Chandler Marrs

HRT ‘Largely or Wholly Causal’ in Ovarian Cancer

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Think about that quote for a minute. Hormone Replacement Therapy or HRT may be largely or wholly causal for a significantly increased risk of ovarian cancer in women, according to authors of a recently published study, Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. ‘Largely or wholly causal’ is very strong statement; one that makers of HRT are sure to dispute, but one that nevertheless was supported by data.

Ovarian Cancer Risk with HRT Use

Based upon prospective (17 studies; 12,110 cases) and retrospective (35 studies; 9,378 cases) epidemiological data reviewed by the Collaborative Group of Epidemiological Studies of Ovarian Cancer in Oxford, England and published in the Lancet, out of the 21,488 post menopausal women with ovarian cancer, 9303 had used HRT, most more than 5 years. From a statistical standpoint, the risk for ovarian cancer was significantly greater in women who had ever used HRT versus those who had never used HRT and even greater in those who were currently using HRT or had recently used HRT than those who had ceased HRT years prior. In other words, HRT use accounted for almost half of the cases of ovarian cancer. Moreover, the risk for HRT induced ovarian cancer was greatest while on the medication and soon after ceasing, but declined as time passed. This is an big finding.

Historical Associations between HRT, Cancer and Disease

Since the Women’s Health Initiative (WHI), debate about the safety of HRT has been forefront among millions of women. WHI demonstrated an increased risk of breast cancer and all sorts of other adverse reactions to menopausal hormone replacement therapy. Despite the findings of the WHI, drug companies and supporters were quick to point out that participants in the WHI were largely older, thus skewing the data. In fact there were and continue to be studies and critiques suggesting only minimal risk if younger women were to utilize HRT immediately upon menopause and for a shorter duration. Ovarian cancer was not considered among those risks.

The current study dispels the notion that younger women (those around the age 50) can use HRT safely and adds to the growing constellation of HRT mediated cancers and ill-effects. Indeed, age did not contribute to the overall risk for ovarian cancer, neither did other commonly considered factors like weight/BMI, smoking or oral contraceptive use. Only use versus non-use and recency of HRT usage were found to increase the risk of ovarian cancer.

Another common argument in support of HRT suggests that estrogen only HRT medications are more strongly associated with negative outcomes and that by adding a progestin, the risk for these side effects is minimized. While that may be plausible for some negative side effects, it was not true for ovarian cancer. Both types of HRT, estrogen only and estrogen plus progestin had equally high rates of ovarian cancer.

Utilizing the data reviewed in this study, the authors calculated the relative risk for ovarian cancer and death from HRT in England. The numbers are striking. For every 1000 women who utilize beginning at around 50 years of age and for approximately five years, we can expect one additional case of ovarian cancer and 1/1700 death rate, per year. When HRT is used more chronically (10 years), that risk increases significantly – one in every 600 women will develop ovarian cancer with death in one in 800 of those cases, per year.

An additional finding was the type of ovarian tumors most influenced by HRT. Ninety-eight percent were epithelial, the majority were serous tumors, followed by endometrioid tumors.

HRT, Breast Cancer and Other Risks

When combined with the increased risk of breast cancer (19 in 1000 per the Million Women Study), stroke, embolism, heart attack, gallbladder disease (Cochrane Review, 2012), one wonders why these medications are yet on the market. They are, however, and 6 million women in the US and UK use them regularly for years. From a statistical standpoint, the risk for any one of these side effects is relatively low. With breast cancer for example, HRT use accounts for 8-12% of the total cases each year.

By any standards, a 0.08% increased risk of breast cancer for each year of HRT use is extremely low. After 10 years of use, the cumulative 0.8% increase in risk is still low, but it has become a reasonable fraction of the 8% to 12% total risk of breast cancer diagnosis. Nationally, with millions of women taking HRT, many thousands will presumably have HRT-associated disease…Ken Muse, MD 

Many thousands, indeed, will develop HRT induced breast cancer or HRT induced ovarian cancer each year and some will die. The question one has to ask, is the need to decrease hot flashes, night sweats and vaginal dryness and other symptoms of menopause greater than the increased risk for breast or ovarian, heart attack and stroke and the host of other side effects associated with HRT? Can we not come up with safer therapeutic options to temper menopausal symptoms without increasing the risk for cancers and other diseases. Menopause is a temporary state of hormonal fluctuation, cancer, heart attack and stroke are more permanent.

HRT Post Oophorectomy

Perhaps, even more importantly, what are the risks for cancers and other disease processes in women who have had their ovaries removed and who must replace the hormones lost using HRT? Unlike natural menopause, where hormones decline gradually over years, with oophorectomy, hormones decline rapidly and almost completely (other sources of hormones synthesis are yet available, though generally insufficient to account for the loss of the ovaries). Certainly, their risk for ovarian cancer sans ovaries is eliminated but what about their risks for HRT-induced breast cancer, cardiovascular disease, gallbladder disease, dementia and cognitive decline? Have we removed one risk only to add five others?

The answers to these questions may be especially troubling in those women whose ovaries were removed without consent and/or because of some ill-conceived notion of protection against ovarian cancer. Prophylactic oophorectomy as archaic as it sounds is still quite common. Does this practice predispose an otherwise healthy woman to an exponentially increased risk for cancer and other diseases? It might. Without even the limited production of endogenous ovarian hormones to temper the onslaught of synthetic HRT, I fear we have increased the risk for many disease processes, of which we know little.

Chandler Marrs MS, MA, PhD spent the last dozen years in women’s health research with a focus on steroid neuroendocrinology and mental health. She has published and presented several articles on her findings. As a graduate student, she founded and directed the UNLV Maternal Health Lab, mentoring dozens of students while directing clinical and Internet-based research. Post graduate, she continued at UNLV as an adjunct faculty member, teaching advanced undergraduate psychopharmacology and health psychology (stress endocrinology). Dr. Marrs received her BA in philosophy from the University of Redlands; MS in Clinical Psychology from California Lutheran University; and, MA and PhD in Experimental Psychology/ Neuroendocrinology from the University of Nevada, Las Vegas.


  1. Dr Marrs,
    What is your opinion of bioidentical hormonal replacement? The WHI study did not use these? Do you know of any longer-term studies using bioidentical hormones? In your opinion, is there any difference between the two?
    I have been prescribed Estradiol (oral-1.3mg and a vaginal suppository that also contains Estradiol-0.5mg, testosterone-0.5mg and DHEA-1mg), Progesterone (oral-280mg). I have been taking these for 7 years. I am now 61 but went through menopause at age 50. Do you think women like me are at increased risk for ovarian and breast cancers? I am concerned about taking the Estradiol. The Progesterone has greatly helped me sleep. My Naturopathic Dr. also prescribed Testosterone as I have borderline osteoporosis.
    Thank you!

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