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The announcement from the Women’s Health Initiative (WHI) study that Provera aggravates cardiovascular risk factors has brought new emphasis on using alternative forms of hormone replacement therapy (HRT) in women.  
[Click here for more information on postmenopausal hormone therapy]

Prempro, a combination of Provera (medroxyprogesterone acetate) and Premarin [conjugated equine estrogen (CEE)], was the drug used in the WHI study. The unfavorable result that caused the study to be stopped early is the Provera part of the Prempro as evidenced by the fact that the Premarin arm of the trial is still being conducted. In addition, there were lots of alarms about Provera before this.

The natural form of progesterone (Prometrium) in micronized pill form wasn’t tested in the WHI study. However, it was in the PEPI study, and it, and unopposed (without progesterone) estrogen gave the best lipid results.

In the Postmenopausal Estrogen/Progesterone Intervention (PEPI) trial, which included a placebo group, an unopposed estrogen group, and three different estrogen-progestogen combination groups, high-density lipoprotein (HDL) cholesterol increased in all treatment groups. Women assigned to CEE alone, or CEE plus micronized progesterone (MP) had significantly greater HDL increases than did the other treatment groups. Also, in the PEPI trial low-density lipoprotein (LDL) cholesterol decreased 10-15% in all active treatment groups. Carbohydrate metabolism, measured by two-hour postchallenge insulin level, also decreased in all groups, including placebo; however, two-hour glucose increased in the CEE plus medroxyprogesterone acetate (cyclic and continuous) groups vs. placebo, but was unchanged in CEE alone, and CEE plus MP groups.

Neither systolic nor diastolic blood pressure differed between any of the groups in the PEPI trial.

Estrogen, with or without progestogen, was associated with a lower weight gain as compared to placebo over the course of PEPI study. Also, the newer oral contraceptives have been found to have some deleterious effects on lipids, but fewer than those seen with the earlier preparations (J Reprod Med. 1999;44:221-6).

Although progestational hormones are clearly beneficial in preventing estrogen-induced endometrial hyperplasia and cancer, their effect on other areas is far less clear. Of particular concern is the deleterious effect medroxyprogesterone acetate (MPA) has on the cardiovascular benefits of postmenopausal estrogen treatment. MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, accelerates LDL uptake in arterial wall plaques, increases the blood clotting potential of atherosclerotic plaques, and promotes insulin resistance and its consequent increase in blood glucose levels. These effects may be limited to MPA, and not shared by other progestogens (J Reprod Med. 1999; 44:180-4).

There have been smaller studies which have found no advantage from micronized progesterone on lipids, but they included only small numbers of subjects studied, thus, making their statistical validity difficult to assess, and are less compelling. PEPI is the biggest and the best study done yet on the subject, and its data remains the strongest.

As for estrogens, I think there are very few people who think that there is something especially awful about Premarin estrogen vs. other kinds of pure estrogenic substances (like the estradiol in many other HRT products). Premarin (CEE) consists of all three estrogens, including conjugated estradiol, and one pure estrogen generally does what all the others do in animal studies. And finally, there is the inescapable fact that the WHI Premarin-only arm (for women who have had their uterus removed) is still going on.

Other "natural" estrogens, like genistein, will be weaker estrogens. If a woman is going to use one of them, she might as well use a "Selective Estrogen Receptor Modulator drug (SERM)" like Evista/raloxifen, which almost certainly decreases breast cancer risk.  And finally, hormones, drugs, nutrients and foods are all parts of the same single system of chemistry. Once you realize this, the arguments about "natural" versus "unnatural" evaporate as anti-science hype from unregulated "health food" pitchmen. The real question is: "How much of a particular chemical, and when should I put it into my body for successful Clinical Age Management?"