Every year, a million American women, most in their 40s and 50s, enter perimenopause. Their sleep degrades. Their energy declines. They are overcome by waves of heat. But, what if I told you this condition was curable?

“Menopause is curable. Under proper treatment, nearly all symptoms cease in the vast majority of cases. The bodily changes typical of middle age can be reversed, and sexual functions can be restored, along with a fully feminine appearance.”1

In fact, it gets better! Menopause is not just curable, but preventable entirely!

“Menopause is completely preventable. No woman need suffer menopause or any of its symptoms if she receives preventive treatment before the onset of menopause.”2

Surely, there must be some trade-off here? No woman has made it into her 70s without going through menopause. Of course we now know that loss of ovarian function is what drives menopause. But, what’s the catch?

“There is increasing evidence that estrogen has a preventive effect on breast and genital cancers. In 1962, the Journal of the American Medical Association reported on one of my studies, in which a group of 304 women, aged forty to seventy, had been treated with estrogen for periods up to twenty-seven years. Given normal odds, as established by medical statistics, eighteen cases of cancer—either of the breast or the uterus—would normally be expected in this group. Instead, not a single case of cancer occurred!”3

What a miracle molecule! Estrogen will keep you young! And healthy! Perhaps estrogen is all you need? This incredible news came not from the unsavory pharmaceutical industry. Rather, this was the gospel of Robert Wilson. A community gynecologist, Wilson preached the parables of all-natural (equine) estrogen. His bible, Feminine Forever, was a New York Times best-seller. He was printed in Vogue, Newsweek, and Science Digest. He was eminently qualified—his bestseller dedicates two pages to his degrees, membership, and awards.4 It had to be true… Right?

And yet, it wasn’t. The gospel was largely baseless. In fact, self-reported clinical results compose the near-totality of Wilson’s published work. A collection of case reports and anecdotes, or “anecdotal data” if you prefer. It was pretty straight forward to observe the symptomatic benefits from adoption and withdrawal of estrogen. These effects are large, consistent, and reproducible. However, evidence of longer term efficacy and safety from randomized clinical studies was absent.

But, Wilson was selling a solution to a real problem. In the mid 1960s, much like today, most women go through menopause without any treatment. But, Feminine Forever, with some undisclosed financial support from estrogen manufacturer Ayerst, changed that. By 1975, estrogen prescriptions had doubled. The market for menopause therapy quadroupled.5 Patients wanted to believe the promise. Some estimates put the prevalence of estrogen adoption north of 50% in cities by 1975.6 What followed was a half-century reckoning: with cancer, with statistical rigor, and with the question of what happens when medicine promises more than it knows.

Part 4 of this series traced how estrogen rose from a laboratory curiosity to a cultural phenomenon: Premarin to Feminine Forever. Part 5 asks what happened when that phenomenon collided with evidence.

A Series of Safety Scares

One key selling point was safety. Not only was Ayerst’s Premarin estrogen effective, it was natural! Wilson was simply replacing a missing molecule, albeit with its equine metabolites. Wilson's vision had a philosophical elegance. “Estrogen therapy doesn't change a woman," he wrote. "On the contrary: it keeps her from changing.”7 The medication restored the natural state. Menopause was pathology. So, you’re safer with it than without it, right?

Patients were rightfully concerned. Not long before, a prior popular estrogen mimic, Diethylstilbestrol (DES) had led to cancers. First synthesized in 1938 by Edward Charles Dodds, DES was a structurally simple non-steroid molecule. That made it a cheap, potent, and orally active alternative to human-derived estrogen preparations. Dodds chose not to patent DES, so scores of companies manufactured it freely. The FDA approved DES in 1941, and by the mid-1940s physicians were prescribing it to pregnant women to prevent miscarriage. No clinical trials ever legitimated the practice. Yet, up to two million American women took DES during pregnancy.8

In 1971, Arthur Herbst and colleagues at Massachusetts General Hospital published a devastating NEJM report: a cluster of young women with clear-cell vaginal adenocarcinoma, an extraordinarily rare cancer, were all daughters of women who had taken DES during pregnancy.9 The drug was pulled from obstetric use. Subsequent research found additional adverse effects in exposed sons and daughters, plus increased breast cancer risk in the mothers themselves.10

Intriguingly, the most concerning side-effect of DES didn’t emerge for decades, and in the next generation no less. But, from origin as a structurally distinct synthetic estrogen mimetic, rumors of DES-lined side-effects swirled for decades. The prevailing bias favored natural estrogens, like Premarin. The natural-versus-synthetic distinction became a commercial asset. DES was artificial and dangerous; Premarin was natural and, therefore, presumably safe. The assumption persisted largely unexamined until the mid-1970s.

Endometrial Cancer Emerges

On December 4, 1975, the New England Journal of Medicine published two studies that shook the estrogen consensus. Two independent teams had arrived, separately, at the same conclusion: unopposed estrogen dramatically increased the risk of endometrial cancer.

Smith et al. compared 317 women with endometrial cancer to 317 controls and found that estrogen users faced a 4.5-fold greater risk. Women without typical predisposing factors who took estrogen had the highest likelihood of developing the disease.11 Ziel and Finkle using Kaiser Permanente records found a duration-dependent relationship: risk was up to fourteen times higher for women who took conjugated estrogens for more than seven years.12 Both studies were published alongside two commissioned editorials — an extraordinary editorial decision underscoring the gravity the journal’s editors attached to the findings.²³

Corroboration came rapidly. By 1979, at least six additional studies confirmed the link, with relative risks ranging from 3.1 to 15, all showing dose- and duration-dependence. A natural experiment in Seattle provided the most elegant evidence: as estrogen prescriptions declined in the late 1970s, endometrial cancer incidence declined in parallel.13

According to historian Elizabeth Watkins, the medical profession did not immediately capitulate. For example, Robert Kistner of Harvard Medical School dismissed the epidemiological evidence, attributing elevated cancer rates to misdiagnosis and concluding, memorably, that

‘‘From studying the effects of estrogen, progesterone, and other progestins on the endometrium in animals and women for 20 years, I am convinced that estrogens per se are not a cause of endometrial cancer in the human female… endometrial cancer is a disease of those women who have easy access to physicians.” (Watkins 2007 p. 99)

Two Yale biostatisticians, funded in part by Ayerst Laboratories, published a rebuttal claiming the risk was only 1.7-fold, but the NEJM editors published an editorial dismantling their methodology in the same issue. By 1979, however, “the pendulum had swung decisively in favor of a causal relationship between prescription estrogen and endometrial cancer.”14

The market responded immediately. According to Watkins, “In 1976 alone, dollar sales for menopausal estrogens decreased 11 percent and the number of prescriptions dropped 19 percent.”15 Feminists of the era, some skeptical of hormone therapy for a plethora of reasons, argued

“Estrogen replacement therapy is dangerous. It will raise your cancer risk. It may lead to vascular disease. It may even kill you.” (Rosetta Reitz, Menopause: A Positive Approach. 1977 from Houck 2003 p. 119)16

Adding Progestin

The endometrial cancer crisis was resolved by adding synthetic progesterone to the regimen. Robert Greenblatt proposed combining estrogen with progestin for five to seven days per cycle “to prevent endometrial carcinoma by causing the uterus to shed its lining.”17 The fix worked remarkably well. By the early 1980s, it became standard protocol, and multiple studies showed that “the addition of progesterone... not only negated the increased risk of uterine cancer associated with estrogen alone but actually protected against endometrial cancer; women receiving progesterone with estrogen had a lower incidence of endometrial cancer than women who received no hormones.”18

It is worth pausing on what medicine chose not to do. Some physicians proposed an alternative solution: prophylactic hysterectomy. Remove the uterus and you remove the cancer risk, freeing the patient for continued estrogen therapy. Hysterectomy was incredibly popular at the time. By the mid-1970s, nearly half of post-menopausal women underwent a hysterectomy. Watkins observes, with understated horror, that this:

“reveals a curious disregard for the inherent value of a postmenopausal woman’s uterus… indicates the extent to which menopause had become medicalized: these doctors did not question the widespread practice of major abdominal surgery among older women, but instead condoned the procedure as part of the risk-benefit calculus for estrogen replacement.”19

The progestin compromise resolved the endometrial cancer problem but introduced a new variable whose own risks, particularly regarding breast cancer and cardiovascular events, would not be understood for decades. Combined HRT (estrogen plus progestin) became standard for women. The combination of conjugated equine estrogens (CEE) plus medroxymedroxyprogesterone acetate (MPA), specifically Prempro, that would later be tested in the Women’s Health Initiative.

Meanwhile, the breast cancer question was accumulating; slowly, ambiguously, and without the decisive clarity of the endometrial cancer data. Pre-1985 studies produced inconsistent results; post-1985 studies largely agreed that long-term menopause hormone therapy increased breast cancer risk. Two dueling meta-analyses in 1991 reached opposite conclusions: a Vanderbilt analysis found negligible risk at standard doses (RR 1.08); a CDC/Emory analysis estimated that long-term estrogen use “could be responsible for at least 4,708 new cases and 1,468 deaths from breast cancer each year.”20 By 1992, the situation was untenable.

One thing, however, was becoming clear: observational studies could not resolve the question. The “healthy user” bias contaminated every non-randomized comparison. The call for a large randomized controlled trial became a chorus. That call would culminate in the Women’s Health Initiative.

Realizing Rigor

The Women’s Health Initiative was born from a specific political and scientific moment: the arrival of women in positions of institutional power, and recognition that decades of prescribing rested on an evidence base that could not answer the key questions.

Bernadine Healy, confirmed in 1991 as the first female director of the National Institutes of Health, used her position as a bully pulpit. At Senate hearings on women’s health, she announced the launch of what she called “the largest community-based clinical, prevention and intervention trial ever conducted... to examine the major causes of morbidity and mortality in women of all races and all socioeconomic strata.”21 In a companion NEJM editorial titled “The Yentl Syndrome,” she documented sex bias in cardiac care: women received less aggressive treatment than men unless they presented with symptoms matching the male profile of heart disease.22 Medicine, she argued, could no longer treat women as a smaller variant of men.

The WHI enrolled 161,809 postmenopausal women (aged 50–79) across the country. The estrogen-progestin arm randomized 16,608 women to either Prempro or placebo. The study cost nearly one billion dollars in 1992. It was “big science” arriving in women’s health: a Manhattan Project for menopause.

But even before the WHI reported, the HERS trial (Heart and Estrogen/Progestin Replacement Study) delivered a warning shot. Funded by Wyeth-Ayerst and completed in 1998, HERS found that combined HRT did not reduce heart attacks in women with existing heart disease and nearly tripled the risk of blood clots.23 The investigators were so shocked that they asked Wyeth to verify whether the hormone and placebo pills had been accidentally switched. Yet, HERS barely dented the estrogen consensus. Prescriptions continued to rise. Even Bernadine Healy, after HERS, continued to recommend estrogen for cardiac prevention on CBS Evening News.24 It would take the WHI’s sheer scale and dramatic termination to break through.

July 2002: the end of MHT?

In May 2002, the WHI’s Data and Safety Monitoring Board, reviewing the data for the tenth time, found that breast cancer diagnoses among participants had exceeded the predetermined safety threshold. The estrogen-progestin arm was stopped three years early.

The results, expressed in relative terms: women on Prempro had a 26 percent increase in breast cancer (HR 1.26), a 29 percent increase in coronary heart disease (HR 1.29), a 41 percent increase in stroke (HR 1.41), and a 113 percent increase in pulmonary embolism (HR 2.13). There were benefits too: a 37 percent reduction in colorectal cancer and a 34 percent reduction in hip fracture. In absolute terms, these numbers translated to 8 more breast cancers, 7 more coronary events, 8 more strokes, and 8 more pulmonary embolisms per 10,000 women per year alongside 6 fewer colorectal cancers and 5 fewer hip fractures.25

JAMA fast-tracked the article. NIH issued a press release. Letters went to 16,000 participants instructing them to stop their pills. Headlines: “Study Says Halt Hormone Therapy.” “Health Risk to Women Halts Hormone Study.” Within a year, Prempro prescriptions dropped 33 percent, Premarin’s by 66 percent, and total HRT prescriptions by more than a third.26

There was, however, a second arm of the study, the estrogen-only arm, for women who had previously undergone hysterectomy. When its results arrived in 2004, they told a significantly different story. No increased breast cancer risk. In fact, a 23 percent reduction in breast cancer (HR 0.77). Reduced hip fractures. The increased stroke risk remained, but the overall picture was far more favorable than the combination arm.27 This discrepancy suggested that the progestin, a synthetic progesterone derivative, medroxyprogesterone acetate (MPA), rather than the estrogen, might have been the primary culprit in the combination arm’s adverse findings. The distinction that would become central to the arguments that followed.

The WHI was a landmark study. It answered the question of whether combined estrogen-progestin therapy prevents heart disease with a definitive no. But its design, its communication, and its over-generalization introduced distortions that took more than a decade to correct.

The problems were not trivial. The median age of WHI participants was 63, more than a decade past the typical onset of menopause. The study did not test the population most likely to use HRT: women in their late 40s and 50s experiencing menopausal symptoms.

The WHI tested a single regimen oral CEE+MPA. The results were generalized to all women, all ages, all MHT formulations, and all routes of administration. The 2026 Makary JAMA Viewpoint calls this “a sweeping overreach that... was never warranted by the data.”28

The 26 percent increase in breast cancer the number that drove the headlines, drove the panic, and drove millions of women off their medications “almost reached nominal statistical significance.”29 Almost means it did not. Bluming and Tavris note the exchange at a 2002 continuing medical education conference, when a physician questioned the WHI investigator about the non-significant confidence interval. The investigator’s reply:

“What happens is, if it’s an important question and if it’s a big study... and you can’t do it again because it costs too much money, then they’ll say that’s the best data there is and then the statistical police have to leave the room.”30

Reanalysis: the return of MHT?

The reassessment, when it came, centered on a question the WHI had not been designed to answer: does the timing of hormone initiation matter?

In 2013, Manson et al. published a comprehensive age-stratified reanalysis of WHI data and the results were striking.31 For women aged 50–59 — the clinically relevant population — the risk-benefit balance was fundamentally different from the overall WHI findings. Fewer coronary events. Fewer cancers. Fewer deaths. Fewer fractures. Only modest increases in thrombosis and stroke. In 2016, Manson and Kaunitz published an NEJM perspective arguing that “our understanding of [menopause hormone therapy’s] benefits and risks has never been clearer” and that the absolute risk of adverse outcomes was “much lower in younger women than in older women.”32

The “timing hypothesis” that estrogen may be broadly protective when initiated near menopause but harmful when initiated decades later gained substantial support. It took until February 2026 for these findings to reach the drug label. FDA Commissioner Marty Makary, in a JAMA Viewpoint, argued that the original boxed warnings were “based on a misapplication of WHI results” and that the WHI’s specific findings about one regimen in one age group had been wrongly generalized to all women, all ages, and all formulations.33 The FDA removed cardiovascular disease, breast cancer, and probable dementia risk statements from the boxed warning retaining only the endometrial cancer warning for estrogen-alone products in women with intact uteruses.34

The chilling effect of the original warnings had been severe. In 2020, less than 5% of the women aged 46–65 received an HRT prescription. Modern formulations transdermal estradiol, which bypasses hepatic first-pass metabolism and is thought to reduce clotting risk, and oral micronized progesterone, which appears to have neutral effects on breast tissue, bear little resemblance to the oral CEE plus MPA regimen the WHI tested. The labeled recommendation now advises starting HRT within 10 years of menopause onset or before age 60.

Some WHI investigators have pushed back. Jaques Rossouw, a WHI lead investigator, argued that the FDA’s relabeling is a step backwards into the pre-WHI era and that no new large RCTs had been conducted to change the balance of known risks.

Did we learn anything?

First, acting without evidence is costly in both directions. The Wilson era demonstrated the danger of widespread prescribing based on physiological reasoning and anecdote. The post-WHI era demonstrated the equal and opposite danger: an overcorrection so severe that it denied therapy to the very women most likely to benefit. Both errors harmed women. The former by exposing them to unquantified risks. The latter by subjecting them to years of treatable suffering. Striking a balance here is hard. Only high quality clinical evidence can clarify. We will have to deal with the consequences of largely denying a generation of women access to low-risk menopause hormone therapy for the decades to come. We don’t understand the impacts yet, but I suspect we’ll see more diabetes and broken hips than we did in prior generations.

Second, statistical literacy. The WHI’s 26 percent increase in breast cancer, reported in relative terms, generated international panic. In absolute terms, it meant eight additional cases per 10,000 women per year. It’s a meaningful difference, especially over a lifetime, but the risk might be worth it during the perimenopausal years.

Third, the distance between a molecule and a medicine. Almost every medicine is a molecule, but few molecules prove to be medicines. Part 4 of this series ended with the observation that the distance between a molecule that works and a molecule that is safe is often measured in decades and tragedies. The pattern recurs: a plausible mechanism, observational enthusiasm, commercial amplification, belated RCT testing, overcorrection. It is not unique to estrogen.

Fourth, marketing blocks the generation of the evidence patients need. Once molecules are adopted en masse, resolving causality in the absence of massive increases in risk is difficult. Manufacturers have no incentive to risk the sales of their established products. For estrogen, it took favorable political winds, a billion dollars, and the largest clinical research endeavor in NIH history to get a cursory answer to the safety and efficacy questions. We can argue over the formulations, but CEE/CEE+MPA were the popular forms of the era. These studies should have been run pre-approval. The story of estrogen in Menopause Hormone Therapy is, if anything, an argument for a stronger FDA with more stringent pre-approval evaluation.

I can’t help but think of the enthusiasm for “natural” “peptides” like BPC-157, a 12-amino acid which matches no known human protein yet is marketed breathlessly as a cure for musculoskeletal aches and pains. Salesmen, often less qualified than Wilson but similarly untethered from reality, urge patients—often struggling with major unmet medical needs—to try injecting some of the latest and greatest white powders from China.35 Others sell a “peptides” as an intervention for health optimization: getting older? Take some TB-500 and you’ll feel like yourself again. The evidence in favor almost always boils down to a mixture of anecdotes and “trust me, bro.”

Do these “peptides” work? Are they safe? Who knows! Some of these “peptides” might be medicines in the future. One popular peptide, CJC-1295, a Growth Hormone Releasing Hormone fragment, is a synthetic derivative of an endogenous protein that was being developed by ConjuChem Biotechnologies. In fact, some popular peptides like “Reta” (retatrutide) are currently being developed by pharmaceutical companies and will soon be FDA approved. This is the best case scenario.

But, history tends to rhyme. The FDA is re-scheduling certain “peptides” for compounding. Soon, compounding pharmacies will be selling uninspected, (hopefully) white powders from China for mass consumption. Apparently “compounders” and online not-a-pharmacy sites can market unapproved products without any evidence. I’m not sure that’s a good idea for any involved. But, like with Ayerst and Wilson, I’m sure we’ll see financial relationships emerge between the makers and the boosters. Is that good for patients?

And, for the “peptide” boosters reading this, unless you want your favorite peptide to end up like estrogen—with perpetually vexed safety and efficacy—I recommend you find a way to pony up the cash and run the RCTs patients deserve. The cost of moving fast on weak evidence here is the long-term health and safety of patients. The risks of estrogen, CEE+MPA, and DES didn’t emerge until after years, sometimes decades, of exposure. Let’s not repeat the mistakes made with estrogen. The joy of being human is learning from the experience of others. Let’s make our mothers proud.

Last, separate evaluation from origination. Perhaps the most discomfiting lesson is the one embedded in the ethical debates of the 1930s, traced in Part 4. The conservative physicians who urged restraint—low dose, short duration, symptoms only—turned out to be roughly correct. But they were correct for the wrong reasons: not because they had evidence of harm, but because they believed menopause was a natural verdict that women should accept. The physicians who later championed lifelong estrogen, Masters, Shelton, and Wilson, were more sympathetic to women’s suffering and more willing to take their preferences seriously. They were also completely untethered to the evidence for its safety and efficacy. Good intentions, poor evidence, reputational esteem, and aggressive promotion made a more harmful combination than paternalistic caution. The best way to separate the ideas from the baggage: randomized, double-blind placebo controlled clinical trials.

Coda

If the FDA’s 2026 relabeling represents a genuine correction, an evidence-based acknowledgment that the post-WHI overcorrection went too far, then medicine has, in some sense, learned from this story. The new labels are conditional. They specify age ranges. They distinguish formulations. They trade the blunt instrument of a boxed warning for the finer grain of clinical guidance. That looks like progress.

But if “remove the black box” becomes the next Feminine Forever — if the pendulum swings past the evidence again, propelled by commercial enthusiasm and a cultural appetite for pharmaceutical solutions for aging — then the lesson has been lost

The difference between the two will be measured not in labels, but in evidence. And the evidence, as Bernadine Healy understood when she launched the WHI, takes time and money. I don’t think the estrogen story is over. If anything, it is, for the moment, better informed.

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In theory, a physician could prescribe a specific quantity of a specific substance rather than, say, twenty grams of minced cow ovary in a sandwich. Thyroxine had replaced sheep thyroid extract for treating myxoedema. Perhaps estrone could replace Ovariin?

Pharmaceutical companies raced to bring estrogen to market. Within five years of estrone’s crystallization, a proliferation of products appeared: Theelin (Parke-Davis), Progynon (Schering), Emmenin (Ayerst), Amniotin (Squibb), Folliculin (Girard), Oestroform, each extracted from a different source, each claiming superiority. The underlying question - which preparation was the right one - remained unanswered.

Isolated estradiol, while physiologically ideal, remained uneconomical; Estradiol oxidizes readily to estrone under the acidic conditions of extraction. Four tons of pig ovaries yielded only 12 miligrams of pure estradiol. Each preparation derived from the urine or placental tissue of pregnant women, each promising potency and efficacy, each constrained by the same immutable problem: there were only so many pregnant women, producing only so much urine.

The chemists of the 1930s knew this perfectly well and at work solving the supply bottleneck. The structure of estrone was known. Partial synthesis from cholesterol was achieved by 1939, first by Russell Earl Marker, working with ergosterol, then by Inhoffen and Hohlweg at the German firm Schering. These partial syntheses worked in principle, but they remained prohibitively expensive for manufacturing. The full total synthesis of estrone came only in 1948, when Anner and Miescher published their work in Helvetica Chimica Acta, a painstaking route of more than twenty chemical steps unsuitable for mass production.1 The commercial demand for estrogen was clear. But, the industry sat at an impasse: how could it scale estrogen? What the market needed was a source of estrogen that was abundant, renewable, orally active, and affordable.

That source would not come from improved chemistry. It would come from the barn.

Estrogen, naturally

The breakthrough came not from a chemist's laboratory but from an observation from a familiar animal scientist, Bernhard Zondek. Zondek, whose urine-based pregnancy test had enabled the isolation of estrogen, made a remarkable discovery while investigating estrogen excretion in animal pregnancy. In his 1934 publications in Nature, Zondek reported that pregnant mare urine contained between 100,000 and 500,000 mouse units of estrogen per litre.2 To place this in context: human pregnancy urine, by comparison, yielded a tiny fraction of these concentrations. The pregnant mare was, in effect, an estrogenic factory. The mares produced a biological concentrate so potent that a single mare, during a single pregnancy, could yield more estrogenic material than a small army of women. And unlike pregnant women, mares could be managed industrially. We had the pastures. We had the barns. We had the buckets.

Zondek’s observation transformed a chemical problem into an agricultural one. Ayerst, McKenna & Harrison, the Canadian pharmaceutical firm that had previously commercialized Emmenin—the estrogen preparation derived from human placentas—recognized the opportunity. In 1939, scientists at Ayerst revisited the possibility of extracting potent estrogens from horses' urine. The company's previous product, Emmenin, had been suffering in the marketplace, losing ground to a cheaper synthetic estrogen, diethylstilbestrol (DES). But horses offered something DES could not: a renewable, abundant, scalable supply of natural estrogenic compounds. Ayerst's scientists developed a process to concentrate and isolate conjugated estrogens—specifically the sulfate conjugates of estrone and other estrogenic compounds naturally present in mare urine.

These conjugated estrogens proved to have a distinct pharmacological advantage: the primary component, estrone sulfate, is two to four times more potent than unconjugated estrone, and nearly as potent as DES.3 They were also water-soluble, which meant they could be formulated as oral tablets rather than injectable oils—a practical advantage that would shape physician prescribing habits for decades to come.4

The product launched in 1941 under a trade name that advertised its origin: Premarin, (PREgnant MARe urINe).5 The name implied a “natural” origin transparently derived from a biological source rather than conjured in a synthetic laboratory. Approval from the U.S. Food and Drug Administration followed within a year, and the initial clinical reception was enthusiastic.

By February 1943, the Journal of Clinical Endocrinology published four independent clinical studies from medical centers in Chicago, Louisville, Los Angeles, and Madison, Wisconsin all reporting that Premarin was effective, well-tolerated, easy to administer, and free of the noxious side effects (nausea, vomiting) that plagued DES.6 Physicians, who harbored suspicions about the synthetic DES, found the “natural” horse origin reassuring. As one contemporary commentator put it, “The laboratory cannot quite give the finished product the adsorption advantages that nature conjoins in her slow-working elaboration” (Watkins, 2007, p. 26). Premarin worked, or appeared to work, better than the synthetic alternatives. And it worked at scale. Within a decade, it became the dominant estrogen preparation in the United States and Canada. Premarin would dominate for more than sixty years.

The history of hormone replacement therapy is, in some ways not a story of chemistry, but rather a story of supply chains. Zondek’s observation about pregnant mares transformed the problem entirely. Ayerst’s decision to build an industry around mare urine was, in many ways, inevitable. Not because it was ideal. But because it was possible, scalable, and profitable. Synthetic estrone, though available after 1948, never captured the same share of the market. The total synthesis remained expensive; the industrial infrastructure for producing horses' urine was already established; the medical profession and the public had been persuaded that the "natural" source conveyed an implicit safety. The equine estrogens would alleviate hot flashes, restore vaginal tissue, stabilize mood, and reduce fracture risk. They would also, unbeknownst to those who took them, carry their own set of risks. And they would do all of this not because they were the best possible, nearest bioidentical estrogen—but because they were the most available one.

MHT: controversial before inception

Perhaps unsurprisingly, debates over the ethics of Menopause Hormone Therapy (MHT) are older than the regimens themselves. Starting in the 1920s, with the discovery of estrogen as the primary ovarian substance, physicians argued about what was natural, what was proper, what physicians had the right to alter, and whether the body of an aging woman was a fit vessel for supplementation. In fact, the ethical debate about estrogen replacement preceded the pharmacological evidence by decades. Physicians argued over the moral status of hormone replacement long before they had any real data about its safety or efficacy.

Moral panic

One of the earliest objections came from John Hannan, a London physician at the Maternity Center and Hospital for Women, who wrote The Flushings of Menopause (1927) arguing against the practice of ovarian transplantation—grafting ovarian tissue from younger women (or from the patient herself if she had retained some ovarian function) into the bodies of postmenopausal women. Ovarian grafting was technically feasible; German and Austrian surgeons had been experimenting with it since the 1890s. Hannan’s raised a question that sounds almost quaint now: “

Would we be justified, even if it were possible, in delaying indefinitely, the onset of the menopause? Would the body, as old age advances with generalized degenerative changes, stand the strain of a vigorous sex life?

- John Hannan in The Flushings of Menopause (1927); excerpted from The Estrogen Elixr (Watkins 2007 p. 17)

The argument is worth dissecting, because it reveals something early medical thought about menopause. Hannan does not claim that estrogen is toxic. He does not claim that transplanted ovarian tissue fails to function. He claims something else entirely: that an aging woman’s body should not sustain sexual function, and that attempting to preserve such function through medical intervention would be unseemly and, moreover, physiologically dangerous. The concern possesses a sort of cosmic irony given the enthusiasm for the elder Brown-Sequard’s testicular extract injections. The assumption underneath is stark: menopause marks the end of femininity and sexuality. To defer that end would be to violate nature itself.

This anxiety about propriety would color medical discourse for decades. Physicians of that era, predominantly male, shaped by late-Victorian era views about female sexuality and aging, saw menopause not as a medical condition but as a biological threshold. The menstruating woman was reproductive; the post-menopausal woman was not. This was a verdict, pronounced by nature, by which men in white coats, however well-intentioned, should abide.

By the 1930s, a more ambitious argument began to circulate. If estrogen replacement could mimic the action of the ovaries, wasn't it fundamentally the same as insulin replacement for diabetics? The comparison was seductive. Insulin had been discovered by Banting and Best in 1921. By the early 1930s, it had transformed diabetes from a death sentence into a manageable chronic condition. Here was proof positive that replacement of a lost hormone could be not only safe but life-saving. Why, then, should the loss of ovarian estrogen be treated as a natural and inevitable transition, while the loss of pancreatic insulin was treated as an emergency requiring immediate pharmaceutical intervention?

Elmer L. Sevringhaus, a Wisconsin physician, wrote in the American Journal of Obstetrics and Gynecology in 1932 precisely this argument, comparing menopause to diabetes and suggesting that estrogen therapy was morally equivalent to insulin therapy. But the analogy, however intellectually elegant, had a fatal flaw—one the same physician himself recognized. As Watkins observed, he "acknowledged that menopause did not present the same life-threatening risk as did diabetes, because he acknowledged that 'the conversational method' of psychotherapy—'simply explaining to the patient the nature of her difficulty'—often worked as well as hormone therapy in relieving physical and emotional symptoms" (Watkins, 2007, p. 15-16). You cannot talk a diabetic child out of diabetic coma with mere conversation and reassurance, but, apparently, you could talk a menopausal woman through her hot flashes. Psychotherapy claims aside, there is a truth: diabetes is acutely lethal without intervention; menopause is self-limiting, painful but not acutely lethal.

The pendulum swings

Later, Servinghaus, himself would provide the evidence to undermine his own argument. By 1935, based on six years of clinical experience treating 115 patients, he reported in the Journal of the American Medical Association that none of his patients had required more than 2.5 years of hormone therapy. The clinical observation was simple but momentous: menopausal symptoms remitted naturally over time, with or without estrogen. This suggested something the insulin analogy had obscured: estrogen therapy was not a permanent replacement for a permanently absent hormone, but rather a temporary assist through a transitional biological period. The analogy collapsed, not because the comparison was inaccurate at the chemical level, but because it had been inaccurate at the temporal level. A woman is menopausal for a few years; a diabetic is diabetic for life.

Even as this clinical evidence was accumulating, the medical literature of the late 1930s and 1940s began to codify a new consensus. The titles of articles from this period are themselves instructive. They read almost like cautionary fables:

‘‘The Use and Misuse of Estrogens in Menopause,’’ ‘‘Oestrogenic Therapy: Its Uses and Abuses,’’ and ‘‘Indiscriminate Use of Estrogens in the Menopause’’ … They stressed the importance of prescribing estrogen for a limited time and tapering of gradually, and they warned against any kind of prophylactic use of estrogen in women approaching the menopause. One doctor feared that women might become addicted to estrogen, relying on weekly shots as a panacea for whatever might ail them. (Watkins 2007 p. 34)

The anxiety was not about safety, but propriety and restraint. The emerging consensus was clear: use estrogen only for acute symptoms, use the lowest effective dose, use it only as long as needed, then taper and discontinue. No prophylaxis. No long-term replacement. Do not attempt to preserve youth or femininity indefinitely. Some physicians even raised the specter of psychological dependence. Others feared women develop an addiction to estrogen, relying on estrogen supplements as panaceas.7 The worry was that women might demand ongoing treatment, that they might prefer pharmaceutical solutions to the acceptance of aging. The physicians worried that women, given access to a therapy, might make choices the physicians found troubling.

There is a quiet irony embedded in the medical history of this period, one that prefigures the tragic arc of Menopausal Hormone Therapy (MHT). The conservative physicians who urged restraint - low dose, short duration, symptomatic relief only - turned out to be roughly correct. When the evidence finally arrived decades later, it would confirm that chronic, high-dose estrogen therapy without progestin increased the risk of endometrial cancer. The Women’s Health Initiative study in 2002 would document excess risks of breast cancer, venous thromboembolism, and possibly stroke in women taking long-term hormone therapy. The cautious recommendations of the 1930s and early 1940s—short-term use, low doses, symptomatic indications only—align well with what modern evidence suggests is safer practice.8 But the conservative physicians arrived at these recommendations not because they had evidence of harm. That evidence would not arrive for generations. They arrived at restraint on philosophical and moral grounds, Perhaps right for the wrong reasons

Later, advocates who would champion lifelong estrogen therapy inverted this moral equation. They argued that accepting menopause was not respecting nature but abandoning women. They, again, reframed menopause as a deficiency disease, akin to diabetes or hypothyroidism. The solution? Obvious. Permanent hormone replacement. They would be wrong about the safety profile of chronic therapy, but they responded to something the conservative physicians largely dismissed: the real suffering of menopausal women, the genuine relief that estrogen could provide, and the possibility that some women might rationally prefer a medicated aging to an unmedicated one. The paternalists of the 1930s and 1940s protected women, in a sense, from a harm they did not yet know about. But in doing so, they also denied women the option of making a choice. The later advocates, commercial conflicts and embellishment aside, at least acknowledged that women's preferences mattered. The irony is discomfiting: the physicians who were cautious and perhaps more medically correct were so only because they thought women ought not have a voice.

Gender Trouble

With Premarin on the market and estrogen commercially available by the 1940s, American physicians began experimenting, in the loosest sense of the word, with sex hormone supplementation. The results ranged from plausible to bizarre to deeply unethical. “Pioneering” physicians - did not merely prescribe hormones; they prescribed sex itself. Femininity, masculinity, and a supposed "neutral" state were chemically enforced and thus amenable to chemical correction. Their enthusiasm for these novel concepts dramatically outran the evidence. But, it laid the groundwork for later popularizers of estrogen based MHT.

Enter: William H. Masters

Before he achieved fame as co-author of Human Sexual Response (1966), William H. Masters spent the 1950s at Washington University in St. Louis building a reputation as a researcher on the endocrinology of aging. His interest placed him within a long tradition of physicians who believed that sex hormones held the key to reversing age-related senescence, a lineage stretching back to the physiologist Charles-Édouard Brown-Séquard, who in 1889 injected himself with testicular extracts and claimed rejuvenation, and to the Austrian eugenicist Eugen Steinach, who in the 1920s performed vasectomies on elderly men in the belief that it would stimulate interstitial hormone production.9 But where Brown-Séquard and Steinach had worked with crude preparations and surgical interventions, Masters had the advantage of the recent steroid chemistry revolution: purified, standardized, injectable sex hormones. He operated at the St. Louis City Infirmary, a charitable institution housing the elderly poor—patients in no position to refuse participation. Consent, as the historian Elizabeth Watkins notes, was at best unclear.10

Masters implicated the loss of estrogen as the principal driver of age-related decline in women—not merely hot flashes and vaginal atrophy, but senility, osteoporosis, cardiovascular disease, and a generalized deterioration he associated with hormonal deprivation. While his contemporaries urged restraint - low doses, short durations, symptom relief only - Masters applied sex hormones liberally and claimed extraordinary results. He reported that estrogen could reverse menopause, inducing new menstrual cycles in postmenopausal women (Watkins 2007, p. 36). It is not entirely clear the degree to which his reports corresponded to reality. Watkins points out that, despite death rates of up to 40% in some of his geriatric cohorts, Masters continued to extol his hormone supplementation regimens without apparent reservation. These treatments were not merely ineffective, but also possibly lethal. Yet, Masters didn’t let messy evidence get in the way of a beautiful, elegant hypothesis.

The “Neutral Gender”

Masters’ signature contribution was his 1:20 cocktail of estrogen and testosterone mixed in a ratio of one to twenty. He claimed this preparation:

"This hormone combination [1:20 estrone:testosterone] achieves its effect by what seems to be an arrest, and possibly a partial reversal [emphasis added], of the aging process. This is the result of generally rejuvenated cellular and organ metabolism." (William H. Masters and Marvin H. Grody (1953). Obstetrics and Gynecology II in Watkins 2007, p. 37)

More striking still was the conceptual framework he erected around it. His experiments with the 1:20 cocktail led him to define what he called the "Third Sex" or the "Neutral Gender": the elderly.

In Masters' schema, aging transformed a person - man or woman - through menopause or andropause into a functional "castrate," a being stripped of hormonal sex. The elderly, irrespective of their previous sex, had become neuter. But this hormonal desexualization, though natural, was not irreversible. Masters proposed treating the "Neutral Gender" with injections of his 1:20 E:T cocktail irrespective of "previous sex," on the theory that restoring sex hormones would de-age the patient. It’s not readily apparent which sex the de-aged patient would revert into.

The implications were radical. Masters wanted sex itself to be a hormonal state, not a permanent biological fact. With exogenous hormones, sex could be pharmacologically maintained or restored. If losing your hormones meant losing your sex, then replacing your hormones meant reclaiming it. This represented a dramatic departure from the conservative consensus of low-dose, short-duration symptom management. Masters was not treating symptoms; he was, in his telling, “treating aging” and the “dissolution of sex.” He was constructing a taxonomy of gender defined entirely by endocrine status: man, woman, and neuter—each a pharmacological state, each amenable to chemical intervention.

How did Masters “pioneer” such work? Well, in his era, consent was a murky concept. Masters administered these cocktails to patients at the St. Louis Infirmary. Pre-Belmont Report (1979), before modern Institutional Review Board oversight, the boundaries between clinical care and clinical experimentation were poorly defined, especially for elderly, institutionalized patients.

The parallel to Robert Battey’s mass oophorectomies is striking. In both cases, physicians with strong, yet weakly supported, convictions about the biological basis of their patients’ suffering intervened aggressively, with limited evidence, and with minimal attention to the long-term possible consequences. Battey removed ovaries to cure nervous disorders; Masters injected hormones to cure aging. Both operated on vulnerable populations with limited capacity to refuse. Both framed their interventions as liberation from suffering. Both caused harm. The recurring theme is persistent: when some in medicine encounter a powerful tool—the scalpel, the syringe—they tend to use it first and ask questions later, especially when the patients are vulnerable and desperate.

Shelton: the Case for Lifelong Estrogen

If Masters was the most extreme voice, Shelton was the most quotable. E. Kost Shelton, a practicing endocrinologist and professor of medicine at UCLA, also advocated for the supplementation of estrogen throughout life. Shelton argued that estrogen was essential for a woman:

“to not only capture but to hold a husband’’; estrogen could and should be used to help her maintain her femininity and sexual attractiveness.

Shelton scoffed at those ‘‘therapeutic nihilists’’ who denied estrogen to postmenopausal women: ‘‘The very person who argues that menopause is a natural phenomenon fights nature every day. He pasteurizes his milk, boils his instruments, vaccinates his stock and his children, sprays and buds his fruit trees, flies against gravity, makes new elements and splits the atom. Is the menopause any different?’’ The concerns about estrogen were ‘‘reminiscent of the outworn arguments against anesthesia in childbirth, against cosmetics, against everything progressive in life.’’ (Watkins 2007 p. 45)

To oppose estrogen replacement was to stand against the tide of human advancement—to be a Luddite, a conservative, a therapeutic nihilist unable to imagine a future in which medicine could improve on nature. Estrogen could capture and hold a husband! Symptomatic relief was good too, but Shelton’s menopause was not primarily a medical condition but rather a marital emergency, a crisis of femininity.

Masters had “advanced” the conceptual framework—hormonal depletion as desexualization, hormonal restoration as rejuvenation—and Shelton had provided the cultural rhetoric, casting opponents of estrogen as backwards “nihilists” standing against progress. Together, they were assembling an argument that would become irresistible: if estrogen made a woman a woman, then replacing the estrogen lost in menopause would help women stay womanly. Who would dare deny women their essence?

Enthusiasm Over Evidence

Masters and Shelton were not marginal figures. They held academic positions, published in peer-reviewed journals, and influenced clinical practice. Their confidence and willingness to prescribe aggressively in the absence of controlled evidence reflects a broader pattern in mid-century medicine. The authority of expert clinicians, the prestige of the case report, and the conviction from physiological reasoning were the evidence.

The absence of Austin Bradford Hill-style randomized controlled trials in this domain is not incidental. Hill had run the first modern randomized controlled trial in 1948, assessing streptomycin for tuberculosis. By the 1950s, the methodology existed. It was proven. It was available. But it was not applied to estrogen.

There are probably many reasons why the novel RCT approach wasn’t applied to estrogen. It was already in widespread clinical use. But, perhaps this reflected the fact that menopause was not considered a disease worthy of rigorous study. Partly it reflected the confidence of the clinical establishment in its judgment. And, perhaps principally, it reflected the fact that the pharmaceutical companies selling estrogen had no interest in work that might produce unfavorable results. Why run a study that could undercut your best selling product?

Masters and Shelton published case reports and clinical impressions. They accumulated testimonials from satisfied patients. But they did not test their claims against control groups. The “excursions” in clinical endocrinology reveal not just individual excess but a systematic error: the failure to subject enthusiasm to evidence.

Feminine Forever

By the middle of the twentieth century, Premarin had become the established standard for menopausal symptom relief in American medicine. Physicians prescribed conjugated equine estrogen routinely for the acute disturbances of menopause: hot flashes, night sweats, vaginal atrophy, and the constellation of mood changes that often accompanied the transition. Yet, despite the growing clinical application, the dominant medical consensus remained conservative. Doses remained modest; durations remained brief; the goal remained circumscribed: ease the passage through a difficult season and then, when acute symptoms resolved, to discontinue treatment.

A recognizable cadre of physicians including Shelton and Masters began to argue for a fundamentally different approach: treat menopause as a permanent deficiency of estrogen requiring lifelong compensation.

Central to this intellectual shift was what historians have termed the “cardiovascular hypothesis”—an inference so simple it seemed almost self-evident.The observation was straightforward: premenopausal women experienced dramatically lower rates of coronary heart disease than age-matched men. The inference followed: estrogen must be cardioprotective. And the corollary was irresistible: if menopause removed this natural protection, then replacing estrogen should restore it. Yet this argument inferred causality from uncontrolled observation. No RCT support. No plausible mechanism rigorously established. Still, by the 1960s, the cardiovascular hypothesis had hardened into near-axiom among estrogen advocates. They cited it as settled science. Four decades would pass before anyone bothered to test the claim in a randomized trial.

Beyond the cardiovascular hypothesis, other applications of estrogen quietly expanded the scope of women who might benefit from treatment. The urogenital applications— vaginal atrophy, dyspareunia, and urinary incontinence—rested on mountains of intrapatient interventional clinical evidence and aroused little controversy. Yet these indications had a hidden consequence. They normalized estrogen as a treatment not merely for acute symptoms, but indefinitely. Was menopausal depression truly the result of estrogen deficiency, or was it more plausibly traced to the social circumstances of middle-aged women in a youth-centered, domesticity-obsessed culture of the 1960s? Some physicians prescribed sedatives or tranquilizers for menopause as alternatives to estrogen. The debate remained genuinely open, which meant there was room for ambitious clinicians to argue expansively for hormone use. And no one was more enthusiastic about estrogen than Robert Wilson.

An unlikely advocate

In April 1963, Robert Wilson, a Brooklyn gynecologist, and his wife Thelma published "The Fate of the Nontreated Postmenopausal Woman: A Plea for the Maintenance of Adequate Estrogen from Puberty to Grave" in the Journal of the American Geriatrics Society. To be “nontreated” was to accept a grim “fate.” The article drew directly on the intellectual currents that clinical hormone “pioneers” Masters and E. Kost Shelton had established. But, although Masters, Shelton, and Wilson were all unburdened by the need for evidence for their claims, Wilson amplified them with an unrivaled rhetorical intensity. Wilson’s content consisted of case reports from his private gynecological practice - narratives of individual patients filtered through Wilson's “interpretive lens.” Yet, Wilson was a doctor. A doctor selling solutions for issues pressing patients. He presented his stories with the weight of clinical authority. Their tone: unrelentingly catastrophic.

Wilson’s key rhetorical move was to frame menopause from as a disease process. He returned to the old analogy comparing menopause to diabetes:

The menopause is a disease process. The estrogenic deficiency at menopause, like insulin deficiency in diabetes, would never go away.

This framing was not revolutionary. But, it was effective. Diabetes, after all, is a chronic metabolic disorder requiring lifelong pharmaceutical management. Therefore, menopause is permanent estrogen deficiency, permanently in need of supplementation.

Wilson proposed “preventative” estrogen therapy for younger women approaching menopause and “restorative” therapy for older women already past it.11 “From puberty to grave.” Wilson’s portrayal of untreated menopausal women was unflinching in its darkness. He described them as “castrates” enduring a “living decay.” These women, according to Wilson, suffered not merely discomfort but a kind of existential deprivation. They blamed their hormone loss for osteoporosis, hypertension, depression, melancholia—what he termed “a rapid cock-like feeling called a negative state.” Beyond these physical and psychological symptoms lay what Wilson took to be the gravest consequence of estrogen loss: desexualization. The untreated postmenopausal woman lost not only her hormones but her desirability. She lost, in short, her femininity.

Was she even still a woman?

Estrogen: the panacea

The solution, needless to say, was obvious. Estrogen. And Wilson wrote of estrogen’s curative powers with an almost utopian fervor:

The skin becomes supple again, the muscles repair their tone and strength, the breasts are restored almost their former fullness and contours, the genitals again become supple and distensible, skin cracks and genital inflammations heal. (Wilson 1966 p. 132)

Symptom relief? Nay. Rejuvenation. Estrogen, according to Wilson, could restore a woman to her premenopausal form. He called estrogen “one of the greatest biological revolutions in the history of civilization”.12 He even claimed that estrogen pils could “prevent menopause”. 13 No wonder, then, that women who felt the weight of menopause in their bodies, who had been told by medicine that their complaints were psychosomatic or inevitable, might find Wilson’s promises attractive. Here was a physician who took their suffering seriously offering pharmacological salvation.

Three years later, in 1966, Wilson published Feminine Forever: A New Life for the Postmenopausal Woman. The book took the article’s claims and expanded them into a 300-page manifesto aimed at a mass audience of women and the physicians who treated them. Timing was everything.

As The Pill unleashed the sexual revolution; second-wave feminism gathered steam; women’s magazines fervently pursued health content. The cultural moment was exquisite for Wilson. It was a moment when women were demanding more control over their bodies and their lives, even as Wilson simultaneously insisted that their fundamental identity - their femininity, their womanhood - was contingent on estrogen. The book was bestseller read by hundreds of thousands of American women. The pages were filled with stories of sad, aging women whose lives had been transformed by estrogen. Wilson presented menopause as a treatable deficiency. The cure: estrogen, of course.

Womanhood, quantified

Central to Feminine Forever was Wilson’s invention of what he called the “Femininity Index”—a test based on the maturation pattern of vaginal cells observed through a Pap smear.14 He established “normal” femininity by measuring the average cell pattern in young women in their twenties, and then he applied that standard to women in their fifties and sixties. Any deviation from the pattern established by younger women implied a loss of “femininity”. By this reasoning, all postmenopausal women were, by definition, abnormal. And if they were abnormal, if their bodies no longer produced femininity as young women did. They must turn to medicine to restore normalcy.

Wilson recommended that women have their Femininity Index tested annually:

Every woman over thirty... have her Femininity Index checked once a year. This quick, painless test may prove a turning point in her life, an assurance of continued health and happiness.

The language of “turning point” and “assurance” was calculated to suggest that the test promised not merely information but redemption. The test was a medical confirmation that a woman remained feminine, viable, and herself. Without the test, without the intervention, what were you? A castrate?

Horsing around with Premarin’s maker

What made Wilson’s campaign particularly effective was the machinery of publicity that surrounded it. Wyeth-Ayerst, the manufacturer of Premarin, covertly established the Wilson Research Foundation and funded it lavishly. Wilson traveled on Wyeth’s dime, promoted the book, gave lectures, and became the public face of estrogen replacement.

Wilson Vogue June1966

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In June 1966, Vogue magazine ran an article featuring Wilson, introducing him as “a famous and distinguished gynecologist” and presenting an abridged version of his book arguments along with “key hormone charts” for women in five age groups. Harper’s Bazaar asserted that “the safety and benefits of estrogen therapy have been convincingly demonstrated.” Reader’s Digest offered a more cautious note—”no pill can make one young again”—but acknowledged “hormone value for estrogen-deficient women.” The magazine writers picked up Wilson’s message, amplified it, and carried it into millions of homes.15 Wilson’s financial ties to Wyeth-Ayerst remained undisclosed for decades.16

The results were staggering.

From 1966 to 1975, the annual number of estrogen prescriptions almost doubled, and the market value of non-contraceptive estrogen almost quadrupled. (Watkins 2007 p. 49)

Who didn’t want to remain a woman? Was any price too high? Premarin prescriptions rose from approximately 1.6 million per year in 1966 to nearly 4 million by 1975. By 1975, Premarin had become the fifth-most prescribed drug in the United States (Watkins, 2007, p. 49). Wyeth-Ayerst's financial interests aligned with Wilson's rhetorical success. The more convincingly he argued that women needed estrogen, the more prescriptions filled. The more women who believed they needed estrogen to remain feminine, the more profitable the business became.

Yet what is perhaps most revealing about this pharmaceutical-medical-media complex is not its success but the institutional response to Wilson’s claims. The American Medical Association initiated an investigation into Wilson’s research and his advocacy. But the investigation never produced charges. It never released a conclusion. It simply evaporated into silence.17

The non-resolution was itself telling. Either the evidentiary standards of the era were too loose to support prosecution, or there was institutional reluctance to challenge a physician whose popularity and influence had become undeniable. Either way, the silence allowed Wilson to continue his advocacy. The absence of scrutiny became a form of permission.

The crest of MHT

The popularity of estrogen based MHT would reach its peak in the mid 1970s on the back of enthusiasm from second-wave feminism and sermons from estrogen enthusiasts like Robert Wilson. What would drive the decline?

In the 1970s and 1980s, serious safety signals would emerge from the estrogen replacement paradigm of the time. Those fears created a period of sustained scientific uncertainty and clinical ambivalence. It became clear that question that defined the final decades of the twentieth century, whether the benefits of long-term hormone therapy outweighed its risks, could not be answered by retrospective studies or observational data. Patients needed evidence of a different kind: a large-scale, prospective, randomized controlled trial that could measure the actual clinical outcomes in women treated with modern hormone formulations over extended periods. Following a change at its helm, the National Institutes of Health would later take on the ambitious project - through today, its largest clinical endeavor: the Women’s Health Initiative.

16

Robert Wilson’s son Ron Wilson later came out against the use of Premarin. Why? He believes its production is cruel and causes unnecessary suffering as the product is still made from the urine of pregnant mares. In the book, Robert Wilson also endorsed extramarital affairs.

The popularity of Battey’s operation, the bilateral oophorectomy, left a generation of women in surgical menopause. However, this operation established the causal relationship between ovarian failure and menopause first postulated by Percival Pott in the late 18th century and later described explicitly by Adolf Hegar in Die Castration der Frauen. The ovary had been established as a valuable gland for reproduction and health.

But, medicine couldn’t do much for women with ovarian failure. The pioneering surgeon Robert Tuttle Morris attempted ovarian transplants. Adventurous physicians prescribed organ extracts for menopausal symptoms. It’s unclear the degree to which these benefited patients. Scientists needed to identify, purify, and produce the ovarian hormone before physicians could treat patients at scale.

The Dawn of Endocrinology

Continued interest in the functions of the ovary intersected with the dawn of a discipline focused on the study of internal secretions: Endocrinology. In what became the “Heroic age of Endocrinology,” pioneering physicians and scientists refined and purified the organ extracts of crude “Organotherapy” into their biochemical essences.

The quest to refine the secretions of organ glands started in the late 1800s with the discovery of adrenaline. In 1895, George Oliver and Edward Albert Schäfer isolated adrenaline from adrenal glands.1 Unrealized in the moment, their adrenal extract was the first hormone to be characterized, later purified by the Japanese chemist Jokichi Takamine in 1901, and synthesized by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.

In 1905 the physiologist Ernest Starling refined the concept of “internal secretion,” as first exemplified by Berthold’s experiments transplanting rooster testes, endogenous action substance, or “hormone,” from the Greek verb ‘hormao’ meaning to excite or set in motion. With William Bayliss, Starling had recently discovered “secretin” in 1902, a substance that the intestine released into the blood to activate the pancreas. This discovery overturned the long-held belief that the nervous system activated the pancreas and digestive system in response to food intake.

The discovery of most endocrine hormones followed a fairly similar framework.

1. Identification of the Source - What organ produces the functional secretion? Adrenaline, for example, is produced in the medulla (inner layer) of the adrenal gland

2. Detection Method (Bioassay) - How do you reliably detect the activity of the substance? For Oliver and Schäfer, this was heart rate and blood pressure. Administration of adrenal extract raised the heart rate and blood pressure of humans and dogs

3. Extract Preparation - How do you extract the active substance from the gland? Typically, this involved mechanical disruption followed by dissolution of the gland in water or various organic solvents (oil, ether, petroleum fractions, etc.)

4. Purification and Characterization - Can you isolate a single molecule responsible for the activity? Generally, to prove identity, extracts are refined through fractionation, precipitation, and recrystallization until the substance is homogenous and potent in turn isolating the active component. Then, elemental analysis could be used to determine a molecular formula. Finally, for small, organic molecules, identity can be confirmed by chemical synthesis of the molecule from a simpler components. If the synthesized molecule is identical to the extract in elemental composition, activity, and potency, then the identity and structure of the hormone has been fully elucidated2

For scientists focused on reproductive biology, like Edgar Allen, the hormone concept catalyzed a search for the essential hormones of the reproductive glands. Decades of clinical observation and experimental work — the transplantation experiments of Knauer and Halban, the clinical reports of oral ovary organotherapy, and Tuttle’s ovarian transplants — had suggested that the ovary must produce something essential for reproduction and female health. Now there was a scientific framework in which to ground the search. The belief emerged that ovary must secrete a hormone into the blood that controls reproduction; the disappearance of that hormone explains the loss of menses and the onset of menopausal symptoms; and the replacement of that hormone should restore what the ovary lost in menopause. This logic, speculative yet elegant, turned out substantially correct.

Beneath this seemingly straightforward picture lay complications that would take decades to untangle. The earliest researchers made a fatally simplifying assumption: that they were hunting a single “ovarian hormone,” a unified substance responsible for all ovarian actions. In reality, the ovary produces multiple hormones with distinct roles and timing. Fraenkel’s 1901 demonstration that the corpus luteum was essential for pregnancy had already hinted at this complexity, suggesting that two parts of the ovary - the follicle and the corpus luteum - might secrete different substances.3 But the distinction between estrogens and progesterone would perplex investigators for years. The assumption of unity — one gland, one hormone — was a useful simplification that would eventually have to be abandoned.

The hunt for the ovarian hormone

By the early 1920s, the endocrine function of the ovary had been well established. However, the ovarian hormone remained mysterious. The ovary, in particular, is a complex endocrine organ. In the ovary, follicles grow and mature the reproductive eggs inside the follicular capsule. After ovulation, release of the egg, the follicle retreats into a mass of scar-like tissue known as the corpus luteum before regression. In what sub-structure of the ovary is ovarian hormone produced? Is the hormone in the follicles? The corpus luteum? The interstitial tissue? This was the question that Edward Doisy and Edgar Allen sought to answer.

In 1923, Allen and Doisy identified the follicular fluid, in the mature follicles, as the source of the primary ovarian hormone.4 Three key developments enabled this work.

1. Source: Hog Follicles - the ovaries of hogs had larger ovarian follicles than common laboratory species (rats, mice) and were readily available as byproducts of the meatpacking industry. Doisy painstakingly aspirated the follicular fluid (liquor folliculi) from the ovaries that Allen would use in his animal assays

2. Assay: Juvenile Mice - Edgar Allen developed an assay to assess ovarian activity in an immature mouse. A zoologist by training, Allen systematically classified the stages of the estrous cycle by the cell types present in vaginal smears: nucleated epithelial cells in proestrus, cornified (keratinized, non-nucleated) epithelial cells at estrus, and leukocytes predominating in diestrus. His key observation was that vaginal cornification, the appearance of flat, keratinized cells shed from the vaginal lining, reliably indicated the estrus phase and, by extension, peak estrogenic stimulation.5 Administration of the follicular extract to the juvenile mouse accelerated the sexual maturation, as indicated by vaginal cornification, of the mice

3. Assay: Ovariectomized Juvenile Mice - in his doctoral work, Allen developed the ovariectomized mouse as a model for studying reproduction. Removing the ovaries from immature mice would arrest sexual development and ensure that endogenous ovarian hormones couldn’t contaminate the result. Working with Doisy, Allen inject supplemental follicular fluid into the immature, ovariectomized mice to restore sexual maturation and cornification of the lining of the vaginal walls.

Together, these developments unlocked the ability of Allen and Doisy to assay the sub-compartments of the ovary to determine what portion held the ovarian hormone. A competing theory was that the corpus luteum, the remnant of the post-ovulatory follicle, contained the ovarian hormone. Allen and Doisy’s mouse assays effectively ruled out the corpus luteum as the source.6 Only the fluid of the follicle rescued sexual development on ovariectomized juvenile mice. This assay became known as the Allen-Doisy test. Allen and Doisy’s work pinpointed the location of the ovarian hormone, but their characterization failed to produce the purified substance.

This inability to isolate the pure ovarian hormone was not unexpected. Incredibly potent, endogenous hormones exist in their glands at very low concentrations. For example, during the characterization of thyroxine, the thyroid hormone, 3 tons of pig thyroids produced only 33 grams of pure thyroxine.7 To identify the ovarian hormone, Allen and Doisy needed a new source: abundant, accessible, and ideally concentrated.

Along comes… a reliable pregnancy test?

In the mid-1920s, two German gynecologists, Selmar Aschheim and Bernhard Zondek, were on a quest to solve a problem that now seems mundane: reliably determine pregnancy. Prior to Aschheim and Zondek’s work, physicians primarily diagnosed pregnancy with physical palpations and only well into the first trimester. Moreover, distinguishing an early pregnancy from a tumor or large fibroid sometimes proved challenging. To illustrate the point, Aschhem and Zondek reported that physicians would occasionally diagnose a uterine tumor and begin operation only to find a pregnant uterus.8

The core assumption of Aschheim and Zondek’s work was that the prior observation that many hormonal substances appeared massively enriched in the blood pregnant women. If these hormones were present, Aschheim and Zondek assumed the hormones must be excreted in some fashion.9 And, what do pregnant women excrete? Breast milk and urine. So, Aschheim and Zondek assayed both breast milk and urine for their ability to observe ovarian enlargement, appearance of a corpus luteum, uterine enlargement, and follicle maturation in juvenile mice. To their delight, only the urine of pregnant women drove the signs of sexual and follicular maturation. In 1927, after testing 2000 samples of urine, Aschheim and Zondek reported a 98.9% success rate in positively determining pregnancy!

This method quickly became known as the Aschheim-Zondek Test (A-Z test) for pregnancy. It would later be adapted to rabbits (Freidman test) and then to ovulation in African clawed frogs (Hogben test) and eventually sperm production in male toads (Galli Mainini). The amphibian-based tests remained popular for decades until the development of an immunoassay as both tests could be completed quickly and did not require termination of the animal, in contrast to the A-Z and Freidman tests. What incredibly well conserved hormone drives these transformations? The chorionic gonadotrophin (hCG) from the placenta — not an ovarian hormone.

So what does a pregnancy test have to do with isolating the elusive ovarian hormone? Well, in their seminal work, Aschheim and Zondek reported that the urine of pregnant women had concentrated activity that mirrored Allen and Doisy’s ovarian hormone.10 That observation transformed Allen and Doisy’s hormone hunt.

Isolating estrone

Previously limited to painstaking follicular fluid extraction from porcine ovaries, in Aschheim and Zondek’s report, Allen and Doisy found a cheap, abundant feedstock: urine, from pregnant women. Unbeknownst to the investigators, the placenta, not the ovary, produced the ovarian hormone. But, the urine was active. So, Allen and Doisy did what the early hormone heroes did, collect and process an unfathomable amount of hormone enriched waste.

Doisy set about collecting urine from pregnant women the obstetrics clinic at Washington University St. Louis. At every step, the Allen-Doisy assay guided the purification: extract, fractionate, test each fraction in the mouse, pursue the active fraction, repeat. The work was as laborious as it was unglamorous.

In an autobiographical feature, Doisy recalls that at one point in the project a policeman searching for bootlegged alcohol pulled over his Model T. To the policeman’s disappointment, Doisy’s collection of gallon bottles contained naught but the urine of women, pregnant.

From hundreds of gallons of urine, Doisy extracted the estrogen producing pure white crystals of estrone, the first estrogen. Doisy named the compound "theelin," from the Greek thely, meaning female. Simultaneously, German chemist Adolf Butenandt isolated estrone following a similar process, allegedly after hearing about a presentation of Doisy’s at the 1929 International Physiologic Congress in Boston, although the order of events is disputed.11 Butenandt, too, had used pregnant women's urine as his starting material, guided by the same bioassay framework. He called his compound "Follikelhormon," follicular hormone. The simultaneous discovery of estrone, the first estrogen, created a chaotic nomenclature that required an international conference to resolve.

Yet estrone, it turned out, was only the first of three natural estrogens to be identified, and it was neither the most potent nor the physiologically dominant one. The order in which the three classical estrogens were isolated is counterintuitive, a paradox that reveals much about the practical constraints of early hormone chemistry.

Hormonal Babel

Guy Frederic Marrian, working at University College London, isolated a second estrogen from human pregnancy urine around 1930. This compound, which Marrian called “trihydroxyoestrin,” had three hydroxyl groups, or estriol. It was the weakest of the three natural estrogens, roughly one-tenth the potency estradiol. It is, however, the dominant estrogen of pregnancy, produced in vast quantities by the fetoplacental unit. Doisy and Butenandt isolated estrone, the oxidized product, as a consequence of their purification process.

The most potent natural estrogen, the one whose decline defines menopause. was the last to be isolated. In 1935, Doisy’s group extracted estradiol from sow ovaries. The yield was breathtakingly meager: twelve milligrams of crystalline estradiol from four tons of porcine ovaries.12 The most potent of the three natural estrogens, estradiol is the principal estrogen secreted by the ovary in premenopausal women and the reference standard against which all other estrogens are measured.

The rapid, competitive, multi-laboratory nature of the estrogen isolation race produced a predictable consequence: nomenclatural chaos. Different laboratories assigned different names to what were often the same molecule, creating a literature so confused that even specialists struggled to compare results across publications.

Doisy in St. Louis called his compounds theelin (estrone), theelol (estriol), and dihydrotheelin (estradiol). Butenandt in Göttingen used Follikelhormon, marketed as Progynon. Ernst Laqueur’s group in Amsterdam, which isolated the same compound in 1930, called it menformon. In Geneva, Girard used the name folliculin. Marrian in London referred to estriol as trihydroxyoestrin.13

These were not different substances: they were the same molecules, independently discovered and independently named. The Babel hindered both scientific communication and clinical standardization.

The confusion was diminished by the International Conference on the Standardization of Sex Hormones in 1935. Here the pioneers of estrogen established the nomenclature that persists to this day: estrone for the hydroxyketone (E1), estradiol for the diol (E2), estriol for the triol (E3), systematic names derived from the functional groups on the steroid nucleus.14

Bringing estrogens to patients

Shortly after the reports of isolation, early pharmaceutical companies released a variety of preparations: Amniotin, Progynon, Theelin, Emmenin, Folliculin, and Oestroform. These preparations enriched estrone from the urine of pregnant women. These estrone preparations were naturally supply constrained. Where else could one find a potent and near limitless source of estrogen to treat menopause?

Chemical synthesis, perhaps? The structure of estrone had been elucidated by Budenandt in 1930. But, 1930s era chemical synthesis was not yet advanced enough to create large quantities of estrogens from the available precursors. In fact, it wasn’t until 1946 that Wiesbader and Filler used synthetic estradiol15 to treat menopausal symptoms, finally validating the identity of the key active component of ovarian extracts.

If not synthesis, what might unlock estrogen at the scale needed to treat the world’s women? Where might we find a truly limitless source of estrogen? Once again, the search takes us back to the barnyard.

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In parallel, “organotherapy,” the progenitor of modern Endocrinology, was developing with a series of barnyard-inspired transplantation and extraction experiments. While some of these landmark experiments may have been sensationalized placebo effects, the concept of replacing organs with concentrated extracts catalyzed the emergence of Endocrinology. And, importantly, early organotherapy inspired physicians to canvas the farm for medicine. From that search, the first hormone-based treatment for menopause emerged: bovine ovary sandwiches.

Describing Menopause

The human passage through middle age and the cessation of fertility have occupied human consciousness for millennia, long before medicine developed a unified language to describe these changes. Cultural and religious texts bear witness to an ancient awareness that reproductive capacity does not persist indefinitely. The Book of Genesis, in its account of Sarah’s advanced age, notes that “it had ceased to be with Sarah after the manner of women” (Genesis 18:11, KJV), a delicate acknowledgment that even in antiquity, the cessation of menses was recognized as an inevitable feature of aging. As the medical historian Victor Cornelius Medvei observes, this connection between advancing age and the loss of fertility is “millennia older” than any scientific framework that would later attempt to explain it.1

Throughout the medieval period, this practical knowledge persisted, even if obscured by the limitations of contemporary medical theory. Hildegard of Bingen, the twelfth-century Benedictine abbess and natural philosopher, documented in her medical writings that menstruation typically ceased around the fiftieth year of life.2 Hildegard’s observations, grounded in the direct experience of a woman living in community with other women, represent an early attempt to anchor this universal phenomenon to a specific age. Yet despite such observations accumulating across centuries and cultures, medicine failed to develop a precise, unified concept. Instead, the condition existed in a linguistic fog: physicians and writers employed terms such as “cessation of the menses,” “climacteric,” and “change of life” largely interchangeably, each term carrying different historical and etymological baggage but little consistent meaning.

The first step toward medical precision came in the early nineteenth century, when the French physician C.P.L. de Gardanne coined the term “menopause” in 1821.3 De Gardanne’s 1816 treatise, initially titled De la ménépausie, was revised and republished under the now-familiar term ménopause in its 1821 edition, drawing from the Greek roots menos, meaning month, and pause, meaning stop. This neologism represented more than mere semantic refinement; it signaled medicine’s growing ambition to isolate and name a discrete biological event. Yet the coining of the term, while intellectually tidy, masked a deeper confusion about menopause’s significance and prevalence in human life.4

Hidden Organ: the Ovary

Here lies the fundamental paradox of reproductive biology: the testis revealed itself through brutality, while the ovary guarded its secrets for two thousand years.

Consider the eunuch. From the courts of Rome to the harems of Constantinople, from medieval Christendom to imperial China, the castrated male stood as a living anatomical text. The message was unmistakable and written across his entire body: no facial hair, a soprano’s pitch, breasts that swelled with age, a body that refused to build muscle the way other men’s did, a muted sexuality. You didn’t need to dissect a testis to understand what it did. You simply needed to look at what happened when it was gone. The function of the male gonad was, quite literally, impossible to miss.5 Aristotle could theorize about the nature of semen. Galen could speculate about its composition. But any observer—scholar or slave-keeper—could see that the testis made men into men. The phenotype of castration was so stark, so obvious, that it served as a cruel example demonstration of human endocrine physiology.

The ovary, by contrast, was a locked box.

When anatomists first dissected the female body, the ovaries were there to be found—pale, almond-shaped organs buried deep in the pelvis, hidden behind loops of bowel and peritoneal folds. Herophilus, the third century BC Alexandrian physician, was among the first to describe ovaries, calling them didymi, or “female testes.”6 The name itself is instructive. Confronted with an unfamiliar organ, he reached for the organ that was otherwise absent — testes, but female. But, you could not castrate a woman the way you could a man. The surgical removal of ovaries was far more dangerous, far more likely to result in infection, hemorrhage, or eventually death. There is no tradition of female eunuchs. Locked away, the ovaries obscured their purpose for centuries.

Without the brutal clarity that castration provided for the testis, the ovary was more a matter of philosophy.

Aristotle, writing in the fourth century BC, flatly denied that the ovary was equivalent to the testis at all. In his view, women did not produce true semen (true!). The male contribution was everything: he provided the morphe, the form, the principle of life. The female? She was a vessel of “brute matter”—menstrual blood, inert and passive. She was, a mutilated male, her development arrested by the coldness of the maternal womb.7 In this framework, the ovary had no generative function. It might secrete something? Perhaps a lubricant? But, it was not the female counterpart to the powerful male testis because women, in Aristotle’s estimation, did not possess a counterpart to male semen.

Galen disagreed. The great physician of the second century AD had actually dissected female reproductive organs, and what he saw convinced him that the ovaries were analogous to testes. They must produce a female equivalent of semen. Galen argued both male and female contributions were necessary for the formation of the embryo (true!). Though, Galen conceded, the male contribution was probably more important, since testicles are larger.8 Galen and the Hippocratic corpus also harbored a peculiar conviction: that the right ovary produced male infants, while the left produced female ones.9 One wonders whether this reflected genuine observation or merely the human tendency to impose order on mystery.

Here, then, was the crucial debate of Western reproductive biology for nearly two thousand years: Did the ovary produce semen or not? Was it a true gonad? Or, an ornamental appendage?10 Anatomists through the Middle Ages and Renaissance continued to call ovaries “female testes,” perpetuating Herophilus’s original nomenclature even as they argued about what that name actually meant.11 By the 17th century, advances in microscopy enabled Reinier de Graaf to examine ovaries from recently bred rabbits. Under a microscope, de Graaf identified the ovarian follicles, but incorrectly identified them as “eggs.”12 The identification of follicles as “eggs” led to the term ovaries for the female sex organ.

Yet, the question of ovarian function seemed resolvable only in theory because there was no empirical way to settle it. One could not simply remove a woman’s ovaries and then look at her, the way one might with a eunuch, and infer the organ’s function and contribution to human health.

So, the answer waited for an era of surgical callousness to provide the crude experiment that nature and circumstance had denied to earlier centuries. That experiment would come in the nineteenth century, when physicians – largely Americans – began removing ovaries en masse. It would finally produce the female equivalent of the eunuch phenotype. It would, at last, partially reveal what the ovary actually did.

Menopause: Ovarian Failure

The recognition that the ovaries played a central role in menstruation emerged gradually from clinical observation rather than systematic investigation. The earliest documented case appeared in the surgical records of Percival Pott, a renowned eighteenth-century surgeon, who in 1775 reported treating a young woman with an ovarian hernia. When both of her ovaries were removed during surgical intervention, Pott observed that the procedure was “followed by shrinkage of her breasts and cessation of her menses”.13 Yet Pott himself did not elaborate on the significance of these findings. His account remained a clinical curiosity. A striking but isolated observation.

Yet Pott’s case, dramatic as it was, did not emerge from a vacuum of ignorance about ovarian function. For millennia farmers had been conducting their own crude experiments in oophorectomy. The castration of male livestock had been documented since early antiquity. But, female animals presented a different problem, and spaying—the removal of ovaries from sows, cows, and other breeding stock was practiced throughout the agricultural world. Farmers who spayed their animals observed what any careful observer could not miss: the cessation of estrus, the arrest of reproductive capacity, and often an accelerated tendency toward fattening – perhaps the practical utility of the practice. These were not abstract physiological principles but practices of animal husbandry, passed down through generations of agricultural experience.

By the nineteenth century, this tacit agricultural knowledge began to surface in medical literature with increasing specificity. Albert Puech, in 1873, systematically documented what generations of farmers could have told him—that the uterus ceased to grow after ovarian removal in sows.14 More significantly, George Beatson in 1896 drew explicit inspiration from farmer’s spaying practice, having observed that castrated cows maintained their milk production but failed to develop the full breast tissue of intact animals. This observation—that the ovaries governed not only reproduction but the growth and function of seemingly distant organs—led Beatson to a radical therapeutic leap: the use of oophorectomy to arrest breast cancer in women. The barnyard, it seemed, had been teaching lessons that medical science was only now prepared to learn.

The interpretive leap came two decades after Pott through the work of John B. Davidge, an American medical student studying at Edinburgh. Reflecting on Pott’s case in his 1794 dissertation, Davidge drew an explicit causal connection that his predecessor had left implicit. He concluded that “menstruation is attributable to a peculiar condition of the ovaries serving as a source of excitement to the vessels of the womb.”15 This formulation, represented the first articulation that ovarian function and menstrual function were linked. The ovaries were not merely passive reproductive organs but active agents necessary for menstruation and reproduction.

Yet even this early insight did not immediately transform medical knowledge. The connection between ovaries and menstruation remained largely dormant in the medical literature, more theoretical than clinically actionable. As Medvei notes, “Until 1872, this was the only scientific account of the effect of bilateral oophorectomy on the periods”—a startling acknowledgment that Pott’s 1775 report stood virtually alone in the medical record for nearly a century.16 Corroborating experimental experimental work, conducted before 1861, demonstrated hat menstruation did not occur in women whose ovaries had been surgically removed, yet these findings too remained scattered within the scientific literature.17 The observation was known; the principle was understood in learned circles. But the clinical implications had not yet been widely grasped or systematized.

This gap between isolated knowledge and widespread medical appreciation would narrow dramatically only with the adoption of oophorectomy as a therapeutic practice. When physicians began deliberately removing ovaries in large numbers from the 1870s onward, they could no longer ignore the consequences. The mass clinical experience of the oophorectomy era would force the medical profession to confront what Pott had observed in isolation and Davidge had theorized in abstraction: that the ovaries were indeed the seat of a function essential not merely to reproduction but to the woman’s entire physical constitution. Before this transformation, the knowledge existed in fragments; only systematic clinical practice would make it foundational to medical understanding.

Ovarian necessity: “Battey’s Operation”

Robert Battey’s 1872 popularization of bilateral oophorectomy18—which he termed “normal ovariotomy” or “Battey’s operation”19—represents one of medicine’s most consequential and troubling interventions. Operating under the theoretical framework that ovarian dysfunction caused a cascade of systemic complaints through “reflex irritation,” Battey and his followers applied the procedure with remarkable indiscrimination. Women presenting with “ovarian epilepsy,” menstrual irregularities, insanity, nymphomania, and various ill-defined “nervous” complaints found themselves candidates for surgical removal of both ovaries.20 Battey’s operation promised relief from suffering. Although unclear if patients actually felt relief, Battey’s operation uncovered a new function for ovaries in women at an appalling human cost.

The scale of this surgical enterprise was impressive. A contemporary estimate placed the total number of oophorectomies performed in the United States by 1906 at approximately 150,000, a figure suggesting that bilateral ovary removal had become nearly routine in gynecological practice.21 What renders this statistic particularly striking is the demographic profile of those operated upon. These were not aging women at the threshold of natural menopause. Rather, women in their twenties and thirties at the apex of reproductive life. A generation of young women underwent surgical castration, often for unrelated complaints and experiencing normal human emotions. Battey’s operation was, initially, ‘essential medicine’ without much attention to the potential lasting and irreversible consequences. If anything, there was enthusiasm for the eugenic potential of sterilizing ‘hysterics’ and other mentally ill women. Consideration of other essential functions appears minimal.

The consequences of mass oophorectomy were immediate, consistent, and undeniable. Women who had undergone radical ‘normal oophorectomy’ experienced the sudden onset of debilitating climacteric22 symptoms: hot flashes of startling intensity, vaginal atrophy, negative mood affect, and the abrupt cessation of menstruation. These iatrogenic, surgically induced symptoms appeared eerily similar to menopause. But, instead of appearing at mid-life, these symptoms emerged in thousands upon thousands of young women. Surgeons had created an accidental mass experiment. The women who suffered these symptoms were living laboratories exemplifying a biological truth that had long eluded articulation: menopause is a consequence of ovarian failure.

I find it remarkable how long it took for this truth to be realized. While the essential functions of testes were known to the ancients, the internal location of ovaries prevented elucidation of the ovary-menopause connection until the mid-19^th century. Menopause appears rare among mammals. At the time, it appeared uniquely human. So, to truly prove the connection between “climacteric symptoms” of middle age and ovarian failure, we needed surgeons to brashly and brazenly remove ovaries to understand their essential functions.

The irony of Battey’s work is exquisitely damning. Battey promoted his operation as a cure-all for womanly ills - hysteria, excessive menorrhea, amenorrhea, nymphomania, anxiety, epilepsy, moral insanity.23 The irritated ovary instigated the pathology. Remove the offending organs; eliminate the source of suffering.

Instead, the operation created a new and dramatic iatrogenic menopause. Although, such concerns certainly didn’t stop Battey from promoting his “success” aggressively. The very procedure meant to cure instead demonstrated, through the bodies of thousands of women, that the ovaries were not merely expendable, hysteria-inducing organs. The operation designed to eliminate a hypothesized root of dysfunction instead proved the necessity of ovaries themselves.

This recognition found systematic expression in Adolf Hegar’s 1878 monograph, Die Castration der Frauen, which documented with clinical precision the cascade of symptoms following bilateral oophorectomy.24 Hegar’s work transformed the scattered observations of individual practitioners into a coherent symptomatology; a syndrome of ovarian deficiency that demanded explanation and treatment.

In this sense, the age of Battey’s operation was less an era of therapeutic success than of inadvertent discovery. Thousands of women became the unwitting subjects of what might be called the “necessity experiment”—the mass, unplanned demonstration that ovaries were vital to female health and that their removal precipitated a menopause-like state.

What could medicine do for these women? Could the ovaries be replaced?

Interlude: Organotherapy

The concept of treating disease by administering extracts derived from animal organs sounds almost incomprehensibly foreign to modern medicine. Yet this practice, which flourished from the 1880s into the early twentieth century, represents a crucial and paradoxical chapter in the prehistory of endocrinology. Organotherapy was simultaneously “an appalling chapter in the history of medicine” and the direct intellectual precursor to legitimate endocrinology.25 To understand we must first grasp how physicians came to believe that the body’s internal function could be regulated by the systemic administration of organ extracts—a conviction that, however misguided in most applications, contained a profound biological truth.

The intellectual seeds of organotherapy were ancient.26 Chinese traditional medicine had long employed organ extracts and animal urine preparations to treat ailments.27 Surgical and scientific innovations converged in the nineteenth century to rationalize a basis for previously speculative, empirical remedies. In 1849, Arnold Berthold’s provided the first rigorous demonstration of what we would now call endocrine function.28 Castrating young roosters typically caused them to lose their characteristically male plumage and aggressive behavior. However, when Berthold transplanted testes from another rooster into the abdominal cavity of a castrated recipient, anatomically distant from their original location and therefore disconnected from their innervation, the roosters nonetheless retained their male traits.29 Berthold’s concluded the testes must exert their influence not through neural pathways, but through some substance carried in the blood. This might have been, in essence, the founding experiment of endocrinology. Yet, it appears largely ignored by the contemporary medical world.

During the mid-late 19^th century, Claude Bernard developed the revolutionary concept of the milieu intérieur: “the internal environment.” He demonstrated that the liver actively secretes glucose directly into the blood, independent of nervous system control.30 Bernard’s insight provided the intellectual foundation from which endocrinology would eventually emerge: the body’s internal organs do not merely respond to the nervous system but actively regulate physiology through substances released into circulation. By the time Bernard’s ideas gained currency, the stage was set for a dramatic and deeply misguided experiment that would nonetheless galvanize the entire field.

In 1889, at seventy-two years of age, the French physiologist Charles-Édouard Brown-Séquard, who some consider a grandfather of endocrinology, performed what he characterized as “rejuvenation” experiment on himself. He, an old man, sought vitality. Where might the vitality of young men lie? If eunuchs lack the masculine substance, then it must reside in the testes, of course. He prepared extracts from the testes of dogs and guinea pigs and injected them into himself. Brown-Séquard reported extraordinary results: increased strength, improved urinary function, enhanced mental clarity, renewed sexual capacity, and restoration of a youthful vigor.31 Séquard presented these findings to the Société de Biologie in Paris with such conviction that they created a sensation. The popular press seized upon the news, and what had been a scientific communication became a worldwide phenomenon. Desperate patients and ambitious entrepreneurs rushed to exploit the discovery. Thankfully, the modern world has evolved beyond hype-driven rejuvenation gold rushes where prominent influencers encourage people in need to inject questionable substances to cure their ails.32

Yet Brown-Séquard’s failure was, perhaps paradoxically, extraordinarily productive. Although it remains unclear if his own experiment succeeded in restoring his vigor, it lodged a powerful idea in the medical imagination: blood-borne secretions from organs could be extracted, concentrated, and administered to patients to compensate for organ loss. This conviction, however poorly grounded in his particular case, launched an enormous organotherapy industry. Physicians and manufacturers offered extracts of brain, bone marrow, kidney, spleen, and virtually every organ imaginable. Caveat emptor.

Yet within this chaos lay genuine discovery. The thyroid proved to be the decisive proof of concept. Emil Theodor Kocher and the Reverdin brothers had observed that surgical removal of the thyroid gland caused myxoedema , a severe condition involving metabolic collapse and neurological decline. Prior work linked surgical removal of the thyroid to development of myxoedema.33 Several attempts had been made to transplant thyroids into humans to treat myxoedema with limited success. Geroge Murray, an English physician, had observed that surgical transplantation of sheep thyroid by his mentor Victor Horsley and the Portugese physicians Bettencourt and Serrano led to immediate resolution of the symptoms. Muarry inferred that the resolution occurred to rapidly for vascularization and adoption of the xenotransplanted thyroid gland, therefore the substance must be pre-existing in the thyroid gland, not a function of the vascularized gland. Additionally, injection of thyroid juice to thyroidectomized dogs prevented the expected demise of the animals. So, Murray reasoned that the same might hold true in humans. And it did!34

In 1891, George Murray treated a myxoedema patient with injections of sheep thyroid extract.35 The patient survived and thrived for twenty-eight more years.36 Murray’s kinetic reasoning was ingenious: if a transplanted thyroid worked too quickly for new blood vessels to form, then the active therapeutic substance must be diffusible in the bloodstream. Perhaps, you did not need the organ itself, only its secretion? Oral thyroid extract followed rapidly, and thyroid therapy became the first genuine endocrine replacement therapy. Most other organotherapy was ineffective. But the threshold had been crossed. The notion that glandular secretions could be isolated, administered systemically, and used to restore homeostasis had been validated by clinical success. Within this framework—impure as it was—the future of hormone therapy, including eventually the hormone therapy of menopause, would be constructed.

Grafting Ovaries

In the final decades of the nineteenth century, a bold idea began to take shape among European surgeons and experimentalists: if the ovary secreted vital substances into the bloodstream, perhaps a transplanted ovary could rejuvenate women who had lost their reproductive capacity. This prospect emerged from recent work showing that thyroid grafting was technically feasible. If transplants and grafts could work for the thyroid, why not for the ovary?

Emil Knauer, a young Viennese physician, decided to test this hypothesis experimentally. In 1896, working as an assistant in Vienna, Knauer performed a series of transplantations using rabbit ovaries grafted to ectopic sites within the abdomen. His results proved decisive: when the grafts survived and became vascularized, they prevented the atrophies that normally followed oophorectomy.37 The ovary, Knauer concluded, must produce an internal secretion – not a nerve signal – that circulated through the blood to maintain reproductive tissues. Knauer published his comprehensive findings as a monograph in 1900 answering a fundamental question: the ovary’s influence was not neural but chemical.

Three years later, Josef Halban, also working in Vienna, presented results that powerfully corroborated Knauer’s findings. At a meeting of the Vienna Gesellschaft der Aerzte in 1899, Halban reported transplanting ovarian tissue into oophorectomized infant guinea pigs. Oophorectomized infant guinea pigs failed to develop mature reproductive systems. The outcome was striking: the animals developed normal uteri and fallopian tubes with the translplanted ovarian tissue. Halban’s conclusions paralleled Knauer’s and both men drew an explicit connection to Berthold’s classical rooster experiment arguing that the reproductive organs also had additional endogenous secretory functions.38 The transplanted organs worked through the bloodstream alone, severed from all nerve connections, remained capable of sustaining distant reproductive structures.

If such results could be achieved in animals, could humans benefit? Robert Tuttle Morris, a New York surgeon, believed so. He set out to answer the question clinically. In 1895, Morris performed the first ovarian transplantation in humans, completing twelve operations by 1901. His stated objective was explicit: “the avoidance of premature menopause.”39 Morris claimed that successful ovarian grafts could even restore menstruation in oophorectomized women. He even published a case report of ovarian grafting that claimed to restore reproductive function to an oophorectomized woman. In it, a young woman with degenerated ovaries received an ovarian graft in February 1902. Three years later, she became pregnant. In 1906, she delivered a healthy girl.40 Morris argued the result vindicated the entire enterprise. If transplanted ovarian tissue could sustain pregnancy, it must be producing substances vital to reproduction. With a modern understanding of reproductive physiology and transplantation, it’s unclear if the grafts enabled the pregnancy, or if the pregnancy was merely a fortunate result of an incomplete oophorectomy.

These grafting and transplantation experiments, taken together, demonstrated the ovary likely produced a blood-borne substance essential for reproductive function and female sexual development. However, organ grafting was an extreme, risky procedure unsuitable for many (if not all) patients. Was there another way that physicians could supplement for lost ovaries?

Eating Ovaries

The logical framework of organotherapy, which had achieved genuine success in treating thyroid deficiency with thyroid extract, suggested an obvious parallel for oophorectomized patients symptoms. If thyroid extract could be replaced to treat myxoedema resulting from thyroid failure, then perhaps the ovary could be replaced with ovarian extract to treat ovarian failure. This reasoning, as unsound as it appears, would drive physicians throughout the 1890s to attempt what seemed like the straightforward application of a proven therapeutic principle.

Clinical attempts at ovarian supplementation began almost immediately after Murray’s success treating myxoedema with thyroid extract. Ferdinand Mainzer, in 1896, reported treating climacteric41 symptoms with dried bovine ovarian extract, contributing one of the earliest clinical reports of this therapeutic approach. Within a year, the method had gained sufficient credibility in medical circles that Hubert and Fosbery published their findings on ovarian extract for menopausal symptoms in the British Medical Journal in 1897, lending the approach the authority of a prestigious journal. By 1899, bovine ovarian extract had achieved commercial recognition: Ovariin appeared in the Merck Manual as a pharmaceutical product, signaling that the medical profession had embraced it as a therapeutic option.42

What emerged over the early 1900s, however, was less a standardized treatment than a bewildering array of preparations. Some came as solutions in water, glycerin, or alcohol; others as tablets of dried ovarian material. Perhaps most remarkably, some physicians prescribed fresh sow or cow ovaries “minced in sandwiches” for their patients to consume.43 This remarkable lack of standardization reflected the fundamental problem underlying the entire enterprise: what was the active component? How much should patients take? Did ovary sandwiches work at all?

The gap between clinical enthusiasm and scientific evidence did not go unnoticed. By 1924, the physiologist A.J. Carlson articulated the fundamental objection with precision: “Until it has been conclusively shown in spayed females that these extracts prevent the atrophy of the uterus and maintain oestrus periods typical for the species, it seems clear that experimental ovarian organo-therapy has not been placed on a scientific basis”.44 Carlson’s skepticism identified a real problem. The clinical reports rested on subjective symptom improvement and physician anecdotes. Well controlled biological evidence? Absent.

Yet, physicians continued to dispense them for decades, sustained by a combination of clinical conviction, patient reports of benefit, and the compelling theoretical framework of organotherapy itself. The preparations may well have contained estrogenic material from residual estrogen in bovine ovarian tissue, enough perhaps to produce modest effects. But without standardization and controlled trials, the question of whether they genuinely worked remained perpetually unanswered. What emerged was a pattern that would recur throughout the history of hormone therapy: a compelling therapeutic logic combined with patient-reported improvement could sustain medical practice far longer than rigorous evidence would ordinarily permit, creating an enthusiasm for hormonal supplementation that often ran ahead of what the science actually demonstrated.

And, treatment for women with ovarian failure—age-related or surgically induced— would remain focused on patient testimonials for organ extracts for decades. It would take two decades for chemists and physiologists pursuing the female reproductive, biology to reveal two key hormonal signals of the ovary, estrogens and progesterone.

In essence, a generation of women went through menopause without MHT support. And, a generation of clinicians trained in a practice that eschewed MHT for menopause. Can a change in labeling expand access and improve quality of life for patients?

A Transition

Menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is diagnosed retrospectively, after 12 consecutive months without a menstrual period. The average age of onset in the United States is 51.1 But menopause is not an event; it is a transition. Functionally, menopause symptoms emerge as a consequence of ovarian ‘failure.’ The perimenopausal years preceding it are marked by rapid hormonal fluctuations as the ovary’s pool of follicles dwindles. The decline in estradiol, the principal estrogen produced by the premenopausal ovary, proceeds unevenly. The hypothalamic-pituitary axis, sensing the shortfall, ramps up gonadotropin secretion in an increasingly futile attempt to stimulate follicles that are no longer there. The result is a rapidly fluctuating hormone profile resulting from diminished feedback from the follicle. While humans are not uniquely capable of experiencing menopause, it does appear that a extended post-reproductive life period is relatively rare across the animal kingdom with toothed whales and chimpanzees as the best documented examples.2 So, how does this transition manifest for patients?

The clinical consequences of menopause are familiar to nearly every woman who reaches middle age. Nearly 75% of menopausal women experience vasomotor symptoms: hot flashes and night sweats. For some, these are transient nuisances. For others, they are debilitating: sleep-destroying, career-disrupting episodes that persist for years. Beyond the vasomotor symptoms, estrogen withdrawal accelerates age-related bone loss increasing fracture risk, alters blood lipid profiles, contributes to urogenital atrophy, and may affect cognition and mood. Although disease may not be the correct term for menopause, the phase exacts a physiological and psychological toll on many women. MHT emerged as a way to supplement estrogen with the goal of mitigating the debilitating vasomotor symptoms of menopause.

Replacing what is lost?

MHT is among the most effective therapies for symptoms emerging from menopause. The intervention has adopted several names: hormone replacement therapy (HRT), estrogen replacement therapy (ERT), or the currently preferred clinical term, menopausal hormone therapy (MHT). The alphabet soup reflects shifting attitudes more than shifting chemistry. While “HRT” and “ERT” imply restoring something lost, “MHT” may appear more neutral.

The pharmacology, however, is relatively straightforward. Estrogen is the primary active therapeutic agent. Many regimens incorporate a progesterone component to limit uterine endometrial hyperplasia.3 MHT is available in several forms: oral estradiol, transdermal patches and gels, vaginal rings and creams, and the older CEE (Premarin).4

The primary goal for MHT is the treatment of vasomotor symptoms. Estrogen is, by a wide margin, the most effective pharmacological intervention for hot flashes, reducing their frequency and severity by ≥75% in randomized trials. For the millions of women whose vasomotor symptoms impair their sleep, work, and quality of life, estrogen transforms their quality of life.

Beyond symptom relief, MHT/ERT has the well-documented ability to slow bone loss through osteoclast-mediated bone resorption. By preserving bone mineral density, estrogen MHT can reduce hip fracture risk by 1/3rd.

However, for decades, clinicians and researchers debated additional benefits: cardiovascular protection, reduction in colorectal cancer, improvements in mood and cognition. Some of these claims have been supported by evidence; others have not. The contested benefits, particularly cardiovascular protection, propelled MHT into one of the most consequential clinical controversies of the past half-century. In an attempt to settle the debate, the NIH’s Women’s Health Initiative (WHI) commissioned large, randomized controlled trials to evaluate the risks and benefits of MHT in post-menopausal women.

In the early 1990s, the NIH launched the WHI to study the impacts of MHT/HRT in, largely, post-menopausal women. To date, this remains one of the largest public clinical RCT efforts. Investigators anticipated positive results supporting widespread utilization of MHT. In 2002, the WHI’s trial of CEE+MPA in post-menopausal women was halted early. Contrary to expectations, MHT appeared to increase risks across the board.

Summarized above in Figure 3 from the JAMA publication, MHT appeared to increase the risk of breast cancer, dementia, and cardiovascular disease. However, the trial did confirm the benefit of MHT in reducing fracture risk. The balance of risk led the FDA to apply a blanket black-box label to all estrogen containing MHT products.

Ripping the bandage

However, in February 2026, the FDA approved labeling changes to the first batch of menopausal hormone therapy products, removing risk statements about cardiovascular disease, breast cancer, and probable dementia from the boxed warning. This issue has been a pet-project of FDA Commissioner Marty Makary.5 A surgeon and public health researcher, Makary has gone on record calling the decades-long stigmatization of HRT “one of the greatest mistakes in modern medicine.”

A 2013 post-hoc reanalysis of the WHI (2002) results suggested that risks of MHT clustered largely in women >10 years post-menopause. Women 50-59 on MHT appeared to have reduced all cause mortality, but still observed increased cardiovascular and cancer risks. Across all groups, MHT appeared to reduce colorectal cancer and hip fracture risk. Therefore, MHT may provide symptomatic benefit during menopause and may be effective primary-prevention

The reasoning, laid out in a JAMA Viewpoint authored by Makary, rested on four pillars.

1. Misapplication of the 2002 WHI results. The trial tested a specific oral regimen, CEE plus MPA, in a population averaging 63 years old implying many women were a decade post-menopausal. However, the warnings were applied to all formulations, all ages, all MHT indications. Makary argues this application was overly broad.

2. Age-stratified benefit. The age-stratified re-analyses reversed the risk-benefit calculus for younger women. For women initiating therapy within 10 years of menopause, the randomized data show reductions in all-cause mortality and fractures, with no apparent increase in cardiovascular events.

3. Newer, safer formulations. The formulations prescribed today are not the formulations the WHI tested. Transdermal estradiol patches and gels bypass the liver’s first-pass metabolism that is thought to drive the clotting risk of oral estrogens, as observed in some oral contraceptive formulations. Oral micronized progesterone has replaced the synthetic MPA that the WHI implicated in the breast cancer and cardiovascular risk increases. The WHI investigators themselves acknowledge they never tested these newer formulations.

4. Potential for broad impact. The black box created a chilling effect that harmed women. In 2020, there were 40 million American women aged 45-64, but only about 2 million received an MHT prescription. A generation of physicians trained after 2002 received little instruction in prescribing menopausal hormone therapy. In his MHT review, Lobo (2016) called them “the lost generation of trainees.” The result: an entire cohort of clinicians uncomfortable prescribing a menopause therapy that may be broadly beneficial.

The specific changes: cardiovascular, breast cancer, and dementia risk statements were removed from the Black Box Warning. The updated label will recommend initiation before age 60 or within 10 years of menopause onset. The endometrial cancer warning for estrogen-alone products, which the re-analyses did not overturn, remains. Risk information about cardiovascular disease and breast cancer stays in the label, but in the “Warnings and Precautions” section rather than as a Black Box Warning. Major MHT drug companies submitted proposed labeling changes at the FDA’s request.

Will a new label broaden access?

The relabeling matters because the Black Box was not merely informational—it was behavioral. A boxed warning is the most prominent warning signal the FDA can attach to a drug. It shapes formulary decisions, insurance coverage, malpractice exposure, and patient willingness to fill a prescription. For two decades, the Black Box on HRT products told physicians and patients, in the starkest possible terms, that this class of medication could cause heart attacks, breast cancer, and dementia. The nuance, that these risks applied primarily to older women starting a specific oral regimen years after menopause, was invisible on the label.

For the millions of women in their 40s and 50s experiencing debilitating vasomotor symptoms, the practical effects of relabeling could be transformative. The gap between the 40 million women who might benefit and the 2 million who currently receive therapy is not explained by clinical contraindications alone. Importantly, this gap - two decades of women who went through menopause with MHT support - won’t benefit from this relabeling change. These women, now in their 50s, 60s, and 70s have already preserved through menopause and experienced irreversible changes to their physical health, including the silent bone loss that will likely go undetected until fracture. Much of this impact appears explained by fear rooted in a warning that, for the intended population of younger menopausal women, that may be overstated given the magnitude of risk observed in the WHI.

In some ways, the MHT story has come full-circle. In the 1960s, drug companies sold estrogen as a cure-all for menopausal women. Evidence? Not much. Yet, estrogens were widely adopted among peri- and post-menopausal women. That, in turn, inspired the WHI which read out in 2002. As, Makary et al. argued, the FDA overgeneralized from WHI inaugurating a quarter-century of therapeutic nihilism. Now, with relabeling, the FDA attempts to restore a nuanced, population-specific understanding of HRT’s risks and benefits.

Perhaps this change represents a genuine correction. Or, perhaps, it is another pendulum swing back toward enthusiasm. Will patients benefit? It’s not totally clear. Ultimately, only rigorous evidence can inform the decision to initiate and continue MHT. Yet, given the diversity among MHT formulations and regimens, we still have many degrees of freedom to flex before we get a clear answer to the risk-benefit of MHT across all peri- and post-menopausal women.

How did we get here?

But, how did we get here? Why did the NIH sponsor the multi-decade Women’s Health Initiative? How did MHT become so popular such that over 1-in-4 postmenopausal women were taking at the turn of the century? And, how was it discovered in the first place?

The history of menopausal hormone replacement therapy is a long and fascinating road. I became interested in the origins of HRT after learning about how estrogen supplementation was developed as a front-line preventative for osteoporosis. The relabeling is the most recent chapter in a story that starts in the late 1700s, runs through the barnyard, catalyzed the emergence of a new discipline of medicine, and is still being written. As I see it, the story has five parts:

• Part 1 - Reviving Estrogen Replacement Therapy

• Part 2 - Organ Replacement

• Part 3 - Hunt for the Hormone

• Part 4 - Estrogen Rush

• Part 5 - Weighing the Scales of MHT

After tracing the history of MHT, it’s not clear to me that we’ll ever have concise answers to the plethora of questions around MHT. The argument over whether medicine should provide MHT is possibly older than MHT itself. In many ways, MHT is a vestige of a different time in medicine where discoveries arrived and scaled rapidly on what we would now consider weak a evidentiary basis.

In some ways, the story of MHT reflects the difficulty of generating high quality evidence to inform patients and providers. The NIH paid for a large, decade-long randomized controlled trial of MHT with the Women’s Health Initiative. Yet, the answers remain unclear! Further, I believe that the story of MHT highlights the tension between speed and rigor. The pace of medical progress can accelerate, but the certainty we can have about the benefits and risks of a therapy necessarily diminish. Enthusiasm about the potential benefits bolstered by testimonials from patients and providers, amplified by the drugmakers themselves, brought MHT into the mainstream. Few interventions have been adopted as broadly as MHT with so little high-quality evidence. Yet, some people clearly benefit from MHT. And, the FDA has MHT slated for a grand comeback.

So, how did Estrogen Replacement Therapy develop in the first place?

One of the chief complaints of people as they age is the gradual loss of vision. As humans enter their 4th decade of life, the cornea begins to stiffen and manifests as presbyopia limiting the eye’s ability to focus on close objects. For most people, cataracts begin to emerge in the sixth-to-eighth decade.

By 80, more than half of Americans will have developed cataracts. As we age, the clear protein components that form the lens of our eye begins to degrade. Accelerated by diabetes, hypertension, and UV exposure, we progressively lose vision as the lens of the eye becomes increasingly damaged and cloudy. Cataracts have been recognized as a problem for older adults since antiquity.1

Cataract surgery is inspired by a singular question: can one restore vision by removing the cloudy lens? The first description of cataract surgery is contested. The first examples of “couching,” or displacement of the cloudy lens to expose the retina to unfocused light, may date to as early as the 6th century BC. Removal of the lens by surgical aspiration was described as early as the 2nd century AD. In the 18th Century, two physicians demonstrated it was possible to remove the lens of the eye.

Samuel Sharp is credited with the first lens extraction, removing the lens and capsule. However, removing the lens does not restore vision.2 Thick refractive glasses can help focus the light, but patients struggled to resolve objects.

Solution: Replacement?

So why not put in a transparent glass lens? The idea of lens replacement is known as pseudophakia.3 Simply, you can! And, it restores vision! But, it has to be the right type of lens. Many materials induce an inflammatory foreign body response in the body.4 But, British physician Sir Harold Ridley had an idea.

During WWII, Ridley observed that British WWII fighter pilots tolerated shards of acrylic (poly(methylmethacrylate), PMMA) in their eyes without an inflammatory immune response. Sir Harold Ridley speculated that if one could create a transparent, biocompatible plastic lens, then one could restore vision. With the help of ophthalmologists John Holt and John Pike, Ridley carefully crafted a plastic lens that mimicked both the shape and refractive properties of human lenses.5

In November of 1949, Ridley implanted the first intraocular lens.6 Handcrafted, he chose plastic because it was light, flexible, and biocompatible. Additionally, the lens could be chemically sterilized with cetrimide. Heat and temperature would distort the plastic lens and gamma-irradiation sterilization had not yet been developed. In creating the plastic lens, he replaced a deteriorated component of the body with a synthetic mimic to restore visual function in patients.

Ridley presented his results in July of 1951 at the American Academy of Ophthalmology in Chicago. He had kept his work private to avoid other surgeons copying his experimental procedure. However, the field received Ridley’s work largely with hostility. Derrik Vail, the former Editor in Chief of the American Journal of Ophthalmology, described Ridley’s lens replacement operation as having “considerable recklessness” indicating that the risk was not worth the benefit and that he wouldn’t advise it for his patients or himself.

Ridley was ostracized from mainstream ophthalmic surgery and abandoned posterior chamber lens implantation research. Ridley also claimed that fellow ophthalmologists threatened to pursue legal charges of malpractice for his experimental work. According to ophthalmic historians Apple and Sims, as late as the 1980s, academic ophthalmologists would recommend against IOL implantation. The head of the British Institute of Ophthalmology, Sir Stewart Duke-Elder, openly derided Ridley’s intraocular lens implantation as “misguided.”

Refinement promotes widespread adoption

However, Ridley’s technique continued to develop. In 1967, American Ophthalmologist and Broadway producer, Charles Kelman developed phacoemulsification. Here, surgeons apply of ultrasonic energy to liquify the lens for easy aspiration. Dissolving the lens prior to extraction minimized the surgical incision transforming the procedure from an inpatient operation to a same-day outpatient operation.

As ophthalmic surgeons further refined the technique with better incision and lens dissolution techniques, cataract surgery was rapidly adopted in the 1980s. When it was introduced into the US in 1970 as an experimental procedure, cataract surgery and the intraocular lens were largely unregulated.7 In 1978, the FDA began tracking cataract surgeries. From 1978 to 1982, the number of intraocular lens implantations nearly tripled to 400,000 annually in the US. Today, nearly two million Americans receive cataract surgery annually.

Today, the operation is fast and low-risk. A fractional percent of patients experience complications. Many patients walk away from the 20 minute operation with at least 20/40 vision the next day. And, innovation hasn’t stopped. Modern surgical techniques and lenses have continued to innovate becoming flexible, multi-focal, and vision enhancing. So, perhaps, one might forgive ophthalmic surgeons for their minor God complexes considering they routinely perform what was once considered a Christ-like miracle.

So, what’s the price of a medical miracle? All-in, about $2,000 per eye.8 Medicare spends about $3.4B annually on cataract surgery.9 For most patients, the synthetic intraocular lens lasts a lifetime. The risk is low as complications appear in <1% of cases for high-volume surgeons. Moreover, cataract surgery can reduce the risk of falls by up to 30%. It also happens to be one of the most cost-effective procedures for the elderly adding 2.8 QALYs over the course of 13 years at a cost of ~$1,500 per QALY. Cataract surgery is, in effect, so cheap that, while pharmaceutical alternatives to preserve the native lens have been explored, no chronic pharmaceutical therapy could compete at the $2000 lifetime price point.10

This, of course, is not to say that vision loss in older adults is solved problem. Age-related macular degeneration (AMD) - e.g. wet AMD, dry AMD or Geographic Atrophy (GA) - remains a leading cause of vision loss in the elderly. However, pharmaceutical innovation has drastically improved outcomes for patients here. VEGF inhibitors (Eylea/Aflibercept, Lucentis/ranibizumab, Vabysmo/Farcimab) and complement inhibitors (Syfovre/pegcetacoplan and Izervay/avacincaptad pegol) effectively halt the progression of wet AMD and GA respectively. The leading VEGF inhibitor for AMD, Eylea, sells about $10B of drug annually. But, unlike cataract surgery, once vision is lost, it’s gone for good… For now.

Vision, unsurprisingly, is a top concern for older adults. By inserting a prosthetic intraocular lens, cataract surgery permanently restores lens function after a single, outpatient intervention. Interventions like cataract surgery offer a template for longevity medicine. Identify the dysfunctional component and replace it. For best results, intervene early before the dysfunction leads to larger, mortality driving complications such as falls and fractures.

What else might we replace?

There are a few replacement-based approaches to managing age-related disorders. Joint replacements (hip, knee) were developed to treat osteoarthritis and mobility limitations. Joint replacements have a similarly fascinating history as a miraculous medical development of mid-1900s, albeit with a less direct path to patients. One could make a similar argument for dentures. Organ transplantation is not presently widely practiced to treat “age-related” disease, although many recipients are older adults. Perhaps if organs become more available with xenotransplantation (Revivicor, eGenesis) or syngeneic organ generation (Renwal), exploration of transplantation for age-related disease might follow a similar arc.

Another opportunity is syngeneic hematopoetic stem cell (HSC) transplantation. Coupled with non-genotoxic conditioning, youthful HSC transplantation could help cure idiopathic anemia of aging. Youthful HSC transplantation could also help cure some severe autoimmune diseases where CAR-T and T-cell-mediated depletion therapies are proving our the “immune reset” concept. Youthful HSC transplantation could also help address emerging clinical phenomena like clonal hematopoesis, the expansion of a single, clonal lineage of progenitor blood cell. Clonal hematopoesis appears to increase the risk of a variety of hematopoietic disorders. Its incidence also increases with age; up to 20% of 80 year-old adults have dominant hematopoietic clones. Clonal hematopoiesis increases CV death and all-cause mortality risk.

Surgical replacement of dysfunctional components is attractive. One big advantage over pharmaceutical solutions is the one-time nature of the procedure. Although many highly skilled surgeons are required to treat an aging population, the one-time expense with lasting benefit is a big win for patients and health systems. However, opportunities for replacement strategies are limited. Some organs - bone, brain, vasculature, skeletal muscle - are not amenable to transplantation. Yet, they still degenerate over time. But, the opportunities to replace failing systems remain large.

How might the next ‘cataract surgery’ emerge today?

One remarkable aspect of the development of cataract surgery is the lack of pre-clinical testing. Ridley, although not a “physician-scientist,” was certainly an experimental physician. No history of cataract surgery I found mentioned animal models of cataract surgery or intraocular lens replacement. Animal models of cataract surgery do exist for cataract surgery research, but these appear recently developed.

What might developing cataract surgery today look like? I’d fathom that the procedure would require extensive non-clinical evaluation in animal models before the FDA would green-light human studies. Perhaps, we’d also want to see a long-term tolerability study in animals, and humans, of the intraocular lens material? Assessment of vision for intraocular lens efficacy can occur shortly after the procedure. In fact, so quickly and with such a large improvement (>20/400 → <20/40), would regulators require an RCT for efficacy? I could see regulators requiring half-decade long safety assessments, perhaps randomized. But, once efficacy is demonstrated, is it ethical (or possible) to maintain a sham-treatment group? All in, an aggressive timeline here might run 10 years from conception to FDA approval?

However, adoption of Ridley’s procedure was quite slow. Concerns from fellow ophthalmic surgeons limited dissemination. While the first presentation of tho operation occurred in 1951, just a couple of years after Ridley’s conception, professional concerns limited dissemination for nearly two decades. Other practitioners eager to advance the practice did harm patients with faulty intraocular lens implants. It wasn’t until the early-1980s that intraocular lens implants became common in ophthalmic surgery.

Would a rigorous pre-approval process have enabled rapid clinical adoption?

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GLP-1 receptor agonists have revolutionized weight loss. Prior weight loss drugs were unpleasant (rimonabant), ineffective (Contrave), or dangerous (methamphetamine, fen-phen, 2,4-DNP). For many patients, GLP-1s and multi-agonists like Lilly’s GLP-1/GIP Tirzepatide are godsends. Tirzepatide helps patients lose up to 20% of their body weight over a year. Lilly’s Retatrutide - GLP-1/GIP/Glucagon multi-agonist - helps patients lose more than 24% of their body weight in just 48 weeks. Most patients can reach their target weights and treat co-morbid problems (like sleep apnea) with only moderate discomfort. What’s not to love?

Well, weight loss patients have five chief complaints:

1. Tolerability - GLP-1s can induce GI side-effects, like nausea and vomiting

2. Durability - once GLP-1 therapy is discontinued, patients regain weight

3. Frequency - most GLP-1s are administered sub-cutaneously every week

4. Access - Medicare, Medicaid, and most commercial insurers don’t cover GLP-1s for weight loss; many patients pay cash out-of-pocket

5. Muscle Atrophy - patients lose fat mass, but also muscle mass

Although the first four complaints are very important, I want to focus on the fifth. Many people would prefer to lose weight without losing muscle mass. This desire is both aesthetic and functional. However, for older adults, loss of muscle mass is a major functional concern.

Will GLP-1s make people more frail, faster?

Approximately 40% of older adults in the US are overweight or obese. When patients lose weight, the composition is mostly fat. When the weight comes back, it’s almost entirely fat. Might repeated weight cycling will increase the risk of Sarcopenia, a condition of low muscle mass and impaired muscle function?

Before weight loss, some older adults already meet the clinical criteria for “Sarcopenic Obesity,” or Obesity co-incident with Sarcopenia. So, while GLP-1s might be helpful, the risk-benefit trade off for these groups might not be worth it. On the margin, loss of lean mass in older adults is coupled to loss of strength and function. Could losing weight impair physical function in certain patient populations?

Emerging data suggests yes. GLP-1 use in older adults may impair strength. Earlier this year, Veru reported that stair climb power declined by ≥10% for 42% of older adults with just 16 week on semaglutide in its Phase 2b study an androgen receptor agonist (enobosarm). Only 10% of patients on semaglutide lost ≥10% of their body weight in Veru’s Phase 2b. On GLP-1, power declined more than weight. As strength and power decline with age, patients and providers fear going on GLP-1s as trading obesity risk for early frailty.

Additionally, skeletal muscle mass declines with age. The decline accelerates with age. So, for older adults, the muscle mass lost on a GLP-1 might limit physical function. And, what is lost may not come back. Might widespread GLP-1 adoption among older adults trade a near-term obesity epidemic for a long-term frailty epidemic?

Anorectics and Anabolics

To understand how to improve weight loss, we need to understand how GLP-1s work. Most current-generation weight loss drugs - GLP-1s, amylins - help patients lose weight by, primarily, suppressing appetite in turn restricting calorie intake. These are considered anorectic drugs. By reducing calorie intake, these drugs help patients remain at a negative calorie balance mimicking a caloric restriction diet. During caloric restriction, with or without GLP-1 aids, the weight lost by patients is a mix of lean mass and fat mass.

• Anorectic - appetite suppressant

• Anabolic - agent promoting growth, herein muscle hypertrophy

Anabolic drugs, such as synthetic androgen receptor agonists, promote growth. Growth, especially muscle hypertrophy, increases resting energy expenditure and can create a calorie deficit. Synthetic androgens and hGH are anabolic mechanisms with several FDA approved drugs, but have concerning safety risks.1 Newer anabolic drugs rely on newer mechanisms that can avoid these safety risks. One exciting class is based on the myostatin-activin receptor pathway. Myostatin, and related ligands, signal through the Activin receptor to repress muscle hypertrophy. Humans and animals that lack myostatin display high degrees of muscle hypertrophy, perhaps most famously in “double muscle” cattle. Drugs promote muscle hypertrophy by blocking the signaling of myostatin and related ligands.

So, perhaps one could promote muscle hypertrophy while restricting calories to lose more fat while retaining muscle? To shed fat and retain muscle, body builders pioneered regimens that combine caloric restriction with resistance training.2

1. Will combining an anorectic (GLP-1) with an anabolic preserve lean mass?

2. Can preserving lean mass preserve strength and physical function?

While the answer to the second question remains unclear, we now have good evidence that combining GLP-1s with anabolic agents helps patients lose more fat mass while largely sparing lean mass.

COURAGE to EMBRAZE and BELIEVE

Three recent Phase 2 trials focused on helping patients preserve lean mass while losing weight read out recently; COURAGE from Regeneron, EMBRAZE from Scholar Rock, and BELIEVE from Lilly (Versanis) read out this month. The core concept of all these studies is to pair an anorectic agent (GLP-1 or GLP-1/GIP) with an anabolic agent, such as anti-myostatin or bimagrumab.

Regeneron, Scholar Rock, and Lilly’s anabolic antibodies all block different components of the same pathway, the Activin Receptor Pathway. Lilly’s antibody directly blocks the receptor, in turn blocking Activin Receptor ligands broadly inhibiting signaling. The receptor blocking approach should maximize efficacy, but also inspired concerns about the safety of the strategy. In contrast, Regeneron and Scholar Rock elected to pursue ligand blocking strategies. They argued that selectivity would improve safety while still providing acceptable efficacy. In favor of their argument, genetic deficiency of myostatin in humans increases muscle mass with no obvious deleterious phenotypes. However, previous studies of anti-myostatin antibodies in adult humans failed to noticeably change body composition or improve muscle function. So, how do the approaches stack-up?

Earlier this month, Regeneron released results from their 26 week Phase 2 COURAGE study. By pairing semaglutide with Regeneron’s anti-myostatin, trevogrumab, patients could lose similar amounts of body weight, but the weight lost would be 76-80% fat vs. 66% fat for semaglutide alone. For patients, this would be losing an additional 2-3 lbs of fat. Overall, adding anti-myostatin to GLP-1 improved the composition of weight lost with little change in tolerability. In an additional study group, patients received a “triplet” combination: semaglutide, anti-myostatin, and anti-activin A (garetosmab). As the activin receptor, the receptor for myostatin, transmits the signals of multiple ligands. Regeneron’s hypothesized that blocking activin A in addition to myostatin would further improve the composition of weight loss. This is precisely what they observed. Patients on Regeneron’s “triplet” lost 3% more body weight and >90% of the weight lost was fat mass. But, multiple patient deaths in the “triplet” group sparked safety fears.

On the heels of Regeneron’s combinations, Scholar Rock’s released results from EMBRAZE, a 24-week Phase 2 study of tirzepatide with or without their anti-(latent) myostatin antibody, apetigromab. It’s quite unclear why targeting the latent form of myostatin instead of the active form of myostatin would be therapeutically superior, but Scholar Rock has conviction in the approach. Scholar Rock’s combination helped patients lose about the same amount of weight, but 85% of the weight lost was fat mass vs. 70% for tirzepatide alone. Patients on Scholar Rock’s combo did not lose more fat mass, but they retained an additional 4 lbs of lean mass. This result was promising, but Scholar Rock appears to have discontinued their obesity program to focus on commercializing apetiogromab for SMA.

Monday’s presentation at the ADA of the BELIEVE Phase 2 from Lilly (via acq. Versanis) tests a combination of a GLP-1 receptor agonist with the rather unique anabolic antibody, the activin receptor blocking antibody bimagrumab3 (bima). Instead of blocking the signaling proteins, bima works by blocking the receptor for myostatin, activin A, and other body-composition regulating signals. Lilly’s hope was that by blocking the receptor instead of the ligands, and restricting calorie intake with a GLP-1, patients would lose more fat and more weight.

The 48 week BELIEVE Phase 2 compared a multiple placebo arm to semaglutide4 (1.0mg or 2.4mg), bimagrumab (10 mg/kg, 30 mg/kg), and sema-bima (1.0mg, 2.4mg semaglutide X 10 mg/kg, 30 mg/kg bimagrumab). Lilly saw unprecedented weight loss.

Patients on the high-dose sema-bima anorectic-anabolic combination lost up to 22% of their body weight, 6% more than patients on sema alone. On the high-dose sema-bima combination, patients lost exclusivley fat at 24 weeks and ≥90% fat mass at 48 weeks. For a 250 lb patient, high-dose sema-bima was like losing 50 lbs, but 45 lb of fat. Patients on sema or bima lost 28% of their body fat. Patients on sema-bima lost 45% of their body fat in just 48 weeks. One of the investigators described the average change in waist circumference on sema-bima (-22cm) as going from a 42 → 34 in mens’ waist sizes.

Although efficacy in terms of fat mass loss is best in class, the data do present some concern. Additionally, tolerability of the regimen remains a question. High rates of discontinuations were observed in the bima and placebo groups. The nature and severity of the muscle spasms and twitching, likely on mechanism, remains unclear. The study enrolled adults 18-80 years-old. So, even though Lilly included some exploratory endpoints assessing physical function, we do not know if retaining lean mass will retain muscle function for older adults. Until we do, these data warrant cautious optimism.

Avoiding an unpleasant trade-off

Right now, older adults face an unpleasant trade-off: lose weight and improve your cardiovascular health, but perhaps accelerate your decline? With GLP-1 combination regimens like sema-bima, older adults might not need worry about trading near-term weight loss benefits for early-onset frailty. Although primarily motivated by the desire to improve weight loss for broad markets, the discovery of highly effective fat-mass selective weight loss regimens is a promising development to help meet the needs of older adults. Perhaps, we are on the cusp of a revolution in medicine where we begin to view the loss muscle mass and muscle function with age as a treatable condition, much like Osteoporosis.

Growth and Fragmentation

Lilly re-setting the bar also has implications for the competitive nature of the weight loss markets. Projections of the size of the weight control markets have varied from $40B to $150B annually. The emerging weight control market will be massive. Yet, rather surprisingly, only Novo Nordisk and Eli Lilly have marketed GLP-1 drugs for weight loss. Other companies are still playing catch-up. When newer GLP-1 drugs come to market, they will have to compete with established tirzepatide and generic semaglutide (est. 2031).

How might a new entrant compete with entrenched standard of care tirzepatide and cheap, generic semaglutide? Dosing frequency and tolerability are potential avenues. There are countless competitors searching for oral small-molecule agonists of GLP-1R, but Lilly also leads here. Perhaps, novel mechanisms for incretin resistant patients. Composition of weight lost is another potential axis of differentiation. Aspiring entrants like Regeneron and Scholar Rock were hoping that lean mass sparing weight loss could help them differentiate from generic semaglutide and Lilly’s Obesity franchise. Given the sema-bima results, Lilly will be competitive here. But, substantial opportunity remains. The need is massive and patients are diverse. It appears that Regeneron plans to enter the Obesity and weight control market with a GLP-1/GIP they acquired from Hansoh Pharma. Instead of consolidating in the hands of the dominant GLP-1 players, I think the weight loss market is starting to fragment.

Right now, weight loss is a duopoly of Lilly and Novo.5 As GLP-1 adoption continues, new entrants will start to look for specific needs in specific sub-populations to tailor their weight loss offerings to the needs of patients. A few6 to consider:

• Efficacy - not all weight loss patients need to lose much weight. For some, a few pounds is fine. For high BMI patients with limited mobility or GLP-1 non-responders, sema-bima might be a better option

• Durability - is there a one-and-done solution for weight control? Many patients would be willing to accept unpleasant periods of weight loss for extended periods without weight regain. Amgen’s MariTide is hoping to keep the weight off

• Convenience - Metsera is pursuing a convenience market with monthly weight loss drugs. Some patients will happily accept lower efficacy for more convenient options. Will we soon get an annual weight control shot at your annual check-up?

• Tolerability - some patients won’t accept unpleasant side effects. Here, Regeneron could chart a course for a better tolerated, but less efficacious, lean mass sparing weight loss combination with their anti-myostatin

• Route of Administration - Here, oral options might win if companies like Structure Therapeutics can solve the tolerability issues. Oral lean mass sparing weight loss options remain at the early stages of development

• Fertility - evidence is emerging that GLP-1s can improve fertility for some patients (a la Ozempic Babies). Products tailored to the needs of aspiring parents could become a growth market

• Aesthetics - For patients looking to look better, some patients will prioritizing tolerability (GLP-1 + anti-myostatin) while others will have a strong preference for (GLP-1 + bimagrumab)

• Older Adults - preserving muscle to preserve physical function and delay frailty should be a major concern. The needs are complex. While bima-sema holds promise, it won’t solve weight loss for older adults

Looking forward, GLP-1 based regimens are slated to remain first-line solutions and the backbone of any weight control programs. Companies will continue to innovate to meet the unique needs of different patient populations. I, for one, am excited to see the emerging interest in keeping older adults stronger, longer.

Pharmaceuticals are a cost effective avenue to helping older adults age well. With drugs for age-related diseases like cardiovascular disease and osteoporosis help older adults stay stronger, longer.

While longevity enthusiasts dream of anti-aging cocktails, the story of post-menopausal osteoporosis offers an alternative path. Although post-menopausal osteoporosis is an age-related disorder, drugs that treat osteoporosis do not address underlying “mechanisms of aging,” but rather tackle the pathology directly. Bone frailty hasn’t been solved. But, development of pharmaceuticals has transformed post-menopausal osteoporosis from an unavoidable systemic burden into a manageable chronic condition. So, how did it happen?

Porous Bones

In the 1830s, French pathologist Jean Lobstein first described the porous, trabecular meshwork of bones from elderly skeletons. His observation helped explain what physicians long knew - fracture risk and bone fragility increase with age. Today we consider bone fragility a core component the frailty syndromes that many older adults experience. Many people still consider weak bones a normal, unavoidable consequence of aging. While age-related bone fragility has been known since antiquity, our understanding of bone fragility as a treatable condition emerged only in the 1940s.

From Phenomenon to Diagnosis

In 1940, at Massachusetts General Hospital, physician-scientist Fuller Albright first described the connection between menopause in women and bone loss. A physician-scientist, Fuller Albright developed interests in the medical mysteries of his patients at MGH. One such mystery was the pathological bone loss in largely middle aged women. This idiopathic osteoporosis was puzzling. In 1941, Albright, Smith, and Richardson authored "Postmenopausal Osteoporosis", a clinical description linking menopause, and the loss of endogenous estrogen production, as the probable driver of osteoporosis in middle-aged women.

Primarily interested in pathological fractures, such as compression fractures experienced during daily activities, the authors sought to link the bone fragility of the unexplained osteoporosis with an underlying pathological driver. By analyzing a cohort of young and middle aged women who experienced non-healing fractures, the authors concluded that the cases in their cohort lacked the deficiencies thought to drive bone loss in adults.

At the time, bone loss in adults was attributed to one of three factors: dietary insufficiency of calcium, vitamin D deficiency (as in rickets, osteomalacia), or lack of activity. Serum calcium and phosphorous levels were normal in the cohort. However, the authors’ cohort - active women and regular consumers of milk - had faint bone shadows on roentgenograms (X-ray images) and were susceptible to fractures during daily activities. Strikingly, these women with faint bone shadows were dramatically more likely to be experiencing menopause, early menopause, or artificial menopause via surgical oophorectomy. Rather ironically given the modern perception of post-menopausal osteoporosis as an age-related disorder, Albright, Smith, and Richardson specifically excluded cases of osteoporosis in patients over 65 in their identification because, in these patients, the condition could be confounded by age-related "senescence." Together, the evidence seemed to suggest that loss of ovarian function likely contributed to the increased bone fragility.

To pinpoint the etiology, Albright, Smith, and Richardson relied on new insights from skeletal biology. Recent work demonstrated that bone was not inert. Rather, it was constantly being disassembled and reformed by opposing sets of cells, osteoclasts and osteoblasts. Unlike rickets, osteoporosis is not a disease of calcium metabolism. Instead, osteoporosis appeared to be a disease of increased bone resorption and decreased bone deposition.

At the time, evidence that estrogen supplementation in humans could preserve and enhance bone mineral density was lacking. However, Albright, Smith, and Richardson were familiar with animal experiments in estrogen supplementation. In pigeons, investigators established a link between reproductive cycles and bone density. Estrogens can increase blood calcium levels in pigeons. Intriguingly, male pigeons almost uniformly have marrow filled long bones whereas female pigeons, at different points in the reproductive cycle, have either marrow filled long bones or near solid long bones. In fact, supplementing estrogen in male pigeons densified their bones. Similarly, in mice, estrogen supplementation can ossify long bones such that they nearly completely close marrow cavities. Citing evidence from estrogen supplementation in pigeons and mice, Albright, Smith, and Richardson proposed that estrogen directly promoted bone mineralization in humans and that its loss was the primary driver of osteoporosis in post-menopausal women. Later, Albright demonstrated that supplementation of certain sex steroid hormones - estrogen, progesterone, or testosterone - supplementation could preserve bone mineral content in post-menopausal and ‘senile’ osteoporosis, establishing post-menopausal osteoporosis as a treatable medical condition.

A Silent Epidemic Emerges

Yet, until the 1980s, few considered osteoporosis a major public health issue. What changed? In part, population aging. In the 1980s, the number of older adults grew as medical advances continued to curb major causes of premature mortality. Then, with more older adults, rates of geriatric health issues were increasing. From 1970 to 1984, hip fracture rates increased by 10%. This increase was concerning as, at the time, 20%-40% of women over 65 who fractured a hip would die within 6 months. In 1984, the NIH declared osteoporosis a “major public health problem” estimating that ≥1.3 million fragility fractures occurred in the US annually. Estimates of the annual cost to Medicare ranged from $3B-$5.2B as of 1986. At the time, these costs were about 4%-7% of Medicare’s annual budget ($74B USD). While already concerning, public health advocates feared the costs would grow as the early-Boomers turned 45 in 1990 and began to enter menopause en masse. Although the early-Boomers wouldn’t turn 65 until 2010, debilitating mid-life fractures in post-menopausal women could prematurely drain the workforce, increase disability-related care costs, and impair quality of life for women as they age.

However, some physicians argued that the age-related decline in bone density was merely a change in quantitative state, not a qualitative change from normal bone. Was the decrease in bone actually pathological? Physicians like Marshall R Urist, the co-discoverer of Bone Morphogenetic Proteins (BMPs), argued for a distinction between pathological and age-related osteoporosis. Urist argued that loss of bone mass in older adults is normal, time dependent, and coupled to reductions in muscle mass. In pathological osteoporosis, the rapid loss in bone mass “is characterized by spontaneous collapse of vertebral bodies [vertebrae] in the dorsal spine” (McLean and Urist. 1986. Bone. 239-240.). In patients with post-menopausal and age-related osteoporosis, external forces like accidental falls drove the fractures. So, was bone loss itself actually pathological?

Supplementation and Scare

While physicians argued the merits of estrogen replacement, pharmaceutical estrogens became widely available. Some physicians began supplementing estrogen in peri- and post-menopausal women to alleviate many symptoms of menopause - hot flashes, skin wrinkling, sexual dysfunction. Physicians and patients began to view menopause as a pathological sate of estrogen deficiency, not an unavoidable phase of life.

In 1966, Gynecologist Robert Wilson released “Feminine Forever,” a book extolling the virtues of estrogen supplementation during and after menopause. Reception was, at best, mixed. One scathing review in JAMA criticized the self-aggrandizing nature of the book (Wilson didn’t pioneer hormone replacement therapy as he claimed) and the reductive view of femininity (i.e. estrogen is what makes a woman). Later, it was revealed that the Wilson was paid by the manufacturer of Premarin1, a leading estrogen supplement of the era (Dominius, NYT). That year, prescriptions for Premarin doubled to 3.2M.

Simultaneously, the emergence of new technologies, such as bone morphometry, bone densitometry, and Dual Energy X-ray Absorptiometry (DXA), enhanced the quantification of bone mass and density. These new bone quantification techniques helped physicians more precisely quantify bone density and diagnose osteoporosis. Yet, diagnostic standards were highly variable and the primary treatment available to women was estrogen supplementation. While the NIH rang the alarm to alert the world to the serious public health issue of post-menopausal osteoporosis, concerns about estrogen replacement therapy surfaced.

Large observational studies in the 1980s identified a link between estrogen supplementation and breast cancer risk. The 1987 Cancer and Steroid Hormone (CASH) case-control study identified an 30% increased risk of developing breast cancer for women who had been supplementing estrogen after a bilateral oophorectomy. This cancer signal provided additional impetus for the FDA, and drug developers, to advance novel, non-hormonal osteoporosis therapies.

Drug Boom

At the time, patients lacked effective non-hormonal options to manage osteoporosis. But, that was about to change with the development of the bisphosphonate class.

Initially synthesized as calcium chelating agents for use in industrial applications, bisphosphonates are organic analogs of inorganic pyrophosphates. In patients, bisphosphonates block bone resorption and new bone deposition. In 1969, Fleisch et al. demonstrated that organic bisphosphonates could prevent the formation and dissolution of hydroxyapatite, the major mineral constituent of bone. In that same paper, the authors also demonstrated that bisphosphonates could slow bone loss in an ovariectomized rat model of bone loss. The first bisphosphonate drug, etidronate, was approved in 1977 for use in treating Paget’s disease of bone, a bone formation disorder, and heterotopic ossification, a condition where soft tissue gradually forms bone. Although not approved to treat osteoporosis, the early generation bisphosphonates were used off label to manage the condition. However, in 1994, two decades after initial FDA approval, daily oral etidronate was first evaluated in a randomized controlled trial to assess its ability to treat osteoporosis. For patients with post-meonpausal osteoporosis, etidronate reduced fracture rates by more than 50% over two years.

In 1995, alendronate (Fosamax), a bisphosphonate 100-fold more potent than etidronate, won approval for the treatment of fracture risk in post-menopausal osteoporosis. Although effective, alondronate is not perfect. Up to 10% of patients experience esophageal inflammation while taking alondronate. To complement the bisphosphonate class, Selective Estrogen Receptor Modulators (SERMs), such as raloxifene which mimics estrogen in bone while blocking estrogen in the breast and uterus, were approved in the late 1990s.

Physicians and patients rapidly adopted bisphosphonates and SERMs. National office‑visit data show bisphosphonate or raloxifene use in osteoporosis visits rose from 14 % to 73 % (1994‑2003), while estrogen use fell sharply after 1995.

What helped accelerate the rapid uptake of SERMs and bisphosphonates? The causes are a bit overdetermined. In 1990, the first baby boomers began turning 45 and entering menopause, thus increasing the incidence of post-menopausal osteoporosis. Similarly, throughout the 1990s, there were sustained efforts by the public health establishment to promote the use of non-hormonal bone preserving therapies. Perhaps, most importantly, in 1994, the World Health Organization convened a meeting to define osteoporosis in terms of Bone Mineral Density (BMD) thresholds. The WHO aligned on a definition of osteoporosis as a BMD of 2.5 standard deviations below average *peak* bone mass, stratified by sex. So, a woman at age 70 could be ≤-1.0 SD below the mean for *age* and *sex*, but could also be clinically osteoporotic as their BMD could be below the 2 SD mean.

• Normal: T ≥ -1.0 SD

• Osteopenia (low bone mass): -1.0 > T > –2.5 SD

• Osteoporosis: T ≤ -2.5 SD

• Severe osteoporosis: T ≤ -2.5 SD plus ≥1 fragility fracture

In 2008, the University of Sheffield further refined the risk stratification of patients with the introduction of the FRAX algorithm. With country-specific models of fracture risk, FRAX helps physicians estimate the 10-year osteoporotic fracture risk of individual patients. Using BMD and individual patient history, FRAX can more precisely identify patients of concern (e.g. osteopenic T-score with history of glucocorticoid use).2

Prior to the WHO guidelines, multiple definitions of osteoporosis were in use. By unifying the indication definition with an accessible screening technology, DXA, the WHO opened the doors to widespread diagnosis. Introduction of tools like FRAX helped better identify high risk patients that would be otherwise missed. And, with bisphosphonates and SERMs, diagnosis became safely actionable.

In addition to helping identify patients, standardizing the diagnostic criteria also enabled drug developers to operate on a harmonized understanding of the indication. This certainty helped drug developers plan clinical evaluations of their therapies and project eligible populations. Further, the use of BMD T-scores (and then Z-scores, age-and-sex corrected BMD scales) Although these changes might seem trivial, pharmaceutical companies make decisions on the basis of risk-adjusted Net Present Value models of drug programs. Without an understanding of the eligible population or the anticipated drug effect, companies struggle to underwrite high-risk Phase 2 studies or a long Phase 3 outcomes study. When risk and reward are both highly uncertain, making decisions is uncertain.

From the 1990s through the 2010s, pharmaceutical companies continued to invest in novel osteoporosis therapies. More active and longer acting bisphosphonates, like Ibandronate (Boniva) and Zoledronate (Reclast), continued to enter the market. However, bisphosphonates are not perfect. Interrupting bone-remodeling by osteoclast inhibition appears to increase the risk of atypical femoral fractures and osteonecrosis of the jaw3. To address these limitations, the early 2000s also saw the introduction of novel bone anabolic therapies for osteoporosis patients. In 2002, the FDA approved the first bone anabolic therapy, parathyroid hormone (teriparatide / Forteo, PTH 1-34). In 2010, Amgen brought the RANKL inhibitor denosumab (Prolia), a bi-annual biologic that blocks osteoclast resorptive action, to the osteoporosis market. RANKL inhibition rapidly increases bone mineral density by blocking bone resorption, but chronic RANKL inhibition increases the risk of Amgen extended their blockbuster osteoporosis franchise through the 2019 approval of romosozumab (Evenity), an anti-sclerostin antibody co-developed with UCB, which helps osteoblasts deposit more new bone. In 2017, Radius Health won approval of abaloparatide (Tymlos), recombinant parathyroid hormone related peptide, an alternative bone anabolic therapy.

Yet, osteoporosis is not a solved problem. While the clinical armamentarium of drugs to manage osteoporosis expanded rapidly since 1990, patients with osteoporosis still lack a convenient, long-term option to arrest the disease. Bisphosphonates remain first-line therapy. But, patient patient concerns about side-effects with chronic use limits their utility. While regular, transient exposure to teriparatide (PTH) can increase BMD, chronic use blunts the anabolic benefits of PTH and can lead to BMD decay. Abaloparatide was intended as a safer alternatitive to Lilly’s teriparatide. Sadly, approval of abaloparatide came with a Boxed Warning for increased risk of osteosarcoma (in animals) and hypercalcemia. Abaloparatide’s Boxed Warnings limited patient uptake of the drug. After years of lackluster sales, Patient Square Capital and Gurnet Point Capital took Radius Health private after the FDA removed the Boxed Warning for osteosarcoma. Romosozumab has a Boxed Warning for MI, stroke, and CV death.4 Together, these safety concerns limit widespread uptake of osteoporosis therapies. Today, perception of limited marketability has slowed much of the investment into much of the novel mechanisms.5

Instead, clinical innovation in osteoporosis tends to focus on sequencing existing therapies to maximize clinical benefit while reducing treatment burdens and improving patient experience. The figure below shows BMD changes from RCTs of post-menopausal osteoporosis patients comparing monotherapy interventions with cycling and combination therapies. While bisphosphonates and RANKL inhibitors remain first-line for osteoporosis, physicians lack consensus on optimal drug sequencing regimens.

Losing Ground

Between 1995 and 2010 - exactly the period in which DXA screening and bisphosphonate prescriptions soared - US hip-fracture incidence fell 42 % in adults ≥65 y/o. Other datasets that include vertebral and wrist fractures show a parallel 1-3 % annual decline. Economists estimate that the lives saved and nursing-home days averted generated social value far exceeding drug costs. The momentum stalled after 2012. Medicare claims reveal a slight rebound adding >11,000 excess hip fractures from 2013–2015 relative to prior projections. Three forces converged:

1. Therapy gaps. Only one quarter of women who meet National Osteoporosis Foundation treatment thresholds actually receive medication, and <23 % of fracture patients initiate therapy within a year.

2. Safety fears. Media reports on atypical femoral fractures and osteonecrosis of the jaw—rare but dramatic complications—coincided with a ≥50 % drop in oral bisphosphonate use between 2008 and 2012 after a decade of progress.

3. Screening cutbacks. Reimbursement cuts for office-based DXA in 2007 halved screening capacity, delaying detection of low bone mass just as the baby-boomer cohort entered retirement.

Unfortunately, like many degenerative diseases, prevention is complex. Patients don’t experience symptoms of osteoporosis until a fracture occurs. Osteoporosis is rarely actively painful. Unlike osteoarthritis where patients experience painful functional limitations daily activities, osteoporosis lacks the acute symptoms motivate diagnosis. Therefore, both providers and patients can lack urgency in addressing osteoporosis. Even with regular screening, many high-risk patients can go undiagnosed. Like age-related visual degeneration, symptoms may not appear until disease progression is advanced enough to limit therapeutic efficacy. Therefore, aggressive screening remains crucial to the prevent bone loss that drives fracture risk for older adults.

Lessons in avoiding the unavoidable

Over the course of the 20th century, post-menopausal osteoporosis evolved from a poorly understood phenomenon to a manageable chronic condition.6 Importantly, While post-menopausal osteoporosis is well characterized as driven by the decline in estrogen, the discovery and development of pharmaceutical approaches to prevent and treat age-related osteoporosis happened without a deep mechanistic understanding of the underlying drivers of bone loss with age. In both men and women, bones become more brittle with age.

Longevity enthusiasts dream of the FDA designating ‘aging’ as a disease. Although I think this impulse is directionally correct, it’s unclear what this would accomplish. However, the story of post-menopausal osteoporosis offers an alternative: go narrow. A narrow, functional definition of an age-related disorder effectively mobilized public health infrastructure, pharmaceutical firms, and investment capital. A well-defined patient population helped drug developers better assess both the treatment effect and the potential value to patients with the new drug. More certainty about the development risk, clinical need, and anticipated reward helped companies decide to allocate capital towards developing novel osteoporosis drugs. So, identify the need. Quantify it. Intervene in the highest need patients. Progressively expand to first-line prevention. Then, perhaps, if we follow this roadmap - define, quantify, intervene, expand - we can help older adults stay stronger, longer.