Alvin Pettle, M.D., FRCS(C) (OBS & GYN)
Women's Health Study and DSMB
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), also know as Hormone Replacement Therapy (HRT).
Proven Increased Risk with Use of Synthetic Hormones
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 years, (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.
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 so on throughout the study. In fact, taking a synthetic HRT was more dangerous than not taking it. (except for bowel cancer and osteoporosis)
Early Comparative Studies Overlooked
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 bio-identical 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 bio-identical Progesterone, such as Prometrium or Progesterone transdermal Cream.
What is Provera?
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.
As listed in the Medical Compendium, Provera has any of 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.
What is Premarin?
In the 1950's, a man by the name of Willard Allan extracted estrogens from the urine of horses and a huge international pharmaceutical company (Wyeth-Ayerst) bought the patent for the process and produced it under the name Premarin. In my opinion, Premarin (pregnant mare's urine) belongs in a 1200 pound horse and certainly in my mind, is far more potent than the natural bio-identical hormones that belong in a woman that weighs between 100 and 150 pounds. Also, 80% of Premarin is estrone and we know that this is the most oncogenic (cancer producing) of the 3 estrogens.
Wyeth-Ayerst – Drug Company Sole Patent Holders on Premarin
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.
Negative Side Effects of Premarin
As doctors prescribed Premarin to their patients and a few years went by, some of those patients returned to their doctors with uterine cancer. The patients asked their physicians if their cancer comes from taking the Premarin? The answer, unfortunately, of course was, "YES". It is interesting that nature's own natural estrogens never caused cancers, but when man began to manipulate things by using synthetic drugs to replace natural bio-identical hormones, suddenly uterine cancer increased by 15 times the usual incidence.
Twins – Provera and Premarin
The drug companies reacted to these adverse results by creating a new drug called Provera (synthetic progestin) to be taken along with the Premarin to in fact protect the uterus. This drug with many, many adverse known side effects itself, was given to treat the adverse side effects of the first drug given to the patient. Aggressively marketed, promoted and advertised together, Premarin and Provera became the so-called "Golden Standard" of hormone replacement therapy for the next 40 years (most of the last half of the 20th century).
THE ALTERNATIVE – NATURAL BIO-IDENTICAL HORMONES
During this time however, several other 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 had become so comfortable using Premarin and Provera, many physicians were reluctant to transfer their patients over to Prometrium, for example, which is a natural oral progesterone made from yam and is by far superior to the synthetic Provera.
Other bio-identical estrogen products were made from soy and were slowly getting into the market place, but also having a difficult time replacing the standard Premarin and therefore, reaching patients. These natural bio-identical estrogen products made from soy are, in my mind, far safer to the patient, albeit they were for the most part 100% Estradiol, the most potent estrogen (CES, Estrace, Estragel, Estraderm, etc.)
HERS (The Heart and Estrogen Progestin Replacement Study)
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 because of the cost factors involved, it was funded by the producers of Premarin, none other than the giant pharmaceutical company, Wyeth-Ayerst, with every preconceived expectation that the HERS project would prove that synthetic hormones would prevent heart attacks in post-menopausal women with heart disease.
Two thousand women with heart disease were put on a combination of synthetic 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. (Note: This is only for synthetics)
(c) Affected blood clots with a three times higher incidence in the group that took synthetic hormone therapy (Note: Oral hormones increase thrombosis)
(d) HRT synthetic caused an increase in gallbladder disease.
Once again a large scale controlled medical study shows that synthetic HRT does not belong in the human body and that all of the promotion that was given to the drug replacement therapy as being a wonder drug providing the fountain of youth, was not the case with synthetic hormone replacement therapy (HRT).
THE OTHER SIDE OF HORMONE REPLACEMENT THERAPY -NATURAL BIO-IDENTICAL HORMONES
There is another side to the story of Hormone Replacement Therapy. What bothers me tremendously is that it is only recently in medical history that an attempt has been made to scientifically study the overall balances of the female human body. Had those studies been made earlier, it would have been evident that the best hormone replacement therapy which might be offered by medicine to women would be those natural bio-identical hormones which matched most closely the ones put there by nature and God in the first place, rather than synthetic drugs.
Three Kinds of Estrogen and their Correct Natural Balance
When science, relatively recently, looked at the estrogen levels of all human females, it was found that no matter what time in her monthly hormone cycle, the ratio of the three estrogens present in the female body, would always be the same (i) 10% estrone (E1); (ii) 10% estradiol (E2), and (iii) 80% estriol (E3). The latter, estriol, is the weakest estrogen but also, measurably, by far the most protective estrogen of the three.
Lemon and Fothergil- Estriol- Hormone of Pregnancy- Breast Cancer Implications
In fact, estriol is the hormone of pregnancy produced by the adrenals during pregnancy 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 Fathergil 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.
Dr. Jonathan Wright and Natural Bio-identical Tri-Est Estrogen Hormone
Jonathon Wright, (an admirable pioneering doctor who has proven he thinks for himself) began to formulate Tri-Est. This formula is compounded in a compounding pharmacy* in the exact ratio of 10% Estradiol (E1), 10% estrone (E2) and 80% estriol (E3) and put together entirely from a soy or yam base. The dose of Tri-Est is .625 mgm used twice a day (or 1.25 mg used twice a day) because Tri-Est is found to 50% metabolize within a 12- hour interval. Initially I prescribed Tri-Est in a transdermal form. (*compounding pharmacy such as York Downs Pharmacy 1-800-564-5020)
Dr. David T. Zava and Dr. George Gilson and References Comparing Synthetic and Natural Hormones
Dr David T. Zava, in his excellent advice in the International Journal of Pharmaceutical Compounding (volume 6, No.4 July/ August 2002) has listed 53 references when referring to the estrogen matrix and I refer this excellent article for the consideration of both physicians and patients in the handouts that are available. Dr. David T. Zava and Dr. George Gilson have recently published an excellent paper with 71 medical references comparing synthetic hormones to natural bio-identical hormones.
Boomsna and Pauletti - Natural Bio-identical Progesterone as a Protective Hormone
Along with this article, I would suggest reading Boomsna and Pauletti, also quoted in the International Journal of Pharmaceutical Compounding (volume 6, No.4 July/August 2002) with 35 references, an article which is a superb review from the medical literature to illustrate that natural bio-identical progesterone is, in fact, a protective hormone against breast cancer. The references throughout the literature appear to be now quite solid. However, more studies are needed.
In fact, natural bio-identical estrogen tells the body "grow" and natural bio-identical progesterone tells it to "stop growing." It is like the Ying and the Yang, the natural balancing halves. It is my opinion that the best natural bio-identical hormone replacement would appear to be natural bio-identical Bi-Est or Tri-Est (.625, 1.25mg twice a day or 2.5mg twice a day, along with a natural bio-identical progesterone transdermal cream, either 3% or 6% transdermal cream. If the patient is having trouble sleeping, the use of oral Prometrium, 100 or 200 mg at night, is indicated.
It is recommended that patients take the first five days of each month off from medication, to clear their receptors. Some patients find that taking the five days of rest does not change how they feel. Other patients who take five days off report they are bothered by menopausal symptoms and choose to continue in an uninterrupted manner. Medically, I am more comfortable having a patient take 5 days off.
Withdrawal from Premarin/Provera
Difficulty came when this large mass of women were suddenly faced with the problems of Premarin and Provera and suddenly ceased the Premarin and Provera
because of the results of the study. When the study ceased, they were simply taken straight off the drugs, causing many to return to previous troublesome menopausal symptoms without relief. What should have been done, in my opinion, was to slowly wean these patients off Premarin and Provera, placing them gradually on a soy-based estrogen, such as Estragel, along with a yam based natural bio-identical progesterone such as Prometrium, 100mg during the time they are coming off of Premarin and Provera.
This would have allowed patients to transfer over to soy based and yam based natural bio-identical progesterone and estrogen which would have continued to provide them with benefits, (although the estrogens in these products are 100% Estradiol). It is my intention to have patients in my practice who are on the combination Premarin and Provera gradually come off the estrogen and progesterone and move towards the natural bio-identical Tri-Est or Bi-Est and natural bio-identical progesterone in the transdermal cream form, which I believe is far safer for long tern use.
Treatment after Hysterectomy
Another presenting issue which I have encountered over many years, are the patients who have had a hysterectomy and who have then been placed on unopposed estrogen. Studies are now showing that if a patient does receive unopposed estrogens for many years, that there may be an increased incidence of breast and ovarian cancer in patients who are not protected from the side effects of the estrogen with the use of a natural bio-identical progesterone along with natural bio-identical estrogen.
Over the last 10 years, I have always prescribed natural bio-identical progesterone to these patients, despite the fact they do not have a uterus. I have had other physicians call my office and ask why I would place someone on natural bio-identical progesterone who does not have a uterus. My answer to them usually, is that it is my belief that God and nature did not put progesterone in the body just only to protect one organ. Progesterone is in the body to protect all reactive tissue that have progesterone receptors (such as brain receptors and breast receptors).
Breast Cancer Protection
Progesterone is a major protective hormone for the breast. This is where the dialogue becomes very interesting. It is now recognized by science that if you take a synthetic progestin along with estrogen, that you increase the incidence of breast cancer. As a result, many physicians advise their patients who have hysterectomies not to use progesterone along with estrogen.
Progestin and Progesterone Not the Same
A major issue is that many physicians are mixing and matching progestin and progesterone as if they were the same, but, in fact, they are as different in their effects on the body as night and day. The fact is that the female human body knows the difference between progestin and real progesterone.
Oregon Study and USC School of Medicine
Mivagawa and Frank- The Monkey Tests
Synthetic Hormones Versus Natural bio-identical Hormones
To prove this point, in an Oregon study done by Mivagawa and Frank, a study was combined with the USC School of Medicine This study compared the use of synthetic progestin along with estrogen, versus a natural bio-identical progesterone along with estrogen, in monkeys that had been given surgical menopause. In other words, 18 surgically altered monkeys were divided into two test groups.
One group of monkeys were lucky enough to receive natural bio-identical progesterone and estrogen and the other group 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 had received estrogen and (synthetic) progestin all required a reversing drug to save their lives.
However, the group of monkeys who had received natural bio-identical progesterone and estrogen- and then received the vasospastic drug- all survived the episode without any need of a reversing drug.
Hormones in Heart Attacks
Therefore, it is clear that progestin allows vasospasm, but progesterone causes vaso relaxation. Current pathological science now proves that some women who have had fatal heart attacks have some arteries that contain very little plaque compared to men who die of atherosclerotic heart disease and myocardial infarction. I believe that it is vasospasm that produces heart attacks in females and therefore, progestin is one of the worst possible drugs to be taken by any patient who has an increased risk of heart disease, specifically and women past menopause age generally.
I believe that, in years to come, natural bio-identical progesterone will be shown to help protect a female patient's uterus and heart, but also protect her from cardiovascular disease. Until the age of 50 to 54 (or approximate usual onset of menopause), female patients statistically have far fewer heart attacks than men.
After the age of 50, however, women suddenly begin to be at increased risk of heart attacks and their risk factor catches up to and suddenly equals that of men. For this reason, it is my opinion, that giving natural bio-identical estrogen and natural bio-identical progesterone may well provide protection for the cardiovascular systems of female patients over the age of 50 or past menopause.
The Should and Should Nots of Hormone Use
The error that is commonly made is that patients SHOULD NOT receive synthetic estrogen or progesterone, but SHOULD receive natural bio-identical estrogen and natural bio-identical progesterone. For patient's protection, I recommend natural bio-identical Bi-Est or Tri-Est (estrogen hormones) or the natural combination of natural bio-identical estrogens and natural bio-identical progesterone in transdermal cream form. Patients in my practice who receive natural bio-identical progesterone transdermal cream are not given 100% estradiol preparations. If patients use 100% Estradiol (or Estragel), I prescribe Prometrium. If my patient uses natural bio-identical transdermal Bi-Est or Tri-Est, I prescribe natural bio-identical progesterone transdermal cream.
Dr. Maida Taylor, University of California
Summary of Available Literature on Estrogen
Some people believe that it is only Estradiol component that is the major hormone protecting patient's heart and bones. However, 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.
The title of the article is "Unconventional Estrogens: Estriol, Bi-Est and Tri-Est." I believe that Dr. Taylor has given a very balanced summary of the available literature on estrogen and 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 bio-identical Tri-Est and Bi-Est estrogen hormone made from soy and natural bio-identical progesterone hormone made from wild yam, in combination.
As I grow further into the process of learning about hormones and experience more results in their use, I am very impressed with the use of natural bio-identical progesterone used alone. Peri-menopause should be treated only with natural bio-identical progesterone because it is the first hormone to be lost by the patient and the patient's adverse symptoms are often very quickly reversed with natural bio-identical progesterone transdermal cream.
Dr. John Lee- Menopausal Treatment with Natural Bio-identical Progesterone
I do believe the late, great Dr. John Lee was correct when he stated that two out of every three patients could be treated successfully through menopause with natural bio-identical progesterone transdermal cream alone. I would add that, in some cases, a vaginal estriol along with a transdermal progesterone, would be highly beneficial in some patients who experience vaginal dryness and atrophy and urethritis symptomatology. For patients who do not receive adequate cessation of adverse symptoms on natural bio-identical progesterone alone, I feel very comfortable adding natural bio-identical Tri-Est or Bi-Est to their prescription regime.
Why Aren't There More Studies of Natural Bo-identical Hormones?
Many of my patients ask why there are not more studies being done on natural bio-identical hormones. The answer is very clear. Drug companies can only make money by selling drugs and you cannot patent natural products. It would not be economically desirable for a drug company to prove that natural bio-identical hormones were more beneficial than synthetic drugs, because that would destroy their own market for synthetic drugs.
However, compounding pharmacies are now becoming a stronger voice in the medical community and many papers are being produced through the compounding society by investigators who have revealed that it makes eminent sense to use natural bio-identical hormones versus synthetic, especially in light of the fact that they appear to be far more protective against other medical problems and less dangerous by far than synthetic drugs.
Not all Women Require Hormones- AND Some Women Desperately Need Hormones
Many women do not require any hormone supplementation to travel through the third of their lives called menopause. The issue was raised initially only because of the fact that many women are now living longer lives and therefore now live one third of their life in menopause. Many of them experience substantial, uncomfortable and debilitating symptoms during this period.
We need to sort out for the future whether or not we should stand back and accept the natural aging process taking place after menopause, or whether it would be beneficial to have the protection of the natural bio-identical hormones that women produce up to the approximate age of 50 by themselves continued by the use of natural bio-identical hormone supplementation.
The Other Forgotten Hormone- Natural Bio-identical Testosterone
While we are discussing hormones, let me point out emphatically that natural bio-identical estrogen and natural bio-identical progesterone are not the only hormones that have to be considered in a menopausal patient. The other forgotten hormone is natural bio-identical testosterone. Naturally occurring testosterone levels lower as the patient's progesterone levels lower.
When a woman ovulates, she is more interested in sexual intercourse. A man looks better to her than he usually does throughout the rest of her monthly cycle. That is because progesterone is the precursor to testosterone, which is the hormone of desire.
Susan Rako- Book, The Hormone of Desire
Susan Rako wrote an excellent book called, "The Hormone of Desire" about her experience with the use of testosterone. I found 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 prescribe a natural bio-identical testosterone transdermal cream to be rubbed ¼ tsp. twice a day on the pubic hair, inner thighs and clitoris. This will enhance the patient's ability to not only enjoy intercourse, but to have the thought processes that are required to enjoy the amount of intimacy. Dosages range from 2.5 mgm, up to 5 mgm. The other advantages of using natural testosterone are increased energy, muscle strength and mental clarity.
DHEA and Pregnenalone
Testosterone is a very strong anabolic 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 considered during menopause are DHEA and Pregnenalone. I prescribe methyltestosterone for breast cancer patients. Usual doses are .25 mgm to .5 mgm twice daily.
Summary- Hormone Replacements
In summary, hormone replacement during and after menopause appears to be a very complicated subject. However, in my mind it is becoming increasingly clear that the closer we stay to the original plan -nature's way- the better off patients and their doctors will be. The education of the physician shouldn't end at medical school. It should just begin at that point. I thank my patients for helping me with my education about the wisdom of their menopause.