By Gail Valentine, D.O.

Women of menopausal age are constantly advised these days to take estrogen replacement - and with good reason: There is little doubt that estrogen taken to replace the hormone formerly produced by their ovaries can help postmenopausal women reduce their risk of heart disease, osteoporosis, and Alzheimer's disease.

But as every physician knows, this simple solution is really far more complex than it sounds. Virtually every news report proclaiming the benefits of estrogen replacement has ignored three vitally important facts:

  • All estrogens are not created equal. As authors Jonathan V. Wright, M.D., and John Morgenthaler point out in their important new book, Natural Hormone Replacement for Women Over 45, "estrogen" replacement therapy (ERT), as practiced today in the United States, means taking horse estrogen (Premarin®), or 100% estradiol.1 Premarin is not natural in the human female, and use of pure estradiol is not in accordance with the body's natural estrogen balance. Consequently these substances can cause unpleasant or even dangerous side effects (including cancer). A better solution is the noncarcinogenic estrogen estriol, or, better still, a natural balance of estriol, estradiol, and estrone (80%, 10%, and 10%), which more accurately represents what women naturally have in their bodies.


  • If you replace estrogen, you should also replace progesterone. The Premarin or estradiol commonly used in ERT dramatically increase a woman's risk of endometrial cancer (cancer of the uterine lining) unless these drugs are "opposed" by (given along with) progesterone. If you have any doubts, just read the fine print on the labels of these products. It took many years and thousands of women dying of endometrial cancer before physicians finally woke up to this realization.


  • Provera is not progesterone. Unfortunately, the standard practice in conventional American medicine has been to replace the natural hormone progesterone with an unnatural hormone-like drug called medroxyprogesterone, or Provera. The combination of Premarin + Provera is the most common form of hormone replacement therapy (HRT) prescribed in the U.S. today. While Provera does keep Premarin from causing endometrial cancer, it is not progesterone. As such, it lacks many of progesterone's other important benefits, and may cause a long list unpleasant and dangerous side effects, including increasing the risk of heart disease.

Women who take natural progesterone (and/or natural estrogens) in physiologic doses (i.e., doses that reproduce normal levels in the body), report virtually no unwanted effects. According to John R. Lee, M.D., a California physician who has been studying the effects of natural progesterone in menopausal women since the 1970s, natural progesterone does have one "side effect": "That guy across the room will get better looking." Dr. Lee points out that progesterone is at least partly responsible for the sex drive in women. "Presumably this is nature's way of assuring a meeting of the egg with a sperm after ovulation."2

Figure 1. Molecular structure of natural progesterone and synthetic medroxy-progesterone (Provera).

This is far from the case with synthetic "progestins." A quick look at the Physicians' Desk Reference entry for medroxyprogesterone acetate (Provera) reveals that more than 60% of the text is devoted to Contraindications, Warnings, Precautions, and Adverse Reactions. Provera is a serious drug with many serious consequences, including the possibility of:

  • Birth defects, if taken when pregnant
  • Breast cancer in some cases
  • The formation of blood clots, especially in the lungs or the brain
  • Fluid retention, swelling
  • Breakthrough bleeding, or other menstrual irregularities
  • Depression
  • Impaired glucose tolerance
  • Breast tenderness and milk production
  • Skin rash
  • Acne
  • Hair loss, or hair growth
  • Weight gain

A large proportion of women who start taking Provera or other synthetic hormones find the unwanted effects to be so unpleasant that they stop HRT altogether, thus giving up all its potential life-enhancing and life-extending benefits.

All these progesterone wannabes generally have the same unwanted effects, because not one of them is really progesterone. Notice in Figure 1 that the chemical structures of progesterone and Provera are quite similar. It is that similarity that enables Provera to perform many of the functions that progesterone normally does. But the two molecules also have some important differences, and it is those differences that account for the many unwanted effects that Provera and similar drugs cause.

The ovaries begin producing progesterone in earnest around puberty, and the monthly ebb and flow of this hormone, in harmony with estrogen and other hormones, continues until menopause. Progesterone's primary role during this period is to help make the uterus ready for implantation of a new embryo, the first major event - after fertilization of the egg - in the 9 months of human gestation. If the egg is not fertilized, progesterone production temporarily ceases, and the uterus sheds its endometrial lining.

At the same time it's helping drive the menstrual cycle, progesterone is also performing several other vital but less appreciated functions (see box). Among the most important are building new bone tissue and countering the tendency of estrogen to induce excess growth in the endometrial lining of the uterus. In extreme cases, this growth can turn cancerous. Progesterone is also a major precursor for other hormones, including the estrogens and testosterone. If the progesterone "spigot" is turned off, as occurs at menopause, estrogen and testosterone levels may also fall.

Some of Progesterone's Many Roles

  • Precursor of other sex hormones (estrogen and testosterone) and cortisone
  • Maintains lining of uterus
  • Promotes the survival of the embryo and fetus throughout gestation
  • Protects against fibrocystic breasts
  • Natural diuretic
  • Promotes fat burning for energy (thermogenesis)
  • Acts as a natural antidepressant
  • Aids thyroid hormone action
  • Normalizes blood clotting
  • May help maintain sex drive
  • Helps keep blood sugar levels normal
  • Normalizes zinc and copper levels
  • Promotes proper cell oxygen levels
  • Protects against endometrial cancer
  • Helps protect against breast cancer
  • Promotes bone building and protects against osteoporosis


One of the prevailing myths in U.S. medicine today is that osteoporosis can be treated solely by replacing estrogen. In fact, while estrogen replacement therapy may temporarily slow the progression of bone loss and may decrease the risk of fractures by as much as 50%, it does nothing to restore bone that has already been lost.3 By contrast, natural progesterone - but not Provera or other progestins - has been shown to restore bone lost to osteoporosis by 15% or more.

Bone tissue is constantly being "remodeled" throughout life in two phases. First, cells called osteoclasts travel throughout bone tissue. When they come upon older bone, they dissolve or resorb it, leaving tiny, unfilled spaces, or pores, in their place. Following in the wake of the osteoclasts are cells called osteoblasts, which enter these spaces and begin construction of new bone tissue. Throughout youth and into middle age, bone remodeling reflects a balance between these two processes. Osteoporosis means basically that the osteoclasts are outrunning the osteoblasts, resulting in a relative loss of bone tissue.

In women, bone mass reaches its peak during their early to mid-30s, after which it begins a slow decline until menopause. After menopause, bone loss accelerates 3% to 5% for about 5 years, after which it tapers off to about 1% to 1.5% per year.

Figure 2. Effects of natural progesterone replacement on bone density.

Evidence from many in vitro, epidemiological, and clinical studies support the view that the hormone primarily responsible for building new bone is progesterone.3 The primary study linking natural progesterone and reversal of osteoporosis was conducted by Dr. John Lee.4,5 He treated 100 postmenopausal women (mean age, 65.2 years) for a minimum of 3 years with a program that included natural progesterone skin cream. Dr. Lee was able to carry out serial bone density testing on 63 of these women.

Over 3 years, the women would have been expected to lose about 4.5% of their bone density with no treatment. In fact, the women's bone density increased by 15.4% (Fig. 2). "It was not uncommon," reported Lee, "to observe increases of 10% to 15% within 6 months and 20% to 25% in 3 years."

Lee found that advanced age was no hindrance to improved bone density, since those women who were older than age 70 had the same gains as those who were younger. The only factor that did seem to make a difference was the women's bone density at the start of therapy. Those with the lowest density at the start of treatment had the largest increases after 3 years. Whether or not the women were also taking estrogen supplements made no difference. Progesterone treatment had no side effects, which probably contributed to a high rate of compliance, Dr. Lee noted. The cost of the progesterone cream, about 10% of the cost of an equivalent dose of Provera, was also an important advantage.

Estrogen seems to help control lipid levels, blood pressure, carbohydrate metabolism, coagulation factors, and endothelial function. Indeed, the increase in heart disease risk following menopause is thought to be due, at least in part, to a reduction in estrogen levels. Replacement of estrogen in postmenopausal women increases the levels of HDL (the "good") cholesterol and decreases levels of LDL (the "bad") cholesterol.6

That's the good news. The bad news is that when a woman takes estrogen replacement by itself, she increases her risk of endometrial cancer. Estrogen is an excellent and important stimulator of cell proliferation in uterine tissue. Unfortunately, if this proliferation is not checked, it can get out of hand.

Nature harnesses estrogen's carcinogenic potential by "opposing" it with progesterone. Premenopausal women with normal levels of estrogen and progesterone almost never get endometrial cancer. But women who take "unopposed" estrogen may have a risk of endometrial cancer as much as 14% higher.7

The addition of Provera or other synthetic progestins to an ERT regimen virtually eliminates the risk of endometrial cancer - but, again, there's a price to be paid. Taking a synthetic drug like Provera counteracts the protective effect estrogen purportedly has on the heart. In contrast, natural progesterone does not take away the cardiovascular benefit of estrogen. The PEPI Trial explains why.


Figure 3. Effects of estrogen (Premarin), estrogen + synthetic progestin (Provera), or estrogen + natural progesterone on HDL cholesterol levels in postmenopausal women. HDL levels are expressed in mg/dL. Results are from the PEPI trial.
This assertion was supported most clearly in a large well-controlled National Institutes of Health (NIH)-sponsored trial carried out over 3 years. Known as the "Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial," its results were published in the Journal of the American Medical Association in early 1995.6

The participants in the PEPI trial, 875 postmenopausal women, were randomly assigned to receive either 1) placebo, 2) estrogen (Premarin), 3) estrogen + progestin (Provera), or 4) estrogen + natural (micronized) progesterone (an oral formulation). HDL levels in the placebo group decreased by 0.03 mg/dL, compared with their pretreatment baseline (Fig. 3). By contrast, in those women who received "unopposed" estrogen replacement, HDL levels increased substantially over baseline to 0.14 mg/dL. In the group that received estrogen + Provera, the increase in HDL was almost completely nullified. However, when natural progesterone was substituted for the synthetic progestin, virtually all of estrogen's HDL protection was restored. Both Provera and natural progesterone produced significant improvements in LDL, triglyceride, and total cholesterol levels compared with findings in the placebo group, but there were no differences between the two treatments themselves.

The PEPI investigators were surprised by the superiority of natural progesterone over synthetic progesterone. Noted the prominent cardiology researcher, Elizabeth Barrett-Connor, M.D., of the University of California, San Diego, "If I were treating a woman primarily because she was worried about heart disease or because she had dyslipidemia and low HDL cholesterol, I would probably see if she wanted to take micronized [natural] progesterone. I was quite impressed with the better effect." Another PEPI investigator, the former NIH head Bernadine P. Healy, M.D., who is currently at the Cleveland Clinic Foundation, agreed, stating, "I think the biggest surprise certainly was the HDL effect of micronized progesterone."8

Why should the superiority of natural progesterone come as such a surprise to these prestigious researchers? One reason may be that, for the most part, the U.S. medical community makes no distinction between progestins and progesterone. This is largely the result of a long-term pharmaceutical industry strategy to protect its investment in patentable synthetic progestins. By sponsoring thousands of studies on progestins but none on progesterone, nearly all the large, well-controlled trials in hormone replacement have involved synthetic "hormones."

"Somewhere early in the development of the HRT industry, progesterone was not only forgotten, it was mislabeled and mistaken as its [progestin's] distant cousin," writes John Lee.5 Lee points out that even well-researched books on menopause tend to make this error.

Progestins do not provide "the full spectrum of natural progesterone's biological activity, nor are they as safe," adds Dr. Lee. "It is a sad commentary on the pursuit of profit over women's well-being that the pharmaceutical companies take perfectly good natural hormones that our bodies know and can use and alter them, creating synthetic compounds with similar hormonal effects but toxic side effects. Research on natural progesterone has in the past two decades been essentially nonexistent. Thus does industrial profit influence the path of science," Lee writes.

As a result of this strategy, synthetic "hormones" have become the standard against which all other treatments have been measured. Never mind that they are demonstrably inferior to their natural counterparts. The fact that there have been no large, well-controlled, head-to-head comparisons between synthetic and natural hormones has been enough to convince most medical doctors to opt for progestins. Perhaps the results of the PEPI trial and any future studies it may trigger will begin to change that misperception.

Heart disease is responsible for at least three-fourths of the deaths in postmenopausal women. Although much evidence suggests that estrogen replacement helps reduce the risks associated with heart disease, new data confirm that the common practice of taking the synthetic progestin Provera along with "estrogen" to minimize the risk of endometrial cancer may be increasing women's risk of suffering a heart attack to an unacceptable level. Natural progesterone, however, provides cancer protection but carries no such risk.

This conclusion comes from a new study carried out in rhesus monkeys at the Oregon Regional Primate Research Center.9 Eighteen monkeys had their ovaries removed to simulate menopause. They were then put on a hormone replacement regimen that included estradiol plus either Provera or natural progesterone. After 4 weeks, the researchers injected a substance that causes the coronary arteries (which supply the heart with blood) to constrict, cutting off the flow of blood to the heart muscle.

The researchers reported that the animals receiving Provera would have died within minutes had they not received protective drug treatment. The same thing happened in those animals that received no hormone replacement. By contrast, those monkeys that received natural progesterone quickly recovered from their simulated heart attack with no protective drug treatment.

"The big surprise," noted the primary author of the paper in an interview in Science News, is that Provera poses such a "huge risk." "This is a really dangerous drug (italics added)."10

The results of a British study show that this conclusion is not limited to monkeys. Sixteen postmenopausal women with coronary artery disease also received "hormone" replacement that included an "estrogen" plus either Provera or natural progesterone. Those who received natural progesterone were able to exercise significantly longer on a treadmill test before developing symptoms indicating reduced blood flow to their hearts. Noted one researcher, in terms of heart disease protection, Provera is "worse than no treatment at all."11

Natural progesterone is derived from the wild yam (Dioscorea villosa) which contains the steroid precursor, diosgenin. How, you might well ask, can a wild yam yield a "natural" human hormone? While it's true that you can eat wild yams all day without raising your progesterone level - the human body does not possess the biochemical tools for converting diosgenin to progesterone and other steroid hormones - laboratory processing of diosgenin yields progesterone molecules that are chemically identical to natural human progesterone.

Natural progesterone can be taken by oral capsules or via a skin cream (transdermal). Transdermal hormones are thought to be better because their absorption is more efficient, therefore requiring less hormone, and because the hormones will pass through the body's circulation once. Thus the use of transdermal hormones is likely to provide more consistant results. Notes Dr. John Lee, "We now know that within seconds after oral progesterone is absorbed into the blood, it is passing through the liver and turning into three different water-soluble metabolites that are awaiting excretion in the bile. These metabolites are in the bloodstream, and they actually interfere with the natural progesterone."

When progesterone cream is rubbed on the skin, it is quickly absorbed into the underlying fatty layer and then diffuses into capillaries from where it enters the bloodstream. Like other fat-soluble substances (e.g., vitamin E, vitamin A), it is carried along by red blood cells and is 100% bioavailable.

Natural progesterone cream can improve or correct the hormonal imbalances of menopause and PMS, help prevent or reverse osteoporosis, and help prevent heart disease and endometrial cancer. Natural progesterone is also known to enhance libido, protect against fibrocystic breasts, promote fat burning for energy, contribute as an antidepressant, improve thyroid function, help normalize blood sugar levels, and more. And all this without the disturbing side effects of the synthetic progestins. It makes obvious sense to replace progesterone with an identical human hormone and enjoy the benefits of an enhanced quality of life, and, who knows, possibly the enjoyment of an extended life as well.


  1. Wright J, Morgenthaler J. Natural Hormone Replacement for Women Over 45. Petaluma, CA: Smart Publications; 1997.
  2. Barnard N. Natural progesterone: Is estrogen the wrong hormone? An interview with John R. Lee, M.D. Good Health. 1994;Spring.
  3. Prior J. Progesterone as a bone-trophic hormone. Endocrine Reviews. 1990;11:386-398.
  4. Lee J. Is natural progesterone the missing link in osteoporosis prevention and treatment? Medical Hypotheses. 1991;35:316-318.
  5. Lee J. What Your Doctor May Not Tell You About Menopause. New York: Warner Books; 1996.
  6. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-208.
  7. Estratab® (esterified estrogen tablets). Product Information. Physicians' Desk Reference: Medical Economics; 1996.
  8. Archives Journal Club/Women's Health. Estrogen replacement therapy and heart disease: A discussion of the PEPI trial. 1995; pubs/journals/archive/womh/vol_1/no_1/jcr.htm.
  9. Miyagawa K, Rösch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Med. 1997;3:324-327.
  10. Raloff J. Hormone Therapy: Issues of the heart. Science News. 1997;151:140.
  11. De Ziegler D. Cardiovascular effects of the ovarian hormones. Arch Malad Coeur Vais. 1996;89(suppl):9-16.