Read an Excerpt
Chapter 1
Estrogen: Behind the Headlines
In the 35 years that I've been a doctor and women's health specialist, estrogen has gone from hero to zero and back and forth again. How could this happen? How could the most frequently prescribed medication in America fall out of favor overnight? How could the same medication be so good and so bad, so loved and so hated, so beneficial and so harmful?
In this chapter we go behind the headlines and pull back the curtain to see how we got to this point and the circuitous path that took us there. Once the information becomes clear, it will be easy to understand how estrogen was blamed for problems it wasn't responsible for. The main characters in this story are Premarin (an estrogen only), which we'll call the "good guy," and Prempro (Premarin plus Provera), which we'll call the "bad guy." Prempro is a medication distinctly different from Premarin, though it contains Premarin, and as a result, Prempro has risks and benefits different from those of Premarin alone. I'll explain what these are later in the book and how to deal with them. I'll also show you how the estrogen window influences both of them.
The story begins at the end of a woman's reproductive years, when her reproductive hormones estrogen and progesterone transition from well- synchronized to unbalanced cycles that become progressively more unpredictable as she ages. During that window of time, estrogen levels fall, and the symptoms so typical of menopause begin to appear--hot flashes, vaginal dryness, embarrassing bladder symptoms, lower libido, poor sleep, and more. It just makes sense that since all this happens as estrogen levels are falling, giving estrogen at that time would help decrease those symptoms--and it does.
So for several decades, doctors prescribed estrogen to women to relieve their perimenopausal and menopausal symptoms. But the plot thickens, because as I mentioned previously, there are two main characters, two hormones: estrogen and progesterone. I'll explain this in detail in the section on the history of estrogen.
If you look at a graph of the estrogen and progesterone levels during perimenopause, which is the time leading up to and just beyond menopause, it would look like a graph of the Dow Jones heading from a bull market into a recession. The zigzagging ups and downs trend downward and eventually remain low for the rest of a woman's life.
Perimenopause and early menopause are the times when most women start taking estrogen-containing medications, such as Premarin and Prempro. Women traditionally began taking these medications within the first 10 years of entering menopause, because that's when their symptoms are usually worst.
So why did the Women's Health Initiative (WHI) studies decide to give some women Premarin and others Prempro, and why were the women receiving them mostly between the ages of 60 and 79? It all depended on whether or not each woman still had her uterus. As you will see, this is a key point for understanding your estrogen window and how all the confusion got started.
Estrogen taken alone can lead to changes in the cells of the uterine lining over time; over a decade or more, these can turn into endometrial cancer. So Premarin, which is estrogen only, could not be safely used in women who had not had a hysterectomy. The good news is that if progesterone or a substance that acts in the body like progesterone (called a progestogen) is added, the risk of cancer of the uterine lining is virtually eliminated. So when the WHI studies were designed, women who had not had a hysterectomy were given Prempro, which contained Premarin and Provera. Women who had their uterus removed by hysterectomy were given Premarin (estrogen only).
Progesterone is the name of a hormone your body makes. Its name comes from "pro-gestation," because it prepares the uterine lining, which has been primed with estrogen, to receive and support a pregnancy. The use of Provera rather than progesterone in combination with estrogen in the WHI studies is what caused most of the problems and confusion about the risks and benefits of estrogen. As mentioned on page 1, Provera is the "bad guy."
At the beginning of the WHI studies, progesterone was not available as a pill, but Provera was, so that was prescribed. Prempro, which contained Premarin plus Provera, was a very popular pill at the time. Provera, like progesterone, is a progestogen, the term applied to any hormone that acts like progesterone in the body. Provera is the brand name for medroxyprogesterone acetate or MPA, a synthetic progestogen. Synthetic progestogens are called progestins. This incredibly confusing nomenclature is made even worse because when writing articles, many people use these terms interchangeably and incorrectly. A short biochemistry discussion will make a lot of things clearer when we discuss the WHI in more detail. The flow diagram below will help clarify the information. While there are other synthetic progestins, I'll limit the discussion to Provera for now.
The Women's Health Initiative
In 1991, the WHI under the aegis of the US National Institutes of Health (NIH) began a large-scale, long-term study that consisted of a set of clinical trials and an observational study, which together involved 161,808 "generally healthy" postmenopausal women aged 50 to 79 years. I put quotation marks around generally healthy because you'll see a little later that many of these women did have medical problems. The clinical trials were designed to test the effects of postmenopausal hormone therapy (HT), diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancers.1
A lot of abbreviations are used to describe different hormone regimens, and as I mentioned earlier, they can have very different impacts. HT includes both Premarin and Prempro as well as any other estrogen alone or estrogen in combination with a progestogen. When estrogen is used alone, it is called estrogen therapy or ET; when estrogen is used together with a progestogen, it is called EPT. A major part of the confusion surrounding the WHI studies stems from the fact that the terms for these very different ways of giving estrogen are often used interchangeably. So whenever you read about risks and benefits of estrogen, be sure you understand what treatment the article is specifically referring to.
Abbreviations in this book:
ET Estrogen therapy Estrogen alone: either oral, via skin, or vaginal-- replaces ERT
EPT Estrogen-progestogen therapy Estrogen plus a hormone that acts like progesterone
HT Hormone therapy Estrogen alone or combined with a progestogen (progestin or progesterone)--replaces HRT
HRT Hormone replacement therapy See HT
ERT Estrogen replacement therapy Replaced by ET
MPA Medroxyprogesterone acetate A synthetic progestogen, also called a progestin
MHT Menopausal hormone therapy See HT
The first published WHI study compared a placebo with Prempro, which combines the conjugated estrogen Premarin with the synthetic progesterone medroxyprogesterone acetate (MPA sold as Provera), the most commonly prescribed progestin at the time of the study. Women in this study had a uterus and required the progestin to prevent cancer of the lining of the uterus. The second study compared a placebo to the estrogen Premarin in women who had their uterus removed (hysterectomy) and did not require a progestogen. The WHI study was supposed to continue for 15 years.
On July 9, 2002, after approximately 5.2 years, the WHI issued a news release saying that the Prempro study would be stopped effective immediately, because the data to date showed a definite link between Prempro and an increased risk of breast cancer or suffering a heart attack, blood clots, or stroke. The results made front-page, above-the-fold headlines in newspapers and were the opening stories on evening news programs. The New York Times called the findings "A Shock to the Medical System." The Washington Post declared "A High Price for HT: No One Warned She Might Pay with Cancer."
By 2002, 40 percent of postmenopausal women in the United States were using HT to relieve the debilitating symptoms of menopause--night sweats, hot flashes, heart palpitations, and moodiness. Overnight, thousands of doctors stopped prescribing estrogen--all kinds of estrogen and any medicine containing estrogen. Millions of women, who felt they had been duped and used as laboratory rats, instantly discontinued taking their estrogen- containing medicines. For those who insisted on continuing to use either Prempro or Premarin, many doctors required women to sign informed consents. Fear trumped reason, and front-page news affected doctors and their patients alike. Women and doctors had believed that estrogen was supposed to make women feel better without causing other medical issues; now doctors feared they had done their patients harm and patients believed they had been harmed.
It's difficult for many to remember or understand the panic that ensued when the WHI results were announced. To put it in historical perspective, just 10 months earlier America was attacked on September 11, 2001, and people were still feeling extremely vulnerable. When news of the canceled WHI study broke on July 9, 2002, many women felt as if they had been misled and were at risk of breast cancer, heart attack, and stroke. As many threw away their estrogen, anxiety levels skyrocketed.
I wish we could turn back the clock.
The 2002 WHI study contained a huge flaw that skewed the results and caused many women to forgo what we now know are the positive benefits of estrogen. I call these "estrogen myth-conceptions."
After practicing medicine for so many years and seeing the positive results of prescribing estrogen, I was skeptical about the findings and was reluctant to change my opinion based on just one study. I continued to prescribe Premarin to those women who wanted to continue with it and tried to switch patients from Prempro to Premarin or other estrogens plus a bioidentical progesterone. Remember, the information about side effects of the 2002 WHI study had to do with Prempro, which contained Provera; it was not specifically a report on Premarin or estrogen alone--except that Premarin is an estrogen and Prempro does contain Premarin. Unfortunately, all estrogen-containing medications were lumped together and perceived as one and the same. As you'll find out, they aren't.
Susan was 52 and had gone through surgical menopause at age 49 after her uterus and ovaries were removed. When she came to see me, she was still struggling with hot flashes, and vaginal dryness had become a problem for her, so she decided she wanted to try taking estrogen. She had not taken it earlier because she was afraid of the risks, and now that she was asking for it, her doctor recommended she not take it because she felt that Susan's hot flashes were likely to stop soon. But Susan was just 3 years into menopause and early in her estrogen window, which made her a good candidate to take estrogen. We discussed the symptoms she was having and the options available to treat them, and addressed her fears about taking estrogen. After our discussion, she started on an estrogen patch and is now symptom-free well within her estrogen window.
I began taking a detailed look at the 2002 WHI study and how the news- making conclusions were reached. When I did, I was stunned to discover that the controversy surrounding taking estrogen was based on flawed study design and misinterpreted data. I then began to uncover the flaws within the WHI study.
Up to this date, all the data had been observational, meaning there were no controls for comparisons. This new WHI study pulled the rug out from under all the previously published observations about estrogen. Not only had estrogen been perceived as safe and beneficial, but it was also used as a treatment for advanced breast cancer. This new idea that estrogen was bad and caused breast cancer, among other things, was a total reversal of the existing medical beliefs at that time.
I read and reread the study and its conclusions, spoke with leading doctors and researchers in the fields of women's health and menopause, and studied each new article that came out from the WHI and related sources. Remember that in 2004, just 2 years later, the estrogen-only arm of the WHI study did not show the same negative results; Premarin alone did not cause an increase in breast cancer or heart disease. So there were reasons to question the validity of the 2002 findings. A number of prominent doctors, including Wulf H. Utian, MD, who founded the North American Menopause Society, and Philip Sarrel, MD, of Yale University, didn't accept the study's findings as gospel, but evidence was necessary to prove that the results were wrong. The 2002 WHI study collected data in a quality way, but the big flaw was in the study design, and that caused incorrect interpretation of the information.
I owed it to my wife, Sharon, and my patients to learn everything about the topic, so they wouldn't have to choose between no treatment and treatment that they believed would alleviate their menopause symptoms but perhaps also increase their risk of death. Why should midlife women have to "tough it out" and suffer from their menopausal symptoms or live symptom-free and filled with fear and anxiety just because one study made claims unsubstantiated elsewhere?
My impression was that since participants in the 2004 study took estrogen only, and participants in both the 2002 and the 2004 studies received the same dosages of Premarin, the variable had to be Provera. Provera is known to narrow blood vessels and to undo the benefits of estrogen, which is part of the reason why I earlier referred to Provera as the bad guy. At that point I immediately stopped prescribing Provera, which was the progestogen combined with Premarin, and shifted my patients to bioidentical progesterone (see page 57).
I also noticed differences in the outcomes of the women in the two studies: The women in the 2004 Premarin-only study were also between the ages of 50 and 79, but when the study was stopped roughly 7 years after it began, those same women showed no increased risk of cardiovascular heart disease or heart attack and appeared to have less risk of breast cancer. For another 7 years there would not be enough numbers to prove that estrogen only lowered the risk of breast cancer.2
I saw a story beginning to take shape, but it would take me nearly a decade until further analysis of the same data and newer studies could prove that a woman's age plays a major role when it comes to the risks and benefits of estrogen.
