Does progesterone cream cause cancer?

A response to ‘cancer in a cream’ By Dr Ellen Grant, published in What Doctors Don’t Tell You,
May 2006.

What is wrong with this article? Initially, it must be said that Dr. Grant spends the first half of the article unsuccessfully attempting to show that the synthetic progestogens (called progestins in the US) work identically in the body to natural progesterone - without a shred of real scientific evidence to substantiate this. She then spends the second half of the article successfully showing how dangerous the synthetic progestogens/progestins are. But this proves nothing about progesterone.

In the first place, Dr Grant attempts to confuse the reader by implying that so-called ‘natural’ progesterone is not natural, because it is produced by a laboratory process. But the natural progesterone used in creams and other forms of treatment is called ‘natural’, not because it comes from natural plant sources, which it does, but because it is in fact ‘nature-identical’; that is, it is identical (not approximate as Dr Grant Claims) to the natural progesterone produced in the body.

It is in fact progestogens that only approximate to the natural body progesterone. Chemically, if you change part of a molecule as complex as progesterone, even by small variations, the character and action of the synthetic end product will differ compared to the original. Chemists rely upon this to be able to control the action of the new material. For instance, natural progesterone can never procure an abortion. It is specifically inherent in its role that this is inimical to its natural function, and yet some of the progestogens have been engineered to have that specific action. There are many other such examples of the differences between progestogens and natural progesterone. In fact, only natural progesterone has the functions it has. All the progestogens have different variations of function.

Dr Grant then makes some astonishing statements:

1   That even a woman’s own “endogenous progesterone is potentially dangerous”. She gives no evidence for this and, indeed, it would be a very unusual event for nature to produce such a dangerous substance in the body, especially when progesterone rises to such high levels in the third trimester of pregnancy, thereby exposing the next generation (the foetus) to high levels of this ‘dangerous’ chemical!

2   That progesterone  “is highly immunosuppressive”. In fact, this immunosuppressive aspect is almost entirely confined to its action on the uterus and is poorly reflected in its action in the rest of the body.

3   That it “ is potentially carcinogenic”. Unsurprisingly, this statement is not accompanied by any acceptable evidence.

Dr Grant does refer to previous medical practice in which the ovaries were removed in cases of breast cancer, and implies that this was done to eliminate progesterone.  But, in fact, the prime reason for this was to remove the major source of oestrogen, the hormone that does increase cell proliferation. Later evidence has shown that, under the influence of higher progesterone levels in the second half of the menstrual cycle, removal of breast cancer has a much better prognosis, indicating quite the opposite to Dr Grant’s assertion that progesterone increases the risk of recurring breast cancer.  (Br.J.Cancer,1996;73:1552-5, Serum progesterone and the prognosis in operable breast cancer, Mohr PE, Wang DY, Gregory WM, Richards MA and Fentiman IS).

Dr Grant then claims that “New research using breast cancer cell-lines has discovered that progesterone causes breast cancer to spread rapidly and metastasize”. Firstly, the study to which she refers (J.Clin.Endocrinol.Metab.2005;90:1181-8) was performed in very artificial circumstances on isolated, established cancer-cell lines (in vitro) in a laboratory . But this in no way demonstrates that the same results will be reproduced within the far more complex set of interactions within the human body. (There is also some doubt whether the trial used progesterone or a progestogen as both were supplied for the trial but the supplier (Sigma-Aldrich of Missouri) is not able to certify which was used in the trial.)

In fact the statement that progesterone causes rapid growth and metastases within the body is simply untrue. This was elegantly demonstrated by researchers in a French in vivo study (Chang et al; Fertil.Steril.Vol.63,No.4,April 1995, 785-791). Women who were about to undergo surgery for removal of a breast ‘lump’ applied a gel to their breast containing either oestrogen (oestrodiol), progesterone or a combination during the 10 to 13 days prior to surgery. The results showed that it was oestrogen that increased proliferation of breast epithelial cells, and that progesterone actually reduced the proliferation of cells that had been provoked by oestrogen.

Other more recent investigations have shown that progesterone increases the expression of p53, a protein that encourages cell death in cancer cells by suppressing Bcl-2, a tumour promoting protein also produced by the genes.

Am.J.Pathol. Vol.144 No.6,June 1994, 1195-1202,Bcl-2 Expression in Normal Endometrium during the Menstrual Cycle, Gompel A,Sabourin JC,Martin A,Yaneva H,Andouin J,Decroix Y and Poitout.

Cancer , May 15,1997, Vol.79, No.10, 1944-50, Shi-Zhong Bu, De-Ling Yin, Xiu-Hai Ren, Li-Zhan Jiang, Zhi-Jiang Wu, Qi-Rong Gao and Gang Pei, Progesterone induces apoptosis and Up-Regulation of p53 Expression in Human Ovarian Carcinoma Cell-Lines.

Cancer Research 54, April 15, 1994, 2095-7, Down-regulation of Bcl-2 by p53 in Breast Cancer Cells, Subrata Haldar, Massimo Negrini, Maria Monne, Silvia sabbioni and Carlo M. Croce + J.Natl.Cancer Inst. 1997,Progesterone Inhibits Growth and Induces Apoptosis in breast Cancer Cells: Inversely Affecting the Expression of p53 and Bcl-2, Formby B and Wiley TS)

Dr Grant believes that “natural progesterone and synthetic progestogens both have similar actions in the body”. But this has not been demonstrated by any of the papers she has quoted nor has it been demonstrated by any of the authors and that this is an erroneous conclusion drawn by Dr. Grant, herself. The following paper shows that progesterone had no adverse effect on high density lipoproteins or their subfractions but progestogens had.). (J.Obstet.Gynecol., March 15,1985, Vol.151, No.6, 746-50, Subfractions of High Density Lipoprotein Cholesterol During Estrogen Replacement Therapy: A Comparison Between Progestogens and Natural Progesterone,  Ottosson UB, Johansson BG and von Schulz B.

She believes that she has shown that she has destroyed the evidence base upon which Dr. Lee based his theories. I am afraid she has shown no such thing and has failed abysmally to show any acceptable scientific evidence to support her case.

Her contention that progestogens imitate the effect of progesterone in the body is only partially true. They attempt to imitate but as they are manufactured either from an oestrogen base or a testosterone base they have some residual side effects from their origins and are, therefore, not identical to natural progesterone. THE MAIN DIFFERENCE BETWEEN THE TWO IS THAT NATURAL PROGESTERONE CANNOT PROCURE AN ABORTION WHILST THE SYNTHETICS CAN AND DO. There are other differences that are very obvious such as the effect that natural progesterone has on enhancing the body response to insulin, improving the effectiveness of the thyroid hormone, having specific and beneficial effects on the Limbic System of the brain which allows separation but interaction between thought processes and emotions, the beneficial effect on bone mineral density (Acta Endocinologica 1992, 126:329-37, Progesterone and Promegestone Stimulate Human Bone Cell Proliferation and Insulin-like Growth Factor-2 production, Tremollieres FA, Strong DD, Baylink DJ and Subburaman Mohan) and the ability to be converted into the stress hormones by the adrenal glands. Progesterone and progestogens are very different beasts!

She also totally erroneously asserts that natural progesterone is just another form of

HRT. How can a medically qualified person come to such a ludicrous conclusion?

The work done by Dr. Sebastian Mirkin and colleagues (Fertil.Steril.2005;84:485-91) has been misrepresented in this article.

The statement that a “positive effect on VGEF would indicate a substance that promotes cancer” whilst there may be some truth in it, there are very specific conditions attached to it. This work was performed as a perfusion experiment that resulted in a massively inflated concentrations of progesterone, way above what would ever be encountered in the body, naturally, even under the 600-fold increase of progesterone levels that can occur  from placental production during the third trimester of pregnancy. As we have already indicated, progesterone receptor sites on cells produce very different responses within the cells to those of oestrogen receptor sites. Binding of oestrogen to oestrogen receptor sites has the effect of promoting cell growth and promoting longevity (which can be detrimental to normal cell function beyond a specific age). Progesterone binding to progesterone receptor sites produces the opposite effect, inducing return of the cell to normal status or promotion of apoptosis. Oestrogen cannot bind to progesterone receptor sites but progesterone can bind to oestrogen receptor sites (and so can phyto-oestrogens) having no direct effect upon the cell but reducing the effects of oestrogen by prevention of attachment.

The statement she makes that “natural oestrogen, 17-beta-oestradiol, had no adverse effect in any dose” must indicate a flawed procedure in the study because the natural action of 17-beta-oestradiol is to stimulate cell growth and activity.

Her statement that “MPA, along with megastrol acetate is a ‘pure’ progestogen with no other sex hormone actions” is meaningless. It is not natural progesterone and, therefore, has no relevance (Nature Medicine, Vol.3, No.3, March 1997, Medroxyprogesterone Interfers with Ovarian Steroid Protection Against Coronary Vasospasm, Koichi Miyagawa, Josef Rosch, Frank Stanczy and Kent Hermsmeyer demonstrates that MPA does not protect against cardiovascular spasm but progesterone does).

When she states that “increased angiogenesis leads to cancer” she forgets it leads to other useful events such as cell repair and regeneration – take your choice!

She also makes the true statement that “progesterone inhibits immune cell growth and increases cell death while oestrogens protect against cell death and increase antibody formation”. If followed through, logically, this would mean the opposite to her contention. It means that oestrogens stimulate growth while progesterone promotes normal cell activity and normal cell death, thus preventing cancer growth and spread.

Another erroneous statement Dr Grant makes is “sex hormones in peripheral tissues convert into high levels of carcinogenic, oestrogenic metabolites”: neither Progesterone nor Estrone do this but other oestrogens do.

Clinically, I have found that most cases of autoimmune diseases, various, respond positively to the use of progesterone. Occasionally, only, an individual will respond negatively.

The work of Dr. Anne Harmann (J.Clin.Pharmacol.2005;45:614-9) has been shown to be opposed by other work done on primates (see above reference also)

No transdermal progesterone was used during the BWM trial and therefore it is irrelevant.

Her comments about the “many studies of the Pill and HRT give some idea of the cancer risk” is just not true of progesterone but is true of progestogens (QED)

The WHI (JAMA 2002, 288; 321-33 and Lancet 2003, 362; 419-27) trial was conducted, solely, with progestogens and is therefore irrelevant.

All the remaining quoted journal articles were based on progestogen materials and are, therefore, not valid in the argument.

Her last comment that “the final irony is that progesterone can cause many of the symptoms that menopausal women are trying to alleviate” is again unsubstantiated and untrue. Vaginal dryness is caused by local vaginal oestrogen deficiency and most definitely not caused by progesterone (this can be shown by the simple expediency of performing a saliva progesterone and oestrogen test and demonstrating the low oestrogen level and relatively normal, or slightly low, progesterone levels in almost 100% of cases). It is often alleviated by progesterone applied locally and is always alleviated by local application of oestriol cream.

Vaginal Thrush is not related to the progesterone state and the risk of cervical cancer is much more associated with frequent recurrent sexual intercourse and multiple pregnancies. It is a result of repeated physical irritation.

All in all this has proved to be a very inaccurate, unscientific and incorrect article and, in my opinion, should not have been given the space in print.

Dr. D. F. Smallbone

M.B.,Ch.B.,L.R.C.P.,M.R.C.S.,M.F.Hom.,F.C.O.H.

Dr Smallbone has been in consulting practice for over 40 years and is a Fellow of the Royal society of Medicine and a member of the New York Academy of Sciences.

It is also somewhat foolhardy and unscientific to allow anyone to claim to “have the last word” and she produces no new evidence to support this.

Where Dr. Grant claims that as a consequence of excess xenoestrogens women became progesterone deficient. Dr. Lee never claimed this but merely that the situation highlighted the problem.