Should Users of Bioidentical Hormones be Worried?

Can conclusions from research on hormone replacement therapy (HRT) containing estrogen and a synthetic progestin be applied to bioidentical hormone therapy? The lead author of a study published last week in the Journal of the American Medical Association (JAMA) thinks it can. Lina Steinrud Mørch, MSc and colleagues, the Danish researchers who published “Hormone Therapy and Ovarian Cancer,” showed that conventional hormone replacement therapy (HRT), increases the risk for ovarian cancer by 20 to 30%.

The U.K.’s Million Women Study found much the same result and published it in the Lancet in 2007, concluding: “Women who use HRT are at an increased risk of both incident and fatal ovarian cancer. Since 1991, use of HRT has resulted in some 1300 additional ovarian cancers and 1000 additional deaths from the malignancy in the UK.”

The number of women who get ovarian cancer is small, and the number who die from it is even smaller, so it’s very difficult to get good statistics on this terrible disease. To complicate matters even more, there are multiple risk factors for ovarian cancer. It is a deadly disease. Unless it's caught early, which is the exception, only 46 percent of women survive ovarian cancer.

The Danish study, which followed a million women for ten years, looked more closely at the various types of conventional HRT to find out if any were safer, and concluded, “Regardless of the duration of use, the formulation, estrogen dose, regimen, progestin type, and route of administration, hormone therapy was associated with an increased risk of ovarian cancer.”

Really?! Different Interpretations of the Same Data

This recent JAMA article was picked up by the mainstream media with mixed results in accuracy. In particular, the article Hormones Linked to Ovarian Cancer: What to Do, in the U.S. News & World Report blog, “On Women,” by senior writer Deborah Kotz said:

“The big question: Just how much should this latest news factor into a woman's decision about taking hormones? Morch tells me that it should weigh in pretty considerably. ‘Ovarian cancer is highly fatal, so accordingly this risk warrants consideration when deciding whether to use HT,’ she writes in her E-mail. Women with a family history of ovarian cancer, in particular, should consider not taking hormones, she adds. Unfortunately, bioidentical hormones—which have been touted by some as safer than traditional hormone therapy—are associated with the same increased ovarian cancer risk. Women in the Danish study all took estradiol, a bioidentical hormone that has the same chemical structure as estrogen made by the body. And there was no difference in cancer risk between women who took non-identical synthetic progestin and those who took bioidentical progesterone.”

Yes, estradiol is a bioidentical hormone, and I don’t think there would be any debate from health professionals who use bioidentical hormones that excess estrogen, unopposed by natural progesterone, could increase the risk of ovarian cancer.

But natural progesterone? I carefully searched the entire Danish study for any references to progesterone (vs. progestins) and found no mention of it.

I e-mailed lead author Lina Mørch the following:

“It was implied in a U.S. News and World Report article, “Hormones Linked to Ovarian Cancer: What to Do,” that you stated that bioidentical progesterone was included in your study and that its risk for ovarian cancer was the same as for the progestins. I read your study closely and did not see any mention of bioidentical hormones, or even a distinction between progestins and progesterone.

…Could you tell me whether women using bioidentical progesterone were included in your study and if so, what the risk factors are for progesterone vs. progestins, and what form of progesterone was used (e.g. transdermal vs. oral)?”

Morch was kind enough to reply:

“Dear Virginia Hopkins,
You are quite correct. In our study we included women on natural estrogens but not women on progesterone, as the latter group in Denmark is small. What we have suggested is that until further evidence appears, we have anticipate that women taking natural progesterone in combination with estrogen will have the same increased risk of ovarian cancer as women taking progestins in combination with estrogens.
With kind regards, Lina Mørch”

A Different Point of View from Journal Watch

At the other end of the spectrum, a comment on the Danish research by the Editor-in-Chief of Journal Watch, Andrew M. Kaunitz, M.D. downplayed the association between HRT and ovarian cancer:

“In this large study, menopausal HT was associated with modest elevations in risk for ovarian cancer; however, weak associations in observational studies can result from detection bias. HT users might receive more medical (including diagnostic) services than do nonusers. The observation of excess ovarian cancer risk among women who had just initiated HT suggests the presence of such bias. Moreover, the finding that short-term and long-term HT use were associated with similar risk — and that risk in women who had recently discontinued HT rapidly approached risk in never users — must be taken into account when considering whether the excess risks were caused by HT use. Although risk-reduction strategies for ovarian cancer should remain high priorities, whether these findings should be used to counsel women who are weighing the pros and cons of HT is not clear.”

I responded in the Journal Watch:

I'm always amazed at how completely one's point of view can affect the analysis of a seemingly neutral set of data.

I’d like to offer a different slant on “Hormones and Ovarian Cancer.”

One person’s ‘modest’ elevations in risk are another’s red flag. According to the authors, ‘This approximates 1 extra ovarian cancer for roughly 8300 women taking hormone therapy each year.’ Multiply that times 20 million women and we have 2,409 women with ovarian cancer, some 67% of whom will die from it, or roughly 1,614 women. Relatively speaking that may seem like a small number, but if it's your wife, mother, sister or daughter it’s very personal.

For comparison, some 4,000 women a year die from cervical cancer in the U.S., most of them women who never get a pap smear, and yet there is a push to make an expensive HPV vaccine with a questionable safety record mandatory for school girls.

One cancer’s modest risk is another cancer’s over-reaction. It all depends on point of view.

Along the same lines, one person’s ‘detection bias’ is another person’s gasoline on the fire, meaning perhaps adding HT [hormone therapy] to a nascent ovarian cancer is like throwing gasoline on smoldering embers, turning what might have been a lurking threat into a full-blown life-threatening event. Stop throwing gasoline on the fire and without fuel it quickly returns to embers. Albeit metaphorical, that point of view explains the data equally well.

My personal bias is that physiologic doses of bioidentical, transdermal hormones will eventually be found to be a safe and effective way to provide women with relief from menopausal symptoms. Fournier et al in the E3N Cohort have already provided ample evidence of this, but more studies are needed.”

Granted, the increase in risk is “modest,” but the rub here is that the Kaunitz comment on this study amounts to a defense of HRT, which we already know also increases the risk of breast cancer, heart attack, stroke and gallbladder disease. If mainstream medicine would use transdermal estrogen in physiologic doses, and transdermal natural (bioidentical) progesterone, their terrible HRT statistics would quickly change and millions of women would be safer and healthier.

Ovarian Cancer Risk Factors

The research on estrogen, bioidentical or synthetic, makes it clear that it can increase the risk of ovarian cancer, likely when it’s present in excess, and/or without progesterone. A 2001 study from Emory University and published in JAMA (Rodriguez et al), found that women who used estrogen-only hormone therapy had a 51% increased risk of ovarian cancer. A number of recent studies on hormone receptors in ovarian cancer, including one from the Harvard Nurses’ Health Study, have shown that ovarian tumors with progesterone positive receptors (which means that progesterone can get into the tumor and have effects on it) are less invasive and have a better outcome.

Risk Factors for Ovarian Cancer
According to the Johns Hopkins Ovarian Cancer website the following are the major risk factors for ovarian cancer:

• Have 2 or more relatives who have had ovarian cancer
• Have a family history of multiple cancers: ovarian, breast or colon cancer
• Were diagnosed with breast cancer under the age of 50
• Have a personal history of multiple exposures to fertility drugs
• Are of Ashkenazi Jewish decent
• Have had uninterrupted ovulation (never used birth control pills, or no pregnancies)
• Have the BRCA1 or BRCA2 gene mutation
• Are over the age of 50

You can learn more about the ovaries in What Your Doctor May Not Tell You About Your Ovaries, an article by John R. Lee, M.D.

References

Hecht JL, Kotsopoulos J, Hankinson SE et al, “Relationship between epidemiologic risk factors and hormone receptor expression in ovarian cancer: results from the Nurses' Health Study,” Cancer Epidemiol Biomarkers Prev 2009 May;18(5):1624-30.

Hempling RE, Piver MS, Eltabbakh GH, “Progesterone receptor status is a significant prognostic variable of progression-free survival in advanced epithelial ovarian cancer,” Am J Clin Oncol 1998 Oct;21(5):447-51.

Høgdall EV, Christensen L, Høgdall CK, “Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the 'MALOVA' ovarian cancer study, Oncol Rep 2007 Nov;18(5):1051-9.

Mørch LS, Løkkegaard E, Andreasen AH et al, “Hormone Therapy and Ovarian Cancer,” JAMA. 2009;302(3):298-305.

Rodriques C, Calle EE, Loates RJ et al, “Estrogen replacement therapy and fatal ovarian cancer,” American J Epidemiology 141:828-834, 1995.

Tangjitgamol S, Manusirivithaya S, Khunnarong J et al, “Expressions of estrogen and progesterone receptors in epithelial ovarian cancer: a clinicopathologic study,” Int J Gynecol Cancer 2009 May;19(4):620-7.