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URMC / Obstetrics & Gynecology / UR Medicine Menopause and Women's Health / menoPAUSE Blog / February 2022 / I am on a twice-weekly estradiol patch along with oral progesterone nightly. My friend says that est

I am on a twice-weekly estradiol patch along with oral progesterone nightly. My friend says that estrogen is dangerous in menopause. What can I say to my friend?

Your Menopause Question: I am on a twice-weekly estradiol patch along with oral progesterone nightly. My friend says that estrogen is dangerous in menopause. What can I say to my friend?

Our Response: Hormone replacement therapy (HRT) for women in menopause has had a long and complicated history. The fact that older women have experienced a range of adverse health issues dates back to the time of Aristotle, even though it was not until 1928 that estradiol as a hormone was described (Singh, 2002).

The real HRT battle can be traced back to 1968 when Feminine Forever (Pocket Book, NY) was published in book form by Robert Wilson, M.D., a gynecologist in New York City with a large menopause practice (Wilson, 1968). His experience with HRT advanced the concept that menopause was a physiological state “…with unwelcome expectations…and that hormone therapy may allow a smoother transition into menopause.” At that time, the Women’s Movement harshly criticized the “medicalization of a natural woman’s time,” thus establishing the battle lines (Houck, 2003).

The story of HRT became even more complicated in 1991, when the National Institutes of Health funded a $725 million study of HRT versus placebo. The goal, based on animal studies, was to establish or refute the hypothesis that estradiol improved cardiovascular and bone health (Chlebowski, 2003). The prematurely released results suggested that
PREMPRO® (a combination of oral Premarin® [conjugated estrogens] and a synthetic progestin [medroxyprogesterone acetate]), caused breast cancer in eight more women per 10,000 women’s years (a statistic that remains confusing to most non-statisticians), than those taking a placebo. The lesser-publicized arm of that study, which involved women with a hysterectomy who took only Premarin® and not the synthetic progestin, showed a slight but non-statistical reduction in breast cancer compared to the placebo group. Yet, 20 years later, that decrease in breast cancer for those on Premarin® has been even greater.

Today, the interpretation of that study has turned to the synthetic progestin along with Premarin® as the possible cause of the breast cancer. However, the risk is considered only slightly more than that of one glass of wine at night (Kaunitz, 2015).

The impact of that 2002 report led to worldwide news outlet headlines claiming that estrogen causes breast cancer. Those headlines, prompted by the 2002 lead article in the Journal of the American Medical Association (JAMA), resulted in a dramatic drop in HRT prescriptions, thus forcing many menopausal women into a ten-year period of harsh and untreated symptoms with little help from the medical community (Rossouw, 2013; Simon, 2014; and Kaunitz, 2015).

So, what should today’s conversation on HRT in menopause clarify? First, there is not just one level of estrogen exposure. Often overlooked is the fact that from late puberty into the 40s, at the moment of ovulation during each menstrual cycle, the blood levels of estradiol are between 200 and 400 pg/mL. In contrast, in menopause, estradiol levels in those without HRT often are so low as to be undetectable. Even with HRT, the blood levels are approximately 15 to 30 pg/mL. That means that each menstrual cycle during her reproductive years exposes a woman to ten times the levels of estradiol documented
in menopause (Simon, 2014).

The route of estrogen administration also is important. Oral estrogen, which was studied in the Women’s Health Initiative (WHI), enters through the liver, altering one’s blood clotting factors and increasing the risk of blood clots. However, estradiol administered transdermally, as a patch or cream, does not appear to influence one’s clotting factors (Canonico, 2008, 2014).

Finally, there is no evidence that transdermal estradiol in menopause causes breast cancer or breast cancer recurrence for those who are breast cancer survivors.

Why would such a low level of estradiol work? It seems that the small group of neurons in the hypothalamus, called KNDy neurons (kisspeptin, neurokinin B, and dynorphin), which initiate reproduction, body heat management, and energy expenditure, are highly sensitive to estradiol, even at very low levels (De Tassigny, 2010, and Ebzieva, 2019).

Most recently, the American College of Obstetricians and Gynecologists and The North American Menopause Society have supported the use of a small, pea-sized amount of vaginal estradiol to reverse vaginal dryness and pain on intercourse (Petridis, 2017).

In summary, HRT replenishes natural hormones lost in menopause and at significantly lower levels than are generated throughout the many years of menstruation. This information may help your friend understand how disinformation about estrogen in menopause works against women.

James Woods | 2/10/2022

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