Exclusive Interview: John Lee, MD, and Jonathan Wright, MD

The Many Clinical Benefits of
Natural Progesterone

LIFE Enhancement News (LEN): Dr. Lee, how did you become interested in using natural progesterone, as opposed to the synthetic progestins (like Provera) that are usually prescribed for menopausal women?

Dr. Lee: After 20 years of practice [back in 1978], I was confronted with women who were suffering from osteoporosis, many of whom couldn't take estrogen (generally considered the best bone-building hormone) because of a history of breast cancer or cancer of the uterus, or some other contraindication for estrogen. By serendipity, I heard a talk by Ray Peat, PhD, a biochemist who teaches in Oregon and who has closely studied the multiple roles of progesterone in the body.

His challenge to the doctors attending the meeting was "Why is it that, at menopause, when the ovaries cut back or reduce their hormone production of two hormones, we are giving only one of them back?" This question seemed to make a great deal of sense to me, and in meeting with Ray Peat and reviewing his references, I discovered he really knew what he was talking about.

So I told my patients to go get some natural progesterone cream, and I would monitor their bones with a bone mineral density (BMD) lab that had opened up in the county. To my amazement, after several years, nearly all of those patients were getting denser bones They were also feeling better and a lot of their other conditions had cleared up. During this time, I was learning more and more about progesterone. These results led me to further research, and I soon discovered that use of natural progesterone had already been studied as far back as the 1930's, when it was first synthesized from the fats and oils of certain plants. But conventional medicine abandoned it beginning in the '50s and '60s.

LEN: Why was it abandoned?

Dr. Lee: Because the pharmaceutical companies discovered they couldn't patent natural progesterone. So they created foreign chemical substitutes for progesterone that had some progesterone-like activity. These substitutes were used in birth control pills, and whatnot, and they blocked real progesterone from working.

LEN: When you first heard Ray Peat, why did you go to natural progesterone right away, rather than going to the pharmaceutical versions?

Dr. Lee: This was 1978, and by then we all knew that the commercial versions, like Provera (medroxyprogesterone) were full of toxic side effects. You could just open the PDR (Physicians' Desk Reference) and find six columns of contraindications. I found no reason to contact the pharmaceutical companies. I hadn't realized that real progesterone was available, over the counter, and that it was very inexpensive, and that you could easily get physiological doses of 15 to 20 mg per day just by putting a little dab of cream on.

LEN: That's incredible.

Dr. Lee: It's money and control. Since natural progesterone is sold over the counter, doctors lose control and no one can make much money on it (because it can't be patented.)

LEN: In the years since 1978, have you seen any significant acceptance of natural progesterone by the medical community at large?

Dr. Lee: It's hard to generalize. I tend to divide doctors up into smart ones, average ones, and dumb ones. The smart ones understand immediately what it's about - like Jonathan Wright, and many other doctors all around the world. There are hundreds of them who have written me saying that they don't know how they could have practiced without knowing about progesterone and using it appropriately. The average ones kind of hold back, waiting for some pharmaceutical company to tell them to use it, and the dumb ones don't know what to do.

LEN: Has that been your experience, too, Jonathan?

Dr. Wright: I happened to be at the so-called Anti-Aging Conference here in Las Vegas, and I was very pleased to see that out of all the talk about hormones - and certainly there were many speakers talking about various hormones - that nobody at all had anything good to say about medroxyprogesterone. When anyone mentioned progesterone, they always just mentioned progesterone, and some of them added the word micronized.

Dr. Lee: Beautiful.

LEN: I noticed that in the PEPI trial published in the last couple of years, micronized progesterone was used in one of the treatment groups. They didn't get nearly the increase in bone density that you got, Dr. Lee.

Dr. Lee: No, because they used oral micronized progesterone. The mechanism of its absorption and circulation in the blood has now been examined by gas chromatography. We now know that within seconds after absorption into the blood, it's passing through the liver and turning into three different water soluble metabolites that are awaiting excretion in the bile. These metabolites are in the blood stream, and they actually interfere with natural progesterone.

The whole point of my progesterone treatment is to restore normal physiological levels, and this is not done with the oral micronized version. The subjects of the PEPI study got high levels of these metabolites mistakenly thought to be progesterone. If people would use the normal physiological levels of 15 or 20 mg via natural progesterone cream, they would have much better results.

LEN: And those could be achieved more easily with the cream?

Dr. Lee: Oh, yes, much more easily. Besides, in the PEPI study they did not use progesterone for 25 days a month. Instead, they used it much like Provera, for 12 days out of the month, and you cannot grow bone by giving something, good or not, for just 12 days out of the month.

The recent study, in the 6th of November issue of JAMA shows that the only group in the PEPI study that showed any real increase of bone mass were those that had the synthetic progestin given every day of the month. I don't do that, I do it for 25 or 26 days, which is equivalent, and I think a little better. So we have three tests now that show that Provera will cause a 5% increase. But if they were to use real progesterone, they would have had a 10 to 15% increase over 3 years.

LEN: Interesting. Dr. Bernadine Healey (formerly the head of the National Institutes of Health) was commenting on the progesterone results with regards to HDL in the PEPI trial and she said - and she was talking about micronized progesterone - "Why is it so different from Provera? Physiologically you wouldn't expect it to be."

Dr. Lee: She doesn't understand. In fact, in the New England Journal of Medicine two years ago, there was an editorial that started out by saying all synthetic progestins are not created equal. They pointed out that some are made from progesterone itself; others are made from testosterone and some are made de novo, and they all have different effects. They all hit different receptor sites and some actually antagonize some sites while others are agonists at these sites. So you get a variety of different reactions from the different synthetic progestins, and all of them have side effects that are undesirable.

LEN: Another thing that's very interesting is that most orthodox physicians are still recommending for women who've had their uterus removed, not to take progesterone! That seems to be bizarre in the light of what we know about progesterone and osteoporosis, not to mention breast and ovarian cancer.

Dr. Lee: My response to that is that last year Emory University published, along with the National Cancer Society, a report of an 8-year study of over 240,000 women, which found that those women who were on unopposed estrogen [estrogen without progesterone] had a 72% higher risk of fatal cancer of the ovary.¹

Dr. Wright: We need to take the last 40 years worth of study on so-called "estrogen," jam it in the waste basket, and start over. All of those studies involved giving human beings horse estrogen. The next time I see a menopausal horse, I will be happy to prescribe Premarin, a horse estrogen! But for menopausal people, we need people hormones.

There has not been one, not a single decent study - for that matter, not even an indecent one, either - a well-controlled, long-term study of the use of estrogens that are actually identical to human estrogen as replacement therapy for women. Without that kind of a study, the best we can say is we don't know anything. We've wasted 40 years in studying horse hormones in humans, and it's about time to start studying human hormones in humans. Then maybe we'll know something. But right now, we know nothing scientifically, and we have to fly by common sense and the seat of our pants until we get the real human studies done.

I agree with Dr. Lee one hundred percent that the use of unopposed estrogen - unfortunately in this case it was unopposed horse estrogen - is nonsense, because that's not the way our bodies are built to work. If we're going to recommend even identical-to-human hormones after the menopause, we need to recommend all of them, not just one type of estrogen.

We need to be using the three estrogens that go in the human body - estrone, estradiol, and estriol. We need to use progesterone. We need to use DHEA, because that's down after the menopause, too. We need to be using testosterone. We need to be using physiologic molecules in physiologic quantities on a physiologic time schedule.

If we do that, we are least likely to get into trouble, and hopefully, someone will study that scientifically and prove what the last 200,000 years of human history show, that the right hormones, when used correctly, do the job.

LEN: In your clinical experience using natural estrogens plus natural progesterone, what kind of results do you see?

Dr. Wright: Our star individual from this year is a 70-year-old women who came in with the results of her fourth annual dual proton densitometry bone test. She came in first at age 66 with the results of such a test, showing severe osteoporosis and osteopenia (loss of bone). So we asked her to go onto the proper type of diet for calcium retention in the body - mostly fruits, vegetables, whole grain and less animal protein. We had her take calcium and magnesium supplements backed up with a preparation that has in it every single mineral or vitamin that has ever been studied as being useful in osteoporosis, and that's some 18 to 20 vitamins and minerals. There are a number of those formulations in the health food stores to help your bones. Treating osteoporosis is not just a matter of how much calcium we take, it's a matter of how much our bodies hang on to.

Then we asked her to use the "triple estrogen," as it's called in the compounding pharmacies, in physiologic quantities, not in large quantities, quantities that belong in the body, especially after the menopause. We had her use it on a physiologic time scale, namely 25 days out of the month, not 30. Then we asked her to go buy Dr. Lee's book about progesterone (What Your Doctor May Not Tell You About Menopause), to get some identical-to-natural progesterone, and, as Dr. Lee just said, to use physiologic doses. In her case, we did some follow-up measurements and we found she needed 25 mg of progesterone to bring herself into physiologic range.

But as a parenthesis here, John, I'm really so happy to hear the doses that you're using, the 15- to 20-mg range. We're working in the same neighborhood, sometimes up to 25 mg, and I really hate to see the 200-mg doses coming; they're not physiologic at that age. So we had her use the progesterone during days 12 through 25 of her cycle. We do really try to copy the natural cycle as closely as we can. We also had to bring in DHEA (15 mg), and we had her do that everyday. Because adrenal glands make DHEA, they don't cycle it very hard anyway. Then we had her use a little bit of testosterone.

All of this was done with careful follow-up testing to make sure we were not under doing or overdoing her triple estrogen, her progesterone, her DHEA or her testosterone. She started this hormone replacement regimen when she was 66, and she's been getting a bone mass evaluation every year. At age 70, her most recent bone mass evaluation shows an improvement of 15%. Of course, we told her "go get some light exercise." We don't want her lifting weights and breaking her bones.

I must say, John, that a lot of what inspired me to get going with all this stuff was when you came through with your reports showing that osteoporosis is reversible. How encouraging that is to the rest of us in practice to have some "crazy" doc somewhere saying, "Hey, look. We can reverse osteoporosis!" And not only that, John had gone through the trouble of having the people he worked with do the dual photon densitometry, the best test there is for bone density.
So, I've been working with the identical-to-natural progesterone, DHEA, and testosterone since 1982, when somebody hit me over the head and said, "Excuse me, but even though Premarin is a 'natural' hormone, isn't it a natural horse hormone?" I then called some pharmacies and got them going with the triple estrogen. I got all my ideas and all my inspiration on identical-to-natural progesterone and its use from John Lee. Thank you so much, John. I don't think I would have been quite so inspired without your work.

Dr. Lee: Thanks for the comment. It's the start of a revolution and you and Alan Gaby and others are the ones who are carrying this revolution out to its logical conclusion here, getting the right amounts of the natural things going and seeing them work.

I think you saw the letter that Dr. Hargrove and others at Vanderbilt wrote. They parallel exactly what you said about why have we spent billions on foreign estrogens and progestins, when, in fact, the real stuff exists. They further raise the question, "Why are we spending our tax money on continuing to study these foreign hormones when the real ones exist?" Let the pharmaceutical companies that make those synthetic analogs do the research and pay for it themselves. Let us spend our tax money only on the real stuff.

Dr. Wright: That certainly makes sense.

Dr. Lee: Yes. By the way, this letter by Dr. Hargrove and the professors at the Vanderbilt was sent to the New England Journal of Medicine, which refused to publish it.

LEN: I've seen some mention that estriol does not have a large effect on bone density, compared to estradiol. Is that true or is that just a dosing phenomenon?

Dr. Lee: I don't know if it's true or not. I've made the comment that estriol is made in the largest amount during pregnancy, and it's during pregnancy that bones of the mother can give up the minerals for the baby, so I would love to see further work. The nice thing about Jonathan's formula (triple estrogen) is that he also has estradiol and estrone in there, and it's the estradiol that prevents the osteoclasts from resorbing bone so rapidly.

Dr. Wright: Right. When I finally woke up and decided that we'd better be using identical-to-natural human hormones of all sorts, back in '82, I called several clinical testing laboratories and asked them to send me their normal ranges for circulating estrone, estradiol, and estriol. To my surprise, all of them sent me normal ranges for nonpregnant women that indicated that of these three hormones, estriol was in highest concentration in the blood. Then I asked them for their urine normals which showed more than 60% to 70% of excreted estrogens were estriol.

I did a little more literature checking and, lo and behold, I found some literature from Dr. Henry Lemon - just one paper - in JAMA, following up on women with breast cancer. He had found that, in these women who had just been operated for breast cancer (and none were pregnant, of course), that the ones who had the most estriol in their urine were going to be the long-term survivors, and the ones who had the least estriol in their urine were going to be the short-term survivors.

So, between Dr. Lemon's work and the work from the clinical labs, I decided that I couldn't do any better than improve on nature, so I just drew some averages of what the labs told me were normal circulating levels; I didn't really make up the formula. The formula was built into people, and I just copied it.

Dr. Lee: And yet, in the medical textbooks, they teach that less than 1% of the circulating estrogens is estriol, except during pregnancy.

Dr. Wright: Yes, and you know, if anyone gets out of medical school and starts looking around, they find out that a lot of what's printed in textbooks is entirely true and valuable, but another bunch of it is a lot of baloney, and they just have to learn it over again.

Dr. Lee: I recall that at my 20th medical school class reunion, the Dean brought out the old story about the half-life of the medical knowledge as it's taught, that within 5 to 10 years, half of what was taught was going to be found to be wrong, and he said they were willing to admit that, but the problem is they don't know which half!

Dr. Wright: And half told us that estriol was only relevant for pregnant women.

LEN: Dr. Lee, when you talk about estrogen dominance, what do you mean?

Dr. Lee: Well, estrogen and progesterone tend to have competing effects at many parts of the body. If you have estrogen dominance, all these effects tend to be the estrogen effects. For instance, estrogen wants the body to retain water, whereas progesterone is a natural diuretic, and helps to restore normal cell membranes to maintain the proper concentrations of sodium, magnesium and potassium, on either side of cell membrane. If you have a women who retains water, that would be one sign of estrogen dominance. Also, estrogen wants the body to convert food into fat for storage, whereas thyroid and progesterone want to convert the body fat into energy for life.

Thus if you have a woman who is getting fat on a modest diet and can't lose weight by dieting, then we know that she's probably estrogen dominant. The estrogen effect is the dominant effect. And it goes on and on. You just add them all up. Progesterone does not cause breasts to swell or for cells to multiply, whereas estrogen does. If you're a male that wants to develop nice breasts and do the transsexual thing, you can supply all the progesterone you want, you won't get any breast development. But if you supply estrogen, you can develop some nice breasts. So, when you add all those up, and they're all on the estrogen side, you then say that that person is estrogen dominant.

Once you get in the habit of thinking that way, you can see it clinically. You can stand at the food line at the supermarket and watch the women come through, and you can tell which ones are estrogen dominant.

LEN: How do you tell?

Dr. Lee: Well, they have big buttocks and fat thighs, big breasts, and water retention; their feet are slopping over their shoes.

LEN: And if they use progesterone, would that improve?

Dr. Lee: Of course! They can then lose weight, and their breasts don't swell anymore, and they can take their shoes off on an airplane and get them back on again when they land.

LEN: You also suggest using progesterone for PMS. How does that work?

Dr. Lee: In my experience, I did it out of desperation. These women are very difficult to treat, and most doctors use tranquilizers and diuretics and antipsychotics, and God knows what for them, and have very poor results. These women would come in, and I would notice that in the 5 or 6 days before their periods, their weight would jump 5 to 6 pounds.

Yet, they weren't eating more food or drinking more water, and they said it would happen overnight. Well, this means a sudden surge of water retention, and to me that meant that estrogen was becoming dominant, and something, such as cortisol, was either blocking their progesterone, or there was a surge of estrogen. Without doing any measurements, I just asked these people to increase their progesterone in the 10 days or so before their period, and 85% to 90% of these women became the most grateful patients you ever saw. They would say they now have a handle on what to do to get through the month without having a terrible 10 days just before and around their period time, where they felt like killing their husband.

One of the first patients was a lady who ran a clothing business. She was losing customers before in that portion of the month when she was so abusive to everybody that they never came back. Once she got on progesterone, she was able to get this under control.

LEN: Has that been your experience, too, Jonathan?

Dr. Wright: Yes, and some other experiences, too. Some women do just as Dr. Lee says. They're much better in the premenstrual time with supplemental progesterone. (Of course, he's always talking about natural progesterone and not about any of those synthetic molecules.) But, there are a few rare examples of women who actually are hypersensitive to their own body's progesterone. We desensitize those women to their progesterone, and the desensitization takes away the PMS for some women just as successfully as additional progesterone does for other women.

Now, how someone gets sensitive to a molecule that belongs in the body anyway is one of those big mysteries. But it can happen, so we end up treating some folks with supplemental progesterone, and a few people with progesterone desensitization. And whichever category you fit into, you do better.

LEN: Is that a typical allergy-type desensitization?

Dr. Wright: No, we use minute near-homeopathic doses of progesterone. The exact dose is entirely individual to the women involved. One person needs one strength, and another will need a different one. There is no standard homeopathic strengths for progesterone desensitization. It's a matter of testing. But also, for the folks who need the progesterone supplements, that's all they need. The folks who need the progesterone desensitization, usually turn out to be sensitive to other hormones, too, not just the progesterone.

LEN: One thing that's puzzled me is why natural progesterone is sold over the counter and estriol a prescription item?

Dr. Lee: I think it started because progesterone has been in cosmetics in small doses for years and years; we're talking 30 to 40 years. Because it's so wonderful for the skin, it's a natural moisturizer for the skin. Every woman I've ever dealt with who uses it first notices that she sleeps better, and then she notices her skin looks more youthful, and she doesn't even want to stop during the 4 to 5 days each month, because she's afraid her skin is going to turn back to dry and wrinkly.

But, at any rate, it's been in these products so long that when these other folks moved it up to about 400 mg per ounce, nobody was watching, and it just got going. You see, the FDA has a regulation on the books that you cannot sell it over the counter if you have more than 10 mg per ounce. But there are so many products being sold that way, and the FDA apparently is so busy fighting the cigarette companies, wondering whether nicotine is addicting or not - as if that made any difference - that they just haven't bothered to enforce this regulation. So some of the companies are gambling that it will be enforced, and these are the companies that are selling their progesterone only on prescription. Other companies are gambling that if we can get 40 million women using it, maybe the FDA will just look the other way.

Dr. Wright: Also, the regulations on cosmetics are different than drugs (or what the FDA likes to call drugs) which, of course, does not just cover drugs (the FDA defines anything as a drug if you use it for your health). The regulations on cosmetics are different and quite a bit looser.

Dr. Lee: So they allow the people to sell it as a skin moisturizer.

Dr. Wright: Yes, rather than as a treatment for menstrual dysfunction. If you sell it as a moisturizer it's cosmetic; if you sell if for menstrual dysfunction it becomes a drug - and it's all the same stuff! That's how the government works.

LEN: You mentioned women feel better on progesterone. What other benefits are there of using it?

Dr. Lee: In my patients with fibrocystic breast disease, their breasts return to normal within three or four cycles when they use progesterone. People who tend to be irritable during the day are probably that way because they didn't get a good night's sleep. One of the things that progesterone does is restore a normal sleep pattern. It has a very mild calming effect, equivalent to low-dose Valium without being addicting or habit-forming. Progesterone also gives people more energy, because it coincides with the thyroid's activity, whereas estrogen, unopposed, would tend to block thyroid. So those who use progesterone find themselves more alert, more able to focus.

Also, progesterone is the compound that creates the myelin sheath over all the nerves that travel throughout your body. People who are deficient in progesterone or whose Schwann cells can't make it, or whose Schwann cell receptors are blocked, will end up with a gradual deterioration of the myelin sheath and they'll have lots of aches and pains. Their doctor won't know what to do with them and will probably give them a non-steroidal anti-inflammatory drug. Of course, this doesn't work, and they'll send them to a psychiatrist and a physical therapist. It turns out that after 4 or 5 months on natural progesterone, all these little body aches and pains go away. It's amazing.

That's just a partial list. Libido is another example. It's interesting. There's a lot of animal research on this. I have three excellent references with guinea pigs, mice, and rats. Granted, they're not people, but they find that estrogen is needed in infinitesimally small amounts just to keep those particular nerve centers going. But the thing that sparks off the urge to mate - it's called the "mounting urge" - is actually a little testosterone or progesterone. Those two hormones work interchangeably. So you give a very tiny amount of testosterone and then have the progesterone come in, and then the mounting action happens.

I just got a Christmas card from a lady who had osteoporosis and treated it with progesterone. She's 55, and she said that she can now dance, she can now work in the garden, and, by the way, her husband thanks me, too. That's the good old libido effect.

LEN: With regard to osteoporosis again, that study that came out recently showing that women who had greater bone density had a greater chance of breast cancer. What do you make of that?

Dr. Lee: That was an interesting study. They didn't look back to see how long these people - they were relatively young, I think they were in the 60 to 65 year range - and they didn't say how far they were from menopause, they didn't say whether some had had periods up until late. I suspect that the anti-resorptive quality of estrogen meant that they were estrogen-dominant for a number of years, and this is what maintained their bone density. By being estrogen-dominant for a number of years they were more likely to get breast cancer.

LEN: Did it have anything to do with the fact that they might have been on birth control pills?

Dr. Lee: They didn't have enough data to know that. But my theory is that it was just simple estrogen dominance, resulting in them having a higher bone mineral density. If they had progesterone at the same time, their bones would be better and they wouldn't have had the breast cancer.

LEN: If they were estrogen dominant, though, wouldn't they tend to have a lot of estriol also, that would tend to protect them?

Dr. Lee: Oh, yes, but maybe they were making only estradiol.

Dr. Wright: That's the point that Dr. Lemon was showing in his JAMA article in 1966. Some women do not metabolize their estradiol and estrone to estriol very efficiently, and other women do.

We don't know - no one yet knows - whether that is due just to a lack of one or two vitamins, minerals, or coenzymes that are needed to break down the estradiol or, I should say, to further metabolize the estradiol down - it's not really a breakdown product, it's a further metabolite - or it could be a matter of general liver dysfunction, because the liver is the organ that's supposed to take all of the steroid hormones and turn out the final metabolic end-product.

Well, if we listened to our naturopathic colleagues, they'll tell us over and over again that one of the places to start, if we're trying to get folks better, is to work on the health of the liver, because the liver is the main biochemical factory in the body. So often, because of poor diet, because of too much junk in the diet, pollutants, etc, the liver is just not doing its job as efficiently as it should, so the whole business about not making enough estriol could sometimes be liver malfunction.

Actually, there are tests available, simple, inexpensive, 24-hour urine tests, that will tell any woman who's interested what her ratio of estrogens is.* We did those over and over again for women who have a strong family history of breast cancer and want to know all the risk factors they can find. If we just rely on Dr. Lemon's work, we can have young women in their 20s and 30s do a 24-hour urine check for all three estrogens - it's called the fractionated estrogen test. If estriol is too low, we can try to change the ratio of estriol to the other estrogen, and I think we can say with a high degree of probability that she is lowering her risk of cancer if she does that.

Dr. Lee: You see, it's not the ovary that's making estriol. The ovary makes estrone and estradiol, but there are enzymes and cofactors for the enzymes that turn a portion of the estrone and estradiol into estriol. During pregnancy the placenta makes a lot of estriol.

Dr. Wright: What Dr. Lee is saying is that not having estriol is not so much a production of estrogen problem by ovaries, as it is a metabolism of estrogen problem.

LEN: Right. Is there any beneficial effect of progesterone in preventing breast cancer?

Dr. Lee: Oh, yes. There are some good longitudinal epidemiologic studies, involving several thousand women who were followed for 18 years. They show that those who had a good, high normal progesterone level had only one-tenth the amount of cancer as those who had low progesterone levels during their years of having normal periods. They also had 5.4 times less breast cancer. So over 80% of the breast cancers were prevented if the progesterone levels were at good, normal range.

The more recent studies show that the effect of progesterone on the epithelial cells of breast milk ducts, where the cancers originate, is to suppress multiplication of these cells, to suppress proliferation. A dose of only 20 to 25 mg per day for 8 days will reduce the proliferation rate down to 15% of normal, whereas adding some estradiol without the progesterone, will raise it to 250% of normal, a 2 times faster proliferation rate.

The rate of proliferation, as well as the maturation of the cells, are the two conditions that are the factors in determining whether the cell stays normal or becomes cancerous. Progesterone accelerates full maturation of the cells at which time they are less likely to be cancerous in the future, whereas estradiol tends to just make them multiply and you have more of them that are not fully mature. So there is lots of good evidence that progesterone is a protector against breast cancer.

1. Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW Jr. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol 1995;141:828-835.