Alvin Pettle, M.D., FRCS(C) (OBS & GYN)
In July of 2002 a very important study was suddenly halted by the Data and Safety Monitoring Board of the United States. In the mid 1990's The Women's Health Initiative (WHI) began a study that was sponsored by the National Institute of Health. This study was on the drug Premarin .625 combined with Provera 2.5 mg (synthetic progestin). The study was to run until the year 2005, but was suddenly stopped after only five years of the study. Sixteen thousand, six hundred and eight women in all were put through a double blind placebo study. The double blind placebo study is a study where both the patients and the physicians are unaware of the medication that the patient is receiving. In other words half the patients received placebo (nothing) and the other half of the patients received .625 mg of Premarin (pregnant mare's urine) and Provera 25 mg (synthetic progestin) The reason that the Data and Safety Monitoring Board (DSMB) stopped the study after only 5.2 years was because the group of patients that were receiving the synthetic Premarin and Provera had a higher incidence of complications than the patients receiving the placebo. In fact, calculated out to ten thousand women, in other words two thousand women using the synthetic HRT for five years, the study showed that patients who took the synthetic HRT had a higher incidence of the following complications of 10,000 women using synthetic HRT in 1 year.
• Breast cancer - eight more cases
• Heart attacks - seven more cases
• Strokes - eight more cases
• Thromboembolic phenomena - eight more cases
• Colon cancer - six less cases and fracture five less cases
In other words if 30 women had breast cancer taking a placebo or nothing, then 38 women would be expected to get breast cancer if they were taking synthetic HRT. For every 30 women who had a heart attack 37 women would have heart attacks if they took synthetic HRT and on throughout the study. In fact, taking a synthetic HRT was more dangerous than not taking it. (except for bowel cancer and osteoporosis)
(see diagram #1)
This study however, should not have been a surprise if one had looked at the literature over the past several years comparing synthetic progestin and natural progesterone. The problem really has been that most of the studies over the last 40 years, have always been with Premarin and Provera and very few studies, except the PEPI trial in the early 1990's and the Oregon Trial, had taken the time to compare synthetic progestins, such as Provera to Natural Progesterone, such as Prometrium or Progesterone Cream.
Provera (synthetic progestin) is a synthetic hormone made to look like progesterone, but it is not in fact progesterone and the body knows it. Provera has a half life of 30 hours and therefore, has no biological pathway to break it down and remove it from the body, and in fact, I believe that these biological break down products are more potent than the product Provera itself. Provera has listed in the compendium 150 side effects, many of which are side effects that are already the complaints that the patient comes to a physician for during menopause. These side effects are, for example: weight gain, depression, insomnia, anxiety, water retention and many, many more. Premarin (pregnant mare's urine) belongs in a 1500 pound horse and certainly in my mind is far more potent than the hormones that belong in a woman that weighs between 100 and 150 pounds. In the 1950's a man by the name of Willard Allan extracted estrogens from the urine of horses and a huge company (Ayerst) bought the patent. Since there was no competition for the hormone replacement therapy plus the fact that the Premarin had a tremendous amount of money invested in it and a tremendous amount of advertising, the company flooded the market with this wonderful new drug to keep women young forever. As doctors gave Premarin to their patients a few years went by and patients returned with uterine cancer. The patients asked their physicians if their cancer comes from the Premarin? And the answer of course was, "YES". Interesting that God's own natural estrogens never caused uterine cancer, but when man began to try and use synthetic drugs to replace natural hormones, suddenly uterine cancer increased by 15 times. So the drug companies quickly made another drug called Provera (synthetic progestin) to be taken along with the Premarin to in fact protect the uterus. This drug with many, many side effects itself, was given to treat the side effects of the first drug given to the patient. And so Premarin and Provera became the "Golden Standard" of hormone replacement therapy for the next 40 years. During that time however, several companies began to produce products from natural sources such as soy and yam, which were to compete with Premarin and Provera. Sadly however, because physicians felt so comfortable using Premarin and Provera, many physicians were reluctant to transfer their patients over to Prometrium, for example, which is a natural progesterone made from yam and is by far superior to the synthetic Provera. Other estrogen products were made from soy and were slowly getting into the market place, but also having a difficult time replacing the standard Premarin. These estrogen products were from soy and to my mind were safer to the patient albeit they were for the most part 100% estradiol, the most potent estrogen (CES, Estrace, Estragel, Estraderm, etc.)
In 1994, a large-scale study was begun at 20 medical centers across the United States called the HERS (the heart and estrogen progestin replacement study). It was the second largest study of its type ever attempted and this also was funded by the Pharmaceutical Giant Wyeth-Ayerst with every expectation that the HERS project would prove that synthetic hormones would prevent heart attacks in post-menopausal women. Two thousand women with heart disease were put on a combination of estrogen and progestin. By 1998, the results in the hormone replacement therapy were as follows
(a) Substantially increased heart attacks the first year in the synthetic HRT group.
(b) Had no effect on decreasing heart attacks in subsequent years.
(c) Affected blood clots with a three times higher incidence in the group that took hormone therapy (synthetic)
(d) HRT synthetic caused an increase in gallbladder disease.
Once again a large scale study shows that synthetic HRT does not belong in the human body and that all of the hype that was given to the drug replacement therapy in fact has proved to be fallacious. However, there is another side to the story of hormone replacement therapy.
What bothers me tremendously is that only recently with such people as Dr. Jonathan Wright, have people begun to look at the master plan of the human female and tried to decipher that in all likelihood the best hormone replacement therapy would be the hormone replacement therapy that most matched what God had put into the body in the first place. In other words, if you looked at the estrogen level of any female no matter what time in her cycle, the ratio of the three estrogens present in her body, would always be the same (10% estrone (E1), 10% estradiol (2), and 80% estriol (E3) the weakest estrogen and by far the most protective estrogen of the three. In fact, estriol is the hormone of pregnancy produced by the placenta and we now know that the sooner the patient has a pregnancy in her life, the less likely she is to have breast cancer. Studies done in the past by Lemon and Fathergill proved that the use of estriol, the "forgotten estrogen" should be looked at very seriously, however, until only recently very few physicians have begun to look at estriol as a possible hormone replacement substitute. Therefore, Jonathon Wright and others began to formulate Tri-Est. This was compounded in a compounding pharmacy in the exact ratio of 10% estradiol, 10% estrone and 80% estriol and made from a soy base. The dose of Tri-Est was 1.25 used twice a day or 2.5 mg twice daily because Tri-Est is metabolized within 12 hours. Although initially I used Tri-Est in a transdermal form along with Progesterone I am now more impressed with the use of slow releasing oral Tn-Est to be taken 1 capsule in the morning and 1 capsule in the evening. Dr David T. Zava in his excellent article in the International Journal of Pharmaceutical Compounding (volume 6, No.4 July/ August 2002) has 53 references when referring to the estrogen matrix and I refer this excellent article to both physicians and patients in the handouts that are available. Along with this article I would certainly suggest reading Boomsna and Pauletti also quoted in the International Journal of Pharmaceutical Compounding (volume 6, No.4 July/August 2002) with 35 references.
This article is a superb review from the medical literature to show that natural progesterone is in fact a protective hormone for breast cancer and the references throughout the literature appear to be now quite solid. In fact, estrogen says grow and progesterone says stop growing it is like the Ying and the Yang. So it appears to me that the best natural hormonal replacement would appear to look in the order of Tri-Est 1.25mg twice a day or 2.5mg twice a day along with a natural progesterone cream either 3% or 6% progesterone cream or if the patient is having trouble sleeping the use of prometrium 100mg at night. Many patients find that taking five days off does not bother them. Other people who take five days off seem to be bothered with menopausal symptoms and choose to use it in a continuous manner, with which I have no problem.
The real issue comes when a large mass of women are suddenly faced with the problem of Premarin and Provera and have suddenly stopped the Premarin and Provera because of the study. In fact, what should have been done for these patients would be to slowly wean off Premarin and Provera and then be placed perhaps next onto a soy-based estrogen, such as Estrace or CBS or Estragel along with a yam based progesterone such as Prometrium 100mg during the time they are coming off of Premarin and Provera. This enables them to transfer over to soy based and yam based progesterone and estrogen, albeit the estrogens in these products are 100% estradiol. It is my hope and my plan to have patients on this combination to eventually come off the estrogen and progesterone and move towards the Tri-Est and progesterone cream form, which I feel, is even safer for long tern use.
(see diagram #2)