Information Regarding JAMA Article on Synthetic Hormones

On July 9, 2002, the news media reported on an article to be published in the Journal of American Medical Association next week, entitled "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women"1 This article on synthetic hormones is causing a great deal of concern and confusion among patients and physicians. The purpose of this fax is to review the findings of this study, to offer some advice on applying this information, and to clarify the difference between human bio-identical 'natural' hormones and synthetic hormones like the agents evaluated in this study.

Study Design: To define the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women. A total of 16,608 postmenopausal women (ages 50 to 79 years) with intact uteruses at baseline were randomized to receive hormone replacement therapy or placebo for up to 8.5 years.

Study Medications: 8,506 women were randomized to receive Prempro (conjugated equine estrogen 0.625mg/d plus medroxyprogesterone acetate 2.5 mg/d) and 8,102 women were randomized to receive placebo.

Trial Monitoring and Early Termination: Benefit and adverse event rates were evaluated at predetermined time points during the study. By the 5th time point, a small but consistent adverse effect was seen in cardiovascular outcomes and in the global index (all eight outcome parameters combined) in the treatment group. By the 10th time point, a significant adverse effect was seen for breast cancer and the global index in the treatment group, leading to the early termination of the treatment arm of the trial. The placebo arm of the trial is ongoing.

Results: Patients randomized to the Prempro treatment arm had a 26% increase in the incidence of breast cancer and a 15% worsening in their global index, both considered significant. In addition this group demonstrated a trend towards harm in other categories including coronary heart disease, stroke, and pulmonary embolism, while a benefit was seen with colorectal cancer and hip fractures.

Conclusion: The researchers recommend using this data in the following ways:
• This adverse outcome information is not new, in fact it is consistent with a growing body of literature on the effects of synthetic estrogen/progestin agents like Prempro (three studies have all found an increase in breast cancer)
• Inform patients that this data is being reported in terms of relative risk, the absolute risk of harm to an individual is very small (e.g. for breast cancer 8 additional cases would occur in 10,000 women being treated for one year)
• The risk of harm increases with the duration of treatment (e.g. 1 new case of breast cancer would occur in 100 women being treated for 5 years)
• Long-term use of synthetic estrogen/progestin agents is no longer recommended.
• Synthetic estrogen/progestin agents should not be initiated or continued for primary prevention of coronary heart disease.
• It is important to note that the patients in the study were taking only one drug regimen and that the human bio-identical hormones may provide a different risk-benefit profile.

Differences between Human Bio-identical 'Natural' Hormones and Synthetic Hormones

1. Premarin (conjugated equine estrogen) is derived from the urine of pregnant mares and contains 9 estrogens found in horses in the following amounts.

Estrone 49%, Equilin 22%, 17-alpha Dihydroequiline 15%, 17-alpha Estradiol 3.5%, Equilenin 2.4%, 17-beta Dihydroequiline 2.1%, 17-beta Dihydroeqilenen 1.6%, 17-beta Estradiol 0.7%, and 17-beta Dihyroequilenin 0.6%

The metabolic byproducts of Premarin become biologically stronger in the human body. Our bodies have none of the enzymes and cofactors required to metabolize equilin and the other horse estrogens.

2. The human female body produces three estrogens in approximately the following amounts: estriol 90%, estrone 3%, estradiol 7%. The premise of prescribing human bio-identical 'natural' hormones is to mimic human physiology. The human bio-identical 'natural' hormones, estriol, estrone, estradiol and progesterone were not part of this study. To date, there have been no studies linking the human bio-identical 'natural' hormones, to cancer, and there are studies indicating beneficial cardiac effects with human bio-identical 'natural' hormones.

3. In addition to the conjugated equine estrogens, Prempro contains the synthetic progestin, medroxyprogesterone acetate, which is structurally and functionally different than the progesterone produced by the human body. Several studies have shown that medroxyprogesterone acetate interferes with estrogen's ability to protect against cardiovascular disease.

The progesterone used in human bio-identical 'natural' hormone therapy is structurally and functionally identical to the progesterone produced in the human body. The PEPI trial demonstrated that human bio-identical 'natural' progesterone had no adverse effects on serum lipids. A study by Miyagawa et al demonstrated that natural progesterone protected against vasospasm, while medroxyprogesterone acetate did not.

4. Other brand name hormones that contain the equine estrogens like those found in Premarin and Prempro include: Premphase, Estratab, Estratest, Menest, and Cenestin Other brand names of hormones that contain medroxyprogesterone include: Provera, Cycrin, Amen, Premphase, and Curretab.

Other options available for hormone replacement

Many of your patients may be asking to change or discontinue hormone therapy because of this latest study. In addition to lifestyle adjustments, herbals and soy, there are several other treatment regimen options.

1. Patients wishing to discontinue therapy should be tapered off over 3 to 6 months if they started hormone therapy to treat vasomotor symptoms.

2. Transdermal or oral estradiol and progesterone are available commercially or as compounded prescriptions.

3. For those patients who wish to continue on hormone therapy and cannot tolerate estradiol alone, the following are approximate equipotent doses for prescription human bio-identical 'natural' hormones.

Prempro 2.5mg                 Triest or Biest 3.75mg/Progesterone 100 mg SR capsules

Premarin 0.625 mg            Triest or Biest 3.75 mg SR capsule

Provera 2.5 mg                 Progesterone 100 mg SR capsule