+medroxyprogesterone study, women who were within ten years of menopause had slightly fewer cases of heart disease. Overall, therefore, estrogen in young women does not have the same risks as estrogen in older women!
The findings related to osteoporosis are not surprising to anybody who understands bone physiology. This is "grade A" evidence that estrogen prevents fractures, including hip fractures, in postmenopausal women. The new results confirm many observational results of beneficial effect of estrogen on fractures. These findings are even more important because the WHI study population was not selected for women who had low bone density.
My current recommendation is to use low to moderate doses of estrogen in women within ten years of menopause who have low bone density (bottom 20% of population, T-score lower than -1.6 at age 50) but are otherwise healthy. They should get mammography and endometrial screening. Some people believe that estrogens should not be used for any prevention, and they suggest that bisphosphonates can be used instead. But the bisphosphonates strongly inhibit bone formation rates and there is no evidence that they will prevent fractures beyond 5 years of use. Calcium and exercise alone may not be protective enough in women with low bone density.
In older women (more than ten years since menopause), estrogen is effective for preventing fractures, but it is not the first choice medicine because of side effects on the heart or strokes. Women who have already decided to use estrogen for other symptoms will be getting good bone protection.
The Women's Health Initiative did not address the question about keeping women on estrogen if they have already been taking it for a long time. Observational studies suggest that if estrogen was started at menopause and continued for a long time, there are fewer hip fractures and heart attacks, but slightly more cases of breast cancer. Maybe a very low dose would also work, but the breast cancer risk of low dose or transdermal estrogen has not been evaluated. Therefore, I usually suggest switching to raloxifene after a 10 or 15 years of estrogen.
Conjugated equine estrogens have been used most commonly in the United States, and most of the large epidemiological studies have been done with this form of oral estrogen. Dose-response studies show that 0.625 mg/day of conjugated estrogens give higher increases in bone density than lower doses. A recent study of estratabs showed dose-response between 0.3 and 1.2 mg/d in perimenopausal women. Other forms and routes of administration appear to give similar results in terms of bone density.
A paper by Recker showed that estrogen at a dose of .3mg/day along with adequate calcium and vitamin D was able to maintain bone density in women older than 65. Prestwood found benefits from ultra-low doses of estradiol of only .25mg/day.
 New! A recent report by Lindsay R showed that most early postmenopausal women had stable bone density on lower doses (.3 to .4mg/day conjugated estrogens). Also, Johnson SR found that ultra-low dose transdermal estradiol (.014mg/d) did not cause abnormal endometrial hyperplasia in a 2-year study. |
| Estrogen doses for osteoporosis prevention | ||
| Preparation | Brand name | Dose |
|---|---|---|
| Conjugated estrogens | Premarin, Cenestin | .3 to .625 mg/day |
| Synthetic estradiol | Estrace | .5 to 1 mg/day |
| Esterified estrogens, estrone | Estratabs, Menest | .3 to .625 mg/day |
| Estrone sulfate | Ogen | .6 to 1.25 mg/day |
| Transdermal estradiol | Estraderm, Vivelle, Climera | .02 to .05 mg/day |
| Transdermal estradiol | Menostar | .014 mg/day |
Epidemiological studies have suggested that the maximum prevention of fractures occurs in women who started estrogen within 5 years of menopause. Theoretically it would be beneficial to give estrogen right at menopause to prevent the perforation of plates in trabeuclar bone, with disruption of the trabecular architecture. Once the trabeculae are broken, they do not reconnect again, and bone strength may not be gained even if bone density increases. Read more about the mechanisms of action of estrogen on the bone.
In older women, estrogen increases bone density as well as bisphosphonates, and estrogen prevents fractures. However, as discussed above, there is a greater risk of starting estrogen in women who are more than ten years past menopause. Therefore, it would not be a first choice medication for osteoporosis in older women.
Progestins have been given to women who still have a uterus, because estrogen alone can increase the chance of endometrial cancer. However, in view of the recent studies showing increased risk of breast cancer and heart disease in women taking combination hormone therapy, the entire set of previous recommendations must be reconsidered.
Some studies have shown that progestins do not result in any additional benefits to the bone in women who are taking estrogen, either premenopausal (Prior, J. C., Hergenroeder, A. C.) or postmenopausal (Adachi, J. D., PEPI writing group(1996), Nand, S. L.). However, abstracts at the 2001 ASBMR meetings have shown increased bone density with norethindrone and (slightly) medroxyprogesterone acetate, when added to estrogen.
Progestins have several side effects, including bloating and depression. The beneficial effects of estrogen on the serum lipids are reduced with progestins (not as much with micronized progesterone as with medroxyprogesterone) as shown in the PEPI study (Barrett-Connor, E.). A study (Schairer, JAMA 2000; 283:485) of 46,355 women followed for an average of 10 years (during which time there were 2082 cases of breast cancer) showed that the overall risk for breast cancer was 3.9% per year in women not using hormones, 4.5% per year in those using estrogen, and 5.8% per year in those using both estrogen and a progestin.
Another study of a million women from England shows significantly more cases of breast cancer in women taking combination estrogen and progestin than in women taking estrogen alone. The risk per 1000 women over ten years was 5 extra cases of breast cancer from estrogen alone and 19 extra cases with combination.
Million Women Study Collaborators, Lancet 2003; 362: 419Ð27, used with permission.
Since this data is new, there are no consensus opinions about progestins. Possible approaches for women with a uterus are to take estrogen alone with endometrial biopsies, to take local progestin suppositories or a progesterone IUD. Small studies show that long-cycle therapy (estrogen every day and progesterone for about a week every 3 to 4 months) does not have adverse effects on the uterus. Larger studies are underway.
Many physicians do not realize that estrogen improves the bone density as well or better than alendronate. Below is a table of bone density results from randomized trials comparing estrogen to bisphosphonates, and a graph from the study in women younger than 60 (Ravn). There are additionally dozens of studies in postmenopausal women showing that estrogen improves bone density better than placebo or calcium.
| CARDIOVASCULAR AND LIPID |
|---|
| The effects of estrogen on the cardiovascular system are complicated. There is good evidence that estrogens increase HDL and decrease LDL cholesterol. In primate models, estrogen has been shown to have beneficial effects on the development of arteriosclerotic plaques in the coronary arteries, which were independent of the effects on the lipids. Estrogen also modulates vasoreactivity in human studies.
There is a discrepancy between long-term observations of women who decided to take estrogens, and relatively short-term randomized trials. The observations have strongly suggested a benefit of estrogen on cardiovascular disease. The Women's Health Initiative results were described above, showing negative effects of estrogen-progestin and neutral effects of estrogen alone and beneficial effects of estrogen alone in the younger women. There are several theories to explain these differences, and so far none have been proven, although some are more popular than others.
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| ENDOMETRIAL CANCER |
| Unopposed estrogen increases the risk of endometrial cancer from 1/1000/year to about 6/1000/year. This type of cancer has a high cure rate with hysterectomy. The rate of endometrial hyperplasia is 34% over 3 years. In women taking postmenopausal hormones, there is a trade-off between breast cancer and endometrial cancer. |
| THROMBOPHLEBITIS |
| Estrogens increase some of the proteins in the clotting cascade. This causes measurable changes in laboratory tests of coagulation but only minor clinical adverse events. Several studies ( Perez Gutthann, Varas-Lorenzo, Miller) have suggested that the incidence of thrombophlebitis increased with estrogen, especially during the first year of therapy. The annual risk was 1.3 cases per 10,000 women who didn't use estrogen and 2.6 cases per 10,000 women using estrogen. The Women's Health Initiative also found an increased relative risk of venous thromboembolism (16 per 10,000/yr without and 34 per 10,000/yr with hormones). Estrogens should not be used in women with a history of coagulopathy, although a remote history of a single episode of thrombophlebitis associated with surgery, trauma or pregnancy is not a contraindication. The recent HERS study showed a higher incidence of thrombophlebitis in women who already had coronary artery disease. Again, women in the estrogen group had about twice as many side effects related to this than women in the placebo group. |
| OTHER EFFECTS |
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Click to read more about estrogen's mechanisms of action
