Postmenopausal women were encouraged to take estrogen therapy for the rest of their life, and millions of American women did just that. In 2001, approximately 67 million women were filling prescriptions for Premarin or Prempro (conjugated estrogens and medroxyprogesterone).  

In 2002, the belief in ERT as the solution to women’s declining estrogen levels changed dramatically. The Woman’s Health Initiative (WHI), the largest federally funded study of long-term estrogen replacement, revealed that rather than having their health protected, patients on ERT were experiencing stunning adverse side effects. Women who were receiving estrogen were experiencing more heart disease, breast cancer, strokes and blood clots, compared with those taking a placebo. At first, in 2002, only the estrogen and progesterone arm of the study was closed, but then in 2004, subjects in the estrogen-only arm were found to have an increased risk of strokes.11

What the general public and many health care professionals did not know then — and may not know today — is that the only form of estrogen used in the WHI was equine-derived estrogen in the form of Premarin or Prempro.12


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FDA-approved estrogens. Researchers and medical professionals questioned whether these same adverse events would have been observed with the newer estrogen formulations. The agents currently approved by the FDA include:

  • Premarin — the most-prescribed formulation of estrogen replacement used clinically to treat hypogonadal girls. It contains more than 100 individual estrogenic compounds of different biologic potency and cannot be measured in conventional assays. Premarin is derived from the urine of pregnant mares.
  • Esterified estrogens — a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, derived from yams.
  • Estradiol — identical to the E2 produced by the human ovary. A white, crystalline solid, chemically described as “bioidentical” 17β-estradiol, it is derived from soy or yams.13

Defining bioidentical. Some of the estrogens listed were defined as “bioidentical.” There is much confusion surrounding the meaning of this term, and we needed a clear understanding of what it meant before choosing the formulation we would prescribe.

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.”14 Shortly after the Endocrine Society published its position statement on bioidentical compounds, the American Medical Association also adopted the society’s official definition. Information found in The Handbook of Clinical Drug Data allowed us to create charts comparing the estrogens15 (Table 1).

We shared the charts with Ashley and her parents and explained the different formulations. Together, they chose bioidentical estradiol-17β. However, converting Premarin to the equivalent estradiol dose was challenging (Table 2).

Choosing the route of administration. The next decision was to determine the best route of administration. Ashley was on growth hormone (GH) therapy. Studies show that oral estrogen in any form interferes with GH serum levels and decreases the levels of insulinlike growth factor-1 by up to 30%, potentially counteracting the benefits of GH.16