California Healthspan Institute's Analysis

Bio-Identical Estrogens and Progesterone in Preventive and Anti-Aging Medicine

CHI was not surprised at the headline-making preliminary results of the Women's Health Initiative Randomized Controlled Trial which was published in the July 17, 2002 issue of the Journal of the American Medical Association Vol. 288 No. 3, showing that PremPro, the combination of Premarin (non-human estrogens derived form pregnant mare (horse) urine) and Provera or medroxyprogesterone acetate (MPA) was dangerous.

This type of "hormone replacement therapy" is not really true hormone replacement therapy since to be categorized as a "hormone" the substance must naturally exist in the human female or male body. The results of the PremPro study do not apply to bio-identical hormone replacement. To assist you further, Dr. Rothenberg has fully evaluated the study below:

The study:

As you can see, one group in the study received what the study calls "Estrogen" but in fact, the medication was not "estrogen" at all; it was "Premarin." They also received a progestin, Provera (MPA) which is not the natural micronized progesterone that CHI prescribes. Unfortunately, many health professionals think Provera is progesterone and that simply is not true.

Study Results:

Per 10,000 women - years on PremPro
7 more CHD events (heart attacks)

8 more Pulmonary Emboli (blood clots in lungs)

8 more strokes

8 more breast cancer

6 less colorectal cancer

5 less hip fractures

The numbers don't seem very large but when multiplied by all of the women taking PremPro there would be considerable additional deaths and serious medical problems.

Why do women need youthful levels of estrogen and progesterone? What hormones should be used? What methods should be used?

Quality of Life: Physical, mental and emotional factors should always be the first priority. To "cut to the chase," bio-identical hormone replacement therapy improves quality of life dramatically. Menopausal symptoms are related to a deficiency of estrogens and progesterone. The vasomotor symptoms of menopause include hot flashes and night sweats. The genito-urinary symptoms of menopause include vaginal dryness, pain with intercourse and urinary problems. Symptoms in other systems include dry skin, sagging breasts, osteoporosis, cardiovascular disease, cognitive impairment and Alzheimer's dementia.

"Estrogen" does not exist in human females. Estrogen is a broad term commonly used to address the three estrogens found in the human body. The three forms of estrogen present in the human female are:


E1 Estrone

E2 Estradiol

E3 Estriol


Foreign estrogens that do not belong in the human body are called xeno-estrogens. Unfortunately, xeno-estrogens are rampant in our environment and have potentially dangerous effects. Insecticides and plastic bottles contain xeno-estrogens. The biggest xeno-estrogen of them all is Premarin (also called conjugated equine estrogens) which, as you know, obtained its name from Pregnant mare urine.

The principal estrogen in Premarin is eqiillin (like equs, which means horse in Latin). Premarin also contains 40 additional xeno-estrogens, estrone (E1) and estradiol (E2). Eqiillin is 1000 times more potent on the endometrium (inner lining of the uterus) than the human estrogens and it may be responsible for many adverse effects. Estriol (E3) may be cancer protective and is known to balance the effects of estradiol (E2).

At this time, the best form of estrogen replacement in the human female is a combination of Estradiol (E2) which protects the heart, bones and brain and Estriol (E3) which may protect against cancer. A compounding pharmacists can make a gel or cream called Bi-Est, made from soy, which is 80% Estriol and 20% Estradiol that is applied to the skin and absorbed. At CHI, we get blood tests to asses the level of estrogens in the blood before and after this bio-identical Bi-Est" prescription. There is no commercial drug manufactured by a drug company that contains this mixture.

Now, on to progesterone. Progesterone balances the effects of estrogens. It protects against the development of edometrial cancer. Once again, Provera is not Progesterone. Many of the adverse effects of PremPro are due to Provera. While Provera appears to increase the rate of breast cancer, progesterone may decrease the chance of breast cancer. (Desreux J., Progesterone receptor activation. an alternative to SERMs in breast cancer. Eur J Cancer 2000 Sep; 36 Suppl 4:S90-1).

Progesterone should be replaced with compounded micronized progesterone. Natural progesterone does not have the unwanted side effects of Provera: fluid retention, breast tenderness and weight gain. (Hargrove JT et al. An Alternative Method of hormone replacement therapy using the natural sex steroids. Med Clin North Am 1995 Nov; 79(6): 1337-56)

Even worse, Provera increases heart disease and diabetes risk. Progesterone does not. The PEPI study gives us a clue as to why. In the PEPI study, women were on Premarin (too bad it wasn't bio-identical Estrogen) and some of the women were also on Provera. Some women in the study took bio-identical estrogen. Premarin improved HDL (the good cholesterol) and Provera cancelled this effect.

Provera also increases insulin resistance. We have been stressing the need to control insulin resistance as one of the first priorities in preventive and anti aging medicine. Keeping insulin resistance low is correlated with prevention of heart disease, stroke, high blood pressure and cancer. Provera increases insulin resistance and raises blood sugar levels. (Clarkson see below)

Hundreds of current scientific studies explain why "estrogen" is good for women's cardiovascular systems. The Premarin and Provera studies do not show this because the drugs used are not estrogen and progesterone. Long term effects of "estrogen" replacement therapy show a decrease atherosclerosis and an increase blood flow in the arteries.

The diagram below is from the New England Journal of Medicine, which explains the mechanisms of decreased atherosclerosis and increased blood flow in the arteries. (Mendelsohn, M., The protective effects of estrogen on the cardiovascular system. NEJM 6/99. Provera but not progesterone eliminates this protection. MPA reduces the dilatory effect of estrogens on coronary arteries. (Clarkson TB, Progesterone and cardiovascular disease. A critical review. JreprodMed, 1999, Feb; 44 (2Suppl): 180-4)

Why haven't there been large studies of bio-identical estrogens and progesterone? The reason is: bio-identical hormones occur naturally in the human female and cannot be patented. There is no economic motivation for the large pharmaceutical companies to finance a study using bio-identical estrogens and progesterone. We hope a study will be done someday.

The authors of the Women's Health Initiative study comment that the results might be different if natural hormones were used. Quoting from the actual study in JAMA: "The results do not necessarily apply …to estrogens and progestins administered through the transdermal route. It remains possible that transdermal estradiol with progesterone, which more closely mimics the normal physiology and metabolism of endogenous sex hormones, may provide a different risk-benefit profile."

So what's the bottom line? Millions of years of evolution have created bio-identical hormones in our bodies. Let's stick with them. Bio-identical hormone replacement is essential to maintaining quality of life.

Let's do everything else we can to stay healthy and prevent cardiovascular disease and cancer. Eat a Zone-type diet to limit insulin resistance and maximize your vegetable intake. Exercise, doing both aerobic and resistance training and use dietary supplementation with high dose pharmaceutical grade fish oils as well as other key supplements.