Looking For The Truth In Hormones

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.


Another issue I've had over many years is the patients who've had a hysterectomy and have their ovaries left within the pelvis and who are then placed on unopposed estrogen. There are studies now showing that if a patient does not receive unopposed estrogens for many years that their incidence of ovarian cancer will be markedly increased over patients who are protected from the estrogen with the use of a progesterone along with the estrogen. Therefore, over the last eight years I've always asked patients to use progesterone despite the fact they do not have a uterus. I have had physicians call my office and ask me why I would place someone on progesterone who does not have a uterus and my answer to them usually is that God did not put progesterone in the body just to protect one organ; it is in the body to protect all reactive tissue that has progesterone receptors against the effects of estrogens (ie: brain receptors and breast receptors). In other words, it is a major protective hormone for the breast. Now here is where it gets really interesting, because many people now realize that if you take a synthetic progestin along with estrogen that you increase the incidence of breast cancer. Some physicians tell patients not to use progesterone along with estrogen in a hysterectomized patient. But in fact that's where the real issue is; many physicians are mixing and matching progestin and progesterone when they are as different as night and day. The truth is, the body knows the difference between progestin and real progesterone.

(see diagram #2)


To prove this point, an Oregon study was done by Mivagawa and Frank a study that was combined with the USC school of medicine This study compared the use of synthetic progestin along with estrogen, versus a natural progesterone along with estrogen, in monkeys that had been given surgical menopause. In other words 18 monkeys were surgically given menopause and divided into two groups. One group of monkeys were lucky enough to receive natural progesterone and estrogen and the other group of monkeys were unlucky enough to receive progestin and estrogen. The two groups were then given a drug, which was going to produce a vasospasm, in other words a heart attack in the animal. The group of monkeys that received estrogen and progestin required a reversing drug to save each of their lives. In the group of monkeys that had natural progesterone and estrogen and received the vasospastic drug, all survived the episode of the drug without any benefit or any need of a reversing drug. In other words, progestin causes vasospasm, but progesterone causes vaso relaxation. In fact, it is known now that in women who have had heart attacks and die, their arteries usually have very little plaque compared to men who die of atherosclerotic heart disease and myocardial infarction. I believe that it is vasospasm in females that produces heart attacks and therefore the synthetic progestin is absolutely the worse possible drug to be taken in a patient who has an increased incidence of heart disease. However, I believe that the natural progesterone in years to come will be shown to help not only protect the patient's uterus and heart, but also I believe will protect the patient from cardiovascular disease.


A female patient, until the age of 50, has definitely less incidence of heart attacks than men. After the age of 50 women suddenly has an increased incidence of heart attacks and catches up to the incidence of men. This is why it was felt that giving estrogen and progesterone might be protective for the patient's cardiovascular system. The mistake that was made was that patients should have received natural estrogen and natural progesterone and to my thinking should have received the natural combination of estrogen in the order of Tri-Est and the natural progesterone either in a cream form or in a pill form to protect them. Patients in my practice who receive natural progesterone cream are not given 100% estradiol preparations because my feeling is that natural progesterone cream is strong enough to protect the patient from Tri-Est, but is not strong enough to protect the patient from a product that has 100% estradiol, the most potent estrogen. Some people believe that it is only estradiol component that is the major hormone protecting patient's heart and bones. Dr. Maida Taylor from the University of California wrote an excellent paper in The Clinical Obstetrics and Gynecology (volume 44, No.4 December 2001) in which she reviews all hormones and the title of the article is "Unconventional Estrogens, Estriol, Bi-Est and Tri-Est." I believe that physicians can make their own decision based on the information that she has provided. In my own practice, I have been overwhelmed with the success of natural Tri-Est from soy and natural progesterone in combination. And to this point and through this dictation I have not had the major complications such as uterine cancer and breast cancer that have been seen from other preparations.


In fact, as I grow further into the process of learning about hormones, I'm very impressed with the use of natural progesterone on its own. In fact, peri-menopause should be treated only with natural progesterone because it of course is the first hormone to be lost by the patient and the patient's symptoms are very quickly reversed with natural progesterone cream. I do believe that Dr John Lee was correct when he stated that two out of every three patients could be treated right through menopause with natural progesterone cream alone. I would add that perhaps a vaginal estriol along with a progesterone would be tremendously beneficial in some patients who have vagina] dryness and atrophy and urethritis symptomatology. However, for patients who do not do well on just natural progesterone alone, I feel very comfortable adding Tri-Est to their regime. I tend to use oral Tri-Est in patients who have an elevated cholesterol because of the action of estrogen and hepatic lipase.


Many of my patients ask me why there are not more studies being done on natural hormones and the answer is very clear. Drug companies can only make money by selling drugs and you cannot patent a natural product. It would not do a drug company a great service to prove that natural hormones were more beneficial than synthetic drugs. However, compounding pharmacies are now becoming a very strong voice in the medical community and many papers arc being produced through the compounding society by investigators who have revealed that it makes eminent sense to use natural hormones, especially in light of the fact that they appear to be far more protective and less dangerous than synthetic drugs.


In fact, it should be said in summary that many women do not require any hormone to travel through the third of their life called menopause. The issue was raised initially only because of the fact that women now live one third of their life in menopause and we have to sort out for the future whether or not we should stand back and allow the natural aging process to take place or whether it would be beneficial to have the protection of the natural hormones that women had up to the age of 50. While I'm talking about hormones, let us very emphatically say that estrogen and progesterone are not the only hormones that have to be looked at in a menopausal patient. The other forgotten hormone is testosterone. Testosterone is lowered as the patient's progesterone lowers and it is of course lost when the patient stops ovulating. When a woman ovulates a man looks better than he usually does, and that is because progesterone is the precursor to testosterone the hormone of desire. Susan Rako wrote an excellent book called "The Hormone of Desire" about her experience with the use of natural testosterone. I find that taking a free testosterone level in a patient who states that she has a lowered libido will usually prove that the testosterone level is indeed extremely low. My preference is to use a natural testosterone cream to be rubbed ¼ tsp. twice a day on the pubic hair, inner thighs and clitoris to enhance the patient's ability to not only enjoy intercourse, but to have the thought processes that are required to enjoy the intimacy. Testosterone is a very strong sexual hormone and men have five times the amount of testosterone that is present in women.


That is why I tell my patients very often that most men don't need a reason to fool around they just need a place! Other hormones that have to be looked at in the menopause are also DHEA and PREGNANELONE, but we will save these and testosterone for future articles.


In summary, although this appears to be a very complicated problem, in my mind it is becoming increasingly clear that the closer we stay to the original plan, the better off we'll be. The education of the physician shouldn't end at medical school, it should just begin, I thank my patients for helping me to be more educated about the wisdom of menopause.