Women reading laptopOver the last decade, the safety of hormone replacement therapy (HRT) has been questioned in the media, in medical journals and in doctor’s offices across the country.  Unfortunately, the discussion is usually over-simplified and delivered to the public in sensationalized sound bites.  Without even getting into the scientific controversy, we can apply some rudimentary logic to the discussion.  If human hormones are the major cause of heart disease and breast cancer in women, wouldn’t you expect to see the greatest incidence when hormone levels are the highest?  For women, that would be their teens and twenties; a time when both breast cancer and heart disease are distinctly uncommon.[i]  But, when hormone levels decline at and around menopause, the incidence of both rises dramatically.  Perhaps there is more to the story than the sound bites suggest.

What are hormones anyway?  Hormones are molecular messengers that regulate your body’s energy production, temperature, growth, immune system, reproductive capabilities and brain activity. Your individual hormone balance is influenced by genetics, the environment, your lifestyle, eating habits and the function of your endocrine (hormone producing) system.  Aging is associated with declining hormones, as well as reduced quality of life and increasing risk of chronic diseases.

Over the years there have been studies both advocating hormone use and warning against it.  The Cancer Prevention Study II (a large prospective cohort of 422,373 postmenopausal women) by the American Cancer Society revealed a 16% reduction in the relative risk of death from breast cancer in women who had ever used estrogen replacement therapy.[ii]  Later, results of the Women’s Health Initiative, a large, randomized study of 16,000 women published in 2002, suggested that the risks of HRT outweighed the benefits.  Subsequent analyses criticized its flawed design and questioned many of its conclusions.  But scores of women were frightened away from HRT and in the ensuing years, breast cancer rates dropped.  Just last month, a Canadian study[iii] attributed the drop in breast cancer rates to the decline in HRT use.  Recently, another new study stated that women were at increased risk of death from breast cancer when taking a combination of estrogen and progestin.[iv] What needs to be highlighted is the fact that these studies evaluated the effects of synthetic hormones on women’s health.

Estrogen and progesterone are the predominant sex hormones in women.  In humans, there are actually three different estrogens (estradiol, estrone and estriol).  Although typically lumped together and collectively referred to as generic “estrogen”, the differences among these related compounds are critical to understanding their individual physiologic effects in women.

Estradiol is the most abundant and powerful estrogen, produced mainly in the ovaries of pre-menopausal women. Estriol is the weakest estrogen manufactured primarily during pregnancy.  Some studies suggest it has a protective effect against breast cancer.  Estrone is the predominant estrogen in post-menopausal women.  It is made mostly in fat cells of the body by converting testosterone derivatives.  Excess body fat is a risk factor for breast cancer development, and overweight post-menopausal women have higher circulating levels of estrone. Some animal studies have linked the increase in estrone production after menopause with an increase in breast tumors.   

Progesterone supports pregnancy, and in the absence of a pregnancy initiates the menstrual cycle.  In the breast and uterus, progesterone counteracts the direct stimulation of cell growth by estrogens.  Because progesterone suppresses estrogen-driven cell proliferation, progesterone in the natural state helps keep breast cell growth in healthy balance.[v]  Progesterone improves cardiovascular function and protects against heart disease.[vi]  Progesterone reduces fluid retention and bloating, improves thyroid function, is a natural “valium” and anti-depressant and improves libido.  It is also the precursor to most other sex hormones and adrenal hormones.  Natural progesterone has recently been found to have favorable actions on the blood vessels in the brain.  It has been dubbed the “protection hormone” after it was shown to reduce death by 50% in traumatic brain injury cases and to substantially reduce disability in those that survived.  It is currently the subject of a $14 million National Institute of Health study for brain injury.[vii]

Bioidentical hormones have the exact molecular structure as those made in the human body. In other words, the two are indistinguishable from each other. Bioidentical hormones produce the same physiologic responses as those of the body’s natural hormones.  The Food and Drug Administration (FDA) considers bioidentical hormones to be natural regardless of their source, and as a result they cannot be patented.

Although HRT as conventionally practiced and studied uses synthetic hormones, the ill-effects have been indiscriminately attributed to all hormones; including natural, bioidentical versions.  This over-generalization persists despite the evidence supporting bioidentical hormones as a safer alternative; particularly with regard to breast cancer and cardiovascular risk.[viii]

Even among medical professionals, the crucial distinction between natural and synthetic hormones has been blurred so the discussion rarely involves the basic physiology of human hormones, and most evidence supporting any benefits of hormone therapy in adults is downplayed.  Most, if not all, of the research investigating the link between hormones and breast cancer doesn’t actually use natural human estrogens or progesterone.  These studies typically use pharmaceutical creations call conjugated equine estrogens (CEE) and progestins.  Most physicians don’t differentiate them but making the distinction is critical.  Why?  The physiologic effects of synthetic hormones differs substantially from that of natural or bioidentical hormones.

Conjugated equine estrogens, like that found in Premarin, are made from the urine of a pregnant horse (mare).  That is where the name was derived Pre-mar-in (pregnant mare urine).  It contains primarily estrone and equillin.  Equillin is an equine estrogen not normally found in humans.  It binds to and blocks human estrogen from attaching to its receptor and is not as easily metabolized.[ix]   The full physiologic effects in humans are not known (or perhaps not disclosed).

Progestins are not progesterone and do not occur in nature.  They are fully synthetic compounds that lack many of the essential beneficial physiologic properties of progesterone.   The synthetic progestin found in Provera is medroxyprogesterone acetate (MPA).  Unlike progesterone, MPA has been associated with adverse cardiovascular effects, increased breast cancer risk, hair loss, increased water retention, and increased risk for depression.  Progestins do not support gestation, are specifically contraindicated for pregnant women and do not provide the anti-proliferative balance of natural progeterone.  Interestingly, progestins are not being used in the brain injury study mention above, but are routinely prescribed for post menopausal women and as birth control for younger women.

Factors other than just hormones likely contribute to overall breast cancer risk in post-menopausal women.  A study of Japanese women found no increase in breast cancer among women receiving HRT.[x]  American women have much higher overall estrogen levels compared to women in Asian countries.  The breast cancer rate in the US is four to seven times higher than China and Japan; that is, until Asian women migrate to the US and adopt our lifestyle.  So, is a woman’s lifetime exposure to estrogen a factor?  Probably.  Early menarche and late menopause are both known to increase the risk and support the lifetime exposure hypothesis.  Birth control pills, contraceptive implants, excess body fat, estrogen-mimicking environmental chemicals and synthetic hormone replacement therapy all add to that lifetime exposure. 

What should you do?  Have a frank discussion with your physician about the pros and cons of hormone replacement therapy and the physiological differences between bioidentical hormones and synthetic HRT.  If your doctor is unable or unwilling to have that discussion, find a physician familiar with the subject who will.  As critics like to point out, there are no large scale trials unequivocally demonstrating the safety of bioidentical hormones, but there is no evidence of their harm.  On the other hand, there is considerable evidence that synthetic HRT (Premarin, Provera and PremPro) raises the risk for breast cancer, heart disease, blood clots, and Alzheimer’s disease.  For the vast majority of women, bioidentical hormone therapy is a safe, effective and beneficial alternative to suffering through menopause.

[i] American Cancer Society. Breast cancer facts & figures 2009-2010. Atlanta: American Cancer Society, Inc. 2009

[ii] Eden JA, Wren BG. Hormone replacement therapy after breast cancer: a review.  Cancer Treat Rev. 1996 Sep;22(5):335-43.

[iii] Giorgi A. Breast cancer incidence in Canada declines as hormone therapy drops. JNCI J Natl Cancer Inst (2010) 102 (19): NP. doi: 10.1093/jnci/djq408. first published online Septemebr 2010

[iv] Chlebowski R, et al. Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in Postmenopausal Women. JAMA. 2010;304(15):1684-1692. doi:10.1001/jama.2010.1500

[v] Ziel H, Finkle W. Increased risk of endometrial carcinoma among users of conjugated

estrogens. N Engl J Med 1975;293(23):1167–70

[vi] Hermsmeyer RK, Thompson TL, et al. Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity?  Nat Clin Pract Cardiovasc Med. 2008 Jul;5(7):387-95. Epub 2008 Jun 3.

[vii] Emory University. “Progesterone for Traumatic Brain Injury Tested in Phase III Clinical Trial.” ScienceDaily 22 February 2010.

[viii] L’hermite S, Simoncini T, et al. Could transdermal estradiol + progesterone be a safer post-menopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. Epub 2008 Sep 5.

[ix] Sawicki, MW; Erman, M; Puranen, T; Vihko, P; Ghosh, D (1999). “Structure of the ternary complex of human 17beta-hydroxysteroid dehydrogenase type 1 with 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+”. Proceedings of the National Academy of Sciences of the United States of America 96 (3): 840–5. PMID 9927655. PMC 15312

[x] Saeki T, Muneo S, et al. No increase of breast cancer incidence in Japanese women who received hormone replacement therapy: overview of a case control study of breast cancer risk in Japan.  Intl J Clin Oncol, vol 13, no. 1, 8-11, DOI: 10.1007/s10147-0728-0