As we all know, menopause is being medicalized. The emphasis in the medical literature has been on the purported adverse effects on women's health and well-being of not taking taking hormones. Much less attention is paid to the adverse effects of taking hormones. Women are repeatedly told that the benefits of hormones outweigh the risks (1). In recent years, however, the alleged benefits of taking long-term hormones have been challenged and the long list of adverse effects found in women who use hormones continues to grow. In some cases, the effects that were thought to be beneficial have now been found to be adverse.

The evidence is overwhelming that estrogen is linked to breast cancer. Women who have had their ovaries removed before menopause are at a substantially lower risk than women who have not. In fact, in the past this common medical knowledge was the rationale used for removing a woman's ovaries after the diagnosis of breast cancer to treat this disease. Now this reduction in estrogen is accomplished chemically. Tamoxifen, sometimes referred to as an anti estrogen because it works by blocking estrogen to the breast, has become a mainstay for the treatment of breast cancer (2).

Because of this very strong association between estrogen and breast cancer, women at greater risk have been discouraged from taking extra estrogen around menopause (3). So, if estrogen had no effect on breast cancer, you would then expect women who are given estrogen to have less breast cancer simply because they were less likely to develop breast cancer in the first place. (This is referred to as "selection bias.") But this is not what the research shows. In most observational studies (but not all) an increased risk among women who used menopausal hormones is found (4). A meta-analysis from 51 epidemiological studies which included 90% of published research world-wide, found an increased risk in women who take estrogen for more than five years (5). In a recent case-control study, women who took hormones for five or more of the last 6 years had a 60% to 85% greater risk than women who never took hormones (6). The authors of this study give us another way of understanding these results. If we extended these results to the larger population, for every 100,000 women who don't take hormones, 253 women will get breast cancer in a given year compared to 419 women who have taken hormones for 5 or more years. So, in a population of 100,000 women, an additional 166 women will develop breast cancer per year (a 66% increase) who would not have, if they had not been given hormones.

There are other cancers also associated with estrogen use. In the past, it was found that endometrial cancer, cancer of the lining of the uterus increased 5 to 10 times what it would be if no estrogen was used. Now that it is common practice to add a progestin to the estrogen, this adverse effect seems to be completely negated, at least for the first five years. After this time, however, the rate of endometrial cancer is about twice as high than it would be if no hormones were taken (7). Ovarian cancer doubles after about 10 years of use (8). But what about colon cancer, doesn't estrogen decrease it? This purported benefit is now being questioned. While estrogen has been credited with reducing polyps in the colon, a precursor of cancer, it has recently been found that this reduction only takes place in women over 65 and older (9). For women under 65, estrogen effects women adversely in that polyps actually increase.

Other serious adverse effects of hormone use include blood clotting (10), worsening of urinary incontinence (11), dry eyes (12) and gallbladder disease (13). Estrogen also increases C- reactive protein, a marker for inflammation that may actually increase risk of heart disease (14). In addition, a testosterone deficiency is induced in women taking estrogen creating a rationale for adding an androgen to the mix (15). Androgens have their own adverse effects such as virilization and liver toxicity (16). Some women who take hormones complain of breast tenderness, intermittent or monthly bleeding, cramps, and headaches (17). In most randomized clinical trials, the drop-out rate among women assigned to take hormones is greater than those assigned to take placebos, much of this due to the hormones' adverse effects (18).

But, you may ask, what about quality of life? Doesn't that improve with estrogen? A quality of life questionnaire assessing physical functioning, emotional health, vitality and depression was given to women who participated in the HERS trial (19). You may recall, this was a randomized clinical trial of women with established heart disease. Quality of life was improved only in women who had distressful hot flashes at entry into the study. Those of us who have experienced this type of distress know that when it is relieved, we feel much better. We can sleep through the night, and indeed our quality of life does improve. For women not experiencing bothersome hot flashes, however, the overall quality of life among hormone users actually decreased. They had a greater decline in physical function and energy compared to those assigned to placebo, while there were no changes in mental health or depressive symptoms. These findings are consistent with other studies.

Proponents of hormones argue that many of the studies showing adverse effects are small and inconclusive. They continue to argue that these risks are worth the benefits and continue to advise women to take hormones after menopause. It is important to note that we cannot say with scientific certainty that taking estrogen causes (or doesn't cause) many of these adverse effects but there is strong evidence that it does. It is equally important to note that the near-certainty of many so-called benefits of hormones have not held up to scrutiny. For example, rather than a decreased risk of heart disease among hormone users, the best evidence shows either an increased risk or a neutral effect among estrogen users compared to women who don't take estrogen (20). The FDA never approved hormones for the prevention of heart disease because there is insufficient evidence that it does. The FDA withdrew its approval of hormones for the treatment of osteoporosis because of insufficient evidence that it is beneficial (21). The FDA has never even considered hormones for prevention of Alzheimer's disease. The best evidence shows that it has no effect on treating this disease (22).

Rather than menopause as a threat to women's health, it is the so- called replacement hormones that are a threat. While women who have distress from hot flashes may benefit from the short-term use of hormones, women without distress are more likely to have a decrease in quality of life. Long term hormones (more than 5 years) for women with or without distress, however, is much more likely to result in net harm.

This article may be criticized for fear-mongering but I feel strongly that the fear-mongering comes from those who are medicalizing menopause. A tremendous amount of money is being spent trying to convince midlife and older women that they are deficient and require hormones to maintain health and increase longevity. The adverse effects of these hormones have been trivialized. Women need to be made aware of the research so they can make health decisions compatible with their own interests and beliefs.

1. Toozs-Hobson, R. and Cardoza, L. Hormone replacement therapy for all? Universal prescription is desirable. Br. Med. J. 313: 350, 1996. Col, N.F., et al. Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women. Arch. Intern. Med. 159: 1458-1466, 1999. Panico, S., et al. Large-scale hormone replacement therapy and life expectancy: Results from an international comparison among European and North American populations. Am. J. Public Health. 90: 1397-402, 2000.

2. O'Shaughnessy, J. Breast cancer risk reduction: it's the standard of care. Primary care and cancer. 2001; 21 (9) 11-12.

3. Hemminki E, Sihvo, S. A review of postmenopausal hormone therapy recommendations; Potential for selection bias. Obstet Gynecol 1993; 82: 1021-28.
Notevolitz M. Estrogen replacement therapy: indicatins, contraindications, and agent selection. Am J Obstet Gynecol 1989; 161: 1832-1841.

4. Colditz, G.A., et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N. Engl. J. Med. 332: 1589-1593, 1995.
Schairer, C., Lubin, J., and Troisi, R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. J.A.M.A. 383: 485-491, 2000.

5. Collaborative Group on Hormonal Factor in Breast Cancer. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047-1059, 1997.

6. Chen, Chi-Ling et al. Hormone replacement therapy in relation to breast cancer. case-control study. JAMA2002; 287: 734-41.

7. Beresford, S.A.A., et al. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestin therapy in postmenopausal women. Lancet , 1997; 349: 458-461.

8. Rodriguez C, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001(March 21); 285:1460-1465.

9. Woodson, K, et al. Hormone replacement therapy and colorectal adenoma recurrence among women in the Polyp Prevention Trial. J Natl Cancer Inst 2001; 93: 1799-05 & 1764- 5

10.The Writing Group for the PEPI Trial. Effects of Estrogen or Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 273:199-208, 1995. Daly. E., et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 348: 977-980, 1996.

11. Grady D, et al. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001; 97: 116-20.

12. Schaumberg, DA et al. Hormone replacement therapy and dry eye syndrome. JAMA 2001; 286: 2114-2119.

13. Petitti, D.B., Sidney, S., and Perlman, J.A. Increased risk of cholecystectomy in users of supplemental estrogen. Gastroenterology 1988; 94: 91-95.

14. Cushman, M., et al. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler. Thromb. Vasc. Biol. 19: 893-899, 1999.

15. Casson, P.R., et al. Effect of postmenopausal estrogen replacement on circulating androgens. Obstet. Gynecol. 1997; 90: 995-998.

16. Urman, B., Pride, S.M., and Yuen, B.H. Elevated serum testosterone, hirsutism, and virilism associated with combined androgen-estrogen hormone replacement therapy. Obstet. Gynecol. 1991; 77: 595-598.

17. These side effects can be found in the Physician's desk reference. In the 2000 edition, see page xxx . It is also included in the package inserts. In most studies, these side effects are typically given as reasons for discontinuing the use of hormones.

18. In the HERS trial, a US study (JAMA 1998; 280: 605-613), 30% of women assigned to hormones dropped out compared to 21% of those assigned to placebo.
In the Papworth HRT Atherosclerosis Study, a European study, the difference was much greater, 39% of women assigned to hormones dropped out compared to only 7% of women assigned to placebo ( European Heart Journal 2000; 21: Suppl: page 212 abstract #P1194)

19. Hlatky, MA. Quality of life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the heart and Estrogen/progestin Replacement Study (HERS) trial. JAMA 2002; 287: 591-597.

20. Hulley, S., et. al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280: 605-613. Herrington, DM et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl. J. Med. 2000; 343; 522- 529. Kolata, G. Estrogen use tied to slight increase in risks to heart: Data is not conclusive. New York Times, April 5, 2000, A1. For an update of the Women's Health Initiative, see www.nhlbi.nih.gov/whi/hrt.htm. For a summary of the heart disease studies click on "Hormones and Heart Disease:..." under heart disease.

21. This change took place in 1999. but has not been widely publicized. In the 2000 edition of the PDR, you can find evidence of the change. Under "Indication and Usage" it states that estrogen is indicated for the prevention of osteoporosis. In the 1999 edition, it reads that it is indicated for the prevention and treatment of osteoporosis.

22. Meyer, V. Alzheimer's disease, menopause, and hormones: cutting through the confusion. Network News, March/April 2002.,