The following sentence, is for me (ST), the kicker observation in the abovementioned article:

“In a study of rub-on progesterone applied to breast tissue, both progesterone "and oestrogen" levels increased by four times, and yet any blood levels of progesterone were short-lived (Mauvais-Jarvis P, Wepierre J & Vickers C, Percutaneous Absorption of Steroids, Academic Press, NY, 1980)”, a fact apparently known since the pioneering days of topical progesterone research (Mauvais-Jarvis P et al, In vivo studies on progesterone metabolism by human skin, J Clin Endocrinol Metab, 29:1580-1585, 1969), but that has been either unnoticed or deliberately ignored by pro-progesterone cream advocates and merchants.

I have long suspected and now contend that it is not the so-called ‘natural/bio-identical’ progesterone that exclusively, or even largely exerts a paradoxical positive effect on menopausal and female complaints, but a logical direct result of the body being forced to attempt to return to hormonal homoeostasis by uprating its synthesis of oestrogen, the specific natural antagonist to the progesterone sneaked-in via the skin by and so by-passing the body’s sentinel, the liver, which would ordinarily detoxify the exogenous progesterone that it would rightly perceive to be an undesirable xenobiotic. Additional exogenous (external) progesterone detected in the bloodstream is determined to be counter to the body’s innate wisdom, which directed and ensured that growth-stimulating (read carcinogenic) hormonal production be appropriately lowered in the face of declining need for reproductive fertility against the ever-increasing risk of malignancy that accompanies life’s many insults and advancing age.

A logical extension of my hypothesis is that women are delaying the body’s protection against hormone-induced carcinogenesis - the menopause (marked by the first non drug-induced missed period). This is a short sighted trade-off for a short period of extended relative youthfulness and reproductivity against a tragic life-long thereafter increased risk of breast cancer, not only from increased exogenous progesterone-induced endogenous oestrogen, but also exogenously introduced progesterone, their endogenous carcinogenic metabolites, their disruption of dynamic natural oestrogen and progesterone receptor balance and their combined synergistic carcinogenicity. I have never felt a need to have to set out proof of these mechanisms – they are after all simple logic. I will however, summarise extensive evidence of several of the mechanisms involved.

The above point by respected researcher Lynne Taggart, indirectly provides a collaborating view of this logic, where it was noted that both progesterone and oestrogen blood levels are initially elevated fourfold following application of progesterone to the skin, yet the supposedly beneficial progesterone levels are comparatively short-lived, leaving precisely the opposite of the claimed effect, in fact, a state of severe oestrogen dominance, good for alleviating troublesome symptoms, but severely increasing the hormonally sensitive cancer risks at this stage of life, a reality that is diametrically opposed to natural progesterone marketing strategies and so compelling me to publish this expose’ in the public interest.

I shall hereafter introduce several concerns raised by Lynne McTaggart for laypersons in recent issues of her ongoing series ‘What Doctors Don’t Tell You’ (WDDTY) and also amplify these concerns as articulated for laypersons and alternative and complementary practitioners in WDDTY and in specialist peer-reviewed journals, by Dr Ellen Grant, a physician and medical gynaecologist currently in private practice, who was a pioneer critic of the abuse of hormones in medicine and made outstanding contributions to alerting and educating the general public (The Bitter Pill, Corgi, 1985); (Sexual Chemistry, Cedar, 1994); (WDDTY 2004, 2005 & 2006) and fellow medical scientists and doctors via more than 60 published papers and communications since 1962 regarding the risks involved in introducing exogenous natural and/or synthetic hormones and congeners, in particular oestrogen and progesterone, into the human body. Grant originally focussed on oestrogen, later oestrogen and/or progesterone analogues and recently, the progestagens, including so-called ‘natural’ progesterone. I will introduce some debate with Dr Lee and his followers to illustrate examples of their naivity. Finally, I summarise my additional supporting research showing beyond all reasonable doubt, that topical/transdermal natural/bio-identical progesterone is a huge breast cancer risk.

In all I have read of Dr Lee’s writings, only one single ‘original’ statement qualifies as truth, confirming how ridiculous his hypothesis really is, since even he admitted that all that is required is a healthy plant food diet: “Just as with phytoestrogens, many plants make progesterone like substances. In cultures whose diets are rich in fresh vegetables of all sorts, progesterone deficiency does not exist. Not only do the women of these cultures have healthy ovaries with follicles producing sufficient progesterone, but, at menopause, their diets provide sufficient progestogenic substances to keep their libido high, their bones strong, and their passage through menopause uneventful and symptom free.” (Lee J, ‘Estrogen Overkill’, WDDTY vol 5 no 4, 1994)

Dr Mercola On ‘Complications Regarding Progesterone Cream’

Dr Joseph Mercola, DO, a peer-reviewed published author and popular online (mercola.com) natural health advocate takes an informed common sense approach to topics, including personal experience and reported:

“Progesterone cream has been one of the most important supplements in my practice, but I have come to a recent realization. If one uses too much, complications can develop in disruption in one's hormone balance. Dr Lee was fond of using the lower dose creams (1/4 teaspoon of 3% daily) to avoid this, but this complication can still occur with low-dose, since in my experience, if one uses more than 1/16th of a teaspoon of a 10% progesterone preparation (ie, 0.3125ml - less than a 3rd of a millilitre) complications appear to be inevitable, since progesterone is highly fat soluble and once applied to the skin will store itself in a woman's fat tissue and contribute to disruptions in the adrenal hormones. I have learned that although progesterone cream is an enormously useful tool, it needs to be used very cautiously.”

“I have also learned that it is far more important to normalize the adrenal hormones first, following which, progesterone levels will frequently normalize in 3-6 months and not require any hormone supplements to keep the balance. The balancing process involves dietary lifestyle changes and regular adequate sleep to stabilise biorhythms. Addressing emotional stress in one's life is the other huge component. Once the lifestyle issues are addressed, one would ideally evaluate the adrenal and female hormones with multiple samples and proper evaluation of the test results and then, if necessary, further balancing the adrenals to recalibrate endocrine control and help the body to start making the hormones by itself, rather than be stuck on hormone treatment for the rest of one’s life.”

“I have been finding that many of the women who were on progesterone cream have terribly elevated levels of this hormone. This is repairable, but may involve going off the cream for as long as two years to wash the progesterone out of the system. I am still in an evaluation stage and learning about how common this is in my own practice. I am convinced that this is a big part of the picture for hormone replacement. There will be a huge shift in the way that we are dispensing progesterone cream in our office without evaluation of one's adrenal and female hormones, rather than blindly slapping on progesterone cream without any appreciation of the potential complication or hormone disruptions.” (Dr Joseph Mercola, ‘Complications Regarding Progesterone Cream’, mercola.com, 2004)

In WDDTY, vol 5, no 5, 1994, Dr Grant responded to Dr John Lee: “The Second Opinion "Estrogen Overkill" by Californian general practitioner Dr John Lee (WDDTY vol 5 no 4) is a disturbing amalgam of fact and fiction. Progesterone is not an essential nutrient, which must obtained from our food all our lives. In contrast, ingested hormones are destroyed in the gut. Animal studies by Dr Gina Schoental have shown that even small amounts of extra progesterone, estrogen or testosterone at key times during pregnancy can interfere profoundly with physical and mental development and sexual orientation. As a safeguard, we make our own sex hormones as and when needed during reproduction. It is impossible to mimic this delicate system by crudely adding hormones from the outside. For the 30 years ‘natural’ progesterone has been prescribed. I have personally seen these patients then suffer from irregular bleeding, severe migraine, depression, weight gain, leg cramps and painful breasts. All the many well documented health risks of the contraceptive pill, are due to it acting predominantly like progesterone (pro-gestation) which is what ‘progestogen’ or ‘progestin’ means. The estrogen influence in contraceptive pills is relatively small.”

“Much is being made of a new syndrome (luteal deficiency syndrome or LDS), when women have low post ovulation levels of progesterone, longer cycles and more risk of foetal abnormalities and recurrent miscarriages if they conceive. However, flagging secretions of hormones cannot be boosted by exogenous oestrogen or progesterone. Adding progesterone, even as cream, will increase the risk of damage to the mother and baby. The underlying causes of the condition are often deficiencies of essential nutrients. Exogenous hormones will only make the problem worse by causing further zinc and magnesium deficiencies and eventually deplete copper stores. When zinc is deficient a woman's own hormone production is impaired. In fact, all exogenous steroid hormones can block the secretion of the body's pituitary and ovarian hormones. A varied, low allergy diet is a safer and more effective way of maintaining or restoring a woman's hormone production”.

“In general, estrogens stimulate immunity, increasing antibody production, while progesterone and testosterone cause immunosuppression at many points on the immune pathways (Immunol Rev, 1984; J of Immunol 1988; 1491:1-8). In fact, progesterone is a more powerful immunosupressant than the adrenal steroids. Progesterone also can act as a co-carcinogen with viruses and chemicals (Potential Carcinogenic Hazards from Drugs, 1967; 7: 162-71, Springer Verlag, Berlin, NY). Both female hormones combine to develop and dilate blood vessels spreading infection and cancer (Sexual Chemistry, 1994, Lancet 1994; 343: 926). Progesterone increases melanin formation, another reason for eschewing skin rubbing (to avoid blotching). Although Lee advocated the use of progesterone to treat osteoporosis, progesterone in DMPA form has been shown to cause the condition (BMJ 1993; 303:13-6). Researchers have demonstrated that osteoporosis is due to nutritional deficiencies.”

In a subsequent edition (WDDTY, vol 5, no 6, 1994), Dr Lee responded to Dr Grant and she in turn to him:

[JL]: “Dr Ellen Grant (WDDTY, vol 5, no 5, 1994) claims that natural progesterone supplementation is dangerous. Her own references do not support this. Indeed, Dr Gina Schoental, whose animal studies are claimed to show that progesterone "can interfere profoundly" with development, says she has never even worked on progesterone!

[EG]: “Dr John Lee fails to understand my work and that of others. Both progesterone and progestogens produce identical changes in endometrial cells, enzymes and blood vessels. Both relate to widespread systemic effects such as headaches and mood changes. Any differences are of degree and individual sensitivity, not of kind. Dr Schoental studied estrogens, but cites other references that progesterone can cause cancer and birth defects (Dangerous Properties of Industrial and Consumer Chemicals, 1994: 581) and can change into oestrogen. For instance, progesterone skin gel induces a fourfold increase in both progesterone and the oestrogen estradiol (Mauvais-Jarvis, Percutaneous Absorption of Steroids, 1980).”

[JL]: “Regarding immunosuppression, another study cited by Dr Grant (J Immunol, 1988; 141: 91) does not actually refer to progesterone, but only to estrogen and testosterone, whereas Immunol Rev, 1983; 75: 117 suggests that progesterone prevents fetal rejection during pregnancy while preserving ‘normal’ systemic immunocompetence against tumours.”

[EG]: “About immune system suppression, the study quoted actually states that immune system function is only ‘relatively normal’ in pregnancy. Progesterone suppresses local immunity by blocking the helper T-cells and enhancing the production of suppressor cells, so preventing rejection of the ‘foreign’ fetus.”

[JL]: “Emerging research shows the increasing frequency of premature follicle depletion in women (probably due to petrochemicals).”

[EG]: “The fact that a 10 fold reduction in migraines can immediately follow withdrawal of prescribed hormones clearly demonstrates that these are much more toxic than background petrochemicals (The Lancet, 1979; i: 581). Removing such causes may restore ovarian function, but progesterone cream cannot.”

[JL]: Nutrition cannot make a woman ovulate (and make progesterone) once her follicles are used up. Regarding safety, progesterone creams have been used in America, with FDA approval, for decades. Finally, Dr Grant insists osteoporosis is due to nutritional deficiencies. But this approach cannot increase bone density by up to 22 per cent over three years, as I have shown with progesterone (The Lancet, November 24, 1990). Dr John Lee, California”

[EG]: “Temporary or permanent ovarian failure is caused by early age exposure of some 97 per cent of women to prescribed hormones, smoking and/or severe nutritional deficiencies. Each separately increase cancer risks. A temporary improvement in osteoporosis among some women is not proof of long-term safety. Progesterone induces breast proliferation; prescribed hormones have been increasing cancers for decades while the FDA has approved their use. Dr Ellen Grant, London”

In published correspondence titled: “Medical treatment for menorrhagia and the cult of progesterone” (Grant E, Rapid Response [to Jane Burgermeister, Medical treatment for menorrhagia may only delay hysterectomy BMJ 2004; 328: 730-d], 29 March 2004), Dr Grant strongly cautioned medical practitioners:

“Exogenous hormones have always been the wrong treatment for menorrhagia in my opinion. Large doses of progesterone may shrivel the endometrium but can cause a disproportionate development of endometrial blood vessels and heavy, irregular bleeding (Grant E, J Obst Gynae Br Com, 74:908-18, 1967); (Grant E, Br Med J, 3:402-5, 1968). My extensive research into the hormone balance of oral contraceptives and the endometrial vascular changes in untreated and treated cycles, showed that irregular bleeding relates to lack of oestrogen or progesterone dominance. Alternative practitioners have been deluded into believing that ‘natural’ progesterone is safe, while it is only synthetic progesterones which cause breast and cervical cancer, vascular and mental diseases and immunosuppression in general. This mistaken belief has developed a cult status. However, enough progesterone may be absorbed locally to be carcinogenic. A possible risk for a breast cancer patient, who has already had a mastectomy, is of contralateral breast cancer if she rubs progesterone on her remaining breast. Further hormone exposures are known to increase the likelihood of a second cancer developing. Localised distended veins on the rubbed skin can also happen.”

In published correspondence titled: “Epidemiologist’s long-term underestimation of harm from hormones” (Grant E, Rapid Response [to Editorial, Jan P Vandenbroucke, Benefits and harms of drug treatments, BMJ 2004; 329: 2-3], 3 July 2004), Dr Grant opinioned: “I think it extraordinary that epidemiologists, who have been consistently miscalculating the risks of hormone use since the 1960s, to the detriment of millions of women world-wide, should now be congratulating themselves, on belatedly getting it right. The original Family Planning Association’s oral contraceptive trial in the UK, which was started in 1962, attempted to record every single event. The results of testing seven progesterones and two oestrogens were disastrous. It was clear that the formulations most likely to cause headaches and migraine were also more likely to cause more serious vascular events like strokes and heart attacks. The endometrial pathology clearly showed an adverse effect on blood vessels in women having vascular adverse reactions. In my anonymous editorial for the BMJ in 1969 (Grant E, Editorial BMJ 1969; 4; 789-91), I said that it was unlikely that merely changing strengths and doses of hormones could solve the problems, because these were an inevitable part of hormone use with peak complaints varying with different hormone balances.”

“Vessey, Doll and Sutton published a paper claiming that oral contraceptives prevented ‘benign’ breast disease (Cancer 1971: 28: 1395-99).  The ‘evidence’ was that significantly fewer longer users had breast disease. This ignored the fact that sore breasts and vascular reactions were reasons for early discontinuation. More of the longer pill takers had breast cancer but the study was then too small for this to be statistically significant. The flawed ‘prevention’ reasoning prevailed and gave rise to equally spurious claims of hormone use preventing heart disease and ovarian and endometrial cancers. Basic research into how hormone use caused immunosuppression, and therefore an increase in all illnesses, was sidelined and ignored. An exact “safe” hormone balance was sought for individual conditions that could be neutralised, even although a progesterone dominant combination is more likely to cause breast cancer. As oestrogens and progesterones can have opposite effects on fat levels, years were spent in finding (seeking) ‘beneficial’ combinations without actually investigating what was really happening by using the most informative tests.”

In published correspondence titled: “Epidemiologists – Friends or foes?”, Dr Ellen Grant wrote as follows: “For many years I have been frustrated by the mistakes by and misinterpretation and misuse of data by epidemiologists who have claimed medical benefits for exogenous hormone use, including progesterones. For too many years faulty epidemiological studies have been given pride of place while the results of basic scientific research has been ignored. Prominent epidemiologists seemed to be genuinely surprised when the US randomised HRT trial, the Women’s Health Initiative Study, found that HRT caused heart attacks, strokes, dementia and breast cancer and previous claims of protection were wrong. Common sense should have warned that adverse outcomes were inevitable with immunosuppressive, vasoactive, thrombogenic and carcinogenic hormones.” (Grant E, Rapid Response [to Claassen J, Epidemiology: friend or foe? BMJ 2004; 329: 467, 21 August], BMJ, 26 August 2004) Later: “The reasons for claiming spurious benefits and underestimating adverse effects are medico-political (control of the world's population growth), social (Casanova's Charter) and financial (drug company sponsored research). Nutrients and sex hormones are key regulators of immune system responses. Unnecessary interference with flexible homeostatic mechanisms is clearly undesirable.” (Grant E, Rapid Response to Claassen J, BMJ, 28 August 2004)

In published correspondence titled: “Katharina Dalton and progesterone dangers” (Grant E, Rapid Response [to S Holton, Obituary: Katharina Dorothea Dalton, BMJ, 2004;329:1048], 1 November 2004), Dr Ellen Grant wrote: “‘Women are indebted to Dr Greene and Dr Dalton for so clearly describing their problems in the premenstrual syndrome’. So began my BMJ review of Dalton's book, ‘The Premenstrual Syndrome and Progesterone Therapy’ (William Heinemann Books, Lond, 1977) in 1978 (Grant E, BMJ 1978; 1: 165). Dalton’s personal charm, energy, enthusiasm and dedication to her patients, were beyond question to all of us who knew and were inspired by her. Unfortunately, I failed to persuade her (Dalton) against the use of progesterone as a ‘therapy’ for premenstrual symptoms. Dalton’s belief that only synthetic progesterones caused side-effects has achieved “cult” status with the sale of progesterone cream and promotion of progesterone “therapy” by the late Dr John Lee.”

“Progesterone induces secretory changes in endometrial glands which increases endometrial and platelet monoamine oxidase activities (MAO) dramatically, increases vascular development and causes irregular bleeding and headaches, and also induces proliferation in breast tissues. Removal of the ovaries has long been used to prevent endogenous progesterone production as a treatment for breast cancer. Recent studies confirm that progesterones cause more breast cancer than oestrogens. Progesterone is also potentially teratogenic (cause birth defects). Progesterone-induced high MAO activities match depressive mood changes in untreated or in treated cycles, whether symptoms last for a few days premenstrually or continuously as adverse effects of progesterone use (Grant E, Pryce Davies J, BMJ 1968; 3: 777-80). Steroid sex hormones may suppress symptoms in some women by a stress -modulating effect but their mental adverse effects are often dismissed as “psychological” by hormone prescribing enthusiasts.”  

“Ivan Oransky’s obituary in the Lancet (2004; 364:1576) points out that Daltons' (negative) vitamin B6 study was questioned in the Lancet and by other researchers but was influential in the 1997 UK Committee on Toxicity restriction of the sale of vitamin B6 to 10 mg per day. Dalton’s advice to eat small frequent starch meals could furthermore cause fluid retention, weight gain and migraine, especially when combined with progesterone ‘therapy’. Severe functional deficiencies of B vitamins are common, especially because (exogenous hormones) cause vitamin B 6 deficiency and 50 mg doses of vitamin B6, along with other B vitamins, are needed for repletion. Common marked deficiencies in women with PMS are essential enzymes co-factors like zinc, copper, magnesium and B vitamins, potassium and essential fatty acids. These basic deficiencies impair hormone production, receptor activities and alter amine pathways. Such impairments of homeostatic mechanisms unmask symptoms when hormone levels fall, even if these levels are already abnormally high, as HRT tachyphylaxsis demonstrates. (Grant E, J Nutr Environ Med, 1998; 8: 105-116).”

Dr Grant, in correspondence titled: “Reduction in mortality from breast cancer: Fall in use of hormones could have reduced breast cancer mortality” stated the terrifying truth about exogenous progesterone thus: “In the Million Women Study and the US Women's Health Initiative (WHI) study, hormone replacement with progesterone caused four times more breast cancer than with oestrogen only. Ten years of progesterone or oestrogen trebles the risk of breast cancer compared with five year's use. Changes in hormone use have played a large part in changes in the incidence of breast cancer mortality and should not be ignored in studies of the effect of treatments.” (Grant E, Lett, BMJ, 330(7498), 2005)  

In response to a naturopath (Gilmore D, Rapid Response to Grant, BMJ, 2 May 2005), who took exception to the foregoing in defence of ‘natural’ progesterone cream, claiming it to be “strongly anti-cancer”, Dr Grant countered as follows: “There is no evidence progesterone is strongly anti-carcinogenic. On the contrary, progesterone is immunosuppressive and prevents foetal rejection in pregnancy. Endogenous progesterone stimulates growth in breast glands during the secretory phase of an untreated cycle and in pregnancy, just as exogenous progestogens do. Progesterone and progestagens increase mitosis and proliferation in breast tissue (Anderson T et al, Hum Pathol 1989; 12; 1137-43). For nearly 200 years endogenous progesterone production has been stopped in premenopausal women by bilateral oophorectomies for the treatment of breast cancer. The first patient I saw who had rubbed progesterone cream on her breast, developed breast cancer in that breast. Progestogen, progestagen or progestin means acting like progesterone, different names because they often have extra actions.” (Grant E, Rapid Response to Gilmore, BMJ, 3 May 2005)

“Naturopaths, alternative medicine practitioners and nutritionists perhaps believe that progesterone cream is a kind of universal panacea, as do many others, a cult status, which seems to be entirely unjustifiable. Researchers were unable to confirm that applying a quarter teaspoon of cream containing 20 mg progesterone to the skin daily had any protective effect on bone mineral density but did confirm a reduction in vasomotor symptoms (Leonetti H et al, Obstet Gynecol, 1999; 94: 225-8). This is alarming evidence that enough progesterone is being absorbed to have the usual steroid-immunosuppressive effect on menopausal symptoms in some women. Menopausal symptoms warn of nutritional deficiencies and allergic reactions and any exogenous hormone use should be contra-indicated. Chasing the holy grail of suppressing warning symptoms with HRT has cost the lives numerous women. The Million Women Study found increases in breast cancer and mortality with hormone use, irrespective of which type of progesterone was used.”

“Any type of progesterone can induce endometrial gland atrophy. The fact that progesterone and progestins induce the same changes in endometrial glandular enzymes and blood vessels was ignored by Dalton and Lee, as were my efforts to enlighten them, that acting-like-progesterone means precisely that as far as important cell enzymes are concerned. In pregnancy and in a normal cycle the immunosuppressive effects of progesterone are balanced by high levels of oestrogens. Recent studies are investigating why taking progesterone caused increases in breast cancer in large prematurely terminated international trials. Progesterone- dependent up- regulation of tissue factor, the initiator of the extrinsic coagulation pathway, is associated with an enhanced risk of metastasis (Kato S et al, Progesterone increases tissue factor gene expression, procoagulant activity, and invasion in the breast cancer cell line ZR-75-1, J Clin Endocrinol Metab, 2005;90:1181-8). It is the same old hormone story - each disciple believes in special magic formulae for treating a physiological condition and chooses to disregard the evidence of much greater harms from using exogenous hormones.”

Dr Grant, having despatched with Gilmore’s arguments and references, concluded: “I don’t know why Lee and Dalton’s disciples never see women with adverse reactions to exogenous ‘natural’ progesterone. I have seen many, ever since I was Clinical Assistant to the late endocrinologist Dr Gerald Swyer at University College Hospital. Many women gained weight, developed migraine, depression or irregular bleeding when using ‘natural’ progesterone. Alternative medicine practitioners seem happy to ignore the basic scientific facts that synthetic progesterones act predominantly like progesterone, even if they may also have extra oestrogenic or androgenic actions. Why they feel compelled to dice with women’s lives in this way is a complete mystery to me. Nutritional Medicine is a powerful tool, which makes hormone use unnecessary in my experience. There is nothing natural about exogenous hormones.” (Grant E, Progesterone and synthetics acting like progesterone, Rapid Responses, BMJ, 26 May 2005)

In response to Dr Grant’s “Cancer in a Cream?” article, Virginia Hopkins, a co-author with the late Dr Lee, who died of a heart attack in October 2003 at age 74, responded in ‘A Special Edition of the Hopkins Health Watch’ on the Official Website of John R Lee, MD, I am tempted to respond to the points made, since the commercially vested interest fora on which this and other hysterical outbursts have greeted the unwelcome truth are unlikely to host dissenting views as generously as WDDTY has done. I shall however resist commenting on what are essentially emotionally immature ravings and intellectually bankrupt rehashings of long ago scientifically defeated arguments by the multifarious followers of Dr Lee and the ideological and lucrative commercial activities they defend at all cost. I might just add that as a fellow anti-fluoridationist, I admired Lee’s writings on that subject and even his early writings on natural progesterone, echoing as they did, the writings of Raymond Peat PhD. It is lamentable that John Lee is not able to reign in over-enthusiastic and irresponsible abuse of his natural progesterone legacy in the face of scientific progress.

Virginia Hopkins wrote: “Dr. Lee greatly admired the early and pioneering work Dr. Grant did exposing the first birth control pills as dangerous, and he felt she had been instrumental in galvanizing drug companies to create safer oral contraceptives, probably saving thousands of lives in the process. The fact that Dr. Grant is now attacking someone who isn’t here to defend himself speaks volumes, but there are many of us who are here to defend Dr. Lee and set the record straight.” Thousands of doctors in clinical practice are turning to bioidentical hormones because they’re safer and work better.”

How ridiculous is this? Dr Grant never attacked Dr Lee, just his steadily faltering message. It is ludicrous in the extreme to expect a campaign intended to save millions of lives from abuse of unregulated ‘natural’ progesterone to be halted just because Dr Lee is no longer there to defend himself from an imaginary attack on his person. As for the fact that thousands of doctors are now once again engaging in a lucrative promotion just another form of deadly HRT foolishly substituted for another, but this time under the misapprehension that progesterone is entirely safe, renders Dr Grant’s totally non-vested interest efforts highly commendable. Another argument is progesterone’s reproductive criticality. Yes, but so are quantity, cycles and stage of life.

Hopkins continued: “After the factual errors (there were none, just wishful thinking - ST), which cast a shadow over all of Lynne McTaggart and Dr. Grant’s assertions (only in the minds of Lee’s ’defenders’ – ST), is the premise that one can declare ‘progesterone causes breast cancer’ based on in vitro (test tube) research with a couple of breast cancer cell lines. Breast cancer researcher Dr David Zava explains, ‘The research Dr. Grant cites is good, solid scientific work, and very interesting, but it is not even close to enough information to declare that progesterone is carcinogenic’

Even Dr Lee’s sometime supporter, Dr Zava, supports the accuracy of the research cited by Dr Grant, but suggests that it falls short of proving McTaggart’s and Grant’s declaration that progesterone is carcinogenic. If Dr Grant’s evidence was indeed insufficient to support her bold conclusions, allow the proceedings of the following meeting and my own database futher below to remedy this now:

Before moving to input other than McTaggart’s and Grant’s, which futher to McTaggart’s preface statement that “Dr Grant has the ‘last’ word about new evidence of cancer risks”, note that the British Society for Ecological Medicine is hosting a ground-breaking international meeting at the Royal College of General Practitioners, titled: “Why Does Progesterone Cause More Breast Cancer Than Oestrogen?” on 19 November 2006 (we will update with coverage in due course). Speakers and topics include:

* Dr Ellen Grant: Effects of progesterone/progestin and oestrogen on blood vessels, nutrition, immunological diseases, and cancer.

* Dr Sebastian Mirkin. Eastern Virginia Medical School, Norfolk, USA: Effect of progesterone/progestins on vascular endothelial growth factor VEGF mRNA in breast cancer cells. Angiogenesis in breast cancer.

* Professor Jan Brosens, Reproductive Sciences, Imperial College, London: Progesterone/progestin breast carcinogenesis –tissue factor TF gene expression, procoagulant activity & invasion in breast cancer cell line.

Note on Semantics: In all of the forgoing I have attempted, wherever possible, to distinguish between the terms progesterone, progestin and progestogen. “Progesterone” means the hormone produced by the body and the nature bio-identical substance synthesised in the laboratory. “Progestin” might mean either: 1) progesterone or 2) any substance, natural or synthetic, which affects some or all the biological changes produced by progesterone. “Progestogen” has the same meaning as part 2) above.

Normally, unless the title or introduction clearly states what substance is under discussion, or more than one distinct substance is referred to, an author will refer to either “progesterone” or “synthetic progestin”, or if all such related substances are inferred, then reference will be to “progestin” or “progestogens”. My focus is exclusively on progesterone, meaning natural (human or other mammalian extract – the only true natural) or the so-called bio-identical (actually synthesised from predominantly natural sources, so still ‘synthetic’), unless stated otherwise. The often used excuse that dangers refer only to synthetic progestins / progestogens, does not at all apply to the evidence to be presented (even thought it might occasionally have to that above).

Note on Chemical Study Materials: Kindly take cognisance of the fact that, contrary to the oft-repeated criticism by progesterone proponents to the effect that epidemiological studies are irrelevant because they do not utilise so-called natural/bio-identical progesterone, the experimental studies to be presented here do use human cells (an in some cases relevant rodent studies) and do use bio-identical progesterone, and still are likely to be stupidly criticised as not utilising human populations, yet these cell studies are ethical, are significantly informative of the risks of exogenous progesterone and suffice as increasing proof of the risks until eventually quantified by epidemiological human studies of bio-identical progesterone, whether by the registrants of such products, the manufacturers or suppliers of unregistered products, regulatory agencies or by independent researchers. The risk data and evidence is already substantial and is increasing exponentially.

For rather obvious reasons, past studies considered the adverse effects of various progestogens in oral contraceptives, fertility drugs or hormone replacement therapy that the study populations were using and more importantly, adverse effects that no manufacturer or supplier of unregistered so-called bio-identical progesterone products are prepared to undertake – yet vigorously deny any likelihood without even looking and it is not like the writing has not been on the wall for the past decade and including the present moment. Progesterone proponents are now clearly on the skids and any previously valid criticisms no longer apply. The only valid criticism is that which proponents are exclusively guilty of - need for their own clinical trials, without which, they have no right to claim any safety or efficacy, let alone peddle their toxic wares as safe.

In the study by Kato and colleagues (Kato S et al, J Clin Endocrinol Metabol, 90(2), 2005) cited in Part 2 above by Dr Ellen Grant (Grant E, Rapid Response to Gilmore, BMJ, 3 May 2005) and detailed further by Gaia Research and several other studies comprising considerable additional evidence presented below, the specific test material referred to is pure natural bio-identical progesterone acquired from Sigma in the USA. In their product specification, Sigma state: “Synonym - 4-Pregnene-3,20-dione; Molecular Formula - C₂₁H₃₀O₂ ; Molecular Weight - 314.46; CAS No. - 57-83-0. Description - Steroid hormone produced by the corpus luteum. Biochemistry/Physiological Action – Induces maturation and secretory activity of the uterine endothelium, suppresses ovulation. Progesterone is implicated in the etiology of cancer.” Sigma dated and referenced its position on their progesterone thus: (Lanari C, and Molinolo A, Breast Cancer Res. 4, 240-243, 2002); (Anderson E., Breast Cancer Res. 4, 197-201, 2002). Hardly hiding the facts, are they?

Whether my earlier hypothesis proves correct or not, transdermal progesterone remains a risk, since both ‘natural oestrogens and progesterone’, are equally scientifically classified as being “reasonably anticipated to be human carcinogens”. (World Health Organization, International Agency for Research on Cancer, IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans, WHO, Vol 72, 1999); (National Toxicology Program, Report on Carcinogens, Eleventh Edition, NTP, 2005) If my previous hypothesis is correct, then we have a doubly tragic genocide situation with progesterone.

An authoritative government agency summary of the Carcinogenic Substance Profile for Progesterone (natural / bio-identical) (National Toxicology Program, 11th Report on Carcinogens, 2005) reported:
“Progesterone is ‘reasonably anticipated to be a human carcinogen’!”

Direct Carcinogenicity:

“Progesterone is ‘reasonably anticipated to be a human carcinogen, based on ‘sufficient evidence of carcinogenicity in experimental animals (IARC 1982). When progesterone was implanted subcutaneously (which is where it migrates from topically - ST), mammary carcinomas were induced at a significantly earlier age and at a higher incidence in female mice. Long-term subcutaneous implants induced ovarian granulosa cell tumors or endometrial stromal sarcomas in female mice (IARC 1974, 1979). Subcutaneous injections of progesterone induced increased incidences of mammary tumors in adult female mice and lesions of the vaginal or cervical epithelia and genital tract lesions in newborn female mice. Hyperplastic alveolar-like nodules and other dysplasias were also induced in female neonatal mice (IARC 1979). Long-term subcutaneous injections in female dogs induced endometrial hyperplasia, inhibition of ovarian development, marked mammary hyperplasia, and some fibroadenomatous nodules of the mammary gland (IARC 1979, 1982)”.

Editorial Note: Co-carcinogenicity is an important toxicological assessment tool, since the phenomenon is responsible for novel or increased carcinogenicity of one substance in combination with another.

“Female mice injected subcutaneously with progesterone showed decreased latent periods for the induction of mammary tumors by 3-methylcholanthrene. Ovariectomised female mice receiving injections of progesterone developed sarcomas of the uterine horn when given an intrauterine implant of 3-methylcholanthrene and developed increased incidences of squamous cell carcinomas of the cervix or vagina when treated intravaginally with 7,12-dimethylbenz[a]anthracene (IARC 1974, 1979). Local applications of 3-methylcholanthrene and subcutaneous implantations of progesterone induced increased incidences of vaginal-cervical invasive squamous cell carcinomas in female mice (IARC 1979). Rats receiving subcutaneous or intramuscular injections of progesterone had decreased latent periods and/or increased incidences of mammary tumors induced by oral administration of 3-methylcholanthrene or 7,12-dimethylbenz[a]anthracene, but only when the known carcinogens were administered first. An increased incidence of mammary tumors was induced in female rats fed 2-acetylaminofluorene in the diet and injected intramuscularly with progesterone. Newborn female rats receiving a subcutaneous injection of progesterone and a subsequent intragastric instillation of 7,12-dimethylbenz[a]anthracene developed increased incidences of mammary adenocarcinomas (IARC 1979).”

“No adequate human studies of the relationship between exposure to progesterone and human cancer have been reported (IARC 1974, 1979, 1982)” (because no-one until recently embarked on such studies, which is mandatory for registered steroid hormones, including natural progesterone, but averted by peddlers- ST).

Exposure

“Progesterone is a naturally occurring steroid hormone produced endogenously by all mammalian species. Human placental extracts, of which progesterone is the main constituent, have been used in preparations for cosmetic use (IARC 1979). Potential consumer exposure through dermal contact could occur from use of these cosmetics. Animal meat may contain an average of 0.33 mg progesterone/kg if the animal was treated with a veterinary progesterone implant and consumers could potentially be exposed by ingestion. Potential occupational exposure to progesterone may occur through inhalation and dermal contact during its production or formulation into pharmaceuticals.”

Conclusion

“Progesterone is ‘reasonably anticipated to be a human carcinogen’. Progesterone in topically applied hormone-containing drugs for over the counter use is “no longer considered generally recognized as safe (GRAS) and effective (National Toxicology Program, Report on Carcinogens, 11th Edition, NTP, 2005).”

Note on references: Although the following references appear to be outdated, it is the nature of scientific data, that when such major monographs are completed, they become standard references of fact, unless qualified by a subsequent revision, which will always also be cited if such a revision exists. When a second authoritative agency cites monographs in a subsequent report, it can be taken as read that the data stands as of the date of the most recent citation. Note that the three major reports cited by me in this section are dated 1999, 2005 and 2006, which is considerably more contemporary than the old routinely cited assurances of the safety of progesterone by suppliers and peddlers of this potentially highly hazardous drug. New data to be presented hereafter, confirms, expands and delineates the already established carcinogenicity.

Text References:

IARC. 1974. Sex Hormones. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 6. Lyon, France: International Agency for Research on Cancer. 243 pp.

IARC. 1979. Sex Hormones (II). IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 21. Lyon, France: International Agency for Research on Cancer. 583 pp.

Note on Animal and Human Cell-Line Studies
It is unethical to test for carcinogenicity on human subjects – as should also apply to animals – though this does not prohibit epidemiological studies of a drug’s use by human populations, as is mandatory with newly registered drugs, including natural progesterone, but which obligation and responsibility is escaped by suppliers and peddlers of unregistered topical progesterone creams, gels and sprays sold fraudulently as cosmetics or supplements. In the absence of mandatory and/or voluntary human study data by manufacturers and suppliers, all national and international public safety classification agencies are forced to mandate and/or consider the available animal data, as is standard practice for all regulated consumer substances, which often leads to restrictions or banning of synthetics, though rarely natural substances, as databases indicate excessive risks and First World activists lobby governments for consumer protection based on results from just such studies. Independent academic researchers affiliated to universities tend to work with human cell-lines, which provide the basic hypotheses and eventual confirmations that constitute the leading-edge molecular biological sciences – the pursuit of knowledge for the advancement of humanity rather than profit.

Remaining with pure bio-identical progesterone, let us review the research evidence chronologically.

Researchers at the Department of Preventive Medicine, School of Medicine, at the University of Southern California, Los Angeles, USA, (Pike M et al, Epidemiol Rev, 15(1), 1993) had already reviewed the scientific data and reported:

“There is overwhelming evidence that ovarian hormones play a crucial role at all stages in the development of breast cancer. Both major ovarian hormones, estradiol (estrogen) and progesterone, play important roles in increasing breast cancer risk. Key epidemiological evidence is that early menopause reduces risk. Therefore, the hormonal pattern of premenopausal women - cyclic production of relatively large amounts of 17/3-estradiol (estrogen) and progesterone - causes a greater rate of increase in risk of breast cancer than the pattern of postmenopausal women - constant low estradiol and very low progesterone. In postmenopausal women, serum estradiol levels are approximately constant at roughly one third of the lowest premenopausal level, and serum progesterone levels are effectively zero.”

“For many years, the increased risk was thought to be solely due to the elevated levels of estradiol (estrogen) in the premenopausal period, and progesterone was considered anti-estrogenic. This is now known to be incorrect. The rate of increase in the breast cancer incidence curve slows considerably after menopause, but the incidence continues to increase. This strongly suggests that whatever happens to increase incidence is, in most instances, not reversible, ie, that factors which increase risk at any particular time will probably cause lifelong increased incidence rates.”

“There has been much debate in the past 15 years over the precise effects of these two hormones on breast epithelial cells. In addition to effect of age at menopause, other epidemiologic observations provide valuable information on the relation of ovarian hormones to breast cancer risk, and when these are considered together with information from studies of breast cell mitotic activity, the nature of the relation of estradiol and progesterone to breast cancer risk can be largely understood. The relation of weight to breast cancer risk is critically dependent on age. Postmenopausal breast cancer incidence increases about 2.1 percent per year of age. Premenopausal obesity decreases risk and postmenopausal obesity increases risk.”

Cell Proliferation and Carcinogenesis

“Many carcinogens act solely by increasing cell proliferation. Recent advances in the molecular genetics of cancer provide for cell division being essential in the complex process of the genesis of human cancer. An agent that increases mitotic activity also increases the probability of converting DNA damage - both exogenously and endogenously induced - into mutations. Copying errors and more profound DNA changes, including reduction to homozygosity of tumor suppressor genes, also occurs more frequently with increased cell division. The actions of the natural ovarian hormones - estradiol (estrogen) and progesterone - (and hormones used in ERT and OCs) on the breast do not appear to be genotoxic, but they do affect breast cell division rates and their effects on breast cancer rates are explicable in terms of this mechanism.”

“It has long been accepted that hormones can be cancer promoters via increased cell proliferation. Initiation is, however, also affected by cell division rates. Considerations of ever/never use of particular exogenous hormones are of little value. Cells that have undergone some changes on the way to a full neoplastic genotype may respond differently than normal cells to a particular hormonal milieu. Many of the genes that are altered during carcinogenesis are growth factors, growth factor receptors, signal transducers, or transcription factors. In the postmenopausal period, when estrogen levels are low and progesterone is absent, rates of breast cell proliferation are very low, strongly suggesting that estrogen alone induces some breast cell division, but the mitotic rate pattern over the menstrual cycle suggests that estrogen and progesterone together induce much more cell division.”

The ‘Estrogen Augmented by Progesterone Hypothesis’ and Key Breast Cancer Risk Factors

“An ‘estrogen augmented by progesterone hypothesis’ provides a highly satisfactory explanation for most of the epidemiologic observations on and the key epidemiologic hormonal risk factors for breast cancer. Early menopause reduces the risk of breast cancer by reducing levels of both estrogen and progesterone. Increased anovulation and frequency of low progesterone levels in the luteal phase (progesterone values are, on average, approximately half of "normal" values) that are associated with premenopausal obesity markedly decrease breast exposure to progesterone, while bioavailable estradiol(estrogen) appears to be almost unchanged during ovulatory cycles and decreased during anovulatory cycles.”

Steroid Hormone Mechanism of Action

“The effects of estrogen and progesterone on promotion of proliferation and cell differentiation in normal breast epithelium and breast cancer cells are mediated through transcriptional activation of specific sets of genes recognized by their particular receptor proteins. The function of the hormone-binding domain in the absence of hormone appears to be inhibitory, preventing the receptor from binding to its response element. A considerably higher proportion of cells express progesterone receptor than express estrogen receptor. Receptor expression in the normal postmenopausal breast is higher for epithelial cells expressing estrogen receptors than expressing progesterone receptors, which is the opposite of the situation in the premenopausal breast. Both major ovarian hormones, estradiol (estrogen) and progesterone, play important roles in increasing breast cancer risk.” (Pike M et al, Epidemiol Rev, 15(1), 1993)

“After short exposure to progesterone, transcriptional profiles were largely unaffected by marked alterations in relative expression of PRA and PRB. However, after longer exposure to progesterone, a different repertoire of genes were regulated and PRA predominance conferred progesterone responsiveness to a distinct subset of transcriptional targets. Progesterone effects on cell shape and adhesion are dependent on the PRA/PRB balance. Our data suggest that an imbalance of PRA and PRB levels results in remodeled progesterone responsiveness and that altered regulation of morphology and adhesion are important components of altered progesterone response, which may have important implications for breast cancer biology.” (Dinny Graham J et al, Molec Endocrinol, 19(11), 2005)

“Angiogenesis, the formation of new blood vessels, is essential for tumor expansion. We have previously shown that natural progesterone and synthetic progestins induce the synthesis and secretion of vascular endothelial growth factor (VEGF), one of the most potent angiogenic growth factors known, in a subset of human breast cancer cells. Many human breast cancers are dependent on sex steroids and much emphasis has been placed on the role of estrogens in the proliferation. We have revealed progesterone induction of vascular endothelial growth factor (VEGF) in cells that contain the progesterone receptor (PR) and mutant p53 protein. Since approximately 50% of all breast tumors are PR positive and 50–60% of all breast tumors carry p53 mutations, it is critical to investigate the functional role of progesterone-induced VEGF in promoting angiogenesis and breast cancer cell growth.”

“We discovered that progestin-induced VEGF increased the proliferation not only of human endothelial cells, but also of breast tumor cells in an autocrine and a paracrine manner. Breast cancer cells were treated with either progesterone or the synthetic progestin MPA, which is used in HRT. Exposure to either, significantly increased proliferation. The results suggest that the VEGF produced by tumor cells was sufficient to cause a proliferative response of endothelial cells either by itself or in combination with certain tumor cell- or endothelial cell-derived factors for which VEGF was the predominant partner. These results indicate that tumor cells can produce angiogenically active VEGF in response to natural and synthetic progestins, which can subsequently increase the proliferation of human endothelial cells.”

“Recent studies have suggested that VEGF can induce the proliferation of breast epithelial cells, indicating that locally produced VEGF from tumor cells can influence not only endothelial cells, but potentially also neighboring breast tumor cells in the vicinity. Such a situation could cause the proliferation of neighboring cells, an insidious possibility, because two of the main soluble isoforms produced generally by breast cancer cells can diffuse from the cells and influence other cells at a distance or in the vicinity. Both isoforms are also known to be active in promoting angiogenesis by increasing the proliferation of endothelial cells. These results suggest that progesterone or MPA treatment in certain breast cancer cells can produce VEGF and cause the proliferation of adjacent tumor cells that are negative for PR and thereby gain a growth advantage over other neighboring cells.” (Liang Y, Hyder S, Endocrinology, 146(8), 2005)

Researchers at the Reproduction and Development Unit and the Department of Obstetrics and Gynaecology, Faculty of Medicine at the Pontifical Catholic University of Chile; researchers at the Institute of Reproductive and Developmental Biology, Imperial College and Hammersmith Hospital, London, UK; and researchers at the Institute and Department of Medicine and Division of Endocrinology at the University of Colorado Health Sciences Center, USA, recently published a peer-reviewed study and concluded that: “Progesterone in hormonal preparations increases the incidence of breast cancer. Progesterone increases tissue factor gene expression, procoagulation and invasion in breast cancer cell line.” (Kato S et al, J Clin Endocrinol Metabol, 90(2), 2005) A summary of this group’s conclusion’s supporting research follows:

“Tissue factor (TF) mRNA and protein are up-regulated by progesterone in breast cancer cell lines. TF is the initiator of the extrinsic coagulation pathway and is associated with metastasis in a wide variety of cancers. Progesterone increases glucose transporters, which corresponding increase in glucose uptake could provide the extra energy required by the breast cancer tumour for potential angiogenesis and metastasis. Because TF expression is associated with an enhanced risk of metastasis, we postulate that the progesterone-dependent up-regulation of TF provides a survival advantage to burgeoning breast cancer.”

“TF mRNA gene expression following progesterone treatment may play a significant role in breast cancer, where elevated TF, the secretion of angiogenic mediators such as vascular endothelial cell growth factor (VEGF), which confers enhanced proliferation, as well as TF bound to its ligand FVII, which provides protection against apoptosis, as well as procoagulant activity (thrombosis) due to the presence of high levels of circulating progesterone, all correlate with increased invasion of cells (incidence of metastasis) and poor cancer prognosis. Although co-administration of progesterone counteracts the mitogenic action of exogenous estrogen on the endometrium, it increases dramatically the incidence of breast cancer.”

“In further regard to this hypothesis, of direct clinical relevance is the timing of surgery in premenopausal women with breast cancer. If performed during the luteal phase of the menstrual cycle, any breast cancer cells that escape into circulation during this procedure have an enhanced metastatic and procoagulant activity due to the presence of high levels of circulating progesterone. This would increase the risk of tumour reappearance and induce a hypercoagulable state, both related to poorer patient prognosis. The majority of breast cancer deaths are attributable to metastases and thrombosis. Based on the correlation presented herein among TF expression, invasion (metastasis), and procoagulant activity (thrombosis), this work presents a mechanism for the clinical observation that the presence of progesterone correlates with the increased risk of breast cancer incidence.” (Kato S et al, J Clin Endocrinol Metabol, 90(2), 2005)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, Department of Biology, University of Western Ontario, Canada, recently published a milestone Review of Progesterone Metabolites in Breast Cancer (Wiebe J, Endocrine-Related Cancer, 13(3), 2006), summarising the latest findings as follows:

“In addition to the reproductive tissues and adrenals, every other tissue that has been investigated appears to have one or more progesterone-metabolizing enzyme. In the past, the actions of the progesterone metabolizing enzymes generally have been equated to a means of reducing the progesterone concentration in the tissue microenvironment and the end products were dismissed as inactive waste metabolites. We propose rather, and review evidence, that these progesterone metabolizing enzymes act directly on progesterone to produce two types of autocrines/paracrines with opposing regulatory roles in breast cancer and with the promotion of breast cancer related to changes in in situ concentrations of progesterone metabolites.”

“In vitro studies on a number of breast cell lines indicate that the progesterone metabolite pregnenes, promote normalcy by down-regulating cell proliferation and detachment, whereas the metabolite pregnanes, promote mitogenesis and metastasis by stimulating cell proliferation and detachment. The hormones influence opposing actions on mitosis, apoptosis, and cytoskeletal and adhesion plaque molecules via cell signalling pathways. Depending on prevailing enzymes activity/expression, the ratio of pregnenes to pregnanes is high in normal tissue and the ratio is reversed in breast tumour tissue and tumorigenic cell lines because of altered progesterone metabolizing enzyme activities/expression.”

“Current estrogen-based theories and therapies based on suppressing estrogen levels or inhibiting its actions apply to only a fraction of all breast cancers; the majority (about two-thirds) of breast cancer cases are estrogen-insensitive and have lacked endocrine explanations. Only a fraction of all breast cancer patients respond to current endocrine estrogen-targeted therapy and the response is only temporary. Mammary tissue in particular has enzymes that catalyze conversion of progesterone to active metabolites. As the metabolites 5-dihydroprogesterone (5P) and 3-dihydroprogesterone (3HP) have been shown to act with equal efficacy on all breast cell lines tested, regardless of their tumorigenicity, estrogen sensitivity, and estrogen receptor/progesterone receptor status, it is proposed that they offer a new hormonal basis for the progression to all the various forms of breast cancer.”

Figure 1 The structure of progesterone and the major classes of steroids resulting from its metabolism. Progesterone, the 21-carbon precursor of all the major steroid hormones is directly altered by enzymes within many, if not all tissues. The enzyme actions lead directly to the 5-pregnane, 5ß-pregnane, and 4-pregnene metabolites of progesterone and indirectly to the corticosteroids, androgens, and estrogens.

Progesterone metabolism in breast tissues and breast cell lines

“Recent studies provide evidence that progesterone metabolites formed in breast tissue have regulatory functions with respect to breast cancer that may previously have been attributed to progesterone, whereas progesterone serves as a precursor (or pro-hormone) and the metabolites as the active hormones within the tumour and its adjacent host tissue. In terms of neoplasia, the presence of progesterone-metabolizing enzymes has been demonstrated in rat testicular interstitial cell tumors, androblastoma (Sertoli-Leydig cell tumor), dimethylbenz(a)anthracene-induced rat mammary tumors, human endometrial carcinoma, human breast tissues, modified breast cancer cell lines and virally transformed adrenocortical cells.”

Changes in progesterone metabolite ratios and metabolizing enzyme activities

“Studies to determine the capacity of tumor and surrounding normal breast tissues to metabolise progesterone, using tissue specimens from premenopausal, menopausal and postmenopausal women with various subtypes and grades of infiltrating duct carcinomas and including tissues that were estrogen-receptor and progesterone-receptor negative and/or positive, confirmed that all biopsies examined converted progesterone, via 5-reductase, to the final irreversibly reduced metabolite 5-pregnane-3,20-dione (5P). Conversion to 5-pregnanes greatly exceeded that to 4-pregnenes, being 30-fold higher.”

“Metabolism studies showed that the altered metabolite ratios was due to significantly elevated 5-reductase activities in breast tumor tissues and tumorigenic cells whereby changes in progesterone-metabolising enzyme activities relate to a shift toward mammary cell tumorigenicity and neoplasia due to changes in expression of the enzyme genes. Several factors can account for changes in enzyme activity. In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme or changes in the milieu in which the enzyme operates, such as pH and concentrations of cofactors, substrates, ions, phospholipids and other molecules.”

“Enzyme activity and expression studies show that both 5-reductase stimulation and 3-hydroxysteroid oxidoreductase (3-HSO) and 20-hydroxysteroid dehydrogenase (20-HSO) suppression are associated with transition from normalcy to cancer of the breast. Changes in progesterone-metabolizing enzyme gene expression are influenced by factors such as peptide hormones, cytokines, and steroids. Examples: Prolactin acts as a paracrine/autocrine mutagenic agent in mammary cells and inhibits 20-HSO expression in corpora lutea (Schroeder M et al, Molec Endocrinol, 16; 45–57, 2002). The expression of 5-reductase is up-regulated by estradiol and progesterone in the uterus (Minjarez D et al, Biol Reprod, 65; 1378–1382, 2001). The expression of 20-HSO is altered by progesterone in corpora lutea (Sugino N et al, Endocrinol, 138; 4497–4500, 1997) and in endometrial cells (Nakajima T et al, Endocrine J, 50; 105–111, 2003).”

Cancer- related actions of the progesterone metabolites

Effects of progesterone metabolites on cell proliferation, mitosis, and apoptosis

“Uncontrolled cell proliferation is one of the hallmarks of cancer and factors that affect cell proliferation rates affect cancer rates. Studies conducted on MCF-7 cells showed significant effects on cell proliferation, with 5-pregnane-3,20-dione stimulating proliferation dose-dependently between 10^–9 and 10^–6 M. In this concentration range, estradiol resulted only in weak stimulation at 10^–8 M and no effects or slight inhibition at higher concentrations. Stimulation in cell numbers was also observed when cells were treated with other 5-pregnanes and stimulation of cell proliferation with 5P were observed in all other breast cell lines examined, whether Estrogen Receptor negative or positive and requiring estrogen or not.”

“Increases in cell numbers can result not only from increased rates of cell division, but also from decreases in rate of cell attrition via programmed cell death (apoptosis). A balance of proliferation and apoptosis provides homeostasis in normal tissues and alteration in this balance sets off changes ultimately leading to malignancy. Studies on cell lines using several methods of evaluating apoptosis and proliferation/mitosis showed treatment with 5-dihydroprogesterone (5P) resulted in decreases in apoptosis and increases in mitosis (Zhang G et al, Endocrine Society 87th Annual Meeting, San Diego, 2005: Abstract #P3-652, 2005). With respect to overall cell proliferation effects, the action of 5P involves cell division. The results correlate with metabolism studies, since levels of this proliferation-inducing hormone were higher and those of the proliferation-suppressing hormone (3HP) were lower in tumorous tissue.”

Effects of progesterone metabolites on cell adhesion

“Cellular adhesion is a critical aspect of cancer biology. Some time during the development of most types of human cancer, pioneer cells are spawned that are capable of moving out of the primary tumor masses to distant sites.  It is these distant settlements of tumor cells — metastases — that are the cause of about 90% of human cancer deaths. To allow the initial escape, adhesion must be decreased and attachment severed. Tests on MCF-7, MCF-10A, T47D and MDA-MB-231 cells showed that 5P caused significant dose-dependent decreases in attachment to, and increases in detachment from, the substratum (Wiebe J et al, Endocrine Society 86th Annual Meeting, New Orleans, 2004); (Pawlak K et al, J Steroid Biochem Molec Biol, 97; 278–288, 2005).  The opposing actions of 5P and 3HP on both cell anchorage and proliferation strengthen the hypothesis that the direction of progesterone metabolism in vivo toward higher 5-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.”

Proof of principle

“Confirmation of the hypothesis that the move from normalcy to neoplasia in breast cells is influenced by the in situ increase in the 5-pregnane to 4-pregnene ratio requires studies in which 5-reductase activity is blocked and also where 5-pregnane and a 4-pregnene are used in combination and in various temporal sequences. We used dutasteride, a known inhibitor and demonstrated that in MCF-7 cells at 10^–6 M, it inhibited progesterone conversion to 5-pregnanes by >95% and increased 4-pregnene production. We also demonstrated that treatment of cells with progesterone alone resulted in significant conversion to 5-pregnanes and concomitant increases in cell proliferation and detachment and that these increases were blocked in cells incubated with progesterone plus dutasteride and in turn, that the suppression by dutasteride was overridden by the addition of 5P. The results are seen as providing proof of the principle that the effects on proliferation and adhesion were due to the 5-reduced progesterone metabolites (Wiebe J et al, J Steroid Biochem Molec Biol, 100 (In press), 2006).”

Effects of progesterone metabolites on cytoskeletal and adhesion complexes

“The transformations in morphology, replication, and adhesion during the transition from normal to cancerous cells have been shown to be accompanied by rearrangements of cytoskeletal and adhesion structures. The cytoskeletal organization differs between normal and cancerous cells and between high- and low-metastatic cells. Vinculin is a protein associated with cell-to-cell and cell-to-substrate adhesion sites. In normal cells, vinculin may be readily detected, while in highly malignant cell lines its organization may be significantly altered or it may not be detected at all, suggesting progression of malignancy.  Treatment of MCF-7 cells with 5P resulted in dose-dependent decreases in vinculin-containing adhesion plaques and vinculin expression, as well as in polymerized actin stress fibers. Similar results were observed with MCF-10A, MDA-MB-231, and T47D breast cell lines, again confirming that the progesterone metabolites are able to target a variety of human breast cells.”

Receptors for progesterone metabolites in human breast cells

Localization, characterization and Regulation of progesterone metabolite receptors

“The actions of hormonal steroids require complexing with specific-binding sites (receptors) on target cells. Our studies show that binding of 5P in human breast cells occurs in the plasma membrane, distinct from nuclear/cytosolic progesterone and estrogen receptors and met the criteria of high affinity, specificity, saturability, and association kinetics required of receptor designation. The action mechanism of hormonal steroids is limited not only by the local concentration of the hormone, but also by the receptor number. Exposure of MCF-7 cells and the nontumorigenic breast cell line, MCF-10A to estradiol or 5P resulted in significant dose-dependent increases in 5progesterone receptor levels. Estradiol binding was demonstrated in MCF-10A cell membrane and explains the estradiol action in these cells, which lack intracellular estrogen receptors. In both MCF-7 and MCF-10A cells, the increases in 5PR due to estradiol or 5P correlated with increases in cell proliferation and detachment, indicating the functional relevance of alterations in 5PR concentrations. Together, the receptor results suggest that the putative tumorigenic actions of 5 P may be significantly augmented by the estradiol-induced increases in 5progesterone binding.” 

Role of progesterone metabolites in regulating ER levels

“Estradiol can influence mitogenicity of estrogen receptor-positive mammary cells. Therefore, regulation of estrogen receptor levels may be important for the progression of estrogen-dependent mammary neoplasias. Estradiol and progesterone are known to play a role in modulating estrogen receptor concentrations. To determine if progesterone metabolites affect estrogen receptor levels, MCF-7 cells were exposed to 5P, 3HP, 20HP, and estradiol and combinations of these steroids, and ER concentrations were determined in cytosolic and nuclear fractions. Estradiol and 5P resulted in significant dose-dependent increases in total estrogen receptors.  In combination, estradiol + 5P resulted in additive increases estrogen receptor numbers in breast cancer cells. The implications for breast cancer are that the stimulatory effects of 5P on cell replication and detachment are significantly modified by exposure to estradiol and 4-pregnenes and that progesterone metabolites may significantly affect estrogen response in estrogen-targeted cells.”

Effect of the progesterone metabolite, 5P, on cell signalling pathways

“The location of the receptors for 5P and 3HP on the cell membrane suggests involvement of nongenomic mechanisms of action via cell signalling pathways. Signaling pathways that control cell proliferation and adhesion involve the mitogen-activated protein kinase (MAPK) pathway and deregulation of this cascade plays a central role in human cancer. Studies on MCF-7 cells showed that treatment with 5P for as briefly as 5 min resulted in significant, dose-dependent increases in activated MAPK. The data suggest that the action of 5P on breast cancer cells involves modulation of the MAPK signalling pathway. Whether other cell signalling pathways are involved or 5P and 3HP act via different pathways in promoting or inhibiting neoplasia in breast cells remain to be explored.”

Implications of progesterone-metabolizing enzymes for synthetic progestin-based contraceptives and hormone-replacement therapy drugs

“The synthetic progestins used for contraception and hormone replacement therapy (HRT) do not behave like progesterone in terms of their metabolism and probably not with respect to their actions at the level of the breast tissue microenvironment. As different formulations may exhibit marked differences in chemical structure, metabolism, and pharmacodynamic actions, it is not possible to generalize about them. To ascertain the possible role of the contraceptive and HRT drugs in breast cancer regulation via the progesterone metabolites, it will be necessary to measure their levels and composition in the breast microenvironment to determine their effects on progesterone metabolism in breast tissue and/or cell lines and to establish whether the progesterone-metabolizing enzymes can further alter the drugs to pro- or anti-cancer moieties.”

Summary, significance, and future prospects

“Mammary gland cells show cyclicity and respond to steroid hormones. Normal breast tissue goes through cycles of imbalance between proliferation and apoptosis during menstrual periodicity, pregnancy, and lactation, but regularly corrects these temporary imbalances. In cancer, changes have occurred such that overall increases in cell numbers continue and result in the development of tumors. The changes are due to the changes in concentration of the ovarian hormones, estradiol (estrogen) and progesterone. Since estrogens have been shown to increase proliferation in some cells, and because about one-third of breast cancer patients show some responses to anti-estrogen therapies, estrogens have been considered the primary hormonal cause of breast cancer. In time, however, estrogen-sensitive neoplasms become unresponsive and the patients experience relapse. Overall, this means the existence of an overwhelming majority of breast cancers for which the current estrogens based explanations and therapies are inadequate.”

“Since progesterone is involved in normal cyclical changes, it too has been implicated in breast neoplasia. The progesterone metabolites, produced within breast tissues, are put forward as candidates that could up- regulate mitogenic and metastatic processes in mammary tissues, resulting in progression to cancer. The suggestion is based on the evidence provided and summarized in the figure below:”

Summary of actions and action pathways of the progesterone metabolites 5P and 3HP in a stylized human breast cell and their proposed roles in maintaining normalcy or promoting cancer. Following binding to separate and specific receptors in the plasma membrane, 5P and 3HP act via cell signaling, and potentially indirectly via genomic, pathways to effect independent and opposite changes resulting in increases () or decreases () in cell proliferation, apoptosis and adhesion. Maintenance of normalcy depends on higher levels of 3HP, and progression to neoplasia and metastasis are promoted by increased levels of 5P.

“The work on the potential role of progesterone metabolites in promoting cancer of the breast is in its infancy and a number of issues need to be addressed. All the observations summarized in this review about the effects/actions of the progesterone metabolites were made in vitro on breast cell lines in culture. To substantiate the hypothesis that the progesterone metabolites play a role in mammary cancer, it is necessary to demonstrate their effects in vivo. Evidence that progesterone metabolites can have similar effects in vivo has come from a pilot experiment conducted by Drs R Schillaci and P Elizalde (NRC, Buenos Aires), who showed (personal communication) that C4HD cells developed into substantial palpable tumors if treated with 5P (40 mg depot). Tumor growth rate was about the same (or slightly higher) with 5P as with an equivalent dose of medroxyprogesterone acetate, a known tumor inducer. It is hoped that the evidence presented will stimulate further research into the potential roles of progesterone metabolite hormones in breast cancer and generate new ideas for its control, regression and prevention." (Wiebe J, Endocrine-Related Cancer, 13(3), 2006)

Sincerely

Stuart Thomson