The Estrogen Errors
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excerpts

From Chapter 1…
Women and hormones
We seem to forget that all of us are a blend of hormones, men and women alike, from insulin (the hormone diabetics lack) to adrenaline, noradrenaline, sometimes referred to the “fight/flight” hormones, thyroid hormone and more. At times any one of these could “rage” (if we were to insist on anthropomorphizing hormones) given that these potent, albeit subtle, glandular secretions are involved in every part of our physiology, from regulating body temperature and metabolism to energy and sleep. So, clearly, more is going here when we talk about women and hormones than mere endocrinology. (page 3)

Even more perplexing is that that hormone in question is inevitably estrogen. Estrogen is “the” quintessential, female hormone, fundamental to being a women; nobody even blinks if a restroom door or a newspaper headline uses the term as shorthand for “women” (just as “testosterone” refers to men). So how did a single hormone, one of many, achieve such iconic status? (page 4)

Progesterone: the forgotten hormone
This book is an answer to that question, delving back in time to cover not only the history of hormones – and the late 19th century scientists and researchers who first identified these active and mysterious substances – but also analyzing a host of other influences that converged during the 20th century, particularly after World War II, all of which made estrogen, and estrogen “therapy,” the fulcrum for women’s biology, identity and destiny. Based in medicine and endocrinology, shaded in with concepts from social science, this book is also an examination of how the diverse elements – war, money, culture, science, medicine, the status of women, language and the laboratory itself – that came into play in the discourse on women’s hormones and their role in health. A counterbalance to the often inaccurate, contradictory and prejudicial advice women are too often given with respect to hormones (from birth control pills to hormone “replacement” therapy, as it is erroneously called), this book clarifies what is usually referred to as the “menopausal transition” and provides women, especially at midlife, with a solid intellectual and medical framework for understanding how hormones function within their lives and health. Those earlier terms, incidentally, are in quotes because it makes no sense to call hormones a “replacement” at a time when all women’s hormones naturally wane – this is not like a diabetic injecting insulin or someone taking thyroxine to replace that of a sluggish thyroid.

Furthermore, calling this time in a woman’s life the “menopausal transition” ignores the difficult years of high estrogen, heavy and irregular cycles, implying that any and all problems with halt abruptly at that “final” menstrual period (which is how menopause is officially defined) as though anyone at that point could know it was really the last menstrual flow. Rather, the time leading up to menopause, (before and for one year after that last flow) during which some 15 to 20% of women have troubling symptoms, is more accurately called perimenopause.

An enormous amount of nonsense has been said and written about women’s “lack” of estrogen as they age. For years, even women not experiencing any problems at all were told to take estrogen for their heart, their bones or to keep their hair and skin youthful. Yet estrogen has been repeatedly demonstrated to increase heart disease, breast cancer, blood clots and so on (most recently in 2002 when the Women’s Health Initiative was stopped early due to hormones’ adverse effects). Nonetheless, it would appear that women’s roles throughout western history have been so inextricably linked to their fertility, their ability to conceive, that anything outside of those middle, menstrual years was expeditiously labeled aberrant, diseased even, and women, unfortunately, believed the experts who told them menopause was an “estrogen deficiency disease” for which “replacement” hormones were necessary. This book is also, therefore, an analysis of the many myths about estrogen (and menopause) and a guide to help women understand their own hormones at various stages of life. And although we have tried to make this book accessible, readable, it is not a lightweight work or an “alternative” book (not that there is anything necessarily wrong with that); we have provided an extensive bibliography, sources and notes. Readers can confidently use this book as a reference or when talking to their family physicians. (page 5)

Estrogen as panacea
By the middle of the 20th century, estrogen was being touted, particularly in the United States, not merely as a “cure” for any midlife symptoms (actually perimenopause), but as a magical substance that could keep women young, taut, healthy and vital – which, on a continent where anything that even vaguely promises to maintain youth and vigor is valorized, estrogen soon became one of the most frequently prescribed drugs in the country. As recently as 2001, 15 million midlife women were filling prescriptions for estrogen (with a smidgeon of a synthetic progesterone, progestin, added to prevent the endometrial cancer that estrogen alone could cause).12 Premarin, the estrogen pill derived from the urine of those pregnant mares13 (the derivation is obvious from the name: pregnant, mare, urine), had indeed become a gold mine for the pharmaceutical industry, all those years after those early Dutch scientists had predicted. (page 11)

Accepting ambiguity
When a physicist describes a distant galaxy, an entomologist describes insect behavior or a biologist describes a cell, the terms, metaphors and ideas they use to frame their hypotheses come from the language and ideas they have. Emily Martin, in The Woman in the Body, describes ways in which western medical descriptions of women’s bodies are suffused with “metaphors of production” – revealing that she herself had enormous problems once she moved her research from China (where she was an outsider) to the United States, where as a white, middle-class, white academic she felt she belonged.41 As she studied reproduction and women’s health issues, Martin often found herself at a loss when attempting to critique the interviews with American women, since so much of what they said seemed like “common sense” to her. For instance, her understanding of uterine contractions during pregnancy came from medical texts, where they are described as involuntary, so it made sense to her that women described them as “separate and distinct” from themselves. She “anguished” that what she was hearing made good, scientific, factual sense and seemed “obvious.” It was only later, as she remembered the “facts” that women in China had told her (certain diseases were “hot” and others, cold, other times the yin and the yang were out of balance), facts that made no sense to her but were simple truths to the interviewees, that it all fell into place. She had so internalized the American perspective that to her these were the facts, what she knew and believed. (page 26)

From Chapter 3…
What is Perimenopause?
Perimenopause is the transition between the normal, adult menstrual years (premenopause) and menopause, the time when menstruation stops. It can be a chaotic and confusing time, with bodily changes and symptoms that range from the relatively benign, albeit disturbing (weird dreams, itching of the vulva, frequent urination, weight gain) to distressing (breathlessness, vertigo, migraines, thinning scalp) and outright terrifying (mysterious bruising, panic attacks, memory lapses, chest pain and palpitations).3 (page 56)

There is no simple “fit” for perimenopause. As Jerome Groopman, the Harvard hematologist and author writes in How Doctors Think: “Clinical algorithms … quickly fall apart when a doctor needs to think outside their boxes, when symptoms are vague or multiple and confusing, or when test results are inexact.”9 Unfortunately for both patient and doctor, vague, multiple, confusing symptoms are the hallmark of perimenopause – and are part of the reason high estrogen is not suspected. In addition, gynecology (the de facto specialty on women’s health) has authoritatively told family doctors that those pesky hot flushes are the cornerstone of menopause and are due to estrogen deficiency. So the majority of the time the doctor will decide that this 40-something woman is going through “premature ovarian failure” (early menopause); that she is estrogen “deficient” and will reach for the prescription pad to recommend “HRT.” (page 58)

Even though medical education ostensibly teaches trainees the “basics” about women’s reproductive changes as they age, most doctors neither know how to identify perimenopause nor how to manage it, since what they were taught implied a clear-cut, definite break between the two recognized stages of a woman’s reproductive cycle – as though women magically switch from fertile to “postmenopausal” overnight, which makes no sense physiologically. Nothing works like that, not even a simple viral illness. No biological phenomenon takes a quantum leap from zero to one without some intervening indication(s). There’s a reason lab results and blood tests are presented along a continuum, with normal being somewhere “between” the two numbers.

Hormones and their regulatory functions in the body, furthermore, are devilishly complicated and not particularly well understood; the subtle interplay of different hormones are involved in all our systems and physiologic processes, from how much energy we have and how well we sleep – to our weight and height, ability to conceive and on and on. A woman’s menstrual cycle, as we saw in the previous chapter, is a subtle dance between the brain (hypothalamus), pituitary gland, ovaries, follicles and more. So while it may be more expedient for medicine not to get too caught up in perimenopause and to resort to reductionist thinking, to consider fertility and its cessation as having finite borders is not an option for the women in question. (page 59)

From Chapter 4…
The Medicalization of Menopause
For centuries medicine has been the art (and, to some extent, the science) of healing, along with the practice of bringing comfort and succor to the sick. Health and illness were obvious, subjective states: your grandmother knew when she was ill or needed to go into the hospital. Today, the medical repertoire has expanded and definitions of pathology, broadened, to include (at least in the west) a vast array of asymptomatic diagnoses which are invisible and imperceptible to the individual in question. For instance, today we use drugs and therapies not only when we feel unwell but because we are “at risk” of disease – our blood pressure is high or our glucose level does not match some previously agreed standard or benchmark. The numbers themselves do not correspond with disease but are biomarkers: statistically derived measures that are considered predictive with regards to one condition or another such as diabetes or coronary artery disease and today, as modern medicine attempts to predict and prevent illness, increasing numbers of us are said to suffer from such invisible and asymptomatic conditions – what critics have called “numbers-created” diseases. So ubiquitous has this “at risk” discourse become that few people realize that until the 1960’s this peculiar construct, in which we focus on measuring individual factors believed to contribute to disease, did not exist.7

This piecemeal, reductionist approach – in which focus has shifted onto biomarkers (surrogate end points) such as lipid levels, versus the person as a whole, has therefore completely altered the face of medicine, medical research and education. Not only has individual care been affected, but by the late 1980’s, as the late Yale physician Alvan Feinstein warned, such efforts had converged on a “taxonomy” of medicine that divided health and health care into what were considered to be its component parts: structure, process and outcomes.8 In other words, the focus of medicine completely moved away from the person and towards the idea of pathology or disease. (pages 82 – 83)

The medicalization of menopause fell into this general category, with the promotion of hormones as prevention encouraging “both doctors and women to view their current health status in terms of their risk of future ill health.”9 Such concerns were (and are) exacerbated by playing on women’s fears of aging – and our general societal preoccupation with how to stave off the diseases of old age. Guidelines, “critical pathways” and “disease management” have become medical bywords over the past few decades, even as medical care has become transformed into an increasingly impersonal discipline. Today, in some ways it no longer matters who you are but what. In other words, nobody cares that you might be a stressed, struggling single mother of two teenagers whose place of work is “downsizing” and who is frantically trying to hold everything together. Or that you are going through perimenopause. What matters is that you are a woman nearing menopause who is overweight and has high blood pressure – which requires treatment of one kind or another. Aside from the obvious and questionable problems with this pithy, modern (some would add peculiarly American) model, is that defining the “normal” (against which pathology can be determined) is not only completely arbitrary much of the time but is all too often is based on norms which have excluded women altogether. Add into this noxious mix the infatuation with estrogen that has characterized the discussion on women’s health and hormones, and the stage is set for potentially disastrous results. (pages 83 – 84)

Menopause as risk factor
As perimenopause and menopause became part of the risk factor approach, women at midlife found themselves not no longer in a “state of nature” but in a “disease state,” terms exacerbated by labels like “estrogen deficiency” and “ovarian failure.”14 Even that majority of women for whom the perimenopausal transition and menopause involved few or no symptoms found themselves being labeled “at risk” – an alarming phrase suggesting the need for medical attention. So hormones, even if unnecessary for symptom reduction (since over three quarters of women do not have problems at midlife), needed to be taken to ward off future disease, or at least the risk of future disease, a bizarre concept. “In women, estrogen and the lack of it are linked to many disorders of aging,” insisted a 2001 JAMA editorial in an issue where several articles made the case for estrogen improving cognition as women aged, even reducing the risk of dementia.15 “What’s the matter with cardiologists?” scolded an epidemiologist in the CMAJ in 1999. Apparently, contrary to the guidelines (read: truth according to the people writing the guidelines), only a scant 21% of women attending a Toronto cardiology clinic were “documented users of HRT.”16 Even though it has turned out that hormones’ ability to ward off disease in healthy women is a myth17 – but this estrogen-is-good belief is so fundamental that it simply seems to refuse to die, at least in the medical and media imagination.18 (pages 85 – 86)

From Chapter 5…
Cardiac Disease
The belief in the efficacy of estrogen in preventing heart disease was so staunch that some years earlier, 5000 older men who had previously had a heart attack were randomized to receive two different regiments of high dose-estrogen (Premarin 5.0 or 2.5 mg.) or placebo. The results were disastrous: the 5 mg dose increased heart attacks and both doses led to higher mortality from cancer, pulmonary embolism and heart attacks. In addition, the men had terrible side effects and became impotent, suffered from sore breasts, shrunken testicles and decreased libido.31, 32 These spectacularly negative results, however, barely saw the light of day – the excuse was that the dose just must have been a little high. (page 115)

Faith in the cardioprotective powers of estrogen ought to have eroded in the late 1990’s with the HERS (Heart and Estrogen-progestin Replacement Study) results, but nothing seemed to dent the American faith in hormones. A randomized, double-blind study undertaken between January 1993 and September 1994, 20 HERS “clinical centers” enrolled 2,763 women with “established coronary disease” (but who were not sick); 1,380 received hormones (a single pill containing 0.625 mg equine estrogen and 2.5 mg medroxyprogesterone acetate) while 1,383 women were given a placebo. The study was funded by Wyeth-Ayerst to obtain FDA approval to label their drug as being cardioprotective, and everyone fully expected the results to be positive. On the contrary, after approximately four years, the HERS found that not only did hormones “not reduce the overall rate of CHD events” but the treatment group experienced “net harm.”65 Undaunted, the researchers pushed on with HERS II. They just knew in their bones that there might be a “decreased risk” of CHD during years 3 to 5” (versus those first three years). Tenaciously, they followed 2,321 of these extraordinary women (93% of the HERS survivors) for another 2.7 years. Randomly assigning 1,250 women to hormones and 1,260 to placebo, again they found that “hormone therapy did not reduce risk of cardiovascular events.” (The trial was stopped early; it had been scheduled to run for four years.)66 Was anyone listening? Not so you’d notice: by 2001 some 15 million women in the U.S. were filling prescriptions for “replacement” hormones annually, perhaps a third solely to prevent heart disease.18 In spite of the calls for “well-designed clinical trials” to establish the cardioprotective effect of hormones at menopause,62 nobody wanted to hear the results.

Finally, a year later in 2002, when the largest randomized clinical hormone trial in history, the Women’s Health Initiative (WHI) was stopped early because the risk/benefit quotient simply did not compute, people listened – at least for five minutes. The WHI was simply too big to ignore. It had taken 25 years and billions of dollars in estrogen sales (and who knows how many unnecessary deaths), but this necessary randomized trial finally reached a conclusion. (page 125)

The Women’s Health Initiative
A massive, $625 million, 14-year, study the WHI had enrolled some 160,000 postmenopausal women between the ages of 50 and 79 into the largest trial ever funded by the NIH. (It was probably no coincidence that a woman, Bernadine Healy, and also a cardiologist, was the director of the NIH at the time.) Designed between 1991-92, and based on what was hopefully (and, as it turned out, erroneously) called “the accumulated evidence at that time,” the WHI focused on “defining the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women.” The study had several arms, a number of them interventional and one, observational, to study various and sundry aspects of women’s health such as a low-fat diet and the efficacy of Calcium/Vitamin D in preventing fractures. “When the WHI is finished” was a throwaway line common throughout the nineties. There were high hopes for cardiac prevention, “based on supportive data on lipid levels” and from primate studies – not to mention all those terrific observational studies.67

Then the unthinkable happened.

The trial was stopped early, at the end of May 2002, after an average follow-up of 5.2 years – when, to their horror, proponents of “HRT” discovered that not only did the women taking estrogen/progestin have a far higher incidence of major cardiovascular events but the “test statistic for invasive breast cancer exceeded the stopping boundary.”68 In other words, even though the researchers had expected the incidence of breast cancer to rise, they had not appreciated just how much estrogen could increase that risk. Hormone therapy simply could not be said to be beneficial in reducing a woman’s risk of future disease.

For once the media did not ignore the results – and, while “millions of women and their physicians wondered what to do next, the scientific community wondered what went wrong.” Of course what the scientific community should have been wondering is how they could have been so wrong, so unscientific, so biased and so stubbornly sure of estrogen, given that the entire basis for science as a form of inquiry is doubt. Such “authoritative” pronouncements are “antithetical to the nature of science” which, by definition, is supposed to be a dynamic, fluid process not an unyielding one carved in stone.70 (page 126)

Never give up, never surrender
When a hypothesis, an idea, like that of estrogen being fundamentally positive, refuses to die – as social scientists and cross-cultural observers have noted – the reason has nothing to do science and everything to do with culture. Just as any evidence, no matter how sound, that does not fit in with prevailing social mores or cultural beliefs of what ought to work is, inevitably said to require “more proof,” as Lynn Payer had pointed out in her comprehensive book, Medicine and Culture, some 15 years earlier. The United States had whole-heartedly embraced the hormone – estrogen – thesis for nearly a century; even the DES debacle (DES was a synthetic estrogen eventually pulled off the market) had not convinced the medical establishment that estrogen (particularly by itself) was simply not the answer and would cause harm. And in the United States, once the rationale for a specific idea has taken hold – particularly if that idea is one of doing something, versus sitting back and allowing nature to take its course – the national character is tenacious. Perhaps this was inevitable in a country painstakingly built on and through the gradual colonization of an unfriendly frontier. But simply because something ought to work – and the theory explaining why it should is an excellent one – does not mean that it does. But a culture that valorizes advance, progress and speed; a country where medicine is characterized in military terms and revolves around the notion that we must do something; in a country that considers aging an enemy to be conquered, giving up is not an option.73 Particularly if what is being given up is a hormone, estrogen, whose essence has been considered fundamental to the concept of women’s health for nearly a century. (page 128)

[Unfortunately, even after the Women’s Health Initiative, another phase of denial seems about to start (yet again!) – with the notion gaining ground that it was not the estrogen itself that was at fault but the dose and timing.] And now the media seems to have picked up the discourse, insisting that there is still a discussion to be had because we “just don’t know.”

Yes. We. Do. Estrogen has not been beneficial in reducing cardiac disease. That ship has sailed. Women need to understand that. Estrogen causes strokes, heart attacks, breast cancer. It did not prevent dementia, heart disease or any of the other terrible things it was supposed to. During perimenopause, when some women experience onerous symptoms, their risk of cardiac disease (and hysterectomy) rises along with their estrogen levels. During that time, taking progesterone to balance out their wildly spiking estrogen might well serve as a physiologic anchor – and prevent some of the potential risks of this stormy transition into menopause. After that, normal, healthy, well women have no reason to consider taking hormones. Estrogen was not and is not useful in preventing disease and has been shown to cause harm. (page 129)

From Chapter 6…
The Basics of Bone
Osteoporosis. A word that few of us had heard when we were young and certainly our grandmothers knew little of, although they did know about the “dowager’s hump” (a forward bending of the upper back) caused by vertebral compression-type fractures. Over the last decades, however, we have heard nothing but bad news about our bones – how they are hollowing out, becoming frail and fragile; putting us at risk of falling and not being able to get up. Advertisements on television remind us of the alarming statistics: once we reach fifty, our bones are on the brink of disaster, “one in four” of us is at risk. Yet again, we are told that we must be proactive, involved; stay on top of it lest we “shrink away” and, who knows, maybe disappear altogether. (Perhaps this is a not-so-hidden metaphor for the way aging women vanish – in films, or ads or as role models throughout the culture, who knows.) Recommendations for scans and screening programs pour in thick and fast, as do the exhortations to take drugs and supplements to ward off this skeletal disaster, “bolstered by advocacy groups, professional societies, educational programs.”2

Hormones naturally have also had their role. In fact, the common term for osteoporosis in women is “postmenopausal osteoporosis” because the current thought process goes something like this: menopause causes “estrogen deficiency” which causes rapid bone loss, therefore women have fractures after menopause and lack of estrogen must be to blame. Although dropping estrogen levels do cause bone loss, this perspective is not only narrow and myopic but just plain wrong. (page 132)

Perimenopause, early menopause and breakage
What most of us associate with the term osteoporosis is broken bones; having a fracture for no obvious reason. These commonly are important clinically and in terms of public health since fractures do seem to be associated with higher mortality – about one year after a fracture the risk of dying rises 20% – plus loss of “functional state,” even having to enter long-term care.14 As alarming as these statistics sound, however, yet again it is important to put these figures in context, and appreciate that they do not routinely mention age, and inevitably it is being older that is the most important factor in, and predictor of, osteoporosis.15 (Of course being older is also a risk for all manner of other conditions, from coronary artery disease to Parkinson’s.) So, contrary to the hype, it is not our 50th birthday (and menopause) that normal, healthy midlife women should be concerned about but (if she insists on being concerned) her 80th, since the frequency of osteoporosis rises to approximately 25% of women by age 80 or 90. That is where that scary phrase “one in four women will develop osteoporosis” comes from. (page 133)

The emotive tone notwithstanding, it is also important to stress that statistics, by definition, are phrased in general, rounded-out terms and subject to error and misrepresentation. (As Mark Twain said, “There are lies, damn lies and then there are statistics.”) And much as we would like to lump all “older” people together, the reality is that as we age the differences between us increase. As an article in The Lancet succinctly explains, physiologically aging is imply a “progressive constriction of each organ system’s capacity to maintain homeostasis in the face of challenge” and is “influenced by diet, environment, and personal habits as well as by genetic factors.” As a result, individuals become more dissimilar as they age, making generalizations increasingly difficult the older we get.16 The authors add that to speak of a “healthy old age” is not a paradox. As such, the numbers on osteoporosis or any other threat of old age ought to be put in context.

These are not the kind of language we tend to hear, however. More common is the advice to have tests, scans or screenings of one sort or another, from colonoscopies and having one’s cholesterol checked to mammograms and, for osteoporosis, bone density scans. But are these strategies truly preventive and are they useful? In terms of bone density scans, it can get tricky, because the evidence connecting bone densitometry or bone density scans to fracture is often contradictory, and perhaps unsurprisingly, those studies finding the strongest link between bone density and fractures are either funded by, or strongly associated with, pharmaceutical companies.17 Yet the large Canadian study, cited above, of over 16,000 women, concluded that “most of the postmenopausal women with osteoporotic fractures had nonosteoporotic bone mineral density values.”12 (our italics) That is because the risks for falling increase as we get older, and we are more likely to fall awkwardly and thus fracture. Because, again, although bone density is what we talk about, it is falls that are more germane. (page 134)

In the same vein, a meta-analysis of some 90,000 person years, published in the BMJ, found that while bone density measurements might predict some fracture risk, they “cannot identify individuals who will have a fracture.” In other words, the predictive value of BMD is fair-to-middling useless. Unless that BMD is coupled with other important things like age, sex, having taken prednisone (a drug used for some autoimmune diseases that both causes bone loss and paralyzes bone gain), or, most importantly having a history of a low trauma fracture or a strong family history of fracture. (page 135)

Bones continually renew themselves through a sophisticated process of de- and re-mineralization. In simple terms the collagen that makes up the bone is first reduced down (resorption) by substances known as osteoclasts, then rebuilt (accretion) by osteoblasts: a process known as remodeling. Soon after puberty, all our bones finish growing in size, even though they continue the remodeling or renovating throughout our lives. This peak bone mass is affected by heredity, childhood activity, overall nutrition and calcium intake and, in women, menstruation and ovulation.30

Interestingly, in women, progesterone (the presence of the luteal phase during our menstrual cycle) also plays a part in that maximum or peak bone mass we achieve; for instance, in the Michigan Bone Health Study, premenopausal women with the lowest progesterone levels seemed to have the lowest peak bone mass.6 In other words, normal ovulatory cycles seem to have an impact on how well our bones form. Until we reach midlife, the bone remodeling tends to be even; there is neither a net gain or loss, but, once we reach a certain point in our adult lives (usually around age 30, but in this as in anything else there is enormous individual variability), both men and women experience gradual bone loss, at a rate of about 0.5% every year.31 (page 138)

From Chapter 7…
Integrating – toward a healthy future
In this book we hope to have given the reader much to think about; not only about hormones and the complexities of physiology and endocrinology, but also about the broader context – the time, place and even position – within which our knowledge, of medicine as anything else, is portrayed, presented and explained.

Most important, what we hope to have helped you realize is that there is no such thing as a “good” or a “bad” hormone – unlike the rhetoric that proponents of estrogen have been so quick to promulgate, even as they vilified progesterone and raised estrogen on a pedestal so high it was bound to fall off and hurt something. As it did. Hundreds of thousands, millions, tens of millions of women if we go back to the earlier part of the 20th century, were told to take estrogen, and, sadly, too many of these women suffered the consequences of this blind faith that there was only one hormone, estrogen, worth bothering about. With this book we have simply tried to put estrogen in its place, where it belongs, next to and alongside progesterone – waxing and waning over time and as our bodies change, from puberty and young womanhood through to adulthood, pregnancy, midlife, menopause and beyond. And it is in their essential balance that these two hormones, estrogen and progesterone, need to be conceptualized. (page 169)