Is Bioidentical Hormone Replacement Safe?

Since the Women’s Health Initiative found that estrogen treatment posed an increased risk for developing breast cancer, physicians and patients have become wary of hormone replacement therapy. Prescription use of estrogen and “progesterone” medications such as Premarin and Prempro have dramatically declined since 2003. Many patients have opted to avoid hormone replacement, attempting to control menopausal symptoms with nonestrogen medications such as antidepressants. While estrogen treatment with conjugated equine estrogen such as Premarin demonstrably provided support for osteoporosis, it failed to reduce risk of cardiovascular disease, a claim touted in the past few decades. Understandably, physicians and patients concerned about increasing breast cancer risks have decided that a lower estrogen and progesterone level is a natural part of the aging process. Much of the promise of menopausal hormone replacement acclaimed in the 1980s has lost its appeal.

In the years following the Women’s Health Initiative, Suzanne Somers’s best-selling books argued that estrogen replacement should still be a consideration in treating menopause and the aging process. Her use of “bioidentical” hormones raised eyebrows because she was using relatively high doses of estrogen after being diagnosed with breast cancer. Somers argued that, compared with conventional hormone replacement, bioidentical hormones are structurally identical to the body’s estrogen and progesterone. Other prescription estrogen and progesterone had been chemically modified and did not match human hormones. Bioidentical hormone replacement derived from plant sources, prescribed by a minority of physicians for the past two to three decades, offered a distinct alternative to horse-derived estrogens and chemically modified progesterone. The question remained whether the benefits from using bioidentical therapy outweighed risks for developing breast cancer.

According to Jonathan Wright, MD, and Lane Lenard, PhD, in their updated edition of Stay Young & Sexy with Bio-Identical Hormone Replacement: The Science Explained (Smart Publications, 2010), the answer is an unqualified “yes.” The major bioidentical estrogens, estrone, estradiol, and estriol, are generally prescribed with progesterone in lower physiologic doses meant to mimic the normal female cycle. Wright explains that estrogen stimulation of alpha receptors tends to increase cell proliferation, while beta receptors tend to decrease cell proliferation. Estradiol stimulates alpha and beta receptors equally; estrone stimulates the alpha receptor five times more than the beta receptor, meaning that estrone tends to provoke much greater cell proliferation than estradiol. Estriol, on the other hand, tends to stimulate beta receptors three times more than alpha receptors, greatly decreasing cell proliferation. Given that estrone and estradiol stimulate cell proliferation, increasing the risk for breast cancer, estriol is the predominant estrogen prescribed, to lessen cell proliferation activity.

Much of Wright’s thinking is based on the work of Dr. Harry Lemon, who headed the division of gynecologic oncology at the University of Nebraska in the 1970s. Lemon observed that estriol was capable of competing with estradiol and estrone for occupation of estrogen receptor sites.¹ He hypothesized that if estriol was not present in adequate quantities and that estrone and estradiol were relatively high, estrogen receptors would be stimulated and the risk of breast cell proliferation would be greatly increased. Lemon derived an estrogen quotient defined as: estriol/(estrone + estradiol) = estrogen quotient. If this ratio of estriol to estrone and estradiol exceeded 1.2, the woman would have a lower risk for developing breast cancer; if the ratio was less than 0.5, the woman had a significantly higher risk for developing cancer. Wright recommends that women who are prescribed bioidentical hormone replacement therapy have a urinary hormone screen of estriol, estrone, and estradiol to measure the estrogen quotient. Those women with lower estrogen quotients would then be able to have their prescriptions modified to increase their relatively low estriol levels.

The French MISSION study on hormone replacement therapy reported in 2007 had very different results than the Women’s Health Initiative.² The study compared the incidence of breast cancer of women who had been treated with estrogen during the past five years with that in women who had received no hormone treatment. There was no increase in breast cancer incidence in the estrogen group compared with the nonestrogen one, despite the fact that the average use of estrogen exceeded eight years. How could these results be so different from the Women’s Health Initiative? According to the French researchers, unlike in the American study, most of the women did not use conjugated equine estrogens and synthetic progestogens. Instead they were prescribed bioidentical topical estradiol and progesterone.

Unfortunately, the MISSION study did not employ estriol, and there are no large studies employing estriol hormone replacement. However, the evidence and theory largely supports including estriol in bioidentical hormone prescribing. Wright and Lenard’s text offers further compelling information on estriol and other hormones, including best means to prescribe and monitor them. Patients and physicians are well served to be cautious in using hormone replacement, but bioidentical hormone therapy appears to be a far lower risk than the horse-derived hormone replacement used in the past three decades.

Jonathan Collin, MD

Notes

1. Lemon HM. Pathophysiologic considerations in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma. Acta Endocrinol. Supple (Copenh). 1980;233;17–27.

2. Espie M, Daures JP, Chevallier T, Mares P, Micheletti MC, de Reilhac P. Breast cancer incidence and hormone replacement therapy: results from the MISSION study, prospective phase. Gynecologic Endocrinol. 2007;23:391–397.