Listening to Oestrogen

Hormones have always been a third rail in female mental health. They may also be a skeleton key.

Lisa MillerDec. 21, 2018

Photo-Illustration: Artwork by CUR3ES

When she was 45, at around the same time her menstrual periods became irregular, Janet developed an obsession with a man at work. Now 61, Janet has the same job she had back then, managing the chemistry-department stockroom at a small northeastern college. But at the time, she was studying for a master’s degree and living in a suburb with her husband and teenage daughter, and Jim was a new addition to the chemistry faculty. He had a quiet, sensitive nervousness that appealed to Janet, and she felt from the outset that they had a bond.

The first time Janet began to feel seriously off was in the spring of 2001, when she was taking Jim’s inorganic chemistry class. Sitting in the lecture hall, listening to Jim talk about metals and compounds, Janet would feel a pain in her head, on the left side, slightly above and behind her ear — she indicates the area as if she were brushing away a fly — “like something was trying to get out of my head. And I knew it wasn’t right. Like a tumor. The weird thing was I would rub it and go, ‘Oh, I wish that would go away,’ and it would go away for about two minutes and then it would come back again. I’d say, ‘Well, a tumor wouldn’t go away if you rubbed it. So it’s not a tumor.’ ”

Janet first heard the voice — male, about 30 years old — while she was out with Jim and a group of co-workers at a TGI Fridays near campus. She was gazing at Jim (whose name, like some others’ in this story, has been changed) in the bar and thinking about how nice it would be to put her head on his shoulder. The voice said, “Go ahead!” It wanted her to snuggle up to him. She didn’t. She knew that would be ridiculous.

But the voice — which Janet decided sounded like Jim’s — persisted.
Within a couple of months, Janet was conversing regularly with it, a telepathic communication she started to imagine was emanating straight from Jim’s brain. “I thought he really loved me and cared about me but couldn’t say anything out loud,” she says. “The voice was talking to me just like it was Jim. It might as well have been Jim, as far as I was concerned.” So real did Janet’s conversations seem that she went to Jim’s house one evening to confront him about his feelings for her. He refused to answer the door, though she could see through the window that he was home.

The voice became Janet’s best company. It was Jim, but it also became more than Jim. She says it sounded exactly like him, but maybe it was God or Jesus or a spiritual guide. Speaking now, Janet sometimes uses the singular, voice, and more often the plural, voices. Together with the voices, she would go on adventures. Janet lives in a small town surrounded by forest and winding highways, and one evening when she was taking a walk she saw glowing orbs floating before her, about the size of grapefruits and at waist height; the voices told her that if she danced between them in a specific order, she could save the world. “So I danced all the way down, about a mile, and all the way back, and then I came home and danced in my apartment, all around the apartment, some more.”

As the months went on, Janet started to feel scared. The voices could be threatening. They always made a big deal out of little things. They yelled at her. During one of our conversations, we are sitting together in the chemical stockroom, a dungeonlike space with concrete floors and walls that is strewn with fast-food wrappers, old textbooks, and barrels of solvents. Janet is perched on the very edge of her swivel chair, leaning forward, and she points to my sunglasses, which are facedown on a long table. The voices, she says, were frequently harsh and critical about unimportant things. If they saw the sunglasses facedown, for example, “they would say, ‘Oh my God, you’ve got to move the glasses! They’re on the table the wrong way! It’s an emergency!’ ”

Janet realized she was barely functioning. She was getting herself to work every day, but she wasn’t eating and couldn’t focus. “Filing was almost impossible,” she says. Her marriage had fallen apart. Her daughter, busy with high school and alarmed at her mother’s strange behavior, went to live with her father. One day, overcome, Janet left work with the idea that, to escape the voices, she would drive her car into a tree. She wrecked the car but was physically unharmed, and when a police officer came to the scene, “I was kind of honest with him, and he got me an ambulance.” At the hospital, Janet was given her first dose of Risperdal, an antipsychotic delivered in pink or orange pills, which quiets the voices but doesn’t silence them completely. Janet had never had a serious mental illness before, and she has no family history of mental illness. She believes her breakdown was activated by Jim’s arrival in her life and by the vulnerable moment at which it happened. Janet was perimenopausal, the period before menopause when a woman’s estrogen levels begin to fluctuate wildly. And she was “very upset.”

Schizophrenia has always been regarded as a disorder of the young — a catastrophic unraveling of the mind in late adolescence or early adulthood. It presents most calamitously among young men, who are frequently diagnosed in their teenage years; for women, diagnosis comes years later. A patient will show up in the emergency room after a period of disorganized behavior, not having eaten or washed for weeks, often speaking incoherently, and presenting with what the DSM 5 calls “positive” symptoms — hallucinations, delusions — as well as some “negative” ones, such as lethargy. Patients may not be able to describe what’s happening to them or even perceive the extent to which their thoughts have become unhinged, but family members do. Schizophrenia is a chronic illness, they learn. There is no cure, only therapies and drugs that can, in some cases, control the symptoms to a manageable degree. Even with treatment, recurrence is a near certainty. And the lifetime prognosis is bad. Life expectancy for people with schizophrenia is ten to 25 years shorter than for those in the general population. Death by suicide is 13 times more likely.

Youth has been a diagnostic criterion for schizophrenia for a hundred years, including within the pages of the DSM, where schizophrenia has sometimes included an age limit: As recently as the 1980s, a person could not be tagged schizophrenic if he or she was older than 40. Some clinics targeting early intervention have cutoff ages as young as 24.

But schizophrenia does not neatly comply with that simplistic understanding. In the early 1990s, three British psychiatrists, curious about why men with schizophrenia had their first psychotic episode so much earlier than women, took a look at the voluminous diagnostic records in doctors’ offices and hospitals in one populous London neighborhood covering a period of 20 years. They found something astonishing: a demonstrable “second peak” of first-onset schizophrenia after 45. These patients were predominantly female.

These older patients compose just a fraction of the total number. About one percent of people worldwide receive a schizophrenia diagnosis, and almost 20 percent of them are diagnosed for the first time after the age of 45. But the data suggested a deeply embedded bias in the way doctors had thought about schizophrenia for a century, overlooking the middle-aged women who came to them with psychotic symptoms, refusing to believe they could have schizophrenia because the official classifications, and medical tradition, excluded them. In their view, “madness” associated with “the change of life” was not madness at all — not a serious affliction to be taken seriously — but a women’s malady to be treated with bleeding and leeches, herbs and ointments, drugs, alcohol, and the desiccated and powdered ovaries of farm animals. Committed to American asylums in the late-19th century, women with mysterious symptoms were labeled “insane from suppressed menses.” And a whole ecosystem of diagnosis and treatment failed to grow.

There is, to be sure, genuine tragedy in lost human potential at a young age. But it is also tragic for a woman to become mentally ill in the middle of her life, at a time when she has, if she’s been lucky, built a universe — a family, a job, friendships, a network of responsibilities and dependencies erected on the assumption of stability. She might have adolescent children and aging parents, professional duties and bills to pay. She might have a classroom of students; she might be the mortgage broker helping a family keep ownership of their home or the doctor advising on a chemotherapy plan.

A psychiatrist in Boston told me about a patient, a devout Christian with no previous history of mental illness, who suddenly believed a devil was occupying her teenage son and she needed to exorcise that spirit with a kitchen knife. The terrorized son called 911 and accompanied his mother to the ER. Another doctor told me about a patient so disconnected and paranoid that, while insisting on her own mental health, she had alienated every single person who might have helped her, including her parents and her husband, who wanted a divorce but instead quit his job to stay at home — so afraid was he of what she would do if he left their two young children with her unattended. A health-care worker in Northern California told me about becoming psychotic, catatonic, and suicidal as she approached menopause. At the time, she lived alone with her youngest daughter, who was 13. “Basically, quite a few times, she saved my life by calling 911. I would take an overdose and then I’d go to the hospital. Then they’d send me home and my poor child was frightened because of all she had to deal with. She’s still recovering. She’s 30.”

It has now been more than 20 years since the official discovery of that second peak, but the fact of it remains almost entirely invisible within the psychiatric Establishment and even more so among general doctors — and thus unavailable as an explanation to women experiencing their first breakdowns later in life and ignored as a guide for how to best treat them. Instead, women who become suddenly psychotic in middle age are typically given diagnoses that indicate an attending doctor’s baffled shrug (“psychosis not otherwise specified” was Janet’s diagnosis) and are treated with powerful antipsychotics that were long tested in clinical trials on men. These women, unclassified and living at the margins of health, are alienated further by medicine’s bewilderment at them.

But over those same 20 years, a tiny group of mainly female psychiatrists working independently all over the world, from inside American universities and organizations like the National Institute of Mental Health to researchers working as far away as Switzerland and Spain, began to study these women. They believe that in some, the dramatic fluctuations in hormones that accompany the onset of menopause may help to trigger schizophrenia. This correlation is called “the estrogen hypothesis.”

This hypothesis is powerful in that it helps to explain a large number of divergent cases. There are those second-peak schizophrenic women, who have breakdowns similar to those more commonly recognized in the young. But the circle of women whose lives and suffering may be illuminated by the estrogen hypothesis is much wider — women with psychosis linked to fluctuations in estrogen at all phases of life. There are women with traditional, early-onset schizophrenia whose hallucinations become more or less vivid in concert with their hormonal cycles, and women who become suddenly and dramatically psychotic — or catatonic or suicidal — when their estrogen plummets in the weeks after childbirth. Beyond that, there are women with previously diagnosed and controlled mental illnesses (bipolar disorder, major depression) who experience a recurrence or exacerbation during the menopause transition, as well as women who feel suicidal when others have PMS.

All women understand themselves to be in constant conversation with their hormones, which they know can wreak havoc with their mood. But they can also bolster and stabilize it. Yet this insight has been boxed away as somehow irrelevant to diagnosis and treatment by doctors unwilling to consider the possibility that the models of illness extrapolated from the experiences of men apply incompletely to women. “If men can’t get an erection, it’s a natural disaster,” says Catherine Birndorf, a reproductive psychiatrist who recently left Cornell to start a freestanding outpatient center in New York City for women with postpartum and perinatal mental illness. “But very little is studied in women because of our reproductive capacity and because of patriarchy. We need to try to understand women better.”

From his perch as the head of psychiatry at Columbia University, Jeffrey Lieberman puts it more bluntly: “Medicine hasn’t paid much attention to these women. Middle-aged women are low priority, like children used to be.”

For her psychiatric residency at Columbia in the early 1960s, Mary Seeman worked at an all-women’s psychiatric ward of Manhattan State Hospital. She was struck by how different female patients with schizophrenia looked and acted compared with what she’d read about in her textbooks. The rap on schizophrenia at the time was that it made people disconnected, but Seeman found her female patients to be just the opposite. They were lively, engaged, and responsive, able to converse with each other and with her in meaningful ways — even when they were medicated with antipsychotics, which frequently make people affectless.

When Seeman moved home to Canada, she found the same thing. In Toronto, she led group-therapy sessions for male and female patients with schizophrenia. In the men’s group, patients sat like lumps, not making eye contact and failing to remember one another’s names. “They seemed on the surface not to have feelings. They were unresponsive, wanting to be alone,” she says. But the women asked about each other’s children, shared knitting patterns, and made dates for coffee. Many of the female patients were diagnosed with something other than schizophrenia because their symptoms looked so different.

Other clinical gender differences struck Seeman too. As the textbooks predicted, men with schizophrenia seemed to improve as they got older, needing smaller doses of antipsychotic medication to control their symptoms. Young women with regular estrogen cycles needed less medicine than young men, but around the time of menopause, they started to fare worse. She remembers one patient in particular, a woman who always had a job and a boyfriend — a steadiness that is very unusual among people with a schizophrenia diagnosis. “She looked smart, was well dressed and never in the hospital,” Seeman says. “Then, roughly around the time of menopause, something remarkable happened. She was no longer working; she broke up with her boyfriend and became suicidal. Once she brought this difference to my attention, I began to notice that she wasn’t alone.”

No one knows exactly how schizophrenia starts — or, for that matter, what it is. Genes definitely play a role. People with a first cousin who has schizophrenia are more than twice as likely to receive the diagnosis than the population at large, and for those with a parent diagnosed, there’s a 15-fold risk. But environment interacts with the genes to turn them on in certain cases, and researchers have sought to pinpoint those triggers — to determine which circumstances or behaviors put a person who is predisposed at increased risk. Pot smoking in adolescence is thought to be a risk factor; so are head injuries during birth and in early childhood. In utero infections may play a role: Psychiatrists talk about the “spring birth” risk, by which they mean that fetuses can contract the viruses that thrive during the winter months in some parts of the world, increasing their susceptibility to schizophrenia later on. These are all hypotheses with some data to support them. The truth is, for all the codifications of the DSM, science still has an extremely rudimentary and tentative understanding of what actually happens in the brains of people we recognize as mentally ill. And political institutions routinely fail to meaningfully fund that inquiry. The estrogen hypothesis is valuable not because it provides a clear-cut answer as to why some women mentally deteriorate in midlife but because it suggests one way, in the face of a terrifying mystery, to begin exploring it.

Mary Seeman is 83 years old, with cropped white hair and a sharp, wise face. She still lives in Toronto, her sixth-floor apartment a jungle gym of rails and poles to accommodate her husband, Philip, who is 84 and has a degenerative muscle disease. Seeman was one of the first psychiatrists to put forward the estrogen hypothesis, an idea inspired, she told me, by Philip.

While Mary was busy training to be a psychiatrist, Philip, a psychopharmocologist, was trying to figure out how antipsychotic drugs worked on the brain. The first antipsychotic, Thorazine, came on the market in 1954. It had the miraculous effect of quieting psych wards overnight, as it switched off the hallucinations and delusions that made patients babble and scream, enabling them to become functional and coherent again. It was also a puzzle. Designed as a companion drug to anesthesia, no one, including its manufacturers, understood why Thorazine also quieted psychosis. Philip applied himself to finding out.

In 1974, he published an extraordinary discovery: All antipsychotic drugs work the same way. Psychosis likely results from excessive levels of dopamine — the brain chemical that gives feelings of pleasure and a “high” — possibly from faulty receptors that allow a flooding to occur. The antipsychotics block the dopamine receptors, creating a barrier like a lid over a pot, preventing the receptors from “encountering” the dopamine at all. (This is why people who take antipsychotic drugs say their emotions feel so muted; the medicine interrupts their pleasure mechanism.) In the Seemans’ apartment, Philip slowly abandons his walker and pulls up a chair. He brightens. Taking a pen from his pocket, he leans over the coffee table between us and starts to draw on a pad, making a big triangle. That’s the key dopamine receptor — D2, as it’s called. Then he draws an arrow intercepting and blunting the triangle’s sharp point. That’s the antipsychotic drug creating a dam against dopamine.

He is disabled and frail, but Philip’s face begins to shine as he gets to his point. He draws another arrow intercepting his triangle from a different direction. This is estrogen. It also blunts the effect of dopamine and acts as an inhibitor, similar to an antipsychotic. “And that’s really why women don’t start wars,” he says.

“I think women have started wars,” Mary says, laughing.

“Not so much,” says Philip.

The Seemans’ discoveries were symbiotic. If estrogen modulates psychosis, it might explain why schizophrenic symptoms in menstruating women were less severe than those in men and why these women needed lower doses of antipsychotics to control them. It might even be protective enough to delay onset for a number of years. Sudden, dramatic fluctuations in estrogen during perimenopause, the months or years before a woman stops menstruating, might explain why a woman with no previous history of mental illness might suddenly come down with a bad case of psychosis. And the absence of estrogen after menopause might explain why a woman’s psychotic symptoms could suddenly resemble those of a very young man.

In 1981, Mary Seeman published one of the first papers suggesting the oestrogen hypothesis in a small journal connected with the University of Ottawa. She was the only author, making a mild plea for her psychiatry colleagues to pay more attention to the role of oestrogen in schizophrenia. The plea fell on deaf ears. Even now, the study of estrogen on psychosis is so diffuse and interdisciplinary that “I can’t really say it’s a field,” she told me.

In 1988, a young psychiatrist named Laura Miller was tasked with opening one of the country’s first women’s reproductive-mental-health clinics at the University of Illinois at Chicago after a patient at a local state psychiatric hospital, who had been delusionally denying her pregnancy, accidentally drowned her newborn in the toilet. There was no established discipline in reproductive mental health at the time, no association for practitioners with specialized expertise. “I contacted everyone who had written a paper on the subject. We were self-taught and formed a coalition. There were about a dozen of us,” Miller says.

Researchers around the world began to explore the connections between psychosis and estrogen at every phase of a woman’s life. They found that early puberty seems to correlate to later onset of schizophrenia, positing that the presence of estrogen delays its debut somehow. They found that in women with preexisting psychotic disorders, severity of symptoms declined during pregnancy — when estrogen surges in a woman’s body — and then rose again after birth when estrogen tanks. Among women of childbearing age with an existing schizophrenia diagnosis, a large minority reported an increased severity of symptoms just before menstruation, when estrogen dips.

In 2013, premenstrual dysphoric disorder became an official diagnosis in the new revision of the DSM, an acknowledgment that for 5.5 percent of women, the phase usually known as PMS can be debilitating, contributing to severe depression, lost days of work, dangerous ruptures in relationships, and even suicide. Older feminists opposed the classification, arguing that it made a pathology of being female, but younger feminists disagreed. By establishing the category, they said, a group of sufferers could finally be acknowledged and receive the treatment they require (and have insurance cover that treatment).

But the medical Establishment still hasn’t really caught on. The DSM hardly mentions reproductive hormones, and the doctors who look to hormonal changes for answers or causes remain a tiny minority. Only 59 percent of psychiatry residencies require any training in reproductive psychiatry at all, and far fewer hold residents to a standard of competency. In the meantime, people like Talia continue to suffer. Talia had been diagnosed with bipolar disorder in her 20s but had it under control with medication. Then around Christmas 2016, just after the election of Donald Trump, when she was 42 and beginning to get hot flashes that forced her to keep her bedroom window open even on frigid nights, Talia came down with a terrible cold and cough that led to ten days of insomnia. She became exhausted and told her regular psychiatrist that she was “delirious.” She felt so disconnected from herself.

At the large midwestern university where she is a professor, Talia had been studying the Nazi program Aktion T4, the wholesale rounding up and extermination of people who were disabled, elderly, or mentally ill, and now she began to fear that she was a Nazi target. It was the worst kind of paranoia, she says, because it was based in her own extensive research. She knew everything about Aktion T4. “I knew how the paperwork was done for Aktion T4. I knew how the bus system worked,” she tells me as we sit one afternoon at her dining-room table. Pale and wide-eyed, she comes across as delicate, like a person who has survived a wreck or a trauma, which she has. “I fell off a cliff,” is how she puts it. The election of Trump amplified her fears. Her rational mind clearly saw the historical analogies between the nationalistic right of 2016 and the Nazi Party. Her irrational mind turned an academic observation into a full-blown reality. To stop Nazi doctors from spying on her, Talia covered the windows in her front hall with white computer paper and kept the blinds in the living room permanently closed. One afternoon when she was home alone, there was a knock at the door and Talia hid in the closet, so sure was she that the Nazis had come to take her away.

It was around this time that Talia started pacing the kitchen ceaselessly, unable to speak. She plastered every inch of the dining table — the same one where we sit with our coffee mugs — with Post-it reminders of things to do. She couldn’t shop or cook or drive or read. “I remember trying to read the directions on a muffin box and it was bewildering to me,” she says. She was able to communicate with her husband, Ted, only by scribbling notes, and Ted, a professor at the same university, was forced to tell Talia’s department chair that she was unwell; he then took a leave from his job to care for her and their daughter. Ted remembers wondering throughout that awful time whether this was the new normal, with his wife mute and the shades always drawn. “In my mind, I’m running a thousand miles a minute,” he says. “So now we’re just going to be writing everything to each other? It’s ridiculous, but I start thinking, If I can accept this, then we’re good.

In the hospital, Talia received a diagnosis of schizoaffective disorder, which is, as she explains to me, as if “schizophrenia and bipolar had a baby.” She spent two weeks there, and longer working out a medication regimen that controls her psychosis but doesn’t make her feel, as she puts it, “blunted.” She now takes Vraylar, an antipsychotic; Lamictal, a mood stabilizer; and, to help with her cognitive impairments, an Alzheimer’s drug called Galantamine. For the first time in two years, she feels like herself, although she still can’t read as she used to: Abstract material is difficult and she doesn’t retain information as easily, a loss that infuriates her. Talia’s periods are irregular  “I’m bleeding on and off all the time,” she says — possibly a symptom of perimenopause or a side effect of the medicine she takes. Her psychiatrist has tried to reassure her that the approach of menopause will not necessarily exacerbate her symptoms, because this does not happen in every case. “I’ve kind of resigned myself to the fact that it probably will recur,” she tells me. “You know, I haven’t had a long enough period of being really symptom free to get comfortable. I’m just kind of like always waiting.”

How might Talia’s — or Janet’s — lives have been different? Imagine a world in which medicine and science really prioritized women, addressing and inquiring into our femaleness, including our menstrual cycles and hormone fluctuations, rather than shoehorning us into categories established by men, substantiated by research on men, and designed to diagnose and treat men? What if the experts who create the disease taxonomies in the DSM established tags and labels for the collections of severe symptoms that can occasionally accompany fluctuations in women’s hormonal cycles so that any internist, anywhere, could flip the book open, make the connection, and know what to do? What if practitioners understood how female hormones impaired or enhanced the effectiveness of medicine? What if women with midlife psychosis formed a recognizable cohort and saw one another as regular travelers through an unmarked and treacherous territory? Imagine if Janet and Talia were visible to one another, and to us.

Lieberman at Columbia concedes that the treatment so often received by outlier patients “doesn’t speak well for the standard of care,” but he points out how many different groups fail to attract meaningful attention from medicine — including women, minorities, most of the mentally ill. Older women are deemed to be “over the hill, so why bother?”

In 2009, an Australian psychiatrist named Jayashri Kulkarni began publishing the results of extraordinary experiments that took the estrogen hypothesis to the next step. If fluctuations in estrogen exacerbated psychosis, then shouldn’t infusions of estrogen — supplemental hormones — regulate and ameliorate it? In a small trial, Kulkarni administered estrogen along with regularly prescribed antipsychotic medication to a group of women of childbearing age diagnosed with schizophrenia; she found that, compared with a control group, their positive and negative symptoms abated. She tried again with a larger group and got a similar result. She tried with a tiny group of men — administering oestrogen together with antipsychotics for one week to avoid the hormone’s feminizing side effects (such as the growth of breasts) — and found the same. By day five, the male estrogen group “showed significant abatement of psychotic symptoms compared to the placebo group,” and by day seven, the men had improved even more.

Cognizant of oestrogen’s risks — in 2002, lead researchers had interrupted the massive Women’s Health Initiative study on hormone-replacement therapy after it showed a dramatic increase in breast-cancer incidence and heart-disease risk — Kulkarni then did another series of experiments, this time on menopausal women with schizophrenia, using drugs that simulate oestrogen, which carry fewer consequential risks. Here, too, she found “a robust therapeutic effect.”

It was dinnertime in New York when I spoke to Kulkarni on the phone. It was early morning the next day in Melbourne, and the doctor was taking a walk on the beach before work; through the cell-phone connection, I could hear the sea wind. Kulkarni’s experiments had gained her so much attention, she told me, that women all over the world — convinced their problems have hormonal causes and unable to get traction with their doctors at home — are seeking her help.

Sometimes women want to make an appointment at her clinic. But often they or their family members just want advice. Recently, a high-ranking member of the Italian military called her. He was desperately worried about his wife. At 50, the wife was a prominent society hostess who enthusiastically supported their “high-flying life,” as Kulkarni put it, “with lots of state dinners.” But very suddenly, over the space of two weeks, the wife began to unravel completely: She heard voices; she believed that her cell phone was bugged; she thought World War III was about to erupt and became super-vigilant, always looking behind her and checking the corners and closets in her house. The husband became anxious at first, then extremely distressed. The wife had no history of mental illness. She had always been fit, fashionable, and energetic, but now she was incoherent. “My hypothesis was that she was definitely in the menopause transition,” Kulkarni said, and the husband confirmed her hunch. The time between his wife’s periods had been lengthening.

Kulkarni then found herself in “a strange, three-way conversation.” She sent the couple to their regular Italian physician and joined them in his office by Skype. Kulkarni suggested to the doctor that he prescribe Tibolone, a tablet containing low doses of estrogen, progesterone, and an androgen, in addition to the antipsychotic she was already taking. The Italian doctor was resistant, but the husband, an influential man, convinced him to prescribe the drug. Kulkarni remembered thinking that a less forceful or prominent person might not have prevailed: “The doctor was having a difficult time making the connection between ‘She’s got psychotic mental illness’ and ‘Why are we treating her this way?’ ”

This is a happy story. The wife got better. Within ten days, she had stopped feeling paranoid, and on Skype “her face looked less worried and tense.” Within eight weeks, she was entirely herself, and when the couple videoconferenced with Kulkarni, the wife was leading the conversation, slapping her husband fondly on the knee when he interrupted.

When I talk to American psychiatrists about Kulkarni’s experiments and raise the notion of treating late-onset schizophrenic psychosis — or indeed any psychosis — in women with estrogen, here is what they say. They urge caution. They say we don’t know what causes schizophrenia, exactly, that estrogen plays a role but no one knows what role. They remind me that many hormones are involved in the menstrual cycle. They say fluctuations in oestrogen interact with the brain, but so does aging and so does stress and all of these conditions are present at the onset of menopause, so who’s to say what the real culprit is. They point to the 128 genes connected with schizophrenia and the research linking it possibly to infection or a faulty immune response. They say there have always been vogues in cures for schizophrenia; because it’s so devastating, the temptation to believe in miracles is great. They point to a large study done recently by Israeli and Romanian researchers that failed to replicate Kulkarni’s results. “I do think that estrogen has some connection to schizophrenia, there’s no question about that, but there have been so many false starts,” says Dilip Jeste, a geriatric neuropsychiatrist at the University of California San Diego. “A few will swear by one medication, but the problem comes in generalizing. That doesn’t mean other women should start taking estrogen.” Even David Castle, the discoverer of the second peak, is skeptical of estrogen’s role. “The estrogen story is rather overstated,” he wrote in an email, before adding, “and oestrogen’s have their side effects, as you will be aware.”

Here is what I have to say in response: Estrogen does not have to be a single or straightforward cause of schizophrenia for it to merit the attention of researchers and doctors; it does not have to be a proven miracle cure to represent an opportunity. The treatment of schizophrenia remains today a matter of trial and error, and estrogen represents one promising path forward. Indeed, Sage Therapeutics is currently seeking FDA approval for a progesterone-like synthetic hormone that promises to alleviate postpartum depression, which makes sense. The links between oestrogen and mental illness are clear and the prospects for treatment too interesting to dismiss, particularly given how poorly women have been served, over centuries, by doctors who did not want to look squarely at their femaleness in treating them or who saw their problems as expressions of that femaleness and therefore not worth treating.

Sometime between the two World Wars, my great-grandmother died on the operating table after suffering from what my grandfather always vaguely referred to as “female problems.” I have always assumed she was having her uterus removed, but maybe the surgery was for something else and I will never know why she needed an operation or how she died, whether from anesthesia or bleeding or some surgical error. Did she have cancer? A mental illness? Heavy periods? In any case, the mystery surrounding her health is passed down to me. I am an enlightened, empowered, 21st-century woman, but when doctors ask if I have a family history of uterine, ovarian, or cervical cancer, I have to tell them I don’t know.

The stigma associated with women’s menstruation — and hormones and uteruses — goes back at least to Leviticus, which establishes a catalogue of all the ways monthly bleeding makes a woman “unclean.” But menstruation has historically signaled more than just female filth; it has been seen as the cause of women’s anger, volatility, instability, unreliability, weakness, frailty, and neuroticism. The ancient Greeks, including probably Hippocrates, believed the uterus could sometimes become unmoored inside a woman’s body and rattle around, resulting in excessive emotion. The best remedy for this, they thought, was rigorous sex.

Even now, when we know better and pay lip service to the idea that monthly bleeding (and its cessation) is normal and natural, and women laugh over dinner about loving the conveniences of their new period-absorbant underwear, the stigma around menstruation persists and constricts women in two ways. Our legitimate emotions, moods, and reactions are discounted to our hormonal cycles — if we are pissed off or weepy, we are said to be “on the rag,” a diminishment of our anger or distress and a denial of whatever’s troubling us — and at the same time any actual health problems that arise from our reproductive cycles or hormones or organs are disbelieved or minimized. Even in the 21st century, the superstition persists that our uteruses are prone to wandering: The mother of my friend G, with whom I trained for a marathon, told her she shouldn’t run so much lest her uterus “drop.” G’s mother feared that her uterus might collapse or crash somehow into her cervix, causing infertility, pain, and other unspecified misery.

Yet just as our reproductive organs are thought to make us fragile, emotional, and irrational, we are expected to endure their effects on our bodies and minds stoically and without complaint. Boyfriends and husbands perpetuate this bias, but so do doctors, even elite ones. And if menstruation remains taboo, even in an era when little girls strut around wearing T-shirts that read the future is female, then menopause is worse, because the only thing more disgusting and shameful in culture than the manifestations of fertility — the blood and the egg-white discharge and the hormonal cloud — is the absence of all of that. In the Bible, an infertile woman is labeled cursed.

A woman approaching menopause who becomes psychotic, then, is buried in stigma. She is middle-aged, on the path to becoming an invisible, voiceless member of society, beset by “female trouble” — her symptoms likely to be diminished and disbelieved. I spoke to an Englishwoman named Val who became very, very ill as she approached menopause, at first staying up all night enrolling in online theology classes and then depressed to the point of paralysis and suicide; even though she had had postpartum psychosis after the birth of her first child, her doctors did not make the connection or identify fluctuating hormones as a plausible trigger for her mental illness. “We tried really every antidepressant. Nothing worked. I had electric-shock treatment. That didn’t work. Had lithium. Went months and months and months with nothing working. Eventually, we tried a tricyclic antidepressant and that worked,” she says. “Oestrogen was the one thing nobody suggested. It seems now with hindsight that hormone treatment might have been the best option.” A woman like Val defies the traditional definitions of psychotic illness, and very few people are engaged in trying to figure out how to help her.

On a bright summer evening, I was walking home from the subway and talking with Pauline Maki on the phone. She works as the director of women’s-health research at the University of Illinois at Chicago, the center Laura Miller helped to establish, and in a long conversation, Maki explained how she views her job as advocacy. “I think we need better science,” she told me. “There is so much paternalism around everything hormonal. I think women need to stand up and demand this kind of work. More women need to tell their stories. You don’t want to pathologize menopause generally; it’s not a problem for most women. But if we fail to recognize that it is a problem for a certain percentage of women, then we do women a tremendous amount of harm.” And it occurred to me that for 40 years, I have kept a private, internal calendar of my moods in correlation to my menstrual cycle, watching my impatience boil the week before my period begins together with the onset of an almost unbearable irritation at being jostled by strangers on the subway. Now, as I approach menopause myself, I would like my doctors to be curious about all that so that in the event of any health crisis, they will see me whole — as a middle-aged woman with a lot to lose — to presume my intelligence and good judgment and to present me or my proxies with a range of options without predispositions for what I should do.

Hormone-replacement therapy, once promoted as a menopause “cure,” a way to rejuvenate and resexualize middle-aged women, became, after the halting of the Women’s Health Initiative study, a cultural sin, widely disapproved of by doctors and wellness bloggers alike. Now women who inquire about hormones for physical or mood symptoms are talked out of them as a matter of course. But the pendulum of public opinion on hormone supplements is starting to swing back, thanks in large part to the determined activism of the trans movement. The truth is the dangers of hormone supplements were overstated in the publicity around the WHI. They are not a universal or certain risk but a dangerous risk in some cases, and with careful oversight some of those risks can be managed. If presented with the awful dilemma of ruinous midlife psychosis or a possible breast-cancer risk, shouldn’t a woman be allowed to choose?

On the day I visit Janet at home, there is a tornado. My phone is blaring warnings as I follow her down back roads, but we keep going, pulling into the parking lot of her condo complex just as the afternoon grows black and the trees blow horizontal and the rain cascades not in drops or sheets but as if the ocean were dumping out of the sky. I wait out the tornado alone in my vehicle, talking to my husband on the phone, while my small car trembles and shakes, until finally the rain abates and Janet knocks on my window. The electricity had gone out in her cluttered apartment so I would need a flashlight to see the pictures on her walls, mostly collages and paintings she had made. She is very lonely, she tells me. Her daughter had just moved to South Carolina, and her relationship to her church community had frayed. “Little by little, one by one, the people in my life have all dropped out, and now I’m back to being kind of solitary again. And I don’t like that,” she says. The voices are still there, Janet tells me, but she is able to dismiss them and they mostly don’t bother her. She takes her Risperdal regularly, in diminishing doses, with a plan to get off it completely. I have to get home, but I can tell she doesn’t want me to leave.

The next day, Janet writes me a long email. After the tornado, and our conversation, she had a difficult night. Her regular isolation had been exacerbated by the blackout, making it difficult to sleep. It is as if in reaching out to me, Janet is searching for a unifying answer that will solve the riddle of her breakdown and cure her loneliness at once. “Here’s my current philosophy,” she said to me when I presented her with the oestrogen hypothesis. “Maybe, just maybe, like God says in the Bible, God is in us, and we are in him. Maybe this is the spirit that God leaves with us that’s talking to me. But I don’t think God intended it to talk to me. I think something happens in menopause. We don’t know enough about nutrition or behavior or menopause or premenopause — whatever — to help people process this age in their lives. I have moments when I think it was all just a chemical imbalance. If I hadn’t had the perimenopausal event, I don’t think any of it would have happened. But I also think there’s so much more going on in our brains than we are aware of.

“And I think there is knowledge out there, but I think it’s old, ancient knowledge that has been lost to the generations through the rapid, rapid changes — I’m talking about the past 50 years — and explosions in population. We don’t live the way we used to. We used to live tribally. The tribes could always share. There was a huge close-knit community that could share. I know what we need. I don’t know how to get it, but I know what we need: We need people who understand what is happening to us to sit down with us and explain it. At some level, we could just use someone to say, ‘Okay, you’re 45 years old. You’re perimenopausal. You’re hearing voices. Here’s what’s helped these three dozen other people. Tell me your story.’ ”

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