Our Bodies, Ourselves (115 page)

In 1993, the Women's Health Initiative set out to answer that question. WHI enrolled women age fifty to seventy-nine in a thirteen-year, large randomized trial of Prempro, the most widely used combination of estrogen and progestin. In 2002, the trial was stopped early because it had demonstrated more breast cancer, stroke, cardiovascular disease, and blood clots in the women on hormones. Continuation of the study was considered unethical because of these effects, even through the same women had less colon cancer and fewer fractures. The estrogen-alone arm of the study (which didn't prescribe a progestin because those women had had hysterectomies and didn't need progestin protection in their uterus) also showed an increase in blood clots and stroke, while fractures were prevented. No significant increase in breast cancer was shown for estrogen alone. Women on estrogen alone had no difference in colorectal cancer risk. Women sixty-five and older taking HT had no protection against mild cognitive impairment, and there was a small increased risk of dementia.

When the results of the WHI came out, many women felt outraged and baffled—especially
those who had been taking HT, sometimes for years—as the results seemed to indicate that they had been misled about both the benefits and the risks of the drugs. Many women stopped taking HT abruptly, preferring to return to hot flashes and other discomforts rather than continue with the medication.

There is significant debate about how to interpret many of the results of the WHI, and ongoing analyses of the large amount of data collected continue. One important limitation of the WHI was that it tested only Premarin, a synthetic estrogen made from the urine of pregnant mares, and PremPro, a combination of Premarin and the progestin Provera (medroxyprogesterone acetate). Those products were used at the time by the vast majority of U.S. women taking HT. (The choice of Premarin and PremPro for the WHI was in part the result of their product being donated by the company, Wyeth-Ayerst, now a part of Pfizer.) As a result, the WHI findings did not answer questions about the safety and effectiveness of other hormone formulations, regimens, and delivery methods (such as patches).

A third of the women in the WHI were in their fifties, making this the largest randomized controlled trial ever done of women in this age group. However, the majority of the participants were more than a decade past their final menstrual period, raising a question as to whether the trial's results apply only to older women. In fact, later analysis of the results for the more newly menopausal women showed a somewhat better safety profile.

The results of the WHI contributed to an evolution away from the concept that menopause begins a time of estrogen deficiency and that hormone “replacement” is a necessary thing. Rather, low levels of reproductive hormones after menopause are normal and may not be problematic.

Understanding of HT continues to change—and tomorrow's headline may contradict today's. In the meantime, decades of drug company ads and promotions have influenced both women and health care providers. You will see many claims being made in the coming years—both pro and con—about different products, including ones sold without a prescription that are unregulated by the FDA. Watch, too, for advertising that tries to redeem the image of PremPro in the minds of the public. Although it's true that the WHI study had many flaws, it's also true that horse estrogens and chemically altered progestins no longer appear to be the best option. Until research identifies the harms and benefits of the variety of available hormone regimens, women should be cautious about unproved claims.

The hormone controversy raises an important bioethical issue. Many of us believe that the standards for using unproved treatments on healthy populations should be more stringent than those for treating people who are ill and are willing to take risks in hopes of a cure. The marketing of bisphosphonates to women with osteopenia is an example of encouraging women to use drugs for a nondisease condition, as was the pre-WHI marketing of HT to women for prevention of possible future problems.

Perimenopause and menopause are not disease states; if we feel well, treatments should not be pushed on us. On the other hand, a certain number of women don't feel healthy during this time, and it's important to have options for treatment. Any type of medication—whether hormones or newer drugs such as bisphosphonates, antidepressants, and statins—may result in unanticipated negative effects, so every woman's decision to use hormones and other medications needs to be a personal, well-researched assessment of potential harms and benefits. And the decision needs to be revisited regularly as more is learned about the drugs and their effects.

Many people use the terms estrogen, hormones, and hormone therapy (or the outmoded “hormone replacement therapy”) interchangeably, as though they are all the same thing. But in fact, research beginning with the WHI has revealed that there are types that pose more risk and some that may pose less. If you decide to use hormones, it's important to learn about the differences.

Many benefits and safety issues may turn out to depend on important details about the type of hormone, who's using it, in what form, and when. As you read through the following information, keep in mind that a great deal more research is needed before much can be said with 100 percent certainty about the risks and benefits of the many kinds of hormone therapy. And each of us is different, and may react differently, to HT.

The three major naturally occurring estrogens in women (made primarily by the ovaries) are: estradiol (es-tra-dye-all), estriol, and estrone. Estradiol is the predominant estrogen during the pre- and perimenopausal years, whereas estrone predominates after menopause. Estriol is a weak human estrogen usually found in substantial amounts only during pregnancy. Some clinicians believe that estriol is safer for the breast than its more powerful cousin estradiol, but there aren't strong data that argue for or against using estriol. Estrone is produced when fat acts on adrenal estrogens after menopause—perhaps explaining why women with a high body mass index suffer from more estrogen-related cancers such as breast and endometrial.

The role of estrogen therapy in perimenopause is one of the many crucial issues on which there are many opinions and insufficient research. There are those who believe that because perimenopausal estrogen levels average higher than premenopausal levels and occasionally surge to double or triple those levels, estrogen-based therapy (including oral contraceptives) in perimenopause may not be safe and may cause harm.
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On the other hand, there are clinicians who have extensive experience treating symptomatic perimenopausal women with oral contraceptives and other estrogens with apparently good effect.

Pills in which some estrogen comes from pregnant mares' urine (conjugated equine estrogens, brand name Premarin) are commonly used in the United States. Other oral estrogens contain the primary estrogen found in reproductive-age women (estradiol) synthesized in the lab from plants. When estrogen first came on the market decades ago, pills were the only option. But now we know that when the body processes oral estrogen through the liver, it stimulates the liver to make clotting proteins, which increase the chances of blood clots. Even with pills made of estradiol and not the urine of pregnant mares, the process of going through the liver converts the estradiol to other substances (such as estrone) and incites the liver to produce some detrimental proteins.

Some data now exist to support the view that estrogen given through the skin (transdermal estradiol) bypasses the liver and is less likely to cause blood clots and possibly strokes than oral preparations (pills), even if the pills are made of estradiol.
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However, transdermal estrogen appears to carry the same breast cancer risk as oral estrogen.
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Watch in 2011 or 2012 for the results of a large randomized study of newly menopausal women called Kronos Early Estrogen
Prevention Study (KEEPS)
, which is comparing transdermal with oral estrogen.

Look for transdermal products that contain estradiol. This comes in estrogen gels (such as EstroGel and Divigel), a spray (Evamist), and many patches. These all appear to have similar risk profiles, so the choice is based on convenience and cost (this can vary depending on insurance coverege). Two benefits of the patch: Most can be cut to adjust or slowly taper your dose, and the patch delivers even levels of hormones twenty-four hours a day. If the patch you are prescribed causes skin irritation, ask to try another one.

Note: Over-the-counter creams in supermarkets and health food stores claiming to be estrogen are not permitted to contain real estradiol, but they may contain the weaker estrogen called estriol. Strengths and standardization vary.

A soft, plastic-like ring releases estradiol into the vagina slowly over the course of three months. This is an option for women who are comfortable enough with their bodies to insert it (it's not much different from inserting a tampon). One type, called Estring, is meant to affect primarily the vagina, for women with only vaginal symptoms such as dryness; the other, Femring, is a higher dose meant to reach the whole body and work systemically.

Women with a uterus who go on estrogen therapy should use a progestogen (progesterone-like product) along with estrogen. Progesterone mimics the work of the body's progesterone in preventing overgrowth of the uterine lining that may lead to endometrial cancer. Progesterone is also used on its own by some practitioners to treat discomforts and irregularities caused by the reduced progesterone levels in perimenopause. (See “What About
Progesterone Used Alone?
”)

Some progestogens are bioidentical—meaning they're the same as in the human body—while others, called progestins, are chemically altered synthetic versions that may resemble progesterone only in how they change the uterine lining and preserve a pregnancy. (See “Bioidentical Hormones and
Compounding Pharmacies
,” for more discussion.)

In the Women's Health Initiative controlled trial and in large observational studies from England and France, this synthetic progestin given with estrogen increased the risk of breast cancer or appeared linked to increased breast cancer risk. Provera is also in the combination product PremPro and is heavily marketed for HT in the United States.

The progestin-releasing IUD (Mirena) releases a low dose of progestin that works primarily within the uterus. This is an effective treatment for heavy bleeding in many women, and because it releases a low dose that works locally, it avoids some of the risks and side effects of progestin taken in pill form. Some women do report systemic effects from Mirena such as headaches and acne. Some clinicians prescribe Mirena to deliver progestins in women on hormone therapy, but it is not FDA-approved for this. For more information on Mirena, see
“Intrauterine Devices.”

For many years no one knew how to make natural, non-chemically-altered progesterone
survive the digestive tract, so pharmaceutical companies invented chemically altered versions that not only survived the digestive tract but had the profitability advantage of being patentable. It wasn't until the 1980s that researchers discovered that they could grind lab-created progesterone extremely fine (micronize it) and put it in oil in a gelcap to keep it from being broken down by the digestive tract.

Prometrium, the first (and so far only) micronized progesterone product to be approved in the United States, was approved in 1998. By that time, Provera and other chemically altered progestins were well established as standard, so the use of micronized progesterone is, to date, less widespread in the United States than in Europe. Bioidentical micronized progesterone is molecularly the same as your body makes and may have a better breast safety profile than its synthetic progestin cousins such as Provera.

Prometrium comes dissolved in peanut oil in a 100-mg or 200-mg gelcap. (For women with peanut allergy, a compounding pharmacist—see below—can dissolve it in olive oil instead, with similar doses and absorption.) A third option, a vaginal progesterone gel called Crinone, is extremely expensive in the United States.

The WHI showed an increase in breast cancer for estrogen and progesterone used together, though not for estrogen used alone; therefore, many suspect progesterone of causing breast cancer even though only the progestin Provera was used in the study. However, in a very large observational study of European women, Prometrium given with estrogen was not associated with an increased risk of breast cancer, while estrogen alone and estrogen with progestin were. This fits with what we know from animal, human, and cell studies, which show that chemically altered progestins have different effects than progesterone does on how cells grow, insulin sensitivity, and other risks of breast cancer.
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Reactions to progesterone vary—a dose that's calming to one woman may make another feel mildly depressed or as though she has PMS—so experimenting with different routes (oral or vaginal) and doses may be necessary. Prometrium capsules can be used vaginally; this results in a slower, steadier release of hormones and has less sedative effect.

Some clinicians think the waning levels of progesterone relative to levels of estrogen during perimenopause are a major factor in the symptoms of perimenopause, and that progesterone therapy is often the best approach. Both the lab-made “natural” progesterone and lab-made progestins can help manage the erratic bleeding in perimenopause.