How Progesterone Protects Against Breast Cancer

from "Hormones Without Fear" by Ivy Greenwell

1. in breast tissue, the presence of estradiol induces a 10-20 times increase in progesterone receptors
2. progesterone induces the enzyme estradiol-dehydrogenase, which converts estradiol to estrone (estradiol is 12 times more potent than estrone)
3. progesterone also induces the enzyme estrone-sulfur-transferase, which conjugates (sulfates) estrone to estrone sulfate, an essentially inactive storage form. This happens with about an 8-day delay by comparison with the endometrium, leading some scientists to theorize that at first progesterone synergizes with estradiol in increasing cell division, but if the exposure to progesterone continues, progesterone acts in several ways to decrease proliferation
4. progesterone induces the maturation of glandular breast tissue (it's undifferentiated tissue that's much more susceptible to cancer)
5. progesterone downregulates (suppresses) estrogen receptors in breast tissue
6. it reduces the production of certain growth factors such as the enzyme Cathepsin D; the lower the levels of Cathepsin D and other growth factors, the better the prognosis
7. it increases the apoptosis of breast cells, meaning a kind of programmed cell death - cells appear to be committing suicide; thus the excess cells in the milk ducts die and are absorbed by the body, restoring a baseline epithelium (this is comparable to the shedding of the endometrium, though fortunately not as messy)
8. it lowers the levels of prolactin, a known breast cancer risk (possibly by increasing dopamine, which in turn suppresses prolactin release; testosterone also increases dopamine release)
9. the well-known tranquilizing, anti-anxiety action of progesterone serves to lower stress, and thus protects against the stress-induced immune suppression
10. progesterone enhances the action of the thyroid and protects the thymus, thus indirectly enhancing immunity
11. melatonin and progesterone may be synergists; some believe that higher levels of melatonin help women produce more progesterone (when pregnancy begins, the levels of melatonin triple)

Even this is not yet full picture, and one could still discuss proto-oncogenes, epidemiological studies, and various animal and clinical studies. However, just on the basis of its physiological action the evidence is pretty overwhelming that progesterone does indeed protect against breast cancer. Usually one sees this statement: "protects against endometrial cancer" and the more tentative "helps protect against breast cancer."

Progesterone is not the only factor - DHEA levels also appear to be very important, as well as keeping insulin low and thyroid sufficiently high, losing weight if obese, exercising, taking antioxidants and fish oil, eating lots of vegetables etc. Nevertheless, it seems that progesterone is a very special "guardian angel" hormone custom-designed by evolution to keep women free from endometrial and breast cancer.

To echo Dr. Lee, it's staggering to consider how many women suffer and even die needlessly when probably in many (most?) cases progesterone supplementation at the first signs of progesterone deficiency would likely prevent both benign and malignant breast disease. (Think also of all the hysterectomies that would be prevented, since progesterone normalizes the endometrium and prevents hyperplasia.)

Breast cancer is the most common cause of death in women between the ages of 35 and 55.

Cancer has been called a disease of aging. Eighty percent of breast cancer occurs after the age of fifty. The average age at diagnosis is 62. Highest incidence is seen in the 75-79 age bracket. The older the woman, the greater the probability that the cancer is not hormone-dependent, and therefore harder to treat. On the other hand, some types of breast cancer are so non-aggressive that the woman may live with the tumor or tumors for many years (generally undiagnosed except at autopsy) and end up dying of something else. The same holds even more true for prostate cancer. Only melatonin appears to protect against both hormone-dependent and hormone-independent breast cancer.

Main source: Wren BG. Hormonal replacement therapy and breast cancer. European Menopause Journal 1995; 2:13-19.

Does Progesterone Inhibit Proliferation?

Chang (1995) flatly states: "Activation of progesterone receptors has been excluded as the growth stimulatory mechanism" for breast cancer cells. There is a type of breast tissue that appears to be briefly stimulated by progesterone in the early luteal phase, and that's the alveolar (milk gland) cells, which progesterone differentiates for their function in lactation.

With sustained (10 days or more) exposure to P, however, Chang found that "increased progesterone concentration significantly decreases the number of cycling epithelial cells."

Chang was familiar with in-vitro studies which show that progesterone decreases the division rate of both normal breast cells and most breast-cancer cells. But in-vitro studies have to be followed up with in-vivo studies in humans to provide more solid evidence. Chang and his co-workers used as subjects 40 premenopausal women, between 18 and 45, who were scheduled for lumpectomy between the 11th and 13th day of their cycle.

The women were randomly assigned to placebo, progesterone gel, estradiol gel, and progesterone plus estradiol gel groups. The gel was applied to the breast scheduled for surgery starting on the first day of the menstrual cycle. The progesterone gel contained 25mg of P, the estradiol gel 1.5mg of estradiol, and the combined gel 1.5mg of estradiol and 25 mg of P. Tissue samples were taken at the time of the surgery to determine the amount of proliferative activity.

In the group using the gel which contained both estradiol and progesterone, the rate of cell division was the same as in the placebo group -- apparently P prevented the increase in cell division that was seen in the estradiol group. In the estradiol group, the proliferation rate (Mitosis Index) was .83; in the progesterone group, it was .17 (mitosis per 1000 cells). In the E2 + P group, it was .52; in the placebo group, .51.

Excessive proliferation, or benign hyperplasia, can be the first stage in the formation of breast cancer.

Continuous versus cyclic hormone replacement

Question: Is prolonged exposure to menstrual cycling good for a woman?

Should her breast and endometrial tissue be stimulated into proliferation on a monthly basis, particularly at an older age? Since the prevailing view is that the more menstrual cycles a woman has in her lifetime, the higher her risk of breast cancer, how come most mainstream doctors insist on the cyclic regimen, in spite of the women's express wish for being done with periods? Women must learn that the continuous regimen is not only more convenient, but also safer, and must insist on it -- just as they must insist on natural progesterone rather than progestins.

More evidence of inhibitory action of progesterone

In a study with athymic mice (mice without a thymus), Laidlaw and Clarke (1995) transplanted human breast tissue subcutaneously, then brought serum levels of estradiol and progesterone to those seen in premenopausal women. Progesterone did not induce proliferation, alone or after estradiol priming.

It would be wonderful to have research exploring the anti-proliferative effect of progesterone, demonstrated so dramatically in Chang's study, in terms of dose or serum levels. On the basis of long-term survival data, a group of British surgeons suggested that P level of 4ng should be the minimum for doing premenopausal breast surgery (Mohr 1996).

One study (Cowan 1981) found that women with progesterone deficiency had 5.4 times the risk of premenopausal breast cancer, while a Mayo Clinic study showed that women with a history of progesterone deficiency as evidenced by symptoms such as irregular periods had 3.6 times the risk of postmenopausal cancer.

References:

Chang KJ et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cycle in vivo. Fertility and Sterility 1995; 63: 785-91.

Cowan LD et al. Breast cancer incidence in women with a history of progesterone deficiency. American Journal of Epidemiology 1981; 114: 209-17.

Laidlaw IJ, Clarke RB. The proliferation of normal cell tissue implanted into athymic nude mice is stimulated by estrogen, but not by progesterone. Endocrinology 1995; 136: 164-71.

Mohr PE et al. Serum progesterone and prognosis in operable breast cancer. British Journal of Cancer 1996; 73:1552-5.

Related References:

Carter CL et al. A prospective study of the development of breast cancer in 16,692 women with benign breast disease. American Journal of Epidemiology 1988; 128:467-71.

Iino Y et al. Oral high-dose medroxyprogesterone acetate treatment for recurrent breast cancer. Anticancer Res 1995; 15:1061-4.

Inano H et al. Estradiol as an initiation modifier for radiation-induced mammary tumorigenesis of rats ovariectomized before puberty. Carcinogenesis 1995; 16:1871-7. [Combined estradiol-progesterone treatment resulted in lower incidence of tumors compared to treatment with estradiol alone.]

Mauvais-Jarvis P et al. Anti-estrogen action of progesterone in breast tissue. Hormone Research 1987; 28: 212-8.

Preston-Martin M et al. Increased cell division as a cause of human cancer. Cancer Research 1990; 50:7415-21.

Wren BG. Hormonal replacement therapy and breast cancer. European Journal of Menopause 1995; 2:13-19.

Zumoff B. Review: biological and endocrinological insights into the possible breast cancer risks in menopausal estrogen replacement therapy. Steroids 1993; 58: 196-204.

Published with permission of the author, July 2002

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