The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial not only validated the beneficial effects of hormone-replacement therapy (HRT) on serum cholesterol, it also turned the spotlight on natural progesterone. That hormone appeared to be more effective than the synthetic progesterone medroxyprogesterone acetate, or MPA, (Provera) in preserving estrogen's beneficial effects on the heart and was just as effective in preventing estrogen -induced overgrowth of the uterine lining.

Moreover, earlier studies had indicated that natural progesterone's side effects are minor. Some women taking it experience some drowsiness, but they are spared many of the symptoms associated with MPA - fluid retention, breast tenderness, and depression.

Many people have asked why doctors aren't suggesting natural progesterone as an option for HRT. The answer is that in the United States natural progesterone isn't available through conventional channels, and it is a relatively untested entity. However, it has a long and intriguing history.

Scientists first purified progesterone in 1934, but they soon found that the hormone was broken down to an inactive form in the intestine before it could be absorbed. In the 1950s chemists bonded progesterone to other compounds, which provided safe passage through the digestive system. These new synthetic compounds came to be known as "progestins."

Progestins such as MPA and norgestrel were patented by pharmaceutical companies, studied extensively in clinical trials, and approved by the Food and Drug Administration for use in treating secondary amenorrhea, a condition in which premenopausal women who have had normal periods stop menstruating.

However, lower doses of progestins than those necessary to treat amenorrhea were found to eliminate endometrial overgrowth - a problem associated with postmenopausal estrogen use - and so progestins were added to HRT regimens. Yet the FDA hasn't approved progestins specifically for HRT because there is little information on their long-term effects.

Researchers who continued to experiment with natural progesterone found that by pulverizing it into minute particles--a process called micronizationthey could make it absorbable in oral form. However, in early tests the oral preparation could not produce the sustained levels of progesterone necessary to stimulate menstruation. In the early 1980s researchers came up with a longer-lasting preparation - a gelatin capsule containing 200 mg of micronized progesterone suspended in oil.

A version of that product called Utrogestan, which is produced by the French pharmaceutical house Besins-Iscovesco, is now widely used for HRT in Mexico and Europe. Schering-Plough Corporation licensed micronized progesterone from LaSalle Laboratories, an affiliate of the French company, and supplied it in 200-mg capsules for the PEPI trial.

Schering plans to market that drug as Prometrium in the U.S., but doctors won't be able to prescribe it for HRT until it is approved by the FDA for treating secondary amenorrhea, as many of the progestins were originally.