Menopausal Hormones & Breast Cancer

A reader writes

Dr. Lasater, may I ask your advice? My new doctor has recommended that I start bio-identical hormone replacement because I’m having fairly severe symptoms of menopause, with my last period having been one year ago, just as I turned 50; he also points out that the hormones may reduce my risk of heart disease, which runs in my family, including my mother. His advice seems quite worthwhile. But then I talked to several of my friends, and they’re strongly advising me NOT to start the hormones because “As you should know, Kathy – they’ll cause cancer!”. I’m now totally uncertain what to do. Please advise!

                                                                                                                                    -Kathy

 

Dear Rachel,

This is a fairly complex issue, and to fully address it would take nearly an entire book. As it is, it will take two of my columns – this month as well as the one in two months. However, in a nutshell, I think that you probably should follow your doctor’s advice and start the bio-identical hormones. There are several reasons why I believe this would be the best approach:

1. Different hormones are different. There are two main classes of hormones a woman produces during the normal menstrual cycle and are replaced in HRT—they go by the names ‘estrogens’ and ‘progestins.’ There is no single molecule called ‘estrogen’; rather it is a general term that is used when talking about a group of molecules that can lock into estrogen receptors and cause them to alter the behavior of estrogen-sensitive cells.  ‘Estradiol’ is the name of the principal estrogen produced by the human ovary; estrone and estriol are metabolites of estradiol. Premarin® is a mixture of some 12 different equine (i.e., horse) estrogens and only one human estrogen, estrone. Similarly, there is no actual molecule called ‘progestin’; rather progestins are a group of molecules that can lock into progesterone receptors and alter the behavior of progestin-sensitive cells. ‘Progesterone’ is the name of the principal progestin of the ovary. ‘Medroxyprogesterone acetate’ is the generic name for the progestin Provera® which has been the most commonly used progestin in the United States for hormone replacement therapy (HRT), and although it contains the term ‘progesterone’ within its name, it really is a very different molecule than bio-identical progesterone. Other progestins such as levonorgestrel, norethindrone acetate, and norgestimate are commonly used in birth control pills. Progestins then are a class of molecules that have similar effects in progestin-sensitive tissues; estrogens are molecules that have similar effects in estrogen-sensitive tissues. Note that there is a dramatic difference between different forms of hormones, even those from the same class. Conjugated equine estrogens (from horses) are different from the types of estrogen (primarily estradiol) that a woman’s ovaries have made during her reproductive years. Estradiol appears to be a more effective choice for reducing cardiovascular risk than oral conjugated estrogens.

There is an even more significant difference between types of progestins than between types of estrogens. The synthetic hormone medroxyprogesterone acetate, or MPA (Provera®), to be honest, is a rather nasty character. MPA increases a woman’s risk of breast cancer, whereas progesterone decreases the risk. (See discussion below.) This difference is lost whenever one asks, Are hormones good or bad? The answer depends on the particular hormones being discussed. Why, then, haven’t the headlines been, “Provera®increases a woman’s risk of breast cancer”?  I believe that this is how the headlines should have been written and therefore instead of stopping hormone replacement therapy (HRT) altogether, women should have gotten off of Provera®.  Alas, that is not how it went.  Instead, the headlines were, “HRT is Dead” or some sensationalistic version of this. While it’s easy to blame only the media for this, the problem lies deeper and comes from a concept that many physicians and researchers have been slow to abandon—class effect.

Physicians and researchers who generalize experimental findings based on a particular type of hormone to all forms of hormone replacement therapy are clinging to the concept that all molecules of a particular class have exactly the same effects in all tissues and it really doesn’t matter which one you use.  So they contend that if MPA (Provera®) causes an increased risk of breast cancer, then progesterone does as well. Or, if conjugated equine estrogen (Premarin®) causes an increase in blood clots in post-menopausal women, then so does estradiol. The problem is that there is ample data to suggest that this is just not true.  These “over-generalizing pundits thus have a problem: these darn FACTS get in the way of their theory! One study by Kramer et al. found that progesterone stimulated a non-malignant breast cancer cell line less than Provera® and other progestins, and concluded by saying, “Therefore, the choice of progestin may be important in terms of influencing a possible breast cancer risk.” Another study by Ghatge et al., looking at the effect of MPA (Provera®) in breast cancer cells in vitro, concluded, “Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone.”

In vivo evidence is another type of evidence – in living persons. In one randomized, double-blind study of women undergoing breast surgery for benign conditions, Foidart et al. found that those who applied topical progesterone to the breast for 14 days before surgery had a decrease in the stimulation of breast cells in the excised tissue. This is direct molecular biological evidence that progesterone and Provera® are different, and thus the associated cancer risks are different as well. In Europe, transdermal estradiol and progesterone are used more frequently than Premarin® and Provera®. In another study, De Lignieres et al. followed a cohort of 3,175 French women who used mostly transdermal estradiol, and progestins other than Provera®, for an average of 8.9 years; they found that there was no increased risk of breast cancer.

 

These studies are part of the growing evidence that the class-effect concept that considers all progestins to have exactly the same effects in all tissues is untenable. If your gynecologist or internist makes a class-effect argument when he or she tells you there is no difference between progesterone and Provera® (I often hear, “It is progesterone”), show him or her these studies. (If you would like to have the actual references cited, please write to me and I will gladly forward them to you.)

2. Even when there has been an increased risk of breast cancer attributed to hormone use, the increase is virtually miniscule.The International Menopause Society (IMS) is the largest menopause society in the world and was the lone voice of reason when the initial results from the Women’s Health Initiative Study were released in 2002 – the study which was hyped as showing an increased risk of cancer from “hormones.” Had the IMS’s incisive analysis of the data been heeded by the media, many women would have been spared the needless turmoil that cessation of HRT caused in their lives. Here is what the IMS has stated:

The risk of breast cancer attributable to MHT (menopausal hormone therapy) is rare. It equates to an incidence of <1.0 per 1000 women per year of use. This is similar or lower than the increased risk associated with common factors such as sedentary lifestyle, obesity and alcohol consumption. The risk may decrease after treatment is stopped, but data are inconsistent. (from the International Menopause Society, in Revised Global Consensus Statement on Menopausal Hormone Therapy, 20 June 2016)

3. Other cancers than breast cancer have been shown to be significantly LESS likely in women taking hormone replacement.

 

Colorectal Cancer is the second most common cancer in women (after breast cancer). Evidence from the Women’s Health Initiative and other trials suggests that current HRT users have a 40% reduction in colorectal cancers. This certainly needs to be factored into the “hormones and cancer risk” equation.

4. There are numerous other benefits to bio-identical hormone replacement therapy (HRT). It should also be pointed out that if the bio-identical HRT consists of estradiol applied on the skin (transdermal) or under the skin (subcutaneous pellets), then most of the other adverse events associated with oral conjugated equine estrogen (Premarin®) such as blood clots, strokes, gall bladder disease, and increased triglycerides and C-reactive protein, are likely to be eliminated as well.  This results in a risk-benefit equation that is quite beneficial for most women undergoing the menopausal transition as well as for continued, long-term therapy. But even oral hormone replacement has considerable benefits, as shown by a study published in the British Medical Journal in 2012, in which over 1,000 women in Denmark who had recently undergone menopause were randomized into two groups, serving either as the treatment group, who were given estradiol and a progestin, or the control group. After being followed for ten years, those women who had received the hormone replacement therapy showed a significantly reduced risk of heart failure, heart attack, and of overall mortality, without any apparent increase in the risk of blood clot, stroke, or cancer! When one also figures in the improved quality of life typically experienced by women receiving hormone replacement therapy – dramatic relief from hot flashes and night sweats, improved sexual well-being, and reduction in fatigue, to name just a few – the decision of whether or not to take hormone replacement therapy should for many post-menopausal women be considered a “no-brainer.”