Do these heavily promoted hormones justify the claims made for them?
Ever since Harvard Women’s Health Watch began publication in 1993, our readers have been concerned about the risks and benefits of postmenopausal hormones. In the past few years, there’s been growing interest in “bioidentical” hormones, which are promoted as safer and more effective than FDA-approved hormones. The interest is driven in no small part by claims made in entertainer Suzanne Somers’ 2006 book, Ageless: The Naked Truth About Bioidentical Hormones (and her January 2009 appearance on the Oprah Winfrey Show).
Somers endorses the use of bioidentical hormones not just for the relief of menopausal symptoms but as a veritable fountain of youth. She says that it “gives you back your lean body, shining hair, and thick skin, provided you are eating correctly and exercising in moderation. This new medicine allows your brain to work perfectly and offers the greatest defense against cancer, heart attack, and Alzheimer’s disease.” According to Somers, bioidenticals work by tricking the body into thinking it’s still “reproductive.” Ironically, similar claims were made for hormone replacement therapy (HRT), now called hormone therapy (HT), in the late 1960s by the British gynecologist Robert Wilson in his book Feminine Forever. Wilson wrote that HRT reversed a postmenopausal woman’s status as a “castrate” and ensured that she wouldn’t “become dull and unattractive.” Like Wilson, Somers appears to view menopause as a deficiency disease and hormone replacement as a lifelong necessity.
It’s understandable that women would be interested in a new approach after hopes that conventional HT would prevent cardiovascular disease were dashed by the Women’s Health Initiative (WHI). In 2002, study researchers stopped giving HT to women with an intact uterus when it became clear that the risks of taking combined hormones (estrogen plus a progestin) — higher rates of stroke, breast cancer, heart attack, and blood clots in the lungs and legs — outweighed the benefits, namely, reductions in osteoporotic fractures and colorectal cancer. In 2004, WHI researchers also stopped giving HT to women who had undergone hysterectomy, because those taking estrogen alone had a higher rate of stroke than those taking the placebo. Finally, in the WHI Memory Study, women over age 65 who took hormones were twice as likely to develop dementia as those taking a placebo.
All the women in the WHI took conjugated equine estrogens synthesized from the urine of pregnant mares, either alone (as Premarin) or with the progestin medroxyprogesterone acetate (as Prempro). Similar data are not available for other estrogens or progestogens (natural progesterone or synthetic progestin).
As a result of the WHI findings, the FDA required manufacturers to add a “black box” warning (the strongest warning in prescription labeling) not just to Premarin and Prempro, but to all approved estrogens and progestogens. And most clinicians now counsel midlife women differently than they once did. Instead of urging women to weigh the risks and benefits of long-term HT for health, most now suggest HT only for short-term symptom relief. But many women want more from HT, and some are now looking to bioidenticals.
What are bioidentical hormones?
The term “bioidentical” doesn’t have a precise medical definition. The Endocrine Society defines bioidentical hormones as “compounds that have exactly the same chemical and molecular structure as hormones that are produced in the human body.” Clinicians usually use the word to describe preparations containing either progesterone or one or more of three estrogens — estradiol (the predominant estrogen in premenopausal women), estrone, and estriol (the main estrogen produced during pregnancy). Somers and other advocates of bioidentical hormones generally mean something more. They are usually talking about the following regimen, called bioidentical hormone replacement therapy (BHRT):
A woman’s hormones are measured via a saliva test, and “deficiencies” are identified.
Her clinician prescribes a mix of hormones to correct any deficiencies and bring the hormones into balance.
The prescription is filled at a compounding pharmacy using hormones derived from “natural” sources, usually soy or Mexican yams.
Besides estrogen and progesterone, the prescription may include other hormones, such as testosterone, dehydroepiandrosterone (DHEA), and adrenal hormones extracted from animal glands.
The woman’s hormone levels are retested periodically and her prescription revised as the clinician deems necessary.
Evaluating the claims for bioidenticals
Here are some of the main claims Somers makes for BHRT, along with the medical evidence.
Claim: BHRT hormones are not drugs because they are molecular copies of the hormones made by women’s bodies.
Evidence: The FDA defines drugs as “articles (other than food) that are intended to affect the structure or any function of the body.” Somers’ claims for custom-compounded bioidentical hormones haven’t been scientifically validated, but if they accomplish any of the things she says they do — such as relieve hot flashes or improve the skin — their effects on the body’s structure or function are undeniable. They’re drugs — just unapproved ones.
Claim: Drug companies don’t invest in bioidentical hormones because they can’t make money from them; you can’t patent natural substances.
Evidence: This is at best a half-truth. A drug company can’t patent a naturally occurring hormone, but it can patent a process needed to render it absorbable as a drug. Several large drug companies have done just that (or have licensed process patents) and are now selling FDA-approved bioidenticals. For example, natural progesterone (Prometrium) is manufactured by Abbott Laboratories, which uses a patented technique called micronization. Micronization permits the oral ingestion of progesterone by pulverizing it into particles small enough to pass through the walls of the intestine and into the bloodstream. Other drug companies market a micronized form of estradiol — a bioidentical estrogen — in pill form (Estrace) and in transdermal (applied to the skin) patches (Alora, Climara, Estraderm, Menostar, Vivelle), sprays (Evamist), gels (Divigel, Elestrin, Estrogel), lotions (Estrasorb), and vaginal rings (Estring).
To bring a drug to market, drug companies invest millions of dollars in research and development, including the randomized clinical trials testing its safety and effectiveness that are required for FDA approval. A drug company must also keep tabs on a drug after it’s in use, reporting side effects and monitoring quality.
Claim: Bioidenticals are safer than synthetic hormones.
Evidence: The WHI results understandably sent some women looking for a safer alternative for symptom relief. Premarin is synthesized from the urine of pregnant mares and contains a mix of estrogens (some unique to horses), steroids, and various other substances. Might some unidentified molecule be responsible for the health risks? To many, the claim that bioidentical hormones are safer because they have the same chemical structure as those produced by our own bodies would seem plausible.
Yet there’s no good evidence to support this claim. Although bioidentical progesterone and the bioidentical estrogen estradiol have been approved, they haven’t been studied in large, long-term trials like the WHI. They’re FDA-approved because they’ve been shown in trials to relieve menopausal symptoms and reduce the risk of osteoporosis. These claims are allowed on their packaging. And because the FDA has applied the results of the WHI to all approved estrogens and progestogens, these bioidenticals also carry black box warnings. Hormones from compounding pharmacies, which aren’t FDA-approved, don’t come with package inserts bearing the black box warning, giving the illusion of being safer than commercially marketed drugs. But the lack of a warning doesn’t mean they’re safer, only that compounding pharmacies aren’t required to detail potential risks. To date, hormones from compounding pharmacies haven’t been tested in clinical trials. Until then, the risks associated with them cannot be fully known. Finally, while compounding pharmacies are regulated by state pharmacy boards, they’re not required — as manufacturers of approved drugs are — to report on side effects or other adverse outcomes from their products.
There actually may not be much difference between an FDA-approved bioidentical and the custom-compounded version. Both are made from the same hormones and manufactured according to the requirements of the United States Pharmacopeia (a nongovernmental authority that sets standards for prescription and over-the-counter drugs). At a compounding pharmacy, hormones are placed in a capsule, gel, cream, suppository, or other vehicle. A pharmaceutical company follows the same procedure, but it must use a standard dose in a specific vehicle because the two have been tested and approved as a unit. In this respect, an FDA-approved bioidentical may be more reliable. In 2001, the FDA randomly tested 37 products from 12 compounding pharmacies and found that nine (24%) were less potent than indicated. In contrast, only 2% of FDA-approved products failed the potency test when randomly sampled.
Claim: Estriol, a weak estrogen used in compounded BHRT, offers women protection from breast cancer.
Evidence: In laboratory studies, estriol has been shown to prevent and even reverse breast tumors in rats — but there’s no evidence that it does so in women.
Claim: Saliva and blood tests are reliable indicators of a woman’s hormone levels.
Evidence: FDA-approved blood and saliva tests indicate a woman’s hormone levels at a moment in time. That can sometimes help in determining whether a woman has entered the menopausal transition — but they are not useful for setting hormone doses. In a menstruating or perimenopausal woman, hormone levels change from hour to hour, and in menopausal women, there’s no stable “normal” value at all for salivary or blood levels of these hormones or levels that correlate with symptoms.
If you’re considering bioidenticals
If you want to use FDA-approved bioidentical hormones for menopausal symptom relief, you can be confident that they are safe and effective, and contain what their labels say they do. (For a list of FDA-approved bioidenticals, go to www.health.harvard.edu/womenextra.) If you want custom-compounded bioidentical hormones, get them through your clinician and not from the Internet. If you plan to rely on saliva or blood testing to establish the dose, bear in mind that you’re venturing into scientifically uncharted territory. And any prescription that adds testosterone or DHEA to your hormonal mix is taking you even farther from the tested path. In effect, you’re experimenting with your body and your health.
Bioidenticals in mainstream practice
Is there a valid role for bioidenticals? We took the question to two gynecologists who have followed the field for decades and treated thousands of midlife women — Harvard Women’s Health Watch advisory board member Dr. Martha K. Richardson, and Dr. JoAnn Pinkerton, who led a workshop on bioidentical hormones at the North American Menopause Society’s annual meeting in September 2011. Both usually prescribe FDA-approved bioidentical hormones, but only for symptom relief and only for the shortest time that works (often three to five years but sometimes longer). Richardson prefers to prescribe transdermal rather than oral estrogen because it doesn’t pass through the digestive system and liver and therefore is less likely to cause gallbladder disease or have a negative effect on blood lipids, in particular, triglycerides or clotting factors.
Pinkerton cautions that transdermal progesterone may not prevent endometrial overgrowth in women who have a uterus: “It’s questionable whether the particles are small enough to be absorbed through the skin.” (Interestingly, Somers says that despite daily applications of progesterone cream, she required a hysterectomy because of endometrial hyperplasia.)
Both Richardson and Pinkerton occasionally prescribe compounded hormones — chiefly for women who are allergic to vehicles used in FDA-approved hormones, or whose symptoms can be managed with a lower dose of estrogen or progesterone than is commercially available. But both physicians are more comfortable with FDA-approved bioidentical hormones, not only because research has shown them to be safe and effective, but also because their purity and potency are held to rigorous standards with periodic testing.