Recently there has been tremendous confusion about the article published in JAMA, July 3, 2002, concerning the use of Prempro. This study involved only the use of Prempro and no other hormones. Prempro consists of the synthetic estrogen (Premarin) from horse urine and the synthetic progestin (Provera). Experts from all fields of medicine are calling for a discontinuation of all hormone replacement based on reported increase in heart disease, breast cancer and thrombosis. This is an inappropriate response as other safe hormones, which were not included in this study, have been incorrectly targeted by reviewers.

The information contained in this latest study is not news – two years ago an article appeared in JAMA (January 2000) that concluded the risk of breast cancer increased 8 times with Provera. This present article is no different. It has been known for some time that Provera increases breast cancer risk, but it has never received the media attention and medical criticism until now. It is not known why all of a sudden the media has chosen to focus attention on this subject. What needs to be clarified is that the concern is only with the synthetic progestin. The media either misquotes the studies by saying that all hormones are damaging or at best, merely omits mentioning that the studies do not pertain to natural hormones.

Further, the recent July JAMA article specifically and clearly states that this study does not apply to natural hormones, but patients will inevitably misinterpret these findings because of the media hype and incorrect assumptions. There are two recent studies indicating that natural progesterone protects against breast cancer by decreasing epithelial cell proliferation in the breast (Fertility Sterility 1998).

Another study showed that progesterone was more protective than Tamoxifen which is a treatment for breast cancer (Japan Journal of Cancer Research 1985), and another documented decreased ductal stimulation by progesterone by 400% (Fertility Sterility 1995).

In the PEPI trial of 40,000 women, it was shown that estrogen and progestin increased the risk of heart disease, whereas estrogen and natural progesterone decreased the risk of heart disease. Provera increased cholesterol and clotting whereas progesterone caused the reverse thereby protecting the heart. The July 3, 2002 study for JAMA essentially shows the same.

It can come as no surprise to the medical community that progestins increase the risk of heart disease when it is so well documented in the literature and it is known that Provera antagonizes the inhibitory effects of Premarin on coronary artery (Arterioscler Thromb Vase Biol 1997 Jan; 17 (1):217-21).

An article in the journal American Family Physician showed that Provera and progestins cause significant side effects of swelling, fluid retention, breast tenderness, bleeding, depression and mood disorders. Natural progesterone is devoid of these side effects – it is the feel-good hormone of pregnancy. The opposite is true of Provera.

The recent JAMA article stated that Premarin by itself did not increase the risk of breast cancer. The National Breast Institute and the National Institute of Health have emphatically stated that there is no conclusive evidence that Premarin alone causes an increased risk of cancer. Overall 75% of all the studies in the medical literature show no increased risk of breast cancer and this article from JAMA is no different – the risk is from adding the synthetic progestin (Provera). However, there are a few studies that show a slight increased risk of breast cancer with Premarin. The overall risk from these few studies is still very low, but the risk significantly increases with the addition of a progestin. In summary, most studies show no increased risk of cancer and a few studies show a very low risk, if any, with use of Premarin by itself.

Nevertheless, Premarin should not be used because of the cancer causing metabolites it produces. Premarin contains equilin which has been reported in two cancer research journals to cause cancer (Chem Res Toxicol 1999 Feb). There is ample evidence now to implicate the synthetic estrogen with a small risk of cancer with the synthetic progestin with the much greater risk of breast cancer and heart disease. The July 2002 JAMA article emphatically states that the concern is with the synthetic progestins and does not include other hormones nor the natural estrogen or progesterone.

We should also look at the absolute risk the JAMA paper discusses versus relative risks. There is an increased absolute risk of breast cancer of 8 per 10,000 women. Thus, there is a risk, but very small. The risk of heart disease increases 7 per 10,000 women. Again, statistically significant, however a very small risk overall.

As far as the cardiovascular risks are concerned, this applies to a very small segment of the population. First of all, we know that menopause causes significant increased incidence of heart disease. There is a plethora of information and literature over 30 years documenting a 50% decrease of heart disease by taking estrogen.

But the most glaring problem with these recent studies and conclusions is that they evaluated women with pre-established coronary disease and possibly genetic predisposition to further heart disease. One cannot extrapolate these abnormal results in patients with pre-established disease to include those without disease when years of study have shown benefits to those patients without heart disease. In addition, these studies utilized a progestin that we well know causes heart disease!

The original intent of using the bio-identical natural hormones is to avoid the side effects and complications of the synthetics that we have known about for years. The solution to the problem is the same that we have been recommending for years – natural bio-identical estrogen, progesterone and testosterone. The landmark papers that document the importance of this therapy over the problematic synthetic hormones are: Infertility and Reproductive Medicine Clinics of North America Vol 6, number 4, Oct 1995 and Obstetrics and Gynecology Clinics of North America Vol 21, number 2, June 1994.

None of these new studies provides any new information – all of this information has been in the literature for years. Where was the media then? If these recent studies are finally the eye opener for both patients and doctors to avoid the synthetic hormones, then perhaps the skewed information will have at least served to open the debate and allow the benefits of natural hormone therapy to finally emerge as the best alternative to replace that which normally occurs in the human body.

Menopause results in a tremendous increased risk of heart disease, osteoporosis, urogenital atrophy and cerebral deterioration – all can be prevented by simply maintaining hormone levels. In addition to the health benefits, we should not ignore the symptomatic improvement and quality of life issues that are the primary reason to use the hormones in the first place. Just use the right hormones in the right doses and monitor the levels.

* This is a condensed version of Dr. Neal Rouzier's more comprehensive response to the JAMA article of 7-3-02.