Gaia Research, being in both the health care and personal care research sectors is well aware that the skin is the largest assimilative organ of the body. So-called ‘natural progesterone cream’ is an unregulated and unproven form of mono hormone replacement therapy that is recklessly marketed and being naively used by very many thousands of individuals world-wide, under the impression that it is ‘natural’ and hence safe, usually to treat the symptoms of the PMS or menopause; or for a hypothesised ‘oestrogen dominance’; or for several equally or even more scandalously absurd and hazardous purposes lucratively suggested by unscrupulous manufacturers and distributors of such products that range from absolutely useless to life-threatening, depending on formulation, concentration, dosage and menstrual cycle, stage of life and overall health/illness.

I am not suggesting that conventional HRT is not equally hazardous; it is, possibly even more so, but there is at least some research, disclosure, cautions, monitoring, and hence some increasing degree of control being exercised over the known human carnage, whereas with so-called natural progesterone cream, there is little to no responsibility at all being  brought to bear and the extent of the resultant carnage, contemporarily probably approaching that of HRT on a daily basis, remains uncalculated and hence unpublicised. This is not to say that professional standardised transdermal bio-identical progesterone, following detailed hormone profiling and health assessment, could not be safely beneficially used, periodically, for limited appropriate conditions, if constantly reliably monitored and adjusted by an experienced gynecological endocrinologist.

That indiscriminate application of topical progesterone cream might moderate some common symptoms of physiological dysfunction, only to later express serious delayed consequences, encourages its use and abuse by consumers and merchants alike. Please examine my opinion-informing, generally unconsidered evidence:

Back in 1996, Lynne McTaggart wrote as follows in her pioneering whistle-blowing book (What Doctors Don’t Tell You, Thorsons, 1996), which was also highly critical of Hormone Replacement Therapy:

“Ordinarily, the body’s pituitary gland and ovaries work in exquisite tandem, constantly adjusting oestrogen levels to fit the body’s need of the moment, like an automatic car, says Dr Ellen Grant, author and a long-time critic of HRT and the pill, which deliver constant levels of oestrogen, like a car stuck in a single gear.”

“Although it is called ‘natural progesterone’, because it is derived from yams, chemists imitate a number of chemical processes in a test tube, tacking on extra parts of molecules to end up with a substance with more or less the same molecular structure that our bodies produce. All such progesterones must go through chemical processing and all share similar side-effects. Some epidemiologists believe that high levels of progesterone may be a risk factor for breast cancer.(David Grimes, Editorial, Fertility and Sterility, 57(3), 1992); (Klim McPherson et al, correspondence, British Medical Journal, 310: 598, 1995)   

Four years later, in the October 2000 Edition of the respected ‘alternative’ British journal, The Ecologist, Lynne McTaggart wrote as follows in an article titled: Progesterone Cream: Unregulated and Unproven Hormone Replacement Treatment, which unfortunately was no match for the hype marketing propaganda:

“The most seductive marketing term at the moment is the word 'natural'. Consider the extraordinary marketing of so-called 'natural' progesterone. Several years ago, an extremely pleasant and enthusiastic Californian doctor named John Lee flew over to the UK to present his theories about the role of 'natural' progesterone in preventing menopausal symptoms. Lee declared that women entering the menopause were not suffering from oestrogen deficiency but 'oestrogen dominance' due to the presence of huge numbers of oestrogen mimics (pesticides, hormones used in farming, industrial waste) in the environment. The problem during menopause isn't too little oestrogen, said Lee, but too little progesterone. His prescription for women entering the menopause or suffering from a variety of female complaints  was to use a rub-on cream containing a certain percentage of 'natural'progesterone to circumvent the body's response to outside hormones as toxic substances, to bypass the liver to reach the bloodstream directly.”

McTaggart continued: “It's important to get something straight. The only progesterone that is ‘natural’ is that produced by the body. ‘Natural progesterone cream’ circumvents the stringent laws for drug safety. There are no standards for the amount of progesterone present, which is important when you consider the minute doses required by the body to keep things ticking over. During the menstrual cycle of the ordinary woman, progesterone blood (plasma) levels range (extend) from 0.5 to 20 nanograms per ml (Harrison's Principles of Internal Medicine), the equivalent of one part per billion in weight. With the rub-on cream, women could be enhancing the progesterone concentration in the blood by four or five times (per application). 'Natural' progesterone is a drug with unknown dangers -- hormone replacement dressed up as a natural supplement. In our zeal to undergo a natural menopause, it's important that we don't fall prey to the same marketing interests that gave us sex hormones and a massive increase in breast cancer.”


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.



Layout of the evidence


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)


Researchers at the Institute of Plant Physiology, Polish Academy of Sciences, Krakow, Poland, reported:
Mammalian sex hormones such as 17beta-estradiol (oestrogen) and progesterone were present in 60-80% of the plant species investigated. Enzymes responsible for their biosynthesis and conversion were also found in plants.” (Janeczko A, Skoczowski A, Folia Histochem Cytobiol, 43(2), 2005)

Cholesterol in association with low-density lipoprotein is the primary blood-borne precursor used for the body’s synthesis of progesterone, making raw materials for progesterone production an unlikely problem in most reasonably healthy persons. Once progesterone is synthesised by or introduced into the body, it can, via physiologic conversion in the corpus luteum, ovaries, testes and adrenal glands, be synthesised to all of the hormones, including oestrogens, androgens, and corticosteroids. Adrenocorticotropic hormone, synthesised by the anterior pituitary gland, stimulates the conversion of cholesterol into pregnenolone, the immediate precursor of all steroid hormones, including progesterone. (Biochemistry, L Stryer (Ed), WH Freeman & Co, NY, 1995) In humans, the final step in progesterone biosynthesis is the conversion of pregnenolone to progesterone. Pregnenolone is the precursor of progesterone and DHEA and its inhibition disrupts normal steroidogenesis of these essential steroids and in turn, those of which these are precursors. The corpus luteum produces a number of normalcy regulatory progesterone synthesis inhibitors.

Sutherlandia herb, heavily marketed as a supplement (another informed concern of mine), is a conversion inhibitor of both progesterone and pregnenolone (Prevoo D et al, Endocr Res, 30(4), 2004). An excess of iron, carotene and free radicals inhibit progesterone synthesis, as does a sunlight deficiency. Transdermal progesterone is not a natural alternative to lifestyle excesses and/or deficiencies. Industrial chemists can convert a constituent of Mexican yam diosgenin into progesterone, but only via unnatural chemical pathways. Aberrant progesterone may, through bio-modulation, affect endogenous progesterone production. Despite all of these avoidable lifestyle factors, it is in fact extremely rare to suffer from an oestrogen excess/progesterone deficiency, as claimed by advocates of ‘natural’ progesterone cream. Soon after its purification in 1933, true natural progesterone became widely used in the treatment of luteal-phase dysfunction, which is appropriate for true luteal defects causing decreased progesterone biosynthesis. However, if the defect involved hypothalamic or pituitary dysfunction or disorders of follicular maturation, then initial treatment was more appropriately directed elsewhere, (Ovarian Endocrinology, S Hillier (Ed), Blackwell Sci Publ, Oxford, 1991), a far more responsible approach than that of the progesterone cream cowboys.


Witness examples of the realisation of this truth and of the hazards of indiscriminate use of even low doses of progesterone cream within of the cautious parameters originally recommended by Dr Lee, but irresponsibly long lost by his followers due to rampant commercial opportunism:

Researchers at the Clinical Pharmacology Research Center at Bassett Healthcare, Cooperstown, New York, following a 2-year study of postmenopausal women using an over-the-counter natural progesterone cream at a network of three hospitals and 21 health centers in central New York, reported:

“Many progesterone studies measure serum, which is blood that has had the cells in the blood filtered out. This gives inaccurate results because progesterone circulates in the blood bound to cell membranes. When progesterone reaches receptors in the organs of influence, the breast, uterus or placenta, it detaches from cell membranes and attaches to the receptors. Therefore, in order to be accurate, whole blood must be measured.

Our data show that one brand of natural progesterone cream (Pro-gest), using a dosage consistent with the higher dose directions on the cream's label, gave equal exposure to the (5-times higher) therapeutic dose of micronised oral progesterone (Prometrium). The use of topical progesterone without medical supervision is concerning because of the possibility of increased risk of coronary artery disease, stroke, thrombosis and breast cancer.(Dr Anne Hermann, Presentation: “The Bio-equivalence of Over-The-Counter Progesterone Cream” at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics in Miami Beach, Florida, USA, 25 March 2004)



This reality is not the exclusive domain of medical researchers. A few responsible practitioners are taking note, doing their own analysis and making significant changes in the use of these products in their practices.

Dr Mercola On ‘Complications Regarding Progesterone Cream’

Dr Joseph Mercola, DO, a peer-reviewed published author and popular online ( 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’,, 2004)



Premenstrual Syndrome (PMS) lacks a consensus definition, but 10 psychologic and 10 somatic chief symptoms tend to be listed in the medical literature in order of frequency of occurrence. Complicating the study of the syndrome is that the fact that placebo responses in controlled clinical trials have been as high as 80%, with no long-term satisfactory treatment emerging with various forms of progesterone, the most commonly prescribed, yet controversial therapy for PMS, given that progesterone deficiency has never been proved to be a cause of PMS, nor progesterone to be superior to placebo, some specialists believing that 80% of patients can be treated with stress reduction and dietary modification alone. (Smith S, Schiff I, The premenstrual syndrome: diagnosis and management, Fertil Steril, 52(4), 1989); (Clinical Pharmacy and Therapeutics, E Herfindal, D Gourley & L Hart, (Eds), Williams & Wilkins, 1992)

Menopause researchers at the Oregon Evidence-based Practice Center and Oregon Health and Science at the University of Portland reviewed 130 studies of alternative therapies for menopause, including transdermal progesterone cream and described its safety and efficacy for hot flushes and preventives for cardiovascular disease, osteoporosis and breast cancer as “bleak” (Speroff L, Intl J Fertil Womens Med, 50(3), 2005). In a subsequent study of 70 previously completed studies of alternative therapies used to treat menopause-related symptoms, their findings showed that a strong placebo effect was about the only consistent result. (Nedrow A et al, Arch Intern Med, 166(14), 2006) The placebo effect can be especially significant for both conditions.

Dr Grant has long ago pointed out that: “Deficiency of progesterone is unlikely to be responsible for the premenstrual syndrome as the week following menstruation is usually the time which is most often free from symptoms and at this part of the cycle there are very low levels of progesterone (Grant E et al, Munch Med Wochenschr, 117(38), 1975); (Grant E et al, Minerva Med, 67(31), 1976).” Should the reader believe themselves familiar with McTaggart’s and Grant’s WDDTY and BMJ evidence and are not yet entirely convinced, please proceed to my additional irrefutable evidence, which proves, via peer-reviewed published scientific literature, that progesterone is carcinogenic and causes breast cancer.


To enlarge these images, click on them


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”


WDDTY, Vol 12, No 2, 2001 reported: New evidence points to a strong link between raised progesterone levels and the ‘eventual’ development of breast cancer. Using data from several countries, researchers analysed progesterone levels in women aged 25-35 during the mid luteal phase of their cycles (from five to nine days preceding the next period) and found that during this phase, an increase in progesterone of more than 70 per cent coincided with a more than eightfold rise in the rate of breast cancer.” (BMJ, 2001; 322: 586-7).


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 mortalitystated 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)


To finish my current coverage from McTaggart and Grant, I jump to the near present, in particular the cover story of the May edition of What Doctors Don’t Tell You, titled “Natural Progesterone: The Cancer Risks Revealed” (WDDTY, vol 17, no 2, 2006).  

In her editorial: Viewpoint: “The end of the debate!” Lynne McTaggart wrote:

“Dr John Lee believed he had discovered the source of menopausal symptoms, osteoporosis – indeed, virtually every female problem on the planet. The culprit, he believed, was ‘oestrogen dominance’ and the solution, ‘natural progesterone’ (administered as a cream). His was a highly plausible line: today’s women are overwhelmed by environmental oestrogens, and so the need for progesterone to hormonally balance themselves. Lee also maintained that since the type of natural progesterone that he advocated was biochemically identical to what the body produced, it was safe to use, whereas hormones that were synthetically produced, were nothing like the real thing and hence were dangerous. As a result of Lee’s proselytising, alternative practitioners began to prescribe natural progesterone with enthusiasm.”

I remained unconvinced.  What bothered me about the story at the time was my discovery that ‘natural’ progesterone was not a natural anything. It was a substance made in the laboratory by taking the sterol base of wild yam and chemically tweaking it, adding molecules here and there until you produced something with the same molecular blue print as ovary-derived progesterone.  It was, in other words, a drug. What also bothered me was that progesterone is primarily a pregnancy hormone.  Women are finished with pregnancy at the menopause.  What is the effect of taking a hormone that you’re not supposed to need anymore? Finally, I thought about the fact that progesterone is an immunosuppressant.  High circulating levels of progesterone allow a woman to carry a foreign protein (ie a foetus) in her body for nine months without expelling it.  Thanks to progesterone, I was no longer allergic to wheat when I was pregnant.  So what was the effect of taking something over the long term that turns your immune system down so low?”

“Lee over the years, recommended rub-on cream for more arcane uses: to prevent premature birth, and as a treatment for reflux and, most dangerously; he began recommending it to prevent breast cancer. Although most of the (alternative) medical community embraced Lee’s theory, one lone wolf besides me remained sceptical.  As a young doctor, Ellen Grant was one of the main UK researches in the first birth control pills of the 1960s and witnessed first-hand what they were able to do to women.  She denounced the Pill, and for than 40 years went on to research the effects of exogenous hormones. She was one of the few people willing to question many of Lee’s basic assumptions. The fruits of her research in this month’s cover story offer stark new evidence that Lee’s simple, well-intended message was not only wrong, but also dangerous. Progesterone of any variety is carcinogenic. Indeed, it is progesterone, rather than oestrogen, that is the most carcinogenic hormone of the two. There are two morals to this story.  First, for all of us in alternative medicine, it’s important to resist a suspension of all disbelief when it comes to products touted as natural. Second, a simple and sobering truth: taking extra sexual hormones at any point in your life is likely to give you cancer. Hormones are finely turned substances.  We tamper with them at our peril.”

Over to Dr Ellen Grant, physician, medical gynaecologist and nutritionist; honorary secretary - Doctors Against Abuse From Sex Hormones; founder member – British Society for Ecological Medicine (originally the British Society for Allergy, Environmental and Nutritional Medicine); and editorial board member, Journal of Nutritional and Environmental Medicine, official journal of the Australian College of Nutritional and Environmental Medicine and the American Academy of Environmental Medicine, who wrote as follows:

“Dr Lee’s main argument was that as the progesterone cream was ‘chemically identical’ to that produced in the body, it was safe. The reality is that even a woman’s own natural endogenous progesterone is potentially dangerous because it is primitive steroid that is highly immunosuppressive and potentially carcinogenic. Progesterone levels are highest during pregnancy and although it is rare to develop breast cancer at that time, when it does, it can spread with the speed of an abscess. In healthy woman, progesterone levels are never high without high oestrogen levels – either in the luteal phase of the menstrual cycle or during pregnancy.  This protects against progesterone-induced immunosuppression, which maintain pregnancy by preventing the rejection of the foreign paternal proteins in the foetus. Although oestrogens increase antibody production, progesterone decreases antibody production, which may be one reason why progesterone is more carcinogenic for the breast than oestrogen.

New research using breast cancer cells has discovered that progesterone encourages breast cancers to spread rapidly and metastasise. Progesterone also induces rapid growth of leaky blood vessels. Professor Gary Owen in Chile and Professor Jan Brosens at Hammersmith Hospital, London, discovered that these breast cancer cells displayed an 18-fold increase in messenger ribonucleic acid (mRNA) tissue factor (TF) expression after only six hours of progesterone treatment. High TF expression is associated with an increased invasive and metastatic potential of many type of malignancy (J Clin Endocrinol Metab 2005; 90; 1181-8). TF increases strongly relate to increased secretion of angiogenic mediators, such as vascular endothelial growth factor (VEGF), which are also important in the growth of cancer. TF bound to clotting factor VII provides protection against cell death, which aids the development and survival of cancer cells.  Over-expression of TF increases the clotting tendencies seen in cancer patients.”

“The authors of the study discovered that both progestin and (or) progesterone cause an increase of epidermal growth factor (EGF) signalling, which in turn provides a survival advantage to new cancer cells. It is this increase in EGF signalling that may contribute to the breast-cancer risk associated with either endogenous progesterone or with progestin-containing HRT. According to the authors, their results show that natural progesterone and synthetic progestogens both have a similar action in the body. This evidence kicks away the main platform on which Lee built his case that natural progesterone is somehow safer than synthetic progesterone. This is hardly surprising as progestogens specifically imitate the effect of progesterone in the body. The evidence is now clear - natural progesterone is just another form of HRT.”

Dr Sebastian Mirkin and colleagues from Eastern Virginia Medical School measured the effect of various concentrations of estradiol, progesterone and synthetic progestogens on two forms of VEGF using two breast-cancer cell lines, one composed of cells rich with oestrogen receptors and the other rich with progesterone receptors.  A positive effect on VEGF would indicate a substance that promotes cancer. Both progesterone and progestogens increased vascular endothelial growth factor (VEGF), with the highest doses having the greatest effect.  However, the natural oestrogen 17-beta-estradiol had no effect in any dose (Fertil Steril, 2005; 84;485-91). So the effect of regular rub-on progesterone (or HRT or the Pill) is continuous exposure to progesterone (or progestogens) that stimulates angiogenesis over longer periods than occurs in the secretory phase of a normal menstrual cycle. Increased angiogenesis leads to cancer.

Professor Maurizio Cutolo, Genoa, Italy, has studied the way in which sex hormones modify the immune system. Progesterone inhibits immune cell growth and increases cell death, while oestrogens protect against cell death and increase antibody formation. He is concerned that, in both men and women with autoimmune diseases, sex hormones in peripheral tissues convert into very high levels of carcinogenic oestrogen metabolites (Rheum Dis Clin North Am, 2005; 31: 19-27). Giving progesterone makes matters worse. The first patient I saw who had used progesterone cream was an American, who after she had a mastectomy for breast cancer, rubbed progesterone on her remaining breast but soon developed a second breast cancer. The final irony is that progesterone can cause many of the symptoms menopausal women are trying to alleviate - vaginal dryness (painful sexual intercourse), vaginal thrush, and cervical cancer. The menopause is nature’s way of protecting women from the dangers of raised levels of progesterone.



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 isreasonably anticipated to be a human carcinogen, based onsufficient 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).


“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.”


“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.

IARC. 1982. Chemicals, Industrial Processes and Industries Associated with Cancer in Humans. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, Supplement 4. Lyon, France: International Agency for Research on Cancer. 292 pp.

The fact that endogenous natural and exogenous bio-identical progesterone is carcinogenic is now beyond scientific doubt. Undetermined are the doses at and circumstances under which the risks are excessive for consumers and who assumes responsibility for their protection. The State of California requires that the Governor annually revises and publishes a list of chemicals known to cause cancer.

The most recent list under Proposition 65, includes both Oestrogen and Progesterone (the natural and synthetic forms) as chemicals known to be capable of causing cancer and likely to do so in humans, so in progressive California, topically applied bioidentical progesterone products must already state: "WARNING: This Product Contains A Chemical Known To The State of California To Cause Cancer." (Proposition 65 List of Chemicals, State of California EPA, Office of Environmental Health Hazard Assessment, Chemicals Known to Cause Cancer or Reproductive Toxicity, September 29, 2006)

Since transdermal natural/bio-identical progesterone proponents are willing to accept Dr Lee’s and other’s assurances that oestrogens (or at least synthesised oestrogens and their mimics) are carcinogenic, I am not going to labour the point that even natural healthy human body-produced oestrogens can be carcinogenic, since their classification as such also by the IARC and the NTP, undisputed world authorities, ought to suffice as proof for all but the most ignorant or criminal New Age health gurus and their unfortunate gullible victims. What I shall expand on is the authoritative scientific proof that progesterone is indeed also carcinogenic, and in particular, is implicated in the aetiology of breast cancer, and as a result of such proof, that the transdermal natural/bio-identical progesterone cream gurus and peddlers claiming absolute safety and recklessly advocating its indiscriminate and unmonitored use for all and sundry are indeed criminal fraudsters.



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.

Since the early 1990’s, evidence already existed indicating that progesterone was not completely safe. (Pike M, Spicer D, Endogenous estrogen and progesterone as the major determinants of breast cancer risk: prospects for control by "natural" and "technological" means. In: Hormonal Carcinogenesis (Li J, Nandi S, Li S (Eds), Springer-Verlag, NY, 209-216, 1991).

Researchers from the University of Southern California, in an authoritative United States government agency report unambiguously reported:
“Mitogenesis and mutagenesis are major driving forces in neoplastic development.
The ovarian hormones, estrogens and progesterone, are major effective (direct or indirect) breast cell mitogens. (Spicer D, Pike M, J Natl Cancer Inst Monogr, (16):139-47, 1993)


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)



Researchers commissioned by the Division of Health Promotion and Disease Prevention Institute of Medicine, Washington DC, reported:
“Interest in the study of anti-progestins in breast cancer is understandable, given the known prognostic importance of the progesterone receptor in this disease.
In contrast to its actions in the uterus, progesterone at low dosage approximating physiologic ranges is growth stimulatory in the normal breast (most mitoses occur in the late luteal phase of the menstrual cycle coincident with the rise in progesterone). Both estrogen and progesterone in low doses stimulate breast cancer growth. Blockade of this mitogenic effect is a potential strategy for breast cancer prevention and anti-progestins have potential as growth inhibitory compounds against breast cancers, in particular in women with advanced (metastatic) breast cancer.” (Donaldson M et al, Committee on Antiprogestins: Assessing the Science and Recommending a Research Agenda, Institute of Medicine, Washington, DC, National Academies Press, 1993)


A researcher with the Molecular Biology Program at the University of Colorado Health Sciences Center, Denver, USA, reported:
Conventional wisdom holds that the mechanisms by which estradiol and progesterone regulate the proliferation and differentiation of uterine epithelial cells, apply equally to the breast. This is inaccurate.
Considerable evidence suggests that in the epithelium of the breast, progesterone, like estradiol, has a strong proliferative effect and physiological levels of endogenous circulating progesterone may serve to enhance breast cancer growth and that progesterone antagonists may be powerful new tools for the management of metastatic breast cancer because they block the local effects of endogenous progesterone on breast cell proliferation.” (Horwitz K, Background Paper, Antiprogestins and the Treatment of Breast Cancer, Appendix B, In Donaldson M et al, Antiprogestins: Assessing the Science and Recommending a Research Agenda, Institute of Medicine, Washington, DC, National Academies Press, 1993)


Researchers at the Cancer Research Laboratory and Department of Molecular and Cell Biology, at the University of California, Berkeley, USA reported:
“Most mammary cancers in humans originate in luminal mammary epithelial cells lining the mammary ducts and alveoli. In vivo studies show that ovarian hormones, estrogen and progesterone are essential for luminal mammary epithelial cell proliferation and also for the development of mammary cancers. Progesterone and prolactin, combined with insulin, markedly stimulated cancer cell proliferation.” (Nandi S et al, Proc Natl Acad Sci, USA, 92; 3650-3657, 1995)


Researchers in the Departments of Medicine and Pathology, Biochemistry, Biophysics and Genetics and Molecular Biology , at the University of Colorado Health Sciences Center, Denver, Colorado, USA reported:
“Progesterone is neither inherently proliferative nor anti-proliferative. Progesterone is tissue-specific capable of stimulating or inhibiting cell growth, depending on whether treatment is continuous or transient.
(Groshong S et al, Molec Endocrinol, 11(11), 1997)

Researchers with the Cancer Research Program at the Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales, Australia reported:
“Many cancers of steroid hormone target tissues, eg the breast, retain steroid responsiveness. Studies using breast cancer cells in vitro and rodent mammary tumors in vivo suggest that the antitumor activity of antiprogestins is mediated by inhibition of proliferation, but other responses, including induction of differentiation and apoptosis are also apparent after several days’ antiprogestin treatment.” (Musgrove E et al, Molecular Endocrinology 11(1), 1997)

Researchers at Westmead Institute for Cancer Research, University of Sydney, NSW, Australia, reported:
There is evidence in support of a role for progesterone in cell proliferation in the breast. Growth factors and growth factor receptors have been proposed as candidate mediators of progesterone effects on cell proliferation. Progesterone also increases insulin receptor expression in cancer cells.
Co-treatment with progesterone and insulin results in a synergistic induction cancer cell growth, suggesting that the progesterone-mediated increase in insulin receptor expression may result in greater sensitivity to the mitogenic effects of insulin. This is consistent with the ability of progesterone to potentiate insulin effects on synchronously growing breast cancer cell cultures. These effects have been postulated to have negative implications for the therapeutic use of progesterone, since growth-stimulatory effects may be seen in breast tumors that express elevated levels of insulin receptors and IGF receptors. (Dinny Graham J, Clarke C, Endocrine Rev, 18(4), 1997)

Researchers at Brown University School of Medicine and Rhode Island Hospital, Providence, USA reported:
“The second major hormone affecting the breast is progesterone. Progesterone increases mitotic activity, making cells more susceptible to random genetic errors and to the influences of carcinogens. Progesterone levels are highest during the luteal phase of the menstrual cycle. The argument for progesterone's role in breast cancer development centers on the known risk factors of early menarche and late menopause. With more total ovulatory cycles (thus, more luteal phases) in a lifetime, the odds of a random genetic error are increased.” (Mustafa I, Bland K, Ann Surg, 228(5), 1998)


Researchers from the Department of Medicine, University of Colorado Health Sciences Center, Denver, USA reported:
“During later stages of breast cancer progression, tumors frequently acquire amplification of epithelial growth factor (EGF) receptors (EGFR), which predicts a poor prognosis. Progesterone selectively increases the sensitivity of key kinase cascades to growth factors, thereby priming cells for stimulation by latent growth signals. The data supports a model in which breast cancer cell growth switches from hormone to growth factor dependence, an entirely new function for progesterone in growth signalling pathways. Progesterone can also increase the sensitivity of downstream cytoplasmic and signalling molecules to the effects of growth factors. Thus, progesterone ‘primes’ cells by up-regulating key signalling molecules, thereby sensitising cells to subsequent growth factor stimulation, which may explain the acquisition of growth factor responsiveness by breast cancer cells. Progesterone but not estrogens, androgens, or glucocorticoids, up-regulates EGFReceptor expression, causing a 2- to 3-fold increase in EGFR number and a 6-fold increase in EGF mRNA levels in human breast cancer cells.(Lange C et al, J Biol Chem, 273(47), 1998)


Researchers in the Department of Cell Biology at Baylor College of Medicine and the Department of Integrative Biology, Pharmacology and Physiology at the University of Texas–Houston Medical School reported:
“We have shown for the first time that ICI 182,780, which is generally considered to be a pure antiestrogen, also blocks transcriptional activation by progesterone and exhibits potent antiprogestin activity. Our results clearly demonstrate that this drug almost completely abolishes the effects of physiological levels of progesterone and hence represents a possible therapeutic mechanism in the treatment of breast cancer.” (Nawaz Z et al, Cancer Research 59, 372-376, 1999)

Researchers in the Department of Cell Biology at Baylor College of Medicine, Houston, Texas, reported:
“To define the functional relevance of progesterone-initiated intracellular signaling in mammary gland tumorigenesis, the progesterone receptor knockout (PRKO) compared with isogenic wild types (WT) mouse model was used in the context of an established carcinogen-induced mammary tumorigenesis system [7,12-dimethylbenz(a)anthracene (DMBA)]. The removal of progesterone receptor function resulted in a significant reduction in susceptibility to DMBA-induced mammary tumorigenesis. Our work confirmed and extended those studies that previously implicated a pivotal role for progesterone in mammary tumor development.(Lydon J et al, Cancer Research 59, 4276-4284, September 1, 1999)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
“The progesterone metabolite, 5alpha-pregnane-3,20-dione (5alphaP), is produced at higher levels in tumorous breast tissue and promotes cell proliferation and detachment. This is the first report of
receptors for the progesterone metabolites, 5alphaP and 3alphaHP, of their occurrence in breast cancer cell membranes, and of the induction of 5alphaP receptors by estradiol. The results provide further support for the importance of progesterone metabolites in breast cancer.(Weiler P, Wiebe J, Biochem Biophys Res Commun, 272(3), 2000)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
“To determine whether breast cancer is attributable to progesterone metabolites, we compared the capacity of non-tumorous and tumorous breast tissue to convert progesterone and then tested the effects of these metabolites on breast cell proliferation and anchorage in tissues from the operated breasts of six patients with infiltrating duct carcinomas.
The results show that tumorous breast tissue has elevated 5alpha-reductase activity, which results in significantly higher total levels of 5alpha-pregnanes, especially 5alpha-pregnane-3,20-dione (5alphaP). The results suggest that a change in in situ progesterone metabolism, resulting in an increased 5alpha-pregnane:4-pregnene (especially 5alphaP:3alphaHP) ratio, may promote breast cancer by promoting increased cell proliferation and detachment. Progesterone metabolites may provide a new hormonal basis for breast cancer.(Wiebe J et al, J Cancer Res, 60; 963-943, 2000)

Researchers at the Center for Public Health, University of New South Wales, the Department of Anatomical Pathology, St Vincents Hospital, and the Division of Virology, Prince of Wales Hospital, Australia, reported:
“In vitro studies of human breast cancer in cell lines have shown that administration of oestrogen followed by progesterone stimulates the expression of human endogenous retroviruses in the genome.”
(Lawson J et al, Breast Cancer Res, 3:81–85, 2001)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
Tumorous human breast tissue readily converts progesterone to 5a-pregnane-3,20-dione (5aP), which metabolite has been shown to stimulate proliferation and decrease adhesion of MCF-7 breast cancer cells. Our study suggests that decreases in adhesion and increases in cell proliferation following 5aP treatment may be owing to depolymerization of actin and decreased expression of actin and vinculin. We conclude that the progesterone metabolite 5aP may be involved in promoting breast neoplasia and metastasis by affecting adhesion and cytoskeletal molecules.”
(Wiebe J, Muzia D, Endocrine, 16(1), 2001)

Researchers at the Institute of Public Health, Jagiellonian University, Poland and the Institute of Community Medicine, Norwegian Cancer Society, Faculty of Medicine, University of Tromso, Norway reported:
We documented a strong, positive relation between mean progesterone concentrations in premenopausal women from five populations and risk of breast cancer. There are data supporting an oestrogen plus progestogens relation with breast cancer risk. Epithelial cells of the breast have the highest mitotic activity in the luteal phase of the menstrual cycle when progesterone production peaks. The use of oestrogen plus progesterone increases risk of breast cancer to a greater extent than does oestrogen alone. The reduction in breast cancer risk observed among obese premenopausal women and among women with polycystic ovary syndrome is most likely a result of frequent anovulatory menstrual cycles and impaired progesterone production. Thus, a causal link between progesterone and breast cancer risk is biologically plausible.” (Jasienska G, Thune I, BMJ, 323:1002, 2001)

Researchers at the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, reported:
"Epidemiological studies have shown that early onset of menarche, delayed entry into menopause, cycle periodicity, nulliparity, and a late first pregnancy represent individual risk factors for breast cancer. However, early menopause and early first parity decrease this risk. Progesterone's presence or absence directly influences the establishment of each of these reproductive endocrine states, implicating a stochastic multistep progression in the development of this disease, which achieves its highest rate during the reproductive years of premenopause. By providing a temporal window of opportunity for the progressive acquisition of genetic errors. As a result of these errors, the transformed mammary epithelial cell is predicted to undergo unchecked clonal expansion to a mammary neoplasm. Prolonged progesterone exposure, either through uninterrupted cyclical ovarian activity or by postmenopausal supplementation, has been linked to increased breast cancer risk." (Soyal S et al, Breast Cancer Res, 4(5), 2002)

Researchers at the Institute of Biological and Experimental Medicine in Buenos Aires, Argentina reported:
“Progesterone and estradiol, and their nuclear receptors, play essential roles in the physiology of the reproductive tract and the mammary gland. The classic view (namely, estrogens = proliferation and progestins = differentiation) has been extrapolated to systems other than the endometrium, such as the mammary gland, and has contributed to a long-held belief that estrogens are the main steroid hormones implicated in the induction of breast cancer. However, this concept has been challenged by growing experimental evidence and clinical data, which points towards progesterone and its related signalling pathways as important players in the induction, progression and maintenance of the neoplastic phenotype in the mammary gland. Estrogens have traditionally been considered associated with an increased risk of breast cancer. However, there is now compelling evidence that progesterone plays an important role in breast cell proliferation and cancer.(Lanari C, Molinolo A, Breast Cancer Res, 4(6), 2002)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, Canada, using natural/bio-identical 14C Progesterone (acquired from Perkin Elmer Life Sciences, Ontario) specifically reported as follows: In hormone-related cancers (breast, prostate, endometrium, testis, ovary, thyroid and osteosarcoma), both endogenous and exogenous hormones
provide the stimulus along the cancer progression pathway. (Henderson B, Feigelson H, Hormonal carcinogenesis, Carcinogenesis, 21:427–433, 2000). Human tumorous breast tissue metabolises progesterone. Our studies suggest that during the breast cancer progression pathway, change in progesterone metabolizing enzyme expression, and hence enzyme activity profile, occur in affected breast tissues. Our studies on breast cell lines further suggest a link between tumorigenicity and increased 5a-reductase activity. Specifically, 5a-reduced metabolites (5a-pregnanes, shown to stimulate cell proliferation and detachment) are produced at a significantly higher rate. The resulting increases in tumor and metastasis promoting and concomitant decreases in inhibitory progesterone metabolites may provide the stimulus for progression and malignancy of breast tumors.” (Wiebe J, Lewis M, BMC Cancer, 3:9, 2003)

Researchers in the Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, at the National Cancer Institute, Rockville, Maryland, USA reported:
“Many hormones, in particular estrogen and progesterone, affect breast tissue and breast cancer risk may reflect the integrated effects of these exposures over time.”
(Althuis M et al, Cancer Epidemiol Biomarkers Prev, 13; 1558-1568, 2004)

Researchers led by Professor P Crosignani at the University of Milan, Italy, reported:
Experimental animal data and analytic human epidemiological studies indicate that estrogen and/or progesterone promote some types of mammary tumours. Both accelerate the rate of breast epithelial cell division, thereby increasing the risk of critical mutational changes. Increasing cell synthesis also may enhance the survival of genetically damaged cells, leading to promotion of breast cancer. Both hormones may have an influence at any time during the 15–19 years from mutation to clinical diagnosis of breast cancer
(Cutuli B et al, Radiother Oncol, 59, 247–255, 2001).” (European Society of Human Reproduction and Embryology Capri Workshop Group, Human Reproduction Update 10(4), 2004)


Researchers at the David and Alice Jurist Institute for Biomedical Research and the University of Medicine and Dentistry of New Jersey, Hackensack, New Jersey, USA:
Although hormones produced in the body are normally beneficial, these can in some circumstances act as carcinogens or carcinogen facilitators. In some such cases increased amounts or changes in the formation of its metabolites might be responsible. In other cases the timing of hormone release plays a critical role. In some cases the hormone acts independently, while in others two or more compounds act in concert to promote cancer. Of the various hormones produced in the body, only aldosterone does not cause cancer! (Bradlow H, Sepkovic D, N.Y. Acad Sci, 1028:216-232, 2004)


Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
The aim of this study was to determine if the differences in enzyme activities between tumorous and non-tumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression. Semi-quantitative RT-PCR was used to compare relative expression in paired

(tumorous and non-tumorous) breast tissues from 11 patients. Expression of 5alphaR1 and 5alphaR2 was higher in the tumor as compared to normal tissues. The mean tumor to normal expression ratios was 35-85-fold higher in tumor than in normal tissue. Changes in progesterone metabolizing enzyme expression levels help to explain the increases in mitogen/metastasis inducing 5alphaP progesterone metabolites found in breast tumor tissues.” (Lewis M et al, BMC Cancer, 4: 27, 2004)

Researchers in the Departments of Medicine, Surgery, Obstetrics and Gynaecology, and Preventive Medicine, at the Keck School of Medicine, University of Southern California, and the Department of Pathology, Olive View-UCLA Medical Center, University of California, Los Angeles, reported:
Progesterone plays an essential role in breast development and in breast cancer formation. The loss of catabolic enzymes in breast cancer leads to increased progesterone levels, which, in combination with increased progesterone receptors, could enhance progesterone-responsive gene expression and thus metabolites of progesterone may have unsuspected effects on cell growth. Transient or sequential administration of progesterone causes cells to enter a mitotic cycle with induction of genes associated with cell growth. The majority of studies in animals and humans find that estrogen alone does not promote cellular proliferation, whereas estrogen plus progesterone does promotes proliferation of cancer.(Ji Q et al, Cancer Res, 64, 7610-7617, 2004)

Researchers in the Department of Biomedical Sciences, University of Missouri, Columbia, and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA reported:
“Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that promotes growth, expansion, and metastasis of breast cancer. Proliferation of many breast cancer cells is under control of the estrogen and progesterone. Two progesterone receptor isoforms, PRA and PRB are expressed in most human breast cancer cells. PRB predominantly regulates expression of VEGF in breast tumor cells and PRB-enriched tumors express a higher level of VEGF and give tumors a significant growth advantage if stimulated by hormone. Both estrogen and natural progesterone and synthetic progestin stimulates PRB-dependent VEGF expression and a consequence is greater tumor expansion.(Wu J et al, Cancer Res, 64(6), 2004)

Researchers in the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, reported:
“Progesterone receptors are expressed exclusively in the mammary epithelium. Progesterone receptor-expressing cells are segregated from proliferating cells in normal mammary glands and the proliferative responses of the ductal and alveolar epithelium to progesterone are associated with local induction of PR-dependent growth factors that act in a paracrine manner on PR-negative cells to control their proliferation. Segregation of the steroid receptor expressing cells from proliferating cells is lost in mammary epithelial cells that have been exposed to carcinogen and in cells of breast tumors and this aberrant change in pattern of receptor expression contributes to abnormal growth of breast cancer cells.(Mulac-Jericevic B, Conneely M, Reproduction. 128: 139-146, 2004)

Researchers at the Department of Biomedical Sciences, University of Missouri, Columbia, USA reported:
“The proliferation of breast cancer cells is controlled by estrogens and progesterone. We evaluated the pathways involved in regulating vascular endothelial growth factor (VEGF) in response to progesterone and synthetic progestins in breast cancer cells. Angiogenesis, the formation of new blood vessels, is essential for tumor growth, expansion, and metastasis. VEGF is one of the most potent angiogenic growth factors and influences permeability, survival and proliferation of endothelial cells. Hypoxia, oncogenes, pH, and steroid hormones are stimuli known to induce VEGF expression in tumor cells. Breast cancer cells metabolise progesterone and synthetic progestins to compounds that may trigger a growth response and increase VEGF production. The synthetic progestins are less easily metabolised than the natural compound. Our findings show that both natural and synthetic progestins induce VEGF expression and secretion and facilitate increased angiogenesis, cellular proliferation, tumor growth and increased risk of breast cancer. (Wu J et al, Molec Endocrinol, 19(2), 2004)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
The promotion of breast cancer appears to be related to changes in the in situ concentrations of cancer-inhibiting and cancer-promoting progesterone metabolites.(Wiebe J et al, Steroid Biochem Molec Biol, 93(2-5), 2005)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
Our results show distribution of 5alphaP-R in several cell types and provides further evidence of the significance of progesterone metabolites and their novel membrane-associated receptors in breast cancer stimulation.” (Palwak K et al, J Steroid Biochem Mol Biol, 97(3), 2005)

Researchers at the Institute of Biological and Experimental Medicine in Buenos Aires, Argentina and the US National Institutes of Health, Bethesda, Maryland USA reported:
“During the past few years the progesterone receptor (PR) pathway has emerged as a likely player in the pathogenesis of breast cancer, with growing experimental as well as clinical evidence pointing to its protagonistic role. Most of the epidemiological evidence for mammary carcinogens reflects prolonged exposure to female hormones, including progesterone. Our findings provide the first evidence that blockade of PRs using antisense oligonucleotides induces inhibition of tumor growth and provide further evidence for a critical involvement of the stimulatory effects of the PR pathway in mammary cancer.
(Lamb C et al, Breast Cancer Res, 7(6), 2005)

Researchers in the Department of Medicine, Division of Hematology, Oncology, and Transplantation at the University of Minnesota Cancer Center, Minneapolis, USA reported:
Ovarian steroid hormones such as estrogen and progesterone are critical for mammary gland development and are implicated in the development and progression of breast cancer. In vitro, both estrogen and progesterone cause proliferation of cell lines derived from human breast tumors, implicating progesterone in disease etiology. In this report, we show that the growth-promoting effects of progestins are due to progesterone receptor’s function as an activator of cytoplasmic kinase cascades rather than its direct activation of transcription. Co-treatment with peptide growth factors, an accurate reflection of the in vivo environment of breast cells, can change cells’ response to progesterone receptor ligands, making progesterone and progestins highly proliferative agent.(Skildum A et al, Molec Endocrinol, 19(2), 2005)

Researchers in the Departments of Surgery, of Obstetrics and Gynaecology and of Physiology, at the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA, reported:
“The normal non-lactating breast is subject to cyclical changes in response to ovarian stimulation with either estrogen alone during anovulatory cycles, or estrogen plus progesterone during ovulatory cycles. These hormones increase breast epithelial cell proliferation, with progesterone having a synergistic/additive effect during ovulatory cycles. The withdrawal of hormones with the onset of a new ovarian cycle causes a wave of apoptosis, eliminating defective cells and maintaining the population balance of the epithelium. Continuous proliferation, however, leads to an accumulation of genetic defects, with the eventual emergence of a transformed cell, leading to the clonal evolution of malignancy. Therefore, factors that increase availability of hormones, augment the proliferative response of the epithelium to hormonal stimulation, or interfere with apoptotic elimination of defective cells, will increase breast cancer risk.
(Khan S et al, Endocrine-Related Cancer, 12(3), 2005)

A researcher at Baylor College of Medicine, Houston, Texas, USA reported:

“Breast cancer is a major cancer of women, with approximately 210 000 new cases annually in the United States and accounting for approximately 32% of new cancers diagnosed in US women. The death of 40 000 women due to invasive breast cancer remains a sobering fact and indicates the need to understand this disease in greater depth. The logic and rationale for understanding the molecular basis for hormone-mediated breast cancer are based on the consistent observations in human epidemiological studies and the strong confirmatory experiments in rodent breast cancer models. Reproductive history is the strongest and most consistent risk factor outside of genetic background and age.”

“Early menarche, late menopause, parity, and late age of first pregnancy are each independent risk factors. Early age of menarche translates into earlier hormone exposure to estrogen and progesterone and to breast epithelial cell growth. The ovarian hormones, estrogen and progesterone, play a pivotal, paradoxical role in normal and neoplastic development of the mammary gland. Long duration of estrogen and progesterone are associated with increased breast cancer risk, while short duration of pregnancy level doses are associated with reduced breast cancer risk. These hormones induce alterations in gene expression in the mammary epithelial cells, which persist for a long time after the hormones are withdrawn from the host.(Medina D, Endocrine-Related Cancer, 12 (3), 2005)



Researchers at Westmead Institute for Cancer Research, University of Sydney, NSW, Australia, reported:

The ovarian hormone progesterone is essential for normal breast development and function, but is also implicated in breast cancer development. Progesterone signals through two nuclear receptors (PRA and PRB). The balanced expression of progesterone receptors in normal human tissues is often disrupted in breast cancer, resulting in a predominance of one form (most often PRA) over low expression of the other. Disrupted expression of progesterone receptors also occurs in normal breast of women with a high risk of breast due to germline mutations, which commonly lack PRB expression, resulting in PRA predominance. This suggests that altered PR signaling may occur in these tissues. Although relative expression is commonly disrupted to result in PRA predominance, both receptor isoforms are generally detected in most breast cancers and transcriptional and clinical studies suggest that the PRA to PRB ratio is likely to be as important a determinant of progestin response as total progesterone receptor level.”

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)


Researchers at the Department of Biomedical Sciences, University of Missouri, Columbia, USA reported:

“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 in the Department of Physiology at Michigan State University, USA, reported:
Progesterone regulates proliferation and differentiation in the normal mammary gland in mouse, rat and human, but has also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is on the role of the progesterone receptor and functional significance of PR isoforms in human mammary cancer.” (Aupperlee M et al, Breast Dis, 24:37-57, 2005-2006)

Jennifer Eng-Wong, a medical oncologist with the National Cancer Institute’s Center for Cancer Research, believes that: “the data indicates that progesterone may fuel breast cancer growth". (National Cancer Institute, US National Institutes of Health, Posted 03/13/2006)

Researchers at the Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario, reported:
Progesterone metabolites such as 5alpha-dihydroprogesterone promote both mitogenic and metastatic activity in breast cells.
(Weibe J et al, J Steroid Biochem Molec Biol, 100(4-5), 2006)

Researchers with the Jones Institute for Reproductive Medicine at the Eastern Virginia Medical School, Norfolk, Virginia, USA reported:
“We determined the effect of 17beta-estradiol, progesterone and the progestin, medroxyprogesterone acetate (MPA) on vascular endothelial growth factor (VEGF). The oestrogen, 17beta-estradiol had no effect. Progesterone (natural) and MPA (synthetic progestin) both individually increased vascular endothelial growth factor in breast cancer cells and these differential effects may be related to breast cancer growth.” (Mirkin S et al, Intl J Gynecol Cancer, 16 (Suppl 2):560-3, 2006)


Researchers at the Department of Biomedical Sciences, University of Missouri, Columbia, USA reported:
Purpose: Synthetic progestins are widely used therapeutically; however, there is controversy regarding their proliferative effects. We used a rat 7,12-dimethylbenz[a]anthracene (DMBA)–induced mammary tumor model to test the hypothesis that progestins increase angiogenesis and increase the multiplicity of tumors.
Results: Medroxyprogesterone acetate (MPA) exposure 4 weeks after DMBA reduced the latency period for appearance of tumors in a dose-dependent manner and increased tumor incidence, whereas administration of progesterone did not reduce the latency period but significantly increased tumor incidence. Administration of RU-486, an anti-angiogenic agent delayed the latency period and decreased tumor incidence, indicating that the progesterone receptor may be partially responsible for proliferative signals. Conclusions: We propose that progestins (synthetic or natural progesterone) can accelerate the development of mammary tumors and that anti-angiogenic agents and/or the use of anti-progestins that can reduce tumor incidence might be a viable therapeutic option for treatment of progestin-accelerated tumors.” (Benakanakere I et al, Clin Cancer Res, 12; 4062-4071, 2006)



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{alpha}-dihydroprogesterone (5{alpha}P) and 3{alpha}-dihydroprogesterone (3{alpha}HP) 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

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{alpha}-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{alpha}-reductase, to the final irreversibly reduced metabolite 5{alpha}-pregnane-3,20-dione (5{alpha}P). Conversion to 5{alpha}-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{alpha}-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{alpha}-reductase stimulation and 3{alpha}-hydroxysteroid oxidoreductase (3{alpha}-HSO) and 20{alpha}-hydroxysteroid dehydrogenase (20{alpha}-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{alpha}-HSO expression in corpora lutea (Schroeder M et al, Molec Endocrinol, 16; 45–57, 2002). The expression of 5{alpha}-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{alpha}-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{alpha}-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{alpha}-pregnanes and stimulation of cell proliferation with 5{alpha}P 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{alpha}-dihydroprogesterone (5{alpha}P) 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 5{alpha}P 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 (3{alpha}HP) 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 5{alpha}P 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 5{alpha}P and 3{alpha}HP on both cell anchorage and proliferation strengthen the hypothesis that the direction of progesterone metabolism in vivo toward higher 5{alpha}-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{alpha}-pregnane to 4-pregnene ratio requires studies in which 5{alpha}-reductase activity is blocked and also where 5{alpha}-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{alpha}-pregnanes by >95% and increased 4-pregnene production. We also demonstrated that treatment of cells with progesterone alone resulted in significant conversion to 5{alpha}-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 5{alpha}P. The results are seen as providing proof of the principle that the effects on proliferation and adhesion were due to the 5{alpha}-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 5{alpha}P 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 5{alpha}P 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 5{alpha}P resulted in significant dose-dependent increases in 5{alpha}progesterone 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 5{alpha}PR due to estradiol or 5{alpha}P correlated with increases in cell proliferation and detachment, indicating the functional relevance of alterations in 5{alpha}PR concentrations. Together, the receptor results suggest that the putative tumorigenic actions of 5{alpha} P may be significantly augmented by the estradiol-induced increases in 5{alpha}progesterone 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 5{alpha}P, 3{alpha}HP, 20{alpha}HP, and estradiol and combinations of these steroids, and ER concentrations were determined in cytosolic and nuclear fractions. Estradiol and 5{alpha}P resulted in significant dose-dependent increases in total estrogen receptors.  In combination, estradiol + 5{alpha}P resulted in additive increases estrogen receptor numbers in breast cancer cells. The implications for breast cancer are that the stimulatory effects of 5{alpha}P 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, 5{alpha}P, on cell signalling pathways

“The location of the receptors for 5{alpha}P and 3{alpha}HP 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 5{alpha}P for as briefly as 5 min resulted in significant, dose-dependent increases in activated MAPK. The data suggest that the action of 5{alpha}P on breast cancer cells involves modulation of the MAPK signalling pathway. Whether other cell signalling pathways are involved or 5{alpha}P and 3{alpha}HP 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:”

Figure 8

Summary of actions and action pathways of the progesterone metabolites 5{alpha}P and 3{alpha}HP 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, 5{alpha}P and 3{alpha}HP act via cell signaling, and potentially indirectly via genomic, pathways to effect independent and opposite changes resulting in increases ({uparrow}) or decreases ({downarrow}) in cell proliferation, apoptosis and adhesion. Maintenance of normalcy depends on higher levels of 3{alpha}HP, and progression to neoplasia and metastasis are promoted by increased levels of 5{alpha}P.

“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 5{alpha}P (40 mg depot). Tumor growth rate was about the same (or slightly higher) with 5{alpha}P 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)


Further evidence of the carcinogenicity of progesterone and its metabolites (without the progesterone there are no metabolites) will be presented in due course, both retrospective and also as the data is generated. There is still time for those promoting natural/bio-identical progesterone to withdraw their endorsements without becoming knowing accomplices to the massive silent genocide underway.


Stuart Thomson


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