Menopause Treatment

 An interesting article for someone considering treatment for her menopausal symptoms. A fairly balanced approach.

Waking up flushed and sweaty several times a night left Cathy feeling tired all day. But when she began to feel hot on and off during the day as well, she went to see Dr. Kent. He told Cathy she was having hot flashes—a sign that she was starting the menopause transition. Dr. Kent talked about several ways to control her hot flashes. One was to use the hormone estrogen for a short time. He talked about the benefits and risks of this choice. Cathy said she remembered hearing something on a TV talk show about using hormones around menopause. Were they helpful? Were they safe? She didn’t know.

A hormone is a chemical substance made by an organ like the thyroid gland or ovary. Hormones control different body functions. Examples of hormones are estrogen, progesterone, testosterone, and thyroid hormone.  In a woman’s body during the menopause transition, the months or years right before menopause (her final menstrual period), levels of several hormones, including estrogen and progesterone, go up and down irregularly. This happens as the ovaries work to keep up with the needs of the changing body.

Menopause is a normal part of aging. It is not a disease or disorder that has to be treated in all cases. Women may decide to use hormones like estrogen because of the benefits, but there are also side effects and risks to consider.

Dr. Kent told Cathy to call back for a prescription if she decided to try using hormones to relieve her symptoms. She read pamphlets from the doctor’s office and talked to her friends. Lily, who had surgery to remove her uterus and ovaries, has been taking the hormone estrogen since the operation. Sandy said she’s had a few hot flashes, but isn’t really uncomfortable enough to take hormones. Melissa is bothered by hot flashes and can’t sleep, but her doctor thinks she should not use estrogen because her younger sister has breast cancer. Each friend had a different story. Cathy wanted more information.

Do hormones relieve menopause symptoms?

Symptoms such as hot flashes might result from the changing hormone levels during the menopause transition. After a woman’s last menstrual period, when her ovaries make much less estrogen and progesterone, some symptoms of menopause might disappear, but others may continue.

To help relieve these symptoms, some women use hormones. This is called menopausal hormone therapy (MHT). This approach used to be called hormone replacement therapy or HRT. MHT is a more current, umbrella term that describes several different hormone combinations available in a variety of forms and doses.

How would I use MHT?

Estrogen is a hormone used to relieve the symptoms of menopause. Estrogen alone (E) may be used by a woman whose uterus has been removed.  But a woman who still has a uterus must add progesterone or a progestin (synthetic progesterone) along with the estrogen(E+P). This combination lowers the chance of an unwanted thickening of the lining of the uterus and reduces the risk of cancer of the uterus, an uncommon, but possible result of using estrogen alone.

Cathy’s friend Stephanie takes a pill containing estrogen and progestin, but Cathy has trouble swallowing pills. If MHT is only available as a pill, that is something she’d consider when making her decision.

Estrogen comes in many forms. Cathy could use a skin patch, vaginal tablet, or cream; take a pill; or get an implant, shot, or vaginal ring insert. She could even apply a gel or spray. There are also different types of estrogen (such as estradiol and conjugated estrogens). Estradiol is the most important type of estrogen in a woman’s body before menopause.  Other hormones, progesterone or progestin, can be taken as a pill, sometimes in the same pill as the estrogen, as well as a patch (combined with estrogen), shot, IUD (intrauterine device), gel, or vaginal suppository.

The form of MHT your doctor suggests may depend on your symptoms. For example, an estrogen patch (also called transdermal estrogen) or pill (oral estrogen) can relieve hot flashes, night sweats (hot flashes that bother you at night), and vaginal dryness. Other forms—vaginal creams, tablets, or rings—are used mostly for vaginal dryness alone. The vaginal ring insert might also help some urinary tract symptoms.

The dose can also vary, as can the timing of those doses. Some doctors suggest that estrogen be used every day, but that the progesterone or progestin be used cyclically—for 10 to 14 straight days every four weeks. A cyclic schedule is thought to mimic how the body makes estrogen and progesterone before menopause. This approach can cause some spotting or bleeding, like a light period, which might get lighter or go away in time. Alternatively, some women take estrogen and progesterone or progestin continuously—every day of the month.

Is there a downside to taking hormones?

A lot of the information Cathy read said that taking estrogen is the most effective way to relieve hot flashes, night sweats, and vaginal dryness. Estrogen also helps keep bones strong. Cathy thought that those seemed like good reasons to use MHT. But she wondered, is there a downside?

Research has found that, for some women, there are serious risks, including an increased chance of heart disease, stroke, blood clots, and breast cancer, when using MHT. There may also be an increased risk of dementia in women when they start MHT after age 65. These concerns are why every woman needs to think a lot before deciding to use menopausal hormone therapy.

Also, some women develop noticeable side effects from using hormones:

  • breast tenderness
  • spotting or a return of monthly periods
  • cramping
  • bloating

By changing the type or amount of the hormones, the way they are taken, or the timing of the doses, your doctor may be able to help control these side effects. Or, over time, they may go away on their own.

What more should I know about the benefits and risks of hormones?

Cathy knows there have been news stories about menopausal hormone therapy research findings. But, several years ago, when she first heard about the risks of using estrogen, she didn’t really pay attention. Now she wants to know more about the risks.

Over the years, research findings have led to a variety of positive, negative, and sometimes conflicting reports about menopausal hormone therapy. Some of these findings came from randomized clinical trials, the most convincing type of research. Historically, clinical trials often used one type of estrogen called conjugated estrogens.  Several other types of estrogen, as well as progesterone and progestins, have also been tested in small trials to see if they have an effect on heart disease, breast cancer, or dementia.

Let’s look more closely at what we have learned from these small studies.

Hot flashes and night sweats—Estrogen will relieve most women’s hot flashes and night sweats. If you stop using estrogen, you may again start having hot flashes. Lifestyle changes and certain prescription medicines also might help some women with hot flashes. For most women, hot flashes and night sweats go away in time.

Vaginal dryness—Estrogen improves vaginal dryness, probably for as long as you continue to use it. If vaginal dryness is your only symptom, your doctor might prescribe a vaginal estrogen. A water-based lubricant, but not petroleum jelly, may also relieve vaginal discomfort.

Cholesterol levels—Estrogen improves cholesterol levels, lowering LDLs (the “bad” kind of cholesterol) and raising HDLs (the “good” kind of cholesterol). The pill form of estrogen can cause the level of triglycerides (a type of fat in the blood) to go up. The estrogen patch does not seem to have this effect, but it also does not improve cholesterol to the same degree as the pill form. But, improving cholesterol levels is not a reason to take estrogen. Other medicines and lifestyle changes will improve cholesterol levels more effectively.

What is the Women’s Health Initiative? What have we learned from it?

Before menopause, women generally have a lower risk of heart disease than men. This led experts to wonder whether giving women estrogen after menopause might help prevent heart disease. In 1992, the National Institutes of Health (NIH), the nation’s premier medical research agency, began the Women’s Health Initiative (WHI) to explore ways postmenopausal women might prevent heart disease, as well as osteoporosis and cancer. One part of the WHI, the Hormone Trial, looked at oral conjugated estrogens used alone (E) or with a particular progestin (E+P) to see if, in postmenopausal women, estrogen could prevent heart disease without increasing the chance of breast cancer.

In July 2002, the E+P part of the WHI Hormone Trial was stopped early because it became clear to the researchers that the overall risk of taking E+P outweighed the benefits:

Benefits

  • Fewer fractures
  • Less chance of colon and rectum cancer

Risks

  • More strokes
  • More serious blood clot
  • More heart attacks
  • More breast cancers

In April 2004, the rest of the Hormone Trial, the E alone group, was also halted because using estrogen alone did not have a positive effect on heart disease overall and increased the risk of stroke.

During the first 3 years after stopping the E+P used in the WHI, women were no longer at greater risk of heart disease, stroke, or serious blood clots than women who had not used MHT. On the other hand, they also no longer had greater protection from fractures. The women still had an increased risk of breast cancer, but their risk was smaller than it was while they were using hormones.

It appears from the WHI that women over age 60 should not begin using MHT to protect their health—it will not prevent heart disease or dementia when started several years after menopause. In fact, older women in the study using MHT were at increased risk of certain diseases. On the other hand, women who were less than age 60 did not appear to be at increased risk of heart disease, and the overall risks and benefits appeared to be balanced.

It is important to remember that the WHI findings are based on the specific oral form (rather than patch, gel, etc), dose, and type of estrogen and progestin studied in the WHI. Which hormones and dose you use and the way you take them might change these benefits and risks. We don’t know how the WHI findings apply to these other types, forms, and doses of estrogen and progesterone or progestin.

The U.S. Food and Drug Administration (FDA) now recommends that women with moderate to severe menopausal symptoms who want to try menopausal hormone therapy for relief use it for the shortest time needed and at the lowest effective dose.

What are some other options?

Cathy is like a lot of women bothered by symptoms of menopause. After learning about some research results, she is concerned about using menopausal hormone therapy for relief of her symptoms. But it’s been several years since some study findings raised concerns, and now Cathy is wondering whether there is anything new.

Women now have more options than when the WHI study was first planned. More types of estrogens are available, and some of them come in a variety of forms. For example, synthetic estradiol, now available in several forms (pill, patch, cream, gel, etc.), is chemically identical to the estrogen most active in women’s bodies before menopause. If it is not taken by mouth, but rather applied to the skin or taken as a shot, estradiol appears to work the same way as estradiol made in the body. Investigators are now studying a low-dose estradiol patch (transdermal estradiol) compared to a low-dose conjugated estrogens pill to see whether one or both slow hardening of the arteries in women around the age of menopause and whether the estradiol patch is as effective and, perhaps, safer than the conjugated estrogens pill. These alternatives are creating more choices for women seeking relief from their menopausal symptoms, as well as a variety of new opportunities for research.

Besides a pill, some estrogens come in different and sometimes new forms—skin patch, gel, emulsion, spray, and vaginal ring, cream, and tablet. These forms work in the body somewhat differently than a pill by entering your body directly through the skin or walls of the vagina. Oral estrogen (a pill) is chemically changed in the liver.  Some studies suggest that if estrogen enters through the skin and bypasses the liver, the risk of serious blood clots or stroke might be lower. Others suggest a lower risk of gallbladder disease. This may also allow a change in dosage—further testing may show that the same benefits might come from lower doses than are needed with a pill.

What questions remain unanswered?

Cathy was beginning to understand more about the benefits and risks of using hormones, but she wondered whether there are still questions about the WHI results and menopausal hormone therapy in general. What else needs to be looked at?

Experts now know more about menopause and have a better understanding of what the WHI results mean. But, they have new questions also.

  • The average age of women participating in the trial was 63, more than 10 years older than the average age of menopause, and the WHI was looking at reducing the risk of chronic diseases of growing older like heart disease and osteoporosis. Do the WHI results apply to younger women choosing MHT to relieve symptoms around the time of menopause or to women who have early surgical menopause (surgery to remove both ovaries or the uterus)?
  • Other studies show that lower doses of estrogen than were studied in the WHI provide relief from symptoms of menopause for some women and still help women maintain bone density. What are the long-term benefits and risks of lower doses of estrogen?
  • In the WHI, women using E alone did not seem to have a greater risk of heart disease than women not using hormones. Does this mean that the risk of heart disease in healthy women in their 50s who can use estrogen alone might not be higher than the risk in women who don’t use estrogen?
  • Would using progesterone or a different progestin than the one used in the WHI be less risky to a woman’s heart?
  • The combination menopausal hormone therapy used in the WHI makes it somewhat more likely that a woman could develop breast cancer, especially with long-term use. Is using a different type of estrogen, a smaller dose of estrogen or progesterone, or a different progestin (instead of medroxyprogesterone acetate) safer?
  • Does using estrogen around the time of menopause change the risk of possible dementia in later life as starting it after age 65 did in the WHI Memory Study (WHIMS)?

The National Institute on Aging and other parts of the National Institutes of Health, along with other medical research centers, continue to explore questions such as these. They hope that in the future these studies will give women additional facts needed to make informed decisions about relieving menopausal symptoms.

What are “natural hormones”?

Cathy’s friend Susan thinks she is not at risk for serious side effects from menopausal hormone therapy because she uses “natural hormones” to treat her hot flashes and night sweats. Cathy asked Dr. Kent about them. He told her that there is very little reliable scientific information from high-quality clinical trials about the safety of “natural” or compounded hormones, how well they control the symptoms of menopause, and whether they are as good or better to use than FDA-approved estrogens, progesterone, and progestins.

The “natural hormones” Susan uses are estrogen and progesterone made from plants such as soy or yams. Some people also call them bioidentical hormones because they are supposed to be chemically the same as the hormones naturally made by a woman’s body. These so-called natural hormones are put together (compounded) by a compounding pharmacist. This pharmacist follows a formula decided on by a doctor familiar with this approach. Compounded hormones are not regulated or approved by the FDA. So, we don’t know much about how safe or effective they are or how the quality varies from batch to batch.

Drug companies also make estrogens and progesterone from plants like soy and yams. Some of these are also chemically identical to the hormones made by your body. These other forms of MHT are available by prescription.  Importantly, hormones made by drug companies are regulated and approved by the FDA.

There are also “natural” treatments for the symptoms of menopause that are available over-the-counter, without a prescription. Black cohosh is one that women use, but a couple of clinical trials have shown that it did not relieve hot flashes in postmenopausal women or those approaching menopause.  Because of rare reports of serious liver disease, scientists are concerned about the possible effects of black cohosh on the liver. Other “natural” treatments are made from soy or yams. None of these are regulated or approved by the FDA.

What’s right for me?

There is no single answer for all women who are trying to decide whether to use menopausal hormone therapy (MHT). You have to look at your own needs and weigh your own risks.

Here are some questions you can ask yourself and talk to your doctor about:

  • Do menopausal symptoms such as hot flashes or vaginal dryness bother me a lot? Like many women, your hot flashes or night sweats will likely go away over time, but vaginal dryness may not. MHT can help with troubling symptoms.
  • Am I at risk for developing osteoporosis? Estrogen might protect bone mass while you use it. However, there are other drugs that can protect your bones without MHT’s risks. Talk to your doctor about the risks and benefits of those medicines for you.
  • Do I have a history of heart disease or risk factors such as high blood cholesterol? Using estrogen and progestin can increase your risk.
  • Do I have a family history of breast cancer? If you have a family history of breast cancer, check with your doctor about your risk.
  • I have high levels of triglycerides and a family history of gallbladder disease. Can I use MHT? The safety of any kind of MHT in women with high levels of triglycerides or a family history of gallbladder disease is not known. But some experts think that using a patch will not raise your triglyceride level or increase your chance of gallbladder problems. Using an oral estrogen pill might.
  • Do I have liver disease or a history of stroke or blood clots in my veins? MHT, especially taken by mouth, might not be safe for you to use.

In all cases, talk to your doctor about how best to treat or prevent your menopause symptoms or diseases for which you are at risk.

If you are already using menopausal hormone therapy and think you would like to stop, first ask your doctor how to do that. Some doctors suggest tapering off slowly.

Whatever decision you make now about using MHT is not final. You can start or end the treatment at any time, although, as we learned from the WHI, it appears that it is best not to start MHT many years after menopause. If you stop, some of your risks will lessen over time, but so will the benefits. Discuss your decision about menopausal hormone therapy with your doctor at your annual checkup.

MHT is not one size fits all

Cathy realized that talking to her friends about what each is doing to relieve menopause symptoms was helpful, but that her decision needed to be just for her. And she was sure that basing her decision just on what she heard on a TV show might not be the best way to choose. She tried to find sources of information that seemed to be unbiased and didn’t have a product to promote. She felt most comfortable with science-based websites like the National Institutes of Health, the U.S. Food and Drug Administration, or doctors’ professional groups.

Each woman is different, and the decision for each one about menopausal hormone therapy will probably also be different. But, almost every research study helps give women and their doctors more information to answer the question: Is menopausal hormone therapy right for me?

For More Information

Other resources on menopausal hormone therapy include:

National Institutes of Health
Menopausal Hormone Therapy Information
www.nih.gov/PHTindex.htm

The National Library of Medicine MedlinePlus www.medlineplus.gov website has information on many health subjects, including menopause. Click on Health Topics. Choose any topic you are interested in, such as menopause, menopausal hormone therapy, or osteoporosis, by clicking on the first letter of the topics and scrolling down the list to find it.

American College of Obstetricians and Gynecologists
409 12th Street, SW
P.O. Box 96920
Washington, DC 20090-6920
1-202-638-5577
www.acog.org

Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
1-888-463-6332 (toll-free)
www.fda.gov

North American Menopause Society
P.O. Box 94527
Cleveland, OH 44101
1-440-442-7550
1-800-774-5342 (toll-free)
www.menopause.org

For more information on health and aging, including menopause, contact:

National Institute on Aging
Information Center
P.O. Box 8057
Gaithersburg, MD 20898-8057
1-800-222-2225 (toll-free)
1-800-222-4225 (TTY/toll-free)
www.nia.nih.gov
www.nia.nih.gov/espanol

To order free publications (in English and Spanish) or sign up for email alerts, go to www.nia.nih.gov/health.

Visit NIHSeniorHealth (www.nihseniorhealth.gov), a senior-friendly website from the National Institute on Aging and the National Library of Medicine. This website has health information for older adults. Special features make it simple to use. For example, you can click on a button to have the text read out loud or to make the type larger.

NIH PUBLICATION NO. 09-7411

Publication Date: September 2009

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Avoiding HRT increases Mortality in Women

 

This important study reaffirms what I have been saying for a long time. Oestrogen is a women’s friend. The scare campaign about oestrogen has been based on a false premise, as a result of which many millions of women have suffered unnecessarily and many have died as a result. (see very thorough study below). Also check my blog of the 8th Sept which is very pertinent to this discussion.

Am J Public Health. 2013 September; 103(9): 1583–1588.
Published online 2013 September. doi:  10.2105/AJPH.2013.301295
PMCID: PMC3780684

The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years

At the time of the study, Philip M. Sarrel was with the Departments of Obstetrics and Gynecology and Psychiatry, Yale University School of Medicine, New Haven, CT. David L. Katz was with the Prevention Research Center, Yale University School of Public Health, Griffin Hospital, Derby, CT; and with the Department of Medicine, Yale University School of Medicine. Valentine Y. Njike was with the Prevention Research Center, Yale University School of Public Health. Valentina Vinante was with the Departemento di Sanita Pubblica, Universita di Firenze, Florence, Italy.
corresponding authorCorresponding author.
Correspondence should be sent to Philip M. Sarrel, MD, Emeritus Professor, Yale-Griffin Prevention Research Center, 130 Division St., Derby, CT 06418 (e-mail: ude.elay@lerras.pilihp). Reprints can be ordered at http://www.ajph.org by clicking the “Reprints” link.
Peer Reviewed

Contributors

P. M. Sarrel directed the literature search and assessment, and wrote the primary draft of the article. P. M. Sarrel and V. Y. Njike acquired the data. V. Y. Njike analyzed the data and developed the data tables. V. Vinante conducted the literature search. D. L. Katz developed the MTEA formula, reviewed and edited drafts of the article. All authors participated in data interpretation and critical article review.

Accepted February 18, 2013.

Abstract

Objectives. We examined the effect of estrogen avoidance on mortality rates among hysterectomized women aged 50 to 59 years.

Methods. We derived a formula to relate the excess mortality among hysterectomized women aged 50 to 59 years assigned to placebo in the Women’s Health Initiative randomized controlled trial to the entire population of comparable women in the United States, incorporating the decline in estrogen use observed between 2002 and 2011.

Results. Over a 10-year span, starting in 2002, a minimum of 18 601 and as many as 91 610 postmenopausal women died prematurely because of the avoidance of estrogen therapy (ET).

Conclusions. ET in younger postmenopausal women is associated with a decisive reduction in all-cause mortality, but estrogen use in this population is low and continuing to fall. Our data indicate an associated annual mortality toll in the thousands of women aged 50 to 59 years. Informed discussion between these women and their health care providers about the effects of ET is a matter of considerable urgency.

In the 1990s, estrogen therapy (ET) became the standard of treatment of the almost 600 000 women a year in the United States undergoing hysterectomy. Clinical studies had indicated ET was effective for treatment of menopausal symptoms and appeared to be bone protective and cardioprotective. More than 90% of hysterectomized women in their 50s used ET, with a continuance rate averaging 4 to 5 years.1–3

In July 2002, the Women’s Health Initiative (WHI) published the results of the Estrogen Plus Progestin Trial and announced that the study was being terminated ahead of schedule because of adverse effects in the women receiving hormones compared with those receiving placebo.4 The media impact was immediate, widespread, and persistent.5 The study’s treatment drug (Prempro) was often referred to as “HT” (hormone therapy) or “estrogen.” As a consequence, the findings were generalized to all varieties of hormone replacement, including estrogen alone, in women without a uterus although only women with a uterus were randomized in this study. Prescriptions for postmenopausal hormone replacement declined precipitously. Within 18 months, half of the women in the United States using systemic HT stopped treatment.1–3 Included were almost 2 000 000 women who had no uterus who were using ET and not using the study drug.

Subsequently, the findings of the WHI Estrogen-Alone Trial (WHI-ET) for women without a uterus were published for the intervention phase (2004) and the postintervention long-term follow-up phase (2011).6,7 These findings showed mortality benefits for ET compared with placebo. Preliminary subgroup analysis of the intervention phase data (2004) indicated reduced total mortality in the women aged 50 to 59 years. However, it is only in the postintervention data (2011) that an absolute total mortality risk reduction of 13 per 10 000 women per year was reported for these women. The mortality decrease was almost entirely owing to a decrease in coronary heart disease (CHD) although reduced cancer mortality and other cause mortalities were also reported among the women who received ET.7

Despite the positive findings for ET, prescriptions for all forms of systemic HT have continued to decline.3,8–11 Currently, less than one third of hysterectomized women are using ET.12 The decline in ET prescription and usage seems to reflect a generalized avoidance of any forms of HT not supported by the WHI data. This raises the possibility that there has been and continues to be a considerable resultant mortality toll. We therefore undertook an analysis, on the basis of published data, to determine the likely toll of excess, premature death among hysterectomized women aged 50 to 59 years in the United States following the WHI publication in 2002.

METHODS

The 2011 WHI publication indicated a 13 per 10 000 per year higher rate of mortality among hysterectomized women aged 50 to 59 years assigned to placebo than among those assigned to estrogen over a 10-year follow-up.7 We considered this figure a point estimate for the mortality burden associated with foregoing estrogen among members of this specific population.

To determine how this rate of excess mortality translated into an aggregate toll of premature death at the population level, we established the following formula to represent the mortality toll of estrogen avoidance (MTEA):

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where

  • t1–t10 = sum for years 1 through 10 (2002–2011),
  • CPF50–59 = size of population of women, aged 50 to 59 years, from US Census data (2002–2011),
  • PctHyst = percentage of women in CPF50–59 who have undergone hysterectomy (specific to year and age),
  • PctEsDec = absolute percentage decline in rate of estrogen use in group of interest, by year, following publication of WHI results, and
  • ExMoRate = excess mortality rate in group of interest as a result of estrogen avoidance.

When a single best estimate was available in the peer-reviewed literature or government data for any given entry in the formula for the entire span of 10 years or the entire population of women across the age range, we used that. If more precise estimates specific to year or age were available, we entered these and we then aggregated the calculations across years and age groups. Because of a distinctly differential rate of hysterectomy for women in the lower than the upper half of the age range of interest, we conducted separate calculations for these 2 populations and aggregated the results. To enhance the accuracy of our calculation, we applied the relevant rates to portions of the specified range and generated an estimate for the entire age range by determining the weighted average.

We calculated the mortality toll estimates on the basis of population estimates from census data, age variability for hysterectomy prevalence reported in the peer-reviewed literature, and different rates of ET use before 2002 affected by whether the women had their ovaries removed (oophorectomy). We applied the WHI absolute mortality estimate for women aged 50 to 59 years (13/10 000/year) in all the calculations, along with the extremes of the 95% confidence interval (CI) around this point estimate.

We derived the annual populations of women aged 50 to 59 years from 2002 to 2011 US Census estimates.13,14 We derived the hysterectomy prevalence rates, with and without oophorectomy, from 1997 to 2005 National Hospital Discharge Survey data.15,16 For women aged 50 to 59 years the rates ranged from 33% to 40%. The rates are consistent with an average of almost 600 000 hysterectomies per year among women of all ages in the United States. The average age for hysterectomy is 46.1 years.15,16

An estimated 54% of women have their ovaries removed at the time of hysterectomy.16 Before 2002, the ET use rate for women posthysterectomy without ovaries was 90% and with ovaries was 53%.17 Therefore, we calculated the mortality associated with a decline in ET use separately for women with and those without ovaries.

Compared with 2001, use of oral estrogen only in women aged 50 to 59 years declined almost 60% by 2004, reached a 71% relative decline by 2006, and remained at that level through 2009.3 Since then there has been further decline in ET use, with 2010 and 2011 showing a 79% decline for these particular women.10,11 We used these figures to generate a year-by-year absolute percentage decline in the use of estrogen beginning with a baseline rate in 2002.

We entered best estimates for each component of the formula to generate a single aggregate estimate for the total excess in premature mortality attributable to estrogen avoidance in the population of interest. We made a particular effort to choose well-validated and conservative entries.

We identified the range of reasonable estimates around the best point estimate when possible for purposes of sensitivity analysis, that is, determining the sensitivity of the calculated estimate to variation in a given entry. For each entry in the MTEA formula, we attempted to identify well-validated figures representing reasonable low- and high-end values.

We calculated the 95% CI around the excess death rate as a result of estrogen aversion using the sample size from the WHI study to generate high- and low-end estimates for the excess mortality in the placebo group relative to the estrogen group.

The range of values we produced in the sensitivity analysis is reflected in the data tables, which indicate how we altered our assumptions, which led to specific estimates of MTEA. There were ranges of relevant values for the rate of hysterectomy, the rate of estrogen use, and the exact mortality excess as derived from the WHI-ET study. Our sensitivity analysis involved entering values at the extremes of the range for each of these parameters and calculating an MTEA estimate accordingly. We analyzed the data using SAS, version 9.1 (SAS Institute, Cary, NC).

RESULTS

Table 1 displays the estimated mortality toll of estrogen avoidance among all women aged 50 to 59 years assuming the rate of estrogen use at baseline and decline in estrogen use over time were common to women both with and without oophorectomy at the time of hysterectomy (Figure 1). Applying the lower estimate for hysterectomy rate in the population,16 the best point estimate for excess mortality over 10 years is 49 128 excess deaths, and the extreme low estimate is 22 677 excess deaths. Applying a higher estimated rate of hysterectomy in the population,16 the best point estimate for excess mortality over 10 years is 59 549 excess deaths, and the extreme high estimate is 91 610.

TABLE 1

Mortality Estimates for All Women Aged 50–59 Years Using 2 Different Rates of Hysterectomy: United States, 2002–2011

FIGURE 1

Mortality toll of estrogen avoidance estimates flowchart.

Tables 2 and and33 show the differential mortality toll of estrogen avoidance for women with retained ovaries and ovaries removed, respectively. Estimates for the entire population thus require summing the totals from Tables 2 and and33 under similar assumptions. Applying the lower estimate for hysterectomy rate3 to both populations, the best point estimate for total excess mortality is 13 462 + 26 830, or 40 292. The low-end estimate is 6216 + 12 385, or 18 601 excess deaths. Applying the higher estimate for hysterectomy rate3 to both populations, the best point estimate for excess mortality is 16 316 + 32 519, or 48 835. The high-end point estimate is 25 098 + 50 027, or 75 125.

TABLE 2

Mortality Estimates of Hysterectomized Women Aged 50–59 Years With Retained Ovaries Using 2 Different Rates of Hysterectomy: United States, 2002–2011

TABLE 3

Mortality Estimates of Hysterectomized Women Aged 50–59 Years With Ovaries Removed Using 2 Different Rates of Hysterectomy: United States, 2002–2011

Thus, across a reasonable range of all assumptions, the excess mortality was between 18 601 and 91 610. Using the best available point estimate values with year-by-year adjustment and adjustment for differential rates of estrogen use among women with and without retained ovaries at hysterectomy, the range was 40 292 to 48 835.

DISCUSSION

Our analysis suggests that between 2002 and 2011 a minimum of 18 601 and as many as 91 610 excess deaths occurred among hysterectomized women aged 50 to 59 years following the publication of the original WHI findings because of the resulting aversion to hormone replacement therapy of all kinds that ensued among doctors and patients alike. The actual toll of excess mortality is likely to be between 40 292 and 48 835.

These numbers translate the WHI statistic for excess mortality in hysterectomized women aged 50 to 59 years who received placebo versus estrogen into an actual number of deaths. We believe that a mortality toll will better communicate the meaning and significance of the WHI-ET findings to women, health care providers (HCPs), and the media. The reported reduction in mortality for women aged 50 to 59 years in the WHI-ET reports was exactly the same (HR = 0.73) in 2004 and 2011.6,7 Neither the 2004 nor the 2011 WHI-ET reports reversed the decline in use of ET. The 2011 report of the 10.7 years of follow-up of ET-treated women, which included the absolute risk reduction in mortality rate of 13 per 10 000 per year in the hysterectomized women aged 50 to 59 years, was barely noticed. Decline in ET use has continued since its publication. Currently, it appears that only about one third of women having a hysterectomy with removal of their ovaries, regardless of age, are using ET.12 Before 2002, 90% of these women used systemic hormone replacement.17,18

Estrogen Therapy and Mortality

ET reduces total mortality primarily through reducing CHD-related deaths. Since 1959 there have been many reports showing increased risk of CHD mortality after early surgical menopause and especially after oophorectomy.19–21 Essentially, estradiol inhibits the development of atherosclerosis and helps maintain normal arterial blood flow.22,23

A 1998 meta-analysis of 25 observational studies reported a 30% lower risk of CHD in ET users.24 The California Teachers Study, in which 97% of the oophorectomized women used HT (almost entirely ET), shows an all-cause mortality reduction similar to the WHI-ET results.25

The WHI-ET and the California Teachers Study results indicate that the decrease in CHD events and all-cause mortality are limited to hysterectomized women younger than 60 years or within 10 years of menopause. A meta-analysis of 23 trials found that HT significantly reduced CHD events in these women.26 In fact, for CHD, the WHI-ET findings among women aged 50 to 59 years are in line with the reduced risks reported in the observational studies and support a “timing hypothesis” for ET cardioprotection when ET is started close to the time of menopause.27,28 The current thinking is that by age 60 years, pathological changes in vascular endothelial cells compromise the ability of estrogen to inhibit atherosclerosis and promote blood flow.27,28

Although prevention of cardiovascular mortality is by far the major benefit from ET in younger women, the WHI-ET and the California Teachers Study also show a reduction in cancer deaths. In 2012, the WHI-ET investigators reported a 63% reduction in mortality because of invasive breast cancer in the almost 12 years of follow-up in the postintervention study of ET users versus placebo users.29

Lack of Impact of the WHI–Estrogen-Alone Trial Findings

Continuing decline in ET prescriptions through 2011 attests to the WHI-ET data’s lack of impact.3,10,11 Numerous reasons for this can be suggested. Knowing the history of HT in the United States helps in understanding why there has been a strong reaction against the use of ET. In the 1960s, enthusiasm about using estrogen for menopause symptoms led to widespread use. In 1975 it was reported that unopposed estrogen in women with a uterus increased the risk of endometrial cancer. These findings led to fear of using estrogen. However, in the 1970s and 1980s, research on the addition of a progestin to ET showed that endometrial hyperplasia and carcinoma could be all but eliminated. At the same time, other research indicated that estrogen had bone-protective and cardioprotective effects. Confidence was restored, and once again there was widespread use of HT.

When the first WHI report came out in 2002 its findings about the health risks of postmenopausal HT were startling and frightening.5 Almost no one emphasized or even seemed to recognize the fact that the worst findings might not apply to hormones other than Prempro or might not apply to all age groups. Deciding not to use HT appeared to be the most appropriate and rational choice for almost all women. Aversion to all forms of HT became almost automatic, and the idea that there might actually be positive health outcomes of ET use was often dismissed.

There are other influences on women’s decisions about ET that are important but are beyond the scope of this study. These include HCPs paying little attention to WHI-ET reports; failure to differentiate between the findings of the 2 different WHI studies; mistrust of pharmaceutical companies and their products; peer group pressure to avoid estrogen; nonhormonal alternative therapies for hot flashes, prevention of osteoporosis, and sleep disturbance; the use of bioidentical hormones not approved by the US Food and Drug Administration; and pendulum swings in medical recommendations, which have created general skepticism about medical treatments.

Presenting Complex Biomedical Findings to the Public

Research findings are often nuanced and need to be reported accordingly in both the peer-reviewed literature and the popular press.30 It is the responsibility of biomedical researchers to report findings in a way that the media and the general public can clearly understand. With most medical interventions, as with hormone replacement, the findings and implications are not merely about what is done. They are also informed by how the intervention is delivered, exactly what preparation is used, under what particular circumstances, and in just what population. When findings pertain to specific preparations or populations, this should be stated explicitly and emphatically. Special effort should be made to explain the study nuances to HCPs. It is also the responsibility of the media and HCPs to convey this information so that it is clearly understood. Distortion of details can prove to be nothing less than lethal.

The WHI findings need to be presented so that the very important differences between the 2 treatment modalities are emphasized and the benefits for hysterectomized women aged 50 to 59 years are appreciated. This effort has clearly been inadequate to date.5,31

Limitations

The growing practice of performing hysterectomy outside hospitals using a laparoscopic transvaginal approach has decreased the number of hospital-based procedures. The prevalence estimate, therefore, may be less than the actual number of hysterectomized women aged 50 to 59 years.15 If so, our mortality estimates are all biased downward.

We used the decline in use of oral ET for our estimates. We did not include data for use of transdermal estradiol, nonsystemic estrogens, and bioidentical preparations, although millions of postmenopausal women currently use 1 or more of these preparations.

We did not include transdermal ET use in the WHI studies. The use of transdermal estradiol in the United States has declined since 2002. Transdermal estradiol has been reported to be more effective than are oral estrogens in preventing cardiovascular events, so decline in its use could contribute further to the mortality toll.

Vaginal estrogen use did show a substantial increase between 2001 and 2009.3 The effects of vaginal estrogen are thought to be local and nonsystemic. However, a recent report shows an unexpected finding of a reduced rate for myocardial infarction in women using vaginal estrogen. Whether vaginal estrogen has an effect on mortality needs further study.

There has also been an increase in the use of bioidentical hormone preparations since 2002, but we are not aware of mortality data for these compounds.

The WHI cohort of hysterectomized women aged 60 to 69 years showed no significant mortality difference between estrogen use versus placebo. For this reason, we did not do a calculation for this age group. For women aged 70 to 79 years in the WHI study, there is an increased absolute death rate of 19 per 10 000,7 and this age group has shown a 78% decrease use in ET since 2002.3 As a result, some reduction in mortality could be calculated because of not using estrogen. However, compared with the younger women, the overall population in this age group is much smaller and the percentage of hysterectomized women living into their 70s is less. Also, the use of ET before 2002 was much lower in these women.2

We did not include women younger than 50 years, as there were no comparable WHI data for this age group. Nevertheless, hysterectomy occurs most often before aged 50 years (the average age is 46.1 years).16 Mortality is increased in younger women who have a hysterectomy and oophorectomy who do not use ET. Therefore, it is likely that nonuse of ET in women younger than aged 50 years has an additional mortality toll. For example, in the California Teachers Study, women aged 36 to 59 years show a 46% reduction in mortality among current ET users.18 This exclusion biases our estimates downward.

We do not address the issue of estrogen plus progestogen therapy for women with a uterus except to recognize that the treatment is different from ET as are the mortality results

This is a recent article from an impeccable source putting the standard HRT treatment into perspective re risks/benefit. Note this does not cover the Bio-identical HRT, and is exactly the reason why BHRT is a better option for most women.
Page Last Updated: April 25, 2012

NAMS Reassures Many Women

The 2012 NAMS Hormone Therapy Position Statement, published in the March 2012 issue of Menopause, further distinguishes the emerging differences in the therapeutic benefit-risk ratio between estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) at various ages and time intervals since menopause onset.

A great deal has been learned in the 10 years since the first results emerged from the Women’s Health Initiative (WHI). Hormone therapy (HT) remains the most effective treatment available for menopausal hot flashes and night sweats. However, there is a growing body of evidence that formulation, route of administration, timing of therapy, and duration of therapy may produce different effects.

It is essential to evaluate a personal benefit-risk profile for each woman considering HT. Individual factors contributing to the HT decision include the severity of menopausal symptoms and effect on quality of life.

The absolute risks of HT in healthy women ages 50 to 59 are low. In contrast, long-term HT or HT initiation in older women is associated with greater risks.

Summary
  • The recommendation for duration of therapy differs for EPT in women with a uterus, and ET in women who have had a hysterectomy.
  • For EPT, duration is limited by the increased risk of breast cancer associated with more than 3 to 5 years of use. ET has a more favorable benefit-risk profile with no apparent increase in risk of breast cancer during an average of 7 years of use, a finding that allows more flexibility in duration of therapy.
  • Individualizing is still key in the decision to use HT and should incorporate the woman’s health and quality-of-life priorities as well as her personal risk factors, such as risk of blood clots, heart disease, stroke, and breast cancer.
  • For relief of hot flashes, women with a uterus should take EPT so that a progestogen will protect the lining of the uterus from the cancer-promoting effects of estrogen alone.
  • Low-dose vaginal ET is advised when symptoms are limited to vaginal dryness or discomfort with intercourse.
  • Neither ET nor EPT increases the risk of heart disease in healthy women under age 60 or within 10 years of menopause. The risk of stroke can be increased but is considered rare in the 50s.
  • Women with premature or early menopause who are otherwise appropriate candidates can use HT until the average age of natural menopause (age 51). Longer duration of treatment can be considered if needed for symptom management.
  • There is a lack of safety data supporting the use of HT in breast cancer survivors.
  • Both ET delivered through the skin and low-dose oral ET have been associated with lower risks of blood clots and stroke than standard doses of oral estrogen, but confirmation of benefits in randomized trials is not yet available.
  • Additional research is needed to understand the different effects of ET and EPT and how they apply to individual women.

The Position Statement is available on the NAMS website, as well as a patient education piece Hormone Therapy for Women in 2012.

Content updated 28 February 2012

Last Updated (Wednesday, 29 February 2012 11:06)

 

CLIMACTERIC2011;14:409–417

HRTindifficultcircumstances:arethereany

absolutecontraindications?

A.H.MacLennan

TheDisciplineofObstetricsandGynaecology,SchoolofPaediatricsandReproductiveMedicine,TheUniversityofAdelaide,

SouthAustralia,Australia

Keywords:HORMONEREPLACEMENTTHERAPY,CONTRAINDICATIONS,BREASTCANCER,THROMBOEMBOLISM,GYNECOLOGICAL

CANCERS,TIBOLONE,TRANSDERMALESTROGEN

  1. Complete awareness is definitely an effective measure on prevention of further symptoms that may has something to do with your menopausal phase. The mere fact that it’s only valid information that can greatly help you find a way out of such agony then I suggest that you must start asking and consulting the expert now.

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