A SUMMARY OF THE SCIENTIFIC EVIDENCE

By Michael L. Williams, updated March 10, 2010

(for full summary click here)

I.  Executive Summary

A.  Important Messages

1. The combination hormone therapy regimens (estrogen plus an imitation progesterone, or “HT”), most popular with physicians treating symptomatic menopausal women, greatly increase the risk of breast cancer, especially ER+ breast cancer.  This increased risk is much higher than conventional wisdom believes. These drugs have caused more than 300,000 breast cancers in the USA alone over the past 30 years.  Even now, HT is still causing about 10,000 unnecessary breast cancers per year. The single most effective action the medical profession can take to prevent thousands of breast cancer cases is to stop prescribing these HT regimens, and to prescribe the safe ones instead.

2. There is a safe companion to estrogen for women with menopause symptoms.  Micronized progesterone, unlike the imitation progesterones used in HT regimens such as Prempro, does not increase the risk of breast cancer, at least when it is used for eight years or less. Evidence published since 2005 demonstrates the safety of natural progesterone and its racemic sister dyrdrogesterone for the breast. This new science also provides human clinical trial and animal experimental data to explain why these natural progesterones are so much safer. Most prescribers are unaware of this information.  The current drug labels for Prempro and other combination HT regimens, which the drug companies have not updated on this issue since 2005, falsely state that all progestogens should be presumed to be equally dangerous (a “class effect” that is now known to be untrue).  The science is solidly to the contrary. 

B.  Outline of Facts

1. Many women, especially those in their early 50’s, suffer from moderate to severe menopausal symptoms and need estrogen supplements to eliminate hot flashes and to treat vaginal dryness and thinning. There simply is no more effective therapy than some form of estrogen supplementation.

2. But, in a woman who still has her uterus, estrogen therapy unopposed by a progestogen greatly increases the risk of endometrial hyperplasia and hormone dependent uterine cancer (cancer of the endometrium, or uterine lining).
 
3. The risk of estrogen-fed endometrial cancer increases with duration of exposure to the estrogen-only therapy. It is universally accepted that the mechanism of this hormone driven cancer epidemic in the 1960’s and 1970’s was by promotion of pre-existing lesions rather than initiation of completely new tumors.

4. Since the late 1970’s, all physicians have recommended that women with uteruses who are going to take estrogen supplements should also take a progestogen to oppose the estrogenic stimulation of their uterine lining.

5.  The three most common progestogens used in the United States are all incomplete imitations of a woman’s own natural progesterone:  

(a) Medroxyprogesterone, or MPA, is the progestogen in the combination single pill, Prempro.®  It is also sold as a separate pill under brand names such as Provera, Cycrin, and as generic MPA without a brand name.

(b) Norethindrone acetate, or NETA, is the progestogen in Combi Patch® and FemHrt, ® and is sold as a separate pill under generic  “brand” names for single pills, such as  Errin® and Aygestin. ®

(c) Norgestrel, or its left-handed isomeric half, levonorgestrel (LNG), is used in Activella,® a single combination pill of estradiol and LNG, and in Climara Pro,® a combination patch sold by Bayer. LNG was sold in the United Kingdom as a companion to Premarin in Pfizer’s Prempak.®

6. All three of these imitation progesterones cause a large increase in the incidence of breast cancer in women using them longer than a couple of years. The most recent and robust studies show that Prempro, for example, increases the risk of all breast cancers more than threefold in women using the combination drug for just four years. The relative risk of estrogen receptor positive (ER+) breast cancer is even higher than 3.0 because Prempro does not feed estrogen receptor negative (ER-) tumors, but ER- tumors were not separated from ER+ tumors in this analysis. The relative risks of breast cancer from NETA and LNG are at least as high as MPA, and possibly even higher.

7. The risk of breast cancer is higher, especially in the first three years of use of Prempro or its equivalents, for newly menopausal women. 

8. Since 2005, a rapidly growing body of scientific evidence demonstrates that oral micronized progesterone (OMP), when used as the companion to estrogen therapy, does not increase the risk of breast cancer in the first five years of use, and then for those rare women who need HT longer than five years, the risk of breast cancer with OMP rather than MPA is much lower. In the first five years, OMP may even eliminate the small increased risk of breast cancer found in women using estrogen alone. It is now well accepted in Europe that the first choice of progestogen for menopausal HT is oral micronized progesterone, or for those women unable to tolerate OMP, its racemic sister, dydrogesterone (same chemical formula as progesterone, but with some subtle three-dimensional structural differences that make it more absorbable than OMP).

9.  Millions of women are still being prescribed the cancer causing imitation progestogens without being told about the safer alternatives. These women deserve to be told that there is one type of HT that has been found not to increase breast cancer in the first five years of use, while all of the others do. This information has not yet been included in the official labels for the dangerous progestins.  The labeling on this topic has not been changed since 2005, despite the enormous amount of data published since 2005 demonstrating that the “class labeling” on progestogens sought by the entire drug industry is simply false. This false labeling contributes to about 10,000 unnecessary breast cancers in the United States alone every year.

10. The mechanism by which MPA, NETA, and LNG cause breast cancer, when used in combination with estrogen, is through promotion of pre-existing lesions, just as we know occurs with estrogen and uterine cancer. These are lesions that would otherwise stay clinically insignificant, below the level of x-ray detection, or would even regress absent stimulation by the imitation  hormone drugs.

11. Many of the largest pharmaceutical companies on the planet have directed a loud and carefully orchestrated drumbeat of misinformation to the public, and especially to the target market of prescribing physicians. The drug industry has invested millions of dollars in revenues to influence the prescribing physicians’ professional organizations and continuing medical education courses. Drug companies have ghost-written and planted a barrage of medical journal articles showcasing unsubstantiated benefits of their progestin drugs.  As a result, most physicians who still prescribing these drug combinations are simply not aware of the real risk of breast cancer that imitation progesterones induce.  Nor are they awarethat there is solid, robust evidence of a safe alternative, oral micronized progesterone, which does not increase breast cancer risk. 

12. Pfizer’s top ObGyn executive in charge of Prempro’s labeling for its subsidiary Wyeth, testified recently that women contemplating beginning or continuing HT should be told about the evidence that Prometrium may be much safer for breast cancer risk than Prempro’s MPA.  However, he claimed that it wasn’t Pfizer’s responsibility to discuss the relative safety of other companies’ products.. Instead, he declared, it was the prescribing physician’s job to tell women about the growing body of data supporting safer alternative progesterones.

13. The combination menopausal hormone therapy regimens using MPA, NETA, or LNG should be taken off the market. Until some company puts dydrogesterone back on the  market in the United States, the progestogens of first choice as estrogen’s escort must be micronized progesterone – the oral formulation for women who are not allergic to peanuts, and the FDA approved vaginal gel for women with peanut allergies.

14. Although this vaginal gel has not received clearance from the FDA for use in MHT to oppose estrogen, the only NIH funded ongoing clinical trial of MHT chose micronized progesterone gel instead of MPA, NETA, LNG or OMP.  Currently, there are two randomized trials of menopausal HT under way. Both studies chose micronized progesterone instead of any of the three imitation progesterones. The KEEPS trial is using Prometrium®, the Solvay brand of oral micronized progesterone, which has been available in the United States since 1998. The ELITE trial, sponsored by the National Institute of Environmental Health Sciences (NIEHS), is using Crinone® gel, which contains micronized progesterone. Women should be informed of these facts, too, if they are truly giving their informed consent to treatment with hormone therapy.