Laurel McCubbin: Dr. Formby, would you please give us a little bit about your professional background.
Dr. Bent Formby: I was born and raised in Copenhagen, Denmark and I have my degrees there. I have two PhDs in molecular biology and in medical biochemistry. I was on the faculty at the University of Copenhagen Medical School where I was a professor in the Department of Medical Biochemistry and Genetics until 1979 when I moved on a sabbatical to University of California in San Francisco, Department of Biochemistry and Biophysics. Here I was a visiting professor. I did diabetes research there as a professor from 1979. I later left my academic position in Copenhagen and stayed in San Francisco on the faculty until 1984 where I was offered the position as associate research director at the Sansum Medical Research Institute here in Santa Barbara. My research was linked to immunology of juvenile diabetes using my background in molecular biology. At that time I also did experimental transplantation of insulin producing cells into diabetic mice. The research led to the first fetal islet transplant done in US into diabetic recipients. Later on, I found a strong interest in molecular oncology and started to study culture of breast cancer cells. My most exciting observation in 1997 was that progesterone could block growth of breast cancer cells and introduce into these cells a genetic program leading to their programmed death (apoptosis). Several scientific publications at that time involve studies of this genetic program. I also became interested in the effect of estrogen and progesterone on normal breast ductal epithelial cells. I realized that human reproductive aging is linked to the interplay between falling sex steroids and their target tissue responses. Blood levels of both estrogen and progesterone decreases during the menopause transition. Climacteric symptoms occur because of the levels of estrogen are very low. I therefore became interested in studying further this transitional phase of a woman’s reproductive life and during the last year have been involved as consultant in clinical studies using very low doses of transdermal administered bioidentical estrogen (0.05 to 0.2 mg) to treat climacteric symptoms. I advocate a protocol where very low doses (5-10 mg) of progesterone are used only in the second half of a treatment period of 28 days. I have more than 100 scientific publications and I am member of several societies including the European Menopause Society, the New York Academy of Sciences and the Danish Academy of Sciences, so yes, I have been working in that field for a long time.
LM: The women who have been trying to do the Wiley Protocol, that is also the dosing schedule in the appendix of Sex, Lies and Menopause, have found that during the progesterone phase we have experienced symptoms such as weight gain, edema, constipation, headache, extreme sedation, hip pain, distended abdomen, interrupted sleep, puffy face, acne, whiskers, hair loss, heart palpitations, anxiety, itching, immune suppression, sore breasts, muscle wasting, lethargy, linea negra and more. We suspect that this is a result first-off of progesterone overdose and we are interested in your comments on this.
DrBF: I wrote that book with TS Wiley, as you know, together with Dr. Taguchi, who is an oncologist in town and actually participated in the work because of her own interest in reproductive hormones and in the field, so for the book I researched and organized all the scientific information which I explained and discussed with TS Wiley so she could write it into a layman’s text. When we came to a treatment protocol, which was somewhat laid out in the book, you know, how do you use these bioidentical hormones in correct doses. So, because there were relatively few scientific studies reported in the literature at that time my opinion was that we could not suggest a protocol with doses before proven correct in a clinical trial. So my concern was that without having performed a clinical trial it would basically be an undocumented protocol I would not take responsibility for. I suggested a small trial which could be run for a period of six months. You line up a group of menopausal women, then you have a control group and then you treat them with the protocol. Do the pharmokenetics – all these basic things to get an knowledge of how it works. Anyway, there was no interest in doing a trial – no interest in doing that by TS Wiley – so I just dropped out.
LM: So you were not around at the completion of the book?
DrBF: I was not around when the appendix was written. I never saw the appendix. I saw that later on. She told about that in the appendix she would put in the protocols and I said I don’t think you can use these protocols you are using for yourself for other people without having tested them first. And then she said well, I’ll do what I want, if you don’t want to get involved that’s fine with me. If there’s any problem, well, you know, that’s my responsibility. So I said, fine, but I know you are wrong.
LM: Women have been told by T.S. Wiley that they should achieve 350 mg BID of transdermal progesterone on day 21 and no less than 250 mg BID on day 21 because they are using so much estrogen and they won’t achieve apoptosis and they are open to cancer. So women are frightened about lowering their doses and we have also been told that half doses are not the Wiley Protocol and that it is dangerous to do half doses. We would like to hear your comments.
Dr. BF: Ok. Let us spread out the whole issue first. What is it we actually want to achieve by the bioidentical hormone replacement therapy. We have a situation where women are in the beginning of their reproduction aging period, which means that they stop ovulating and their hormone profiles slowly go down and down and down and then we end up by being in menopause, and you have not had a period for more than a year. During the menopausal transition we see climacteric symptoms which are: night sweats, hot flashes, mood swings, aches and pains, sleeplessness and urinary problems, etc. But all these unwanted climacteric symptoms can be eliminated by giving transdermally low doses of estrogen because it’s the lack of estrogen that these adverse effects exist. People started a long time ago using Premerin and it worked very well until the Women’s Health Initiative studies were published which somewhat canceled all HRT with synthetic hormones. That’s OK, we can use bioidentical because they’re much better than anything else.
So a long time ago, I’d say more then ten years ago, people in Europe began to use estrogen patches. They were using very low doses of estrogen, and I’m talking about micrograms. Remember 1 mcg is a millionth of a gram, a mg is 1/1000th of a gram, so you’re talking about tiny, small amounts and these investigators reported that climacteric symptoms disappear and sometime in these studies people added a little bit of , not progesterone, but progestin which is a derivative of progesterone which you can take orally and I can live with that because it doesn’t work exactly as progesterone but you can take it orally in low doses the last two weeks of a normal 28-day period, just to protect the endometrium. So all these protocols basically were published, telling you to give low doses of estrogen and then a tiny little bit of progesterone in the last two weeks. You can also start a little earlier, but at least the last two weeks use 5-10 mg progesterone to protect the endometrium and then you can start over again – the cycling. That’s basically what you want to do. This low estrogen protocols reported in more than 200 scientific publications have documented that low dose estrogen and extremely low progesterone (the last two weeks) is a very well functioning treatment modality to eliminate climacteric symptoms. How long time should a woman take bioidentical hormones? At least as long as she has the climacteric symptoms. I would advocate to take low estrogen as long as you feel good. I think most women prefer to take their hormones with cream instead of using a patch because it’s more convenient and the steroids in the cream absorb fast. The patch is always a little sticky and inconvenient when you shower, etc..
So that brings the question about all that progesterone. I think the confusion comes in because in my research when I was at Sansum, I studied the effect of progesterone on breast tumor cells. You can have these cells in a tissue culture in the research laboratory and they grow very, very fast. The breast tumor cells express receptors for estrogen and progesterone. By studying these cells I found that if you add progesterone they will stop growing and if you keep culturing them with progesterone after they have stopped growing they actually will die. I was interested in finding out which genes were involved when these cells, first of all stopped growing and when they begin to die. Because I am a molecular biologist I looked at the genes and discovered that different genes were targeted by progesterone. A group of tumor suppresser tumor genes activated by progesterone that initiated that process called apoptosis, which is what causes programmed cell death. It is a well-known cellular biological phenomenon we see both among tumor cells but also among other cell types, and during fetal development. Since apoptosis in breast tumor cells is regulated by progesterone. I think that T.S. Wiley is confused here because of her inadequate academic knowledge. Maybe she thinks that you can prevent breast cancer by prophylactic use high doses of progesterone?, well you can’t even prevent – the whole thing doesn’t even make any sense because if there is no tumor growth then there is no reason for adding progesterone. If women have cancer there is a totally different kind of situation. It has nothing to do with hormone replacement we talked about before. [emphasis added]
LM: So you think that women would be safe in concluding from what you were saying that we are not doing something dangerous by lowering our progesterone.
DrBF: No, no, no. You basically can do without the progesterone. I have studies where people actually have been with estrogen alone for more than five years, in low doses. They don’t get breast cancer. I mean it has nothing to do with that.
LM: As we have been trying to recover from the Wiley Protocol, some professionals have told us that, for example, I am trying to lower my estrogen but if I even put a small amount of progesterone right now I get a headache and I have been told that’s because I should lower my estrogen, that my progesterone converts to estrogen and that I am having signs of estrogen dominance, but I don’t feel that’s estrogen dominant. So far I have no negative reaction to estrogen when I carefully lower my doses and don’t go too fast.
DrBF: No. Let’s get that straight out also. First of all, where are the hormones produced? We are talking about here estrogen and progesterone. Biogenesis of sex hormones in young women takes place in the ovaries. The theca of the Graafian follicle synthesizes 17beta-estradiol. The granulose secretes progesterone after the corpus luteum is formed. During a normal cycle estradiol rises from 50 pg/ml to 250-400 pg/ml at the preovulatory peak, and remain moderately until menstruation. Progesterone increases from 2 ng/ml in late follicular phase to 1.6 ng/ml at the ovulatory peak and in luteal phase plateaus at 8-10 ng/ml. Sex steroids are synthesized in the ovary basically from cholesterol. Progesterone is converted by specific enzymes into testosterone and then testosterone is converted into estrogen. This is basically the main pathway. You cannot produce estrogen before you have testosterone, but this is all inside that stroma of the human ovary. Progesterone is produced by the corpus luteum. If there is a conception then the blastocyte that grows into the uterine tissue and starts formation of the placenta. The placenta during pregnancy is a huge producer of progesterone which has many, many functions but one of the major ones is to immune suppress the mother so she does not reject her fetus. Since progesterone is produced by corpus luteum and not the theca it is obvious that progesterone given to a menopausal can never be converted into estrogen in her ovaries. Unconverted progesterone will be cleared out by the liver.
LM: In his books, Dr. Lee has told us that if we’re using physiologic doses of progesterone transdermally then that will convert to estrogen and all that we need is a small physiologic dose of progesterone and we will be fine.
DrBF: I have talked to Dr. Lee about that because I disagree with him. I told him in my opinion there is no scientific evidence for progesterone being converted into estrogen in menopausal women. Some menopausal women have a marginal production of estrogen from their adrenal glands and you don’t need that much in order to keep the endocrine machinery going. So I think what he probably saw in his patients was not that progesterone was converted but the effect of some adrenal estrogen that already was there. You cannot do the hormone replacement therapy with low dose progesterone without adding a little bit of estrogen. But Dr.Lee’s patients were doing very well so we have to give him credit for that whatever the physiology might be.
LM: Some of us have speculated that the physiologic dose of progesterone might be fine for awhile because we wondered if it converted to cortisol and gave the woman some energy.
DrBF: No way. No way. If you take progesterone transdermally, the hormone is taken up through the skin and goes into what we call the peripheral circulatory blood system which goes all over the whole body. In the blood volume progesterone is diluted many million times. Where do we have production of cortisol? It is in the adrenals, which means when a certain concentration of progesterone passes into the blood, then you assume that that progesterone should be taken up by the adrenal glands and be converted into cortisol. Since the adrenal gland does not express enough progesterone receptors to take it up it is highly unlikely that any cortisol will be synthesized from transdermal administrated progesterone. Free progesterone in the blood will stay as progesterone until it is cleared out by the liver.
LM: So if we have all these symptoms, well – now that we’re not doing it, we still want to know what happened. It makes us very thirsty, we urinate a lot, we gain weight, we have hair loss, develop whiskers, some women are getting upper respiratory infections, sore breasts…
DrBF: What happens is that, as we talked about before, the reason, one of the major reasons for having the huge production of progesterone during pregnancy is that the pregnancy is basically, if you look at the immunology of pregnancy, like having a transplant. The fetus is a transplant, it is from an immunological point-of-view, non-compatible with the mother, so basically it should be rejected like a skin graft or a kidney or lung that is not compatible. Mother and her fetus are non-compatible. In order to protect the fetus from being rejected the mothers immune system must be suppressed. That’s how progesterone works. Progesterone strongly suppresses the cellular immune system involving B and T lymphocytes. Cellular immunity is the arm of our immune system that fight back mainly viral infections in contrast to bacteria infections that is attacked by macrophages, neutrophiles from the innate arm of the immune system. That means that if you take too much progesterone you become immune suppressed which means if you get any kind of infection your immune T cells are downregulated and cannot fight off foreign viral invades. That’s why you are prone to upper respiratory problems – get more colds and flu like symptoms, because you are immune suppressed. It is a very unhealthy situation.
LM: What would be the hair loss.
DrBF: The hair loss is a difficult one. I have to look that one up.
LM: Women are reporting they are gaining weight, especially around their waist.
DrBF: That is quite interesting. I believe it could be accumulation of fluid. Progesterone is actually working against estrogen by its ability to strongly down-regulate estrogen receptors. Thus, progesterone is anti-estrogenic!
LM: So this is interesting. The dosing on this protocol is canceling the estrogen.
DrBF: Yes, it does actually cancel out the function of estrogen by down-regulating both estrogen receptors.
LM: Well, it sure feels like that to us when we’ve been in the luteal phase and we’re putting the progesterone on and we’re hurting all over and can’t sleep and if we’ve added more estrogen then we feel better.
DrBF: Exactly. Data reported more than five years ago talk about the mechanisms of action and cross-talk between estrogen receptor and progesterone pathways. Progesterone conjugated to its receptor suppress estradiol-stimulated estrogen receptor activity. As I mentioned before the estrogen receptor bound to estrogen does decrease the biologic response of the progesterone receptor to progesterone. Basically we are talking about the work mediated by the steroid receptor after it has conjugated its specific steroid. The steroid is just like the hammer you put into the hand of a worker and the worker, he does or she does the job. The worker is the receptor and the hammer is what we call the ligand..
LM: We felt like estrogen was our lifeline when we were dealing with all this progesterone.
DrBF: Yes, yes, you only need estrogen. Estrogen is the only thing you need but you take a little bit of progesterone to protect the endometrium because estrogen may be proliferative on the endometrium. You also take low progesterone to mimic the secretory pattern of the “young” ovary.
LM: People are under the impression that this protocol would protect them from cancer or that it’s a good thing to do when they’ve got cancer and I would like to address the background where you explored progesterone with cancer.
DrBF: Well, you have to realize that in science, all creative ideas are first tested in the laboratory. We work in the research laboratory for years to test out these different kinds of projects using isolated cells in simple experimental culture systems. The next thing you do is transfer the experience from the cellular experiments to simple animal models. You may transplant tumor tissue into these animals and then treat the animals with progesterone. I got into that. I discovered that progesterone at the single cell level destroy breast tumor cells. But we have yet no clinical evidence to suggest that progesterone prevents or cures breast cancer, albeit we have some anecdotal evidence. It’s all studies waiting to be done. I think they are exciting, they should be done, but it’s still a long way to go before we can say anything about the efficacy of using progesterone in the treatment of ovarian or breast cancer patients.
LM: We have heard that there are stories.
DrBF: Yes, as I said there are anecdotal studies. When you run a clinical trial and you test a huge group of patients for a treatment then you gain results and then you can finally make a decision whether it is a good treatment or not. Sometimes you will have simple cases, which are very, very interesting, and basically they are forerunners for doing the clinical trials for that particular thing. Dr.Julie Taguchi had one patient who treated herself with relatively high doses of progesterone cream. The tumor went into remission. And then we have this study with Dr. Ken T, an older physician friend of mine who had metastatic bladder cancer cells to his lungs. He was a patient of Dr.Taguchi. I suggested he should be treated with relatively high doses of progesterone administered by cream and also orally with micronized progesterone. The lungs completely cleared up and the metastatic cancer cells disappeared. I think that the whole idea of treating certain cancers with transdermal progesterone fits into a bigger picture that we are just beginning to see like light down at the end of the tunnel.
LM: Some of the women have had a bad reaction to the HRT cream that they have used and they switched over to using olive oil. T.S. Wiley told us that wasn’t a good thing to use. We were wondering if there is any evidence that this is a legitimate approach.
DrBF: Well, if you ask an old compounding pharmacist what he would use for steroid treatment for a transdermal therapy he would look up in his book that says use olive oil. Nothing is wrong with olive oil. Basically you could use that all the time. It is probably easier to use a cream because you add it on the skin to be easily absorbed. It’s not sticky like olive oil, but nothing is wrong with olive oil. Or you can use any kind of vegetable oil. It can be peanut oil, yah know, you could diesel oil – nah – take that out! (laughter)
LM: Thank you for this information, Dr. Formby.
Dr.BF: You know. Laurel, these are just basics. I am no guru. I am a scientist and investigator. If you know what you are talking about you are quite safe. You know, as a scientist you cannot speculate. Only scientific documented facts are valid.
