Hormone Therapy is Lifesaving — But Why is No One Studying Its Long-Term Effects?

Photograhy by Benedict Evans.

Charlene Incarnate had been taking Spironolactone, a testosterone-blocking medication, for several weeks when she noticed that she was feeling tired and out of it all the time. "It has a stony effect that just makes you want to lie in bed and sleep all day," she says. The drug plays a central role in male-to-female hormone replacement therapy, but its listed side effects, which include drowsiness and confusion, are sometimes too much for patients. Incarnate isn't alone in her lament. Last fall, her friend, trans musician Macy Rodman, wrote "Lazy Girl," a song about the foggy effects of early gender transition. It contained lyrics about exhaustion and never leaving your bedroom. "I just can't deal with the dehydration -- especially in the summertime -- and the brain fog," Incarnate says. "There's never a clearheaded moment."

Informed physicians have been routinely prescribing cross-sex hormone replacement therapy (HRT) to transgender people for decades. These regimens are designed to produce the secondary sex characteristics of the opposite gender, effectively causing the patient to undergo an alternate puberty. Providers generally agree that this treatment is safe and lifesaving, as does the American Medical Association, which endorsed medical transition for trans people in 2014. There have been other major advancements in trans health care in the United States in recent years. Health insurance companies that have historically denied coverage for trans care are beginning to change their policies, and Medicaid programs in states such as Massachusetts, New York, and California are now obligated to pay for gender transition, as is Medicare nationwide.

Yet there have been few studies looking at the long-term effects of HRT. While observational studies have retrospectively reviewed trans populations and declared hormonal transition to be safe, trans medicine has not had the kind of clinical research that is typically conducted for lifesaving medicine. There are medical guidelines for trans health care issued by organizations like the Endocrine Society and the World Professional Association for Transgender Health, but there are also unknowns -- questions that neither patients nor physicians can answer.

"I haven't really considered an alternate world in which trans health was researched a little better," says Incarnate. She began medically transitioning a couple of years ago. To her, the lack of research into HRT is a symptom of American society, which isn't always friendly to trans people. Attempted suicide rates in trans communities in the United States register at a chilling 41%, housing and job discrimination against trans people is legal in states across the country, and legislators are actively stripping away the civil rights of trans people in states such as North Carolina.

"You're going into uncharted territories -- whether you're on hormones or not," says Incarnate. "Your health care is going to be a guerrilla operation, just like your life is going to be a guerrilla operation."

Incarnate has been on HRT for about a year, but she's still struggling to find a regimen that works for her. Not all trans women choose to hormonally transition. Those who do take a combination of drugs to feminize themselves. This regimen generally includes any of several possible medications, known colloquially as T blockers, that nullify testosterone. Once a trans woman's testosterone levels are diminished, estrogen -- in the form of the generic pill estradiol or the generic injectable estradiol valerate -- is administered.

Dr. Asa Radix, the senior director of research and education at Callen-Lorde Community Health Center in New York City, one of the country's largest providers of transgender medicine, says, "We have close to 4,000 trans clients, and about 80% of them are on hormones, either testosterone or estrogen." This combination of drugs works well enough to be standard practice.

But the medications trans women use to suppress their testosterone have not been designed for that purpose. Spironolactone is a diuretic, used to treat high blood pressure. However unpleasant, brain fog isn't the side effect that caused Incarnate to experiment with her dosage of Spironolactone. For many trans women, the retention of erectile function is important. But while the medications used to block testosterone are crucial for hormonal feminization, they sometimes work too well. "[Spironolactone isn't] just a homing missile on testosterone. It's a nuke," Incarnate says.

She was initially prescribed 200 milligrams of Spironolactone a day, but she cut her dose in half, hoping that would cause her testosterone levels to drop significantly without eliminating them altogether. "Even on [100 milligrams] my testosterone [level registered] at a cold zero," Incarnate says. "That's not a normal human body -- male, female, or otherwise. That's not a normal level of testosterone for anyone." According to the Boston University School of Medicine, the side effects of low testosterone in women include sexual dissatisfaction, muscle weakness, and mood problems. Incarnate recently halved her dosage again, down to 50 milligrams per day.

The side effects that Incarnate is dealing with may seem relatively minor, but they've had a serious impact on her quality of life. She believes that trans people are entitled to further research into drugs like Spironolactone.

"It's frustrating when you take into consideration the risk of not treating someone," said Dr. Madeline Deutsch, a physician at the University of California San Francisco medical center and an expert in the field of trans health. "I have 10 years [of experience in trans care] and 1,500 trans patients [whom] I've put on hormones," Deutsch says. "I've never had a single person not want to take hormones because they're worried about the risk." That's mostly because medical transition alleviates the at times unbearable symptoms of gender dysphoria, a condition of mental anguish due to a discordance between one's internal conception of their gender and their physical sex.

"It got to a point mentally with dysphoria where I knew either I had to start hormones or I was going to kill myself," says Shane, a transgender man in his early 20s. "There was no third option." Shane began taking masculinizing HRT a few years ago while in college. The week he began taking testosterone, he had also been admitted to the crisis unit in a nearby psychiatric hospital. His fellow classmates had realized that he was self-harming and sought help from a resident assistant. The effects of HRT have been rejuvenating. He feels the treatment has corrected a chemical imbalance in his brain. "It's hard to explain," Shane says. "It filled in something that I always knew should be there." When he learned about HRT, he says, it felt like he had been given "a ticket out of hell."

Shane says that he and other trans guys he knows who haven't had a hysterectomy sometimes get abdominal pain and that "no one knows why." According to Radix, many trans men don't go to a gynecologist, leaving that part of their health unaddressed. For patients like Shane, who decide to bite the bullet and go to an ob-gyn, there is another problem. "They're not particularly fond of treating trans men," Shane says, explaining that this makes it even more difficult for trans guys to get a clear picture on how testosterone therapy is affecting their reproductive and sexual health. "Unfortunately, even when you see the most skilled, trained, and caring providers, there's still a lot of questions they can't answer," he says.

Shane considers the Mazzoni Center in Philadelphia to be a lifesaving facility, and his provider to be one of the foremost experts in the field of trans-masculine health. "He's one of the leaders in the country," he says, "[and yet] he still had to make sure that I understood the fact that they have no idea what impact testosterone will have on my ability to have biological children."

Shane says that his doctor has had trans male patients who've become pregnant "both intentionally and unintentionally while taking testosterone." Though it may be uncommon, sometimes guys ovulate even if they're on testosterone. One study out of UCSF researched pregnancy and trans men. Self-identified trans men who'd been pregnant completed an online survey, and 25 of the 41 subjects had used testosterone therapy prior to becoming pregnant.

Devan, a mid-20s trans woman, believes there should be more research into the preservation of fertility for trans women who want to have children. She began self-medicating with hormones purchased over the Internet when she was 14 years old. Without testosterone, testicles stop producing sperm and can atrophy. "There's a resentment there, especially with my fertility and my desire to be a mother one day," Devan says.

She thinks research slowed down once an effective method of hormonal transition was discovered. "It's not like they're trying to save people's grandmothers with Alzheimer's, or people's moms and dads with diabetes," says Devan. For her, the lack of research is telling.

"Now that I'm 24 and it's like a full decade after [I began self-medicating], it feels like my body is betraying me in a whole different way because I don't necessarily know what's going on," she says. "I feel left in the dark."

Deutsch says that "this is an unusual circumstance," because the condition of gender dysphoria is only beginning to be widely recognized and understood but can be treated with medications that have been around for decades. "It is something that is treated almost universally with generic medications," she explains.

The fact that HRT consists of generic drugs that have been on the market for years makes it far less likely that pharmaceutical companies will ever spearhead further research. "There's no money to be made," Deutsch says. "Nobody's going to go do Phase III trials on a medicine that's been generic for 15 years."

Tina White, a transgender woman and a former management consultant at a major pharmaceutical company in the United States, explains that drug companies spend anywhere from $850 million to $1.5 billion just to conduct testing to bring a drug to market. "To get it through [FDA] approval, you need to make all that money back," she says.

For 17 years, from development to market, pharmaceutical companies have exclusive rights over the medication they're developing. According to White, the development stage takes an average of 10 years, leaving seven to make their money back and turn a profit. Many of the drugs these companies invest in never make it to market at all, meaning that drug development is a high-stakes game for manufacturers. Because the company has exclusive rights to its medication for 17 years, no one else can produce it in that time frame, and once it's brought to market, the company can set the price per pill as high as it wants.

"Basically, the day that patent ends, every generic company in the world can go manufacture that drug and they can sell it for a nickel," White says. "And they didn't have to spend $1.5 billion on research."

She believes that the companies that manufacture drugs aren't as motivated by greed as they're often portrayed to be. Their expenses and risks are just astronomically high, and once a drug is generic, it is simply much more difficult for them to make a profit from it.

Pharmaceutical companies are bound by FDA marketing restrictions. They're obligated to label their medication for use specific to the clinical research they conducted.

Doctors, on the other hand, are permitted to prescribe medication for any purpose, even if that use is not
on-label -- a practice known as off-label use. But while physicians can prescribe as they see fit, pharma is unable to market medications for off-label purposes. White says that these regulations are so strict that pharmaceutical companies cannot even market a drug to a physician who primarily treats children, if that medication isn't labeled for use in kids.

Clinical drug trials are performed in phases. Phase III clinical trials measure safety, efficacy, and effectiveness, and Phase IV testing is conducted after a drug has been on the market. White says that Phase IV testing is conducted when pharmaceutical companies want to market a medication for a purpose other than the one for which it was initially tested. According to White, these trials take two to five years and cost hundreds of millions of dollars. Pharmaceutical companies don't conduct Phase IV trials unless there is a clear financial incentive to do so.

There are other factors working against transgender people when it comes to pharma-led research into trans medicine. Prescription medication is profitable when it can be sold to consumers. Like most people, trans people rely on insurance to pay for medications, but many providers exclude coverage for transgender-related treatment. "If we don't have any insurance coverage, it's not a big market for them," White says.

The failure to conduct research into cross-sex HRT could be a failure to ensure the safety of medically necessary, lifesaving medication for an entire demographic of American people. Recent research by the Williams Institute, a UCLA think tank, has estimated the transgender population in the U.S. to be 1.4 million, twice as many as previous estimates. In California, where Deutsch works, transgender adults are estimated to make up 1.3% of the general population. "The population size for Hawaiian Island and Pacific Island origin in this country is about 0.5%," Deutsch says. "If we found out that Hawaiians were getting diabetes at twice the rate of the rest of the population, nobody would be like, 'We're not going to do any research on that.' "

There is a federal designation that is given to drugs that treat minority populations or that serve an important, but not necessarily profitable, need. According to the FDA: "The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug." Deutsch believes that transgender HRT should be granted orphan status. Judging by the FDA's summary of the program, it seems that could be possible.

Though more research is obviously needed, Deutsch doesn't blame the pharmaceutical companies. She knows how high-stakes the pharma game is and that the system itself makes it difficult to take risks on medications. "I would have to put most of the responsibility with the FDA," she says.

When asked whether the drugs used in trans medicine could, or should, be designated with orphan status, the FDA responded: "A decision on the designation on any specific drug would be made once a drug manufacturer submits a request for orphan drug designation, and includes the necessary supporting information about the specific drug and the specific rare disease or condition."

Gaines Parker is a transgender man in his early 20s. He believes transgender people need to inform the questions that researchers ask about trans medicine, because while physicians endorse the relative safety of HRT, there is a lack of research specific to the needs of trans people, such as the brain fog that Incarnate and other trans women have reported as a side effect of Spironolactone. "It's so easy for clinicians to hear people talk about conditions of brain fog and say, 'Oh, that's depression,' Parker says. "[Depression] makes a lot of sense, [given] what you're experiencing as a marginalized person."

Parker points out another way that the medical establishment is not designed in consideration of trans people. Some trans men undergo genital reconstructive surgery called metoidioplasty, which lowers and enlarges their genitalia. According to Parker, the surgeons who perform this procedure prescribe dihydrotestosterone, a medication that is supposed to help genital growth in preparation for the surgery. "But it's completely unavailable in the United States," Parker says, adding that the medication can be purchased only over the Internet. "It's also compounded in alcohol-based gel, which stings when you put it on erectile tissue," he says. "It could pretty easily be compounded in a cream or something."

Transgender people share their personal experiences with one another to fill in the holes left by the lack of long-term data. "You kind of have to advocate for yourself and figure out what works for you and what the chemicals are doing to your body," Incarnate says. "You can only find other stories like yours among your trans friends, the Internet, or zines that have been written. That's where the information is compiled -- in these tiny niche corners of the Internet."

One example of this is the use of progesterone. "I want to go on progesterone," Incarnate says. "I'm all about tits." Like estrogen, progesterone is a female hormone, but its use in male-to-female HRT is not standard. Callen-Lorde's HRT guidelines state: "Progesterone is not recommended as a part of the hormone regimen. It has not been shown to increase breast size, and may contribute to adverse outcomes."

But Incarnate wants to add the drug to her regimen because of the benefits she believes it will bring. "The idea is that it promotes breast growth," she says. "The estradiol boob is kind of pointed. The round, full breast shape is something that's supposed to come easier on the progesterone," she says. "It's supposed to work wonders on your sex drive too."

Incarnate has seen and heard this from her girlfriends who take progesterone, and she argues that they're a trustworthy source because of the lack of thorough clinical research. "I really don't see how the community is any less of a viable, legitimate resource of knowledge than health care providers," she says. "Testing something out on your body with a doctor, as opposed to with another girl who's done it, is kind of like the same thing to me." Incarnate says that, among her friends and community, it is common knowledge that injectable estrogen produces more feminizing effects than pills.

Kibele Selcuk, a Turkish-American trans woman in her early 20s, also believes that injectables can be more feminizing. She recently moved from San Francisco to New York City and says that her previous physician was over-prescribing her injectable estrogen. "They told me that I could go up to a certain dosage, that it was safe," she says, explaining that the San Francisco clinic where she first received her estrogen does not regularly test estrogen levels in the blood. "When I [had my estrogen levels tested] in New York City, they were like, 'Oh my god, you're overdosing. You could get a blood clot.' " Selcuk cut her dose in half.

According to Deutsch, injection is not the ideal delivery method for estrogen. "It brings varying levels of estrogen, and there's no data [to show] that it improves anything. It actually, in my view, could be harmful because of the high levels of estrogen that are associated," she says. Though she doesn't believe it is an ideal method of delivery, Deutsch explains that for some patients, injectable estrogen is the best medication to prescribe. She is glad to have injectable estrogen in her "toolbox," as there are patients, like Selcuk, who may have difficulty with pills or are better suited for injections for other reasons.

There is currently a national shortage of estradiol valerate, or generic injectable estrogen, in the United States. When asked for comment, the FDA affirmed that it is aware that brand-name Delestrogen and generic estradiol valerate are currently unavailable and that it is working with the manufacturers to make the drug available again.

To Selcuk, this shortage shows that governing bodies in the United States and the pharmaceutical companies profiting off of trans women have neglected their health. "I'm an immigrant, like a Muslim immigrant that has to sacrifice so much in terms of my relationship to my family and my culture, and now I have to worry about not accessing medication that I worked so hard towards and sacrificed so much for," she says. "It kind of feels like a joke."

"Pretty much, the only people that are using [injectable estrogen] are trans people," Deutsch says. Yet the medical purpose for which that medication is prescribed has not been researched by the companies selling it. White says that when pharmaceutical companies consider doing research into a medication that is already on the market, they purchase data about drug users from insurance companies.

None of the drug companies that I contacted responded to my request for comment, except for Sun Pharmaceuticals, which responded to say that it has no comment. Few of the major insurance providers that I contacted for this story responded. The responses I did receive were limited. A representative from Cigna told me that the company doesn't "have information about the gender identity of Cigna customers who are using [hormone] replacement therapy, so we wouldn't know how many of them are transgender, nor would we know if they are using HRT for some purpose other than gender transition." A representative from Aetna said that it is unable to provide data on how many people, trans or cis, obtain HRT medicines through their health insurance plans.

Though Aetna couldn't report the numbers, it issued this statement: "Aetna covers hormone replacement therapy and other medications for members undergoing gender transition. We feel that pharmaceutical companies should undertake studies in areas in which their drugs are being routinely used in order to ensure that the use is safe and effective, regardless of the indication."

Dr. Wylie Hembree is an expert in the field of hormonal transition and helped produce the guidelines for cross-sex hormone therapy set by the Endocrine Society. Hembree believes that trans people must represent a small minority of the people who take HRT medications. "I've spent half of my career either treating couples for infertility or giving men who've had deficiencies testosterone, and they were huge numbers. I would guess [that trans patients represent] a very small percentage [of overall HRT consumers], but I can't give you a number."

In addition to the assurance of safety and effectiveness, further testing into HRT meds would mean that the drugs would finally be labeled for gender transition. Though physicians can prescribe off-label, it would still be an important shift.

"Insurance plans are allowed to deny coverage if [physicians are] using experimental or off-label use," Deutsch says. Additionally, the experimental nature of off-label prescription may scare off some physicians who aren't experienced with transgender medicine. "A provider may say, 'Well, you know, I'm not comfortable doing this because it's off-label.' "

All of this helps to push trans people away from official channels of treatment. If they choose to pursue transition without a physician, their only alternative is to buy hormones online or on the street.

Deutsch is less concerned with the risk of these black-market medications than she is with the fact that such transitions aren't being monitored by a physician. "I've had patients that are injecting estradiol daily, at a dose that's supposed to be given twice a month," she says. "I've had a couple patients who've gotten blood clots when they're taking these mega-high doses of estradiol. Maybe they're not aware of the interaction between tobacco and estrogen."

"I have people buying testosterone," Deutsch continues. "If you're not being monitored, you can have a stroke because your blood can get too thick, because your blood count goes too high. It's not so much that the medicines that they're taking at their core are dangerous -- it's that they're taking them in an unmonitored fashion."

So who is responsible?

Pharmaceutical companies are unlikely to spearhead the research into this treatment because the medications have been on the market so long. "There are pharmaceutical companies that literally are factories," Deutsch says. "They just make drugs. They're not gonna do [the research], and I don't think they should have to do it." If such corporations were instructed to conduct further testing or stop production, Deutsch worries they'd choose to stop production. "I think that [pinning the blame on them] is potentially dangerous," she says.

Hembree doesn't think pharmaceutical companies are to blame either. He's been doing clinical research for 40 years, and he believes medical experts are only becoming better and more organized. "Those are the people that should be doing the clinical studies, not drug companies," he says.

"The FDA really needs to step up," Deutsch adds. "The FDA is part of the Department of Health and Human Services, which funds the National Institutes of Health, which is a real funder of all things biomedical research in this country. That's what really needs to happen. There needs to be action at that level."

Asked if it believes there should be clinical trials performed into cross-sex HRT, or if such research should come from pharmaceutical companies, the FDA responded with this statement:

"The FDA does not develop drugs nor do we conduct clinical trials; drug companies, universities, and academic medical centers can make important research contributions to this area and in other settings where there are few or no drug products approved for an intended use. The FDA encourages drug companies and investigators to conduct rigorous clinical studies of medications, including those that physicians may currently be using 'off-label,' to determine their safety and effectiveness for use as transgender hormone therapy and so that physicians and patients can have appropriate dosing and risk information to help them make treatment decisions."

Part of that statement seems to contradict the FDA website, which reads, "FDA scientists conduct laboratory, clinical, and statistical research to proactively address knowledge gaps created by advances in drug development and healthcare technologies, or to address safety questions that arise during post-market drug monitoring."

Deutsch says that several areas of research are needed in transgender medicine. "We need data on long-term outcome with effect on health," she explains. "We need data on long-term outcome with effect on mental health and quality of life. We need to figure out, Is there an optimal dosage? Is there an optimal route to give these medications? Are injections better than oral, and if so, what are the trade-offs?

Radix adds to that list.

"We need funding of trans people throughout the life cycle, on hormones, not on hormones, having a surgery, not having a surgery -- and we still don't even know the answer about what we do for trans guys who've had top surgery," he says. "There's so many different types of chest surgery. Should we be screening them [for breast cancer], or no? We don't even know, for trans women who have been on estrogen, should we be screening them for breast cancer? How many screenings should we be doing? What happens if they've put silicone into their breast?"

In their statements, Aetna and the FDA suggested that pharma ought to conduct research into trans medicine, but Radix, Hembree, and Deutsch all suggest that the answer will not be found in pharma.

"I would rather have independent research being done that was funded by the federal government, like university-type studies that didn't have the issue of conflict of interest," Radix says. "I really would put a lot more faith in a study that was done by universities."

"Somebody needs to stand up and say, 'We need to put this transgender-care question to rest,' " Deutsch says. "Somebody needs to put up a few million dollars and fund a safe, free trial or do some outcome studies. The drugs are already on market and being used. We need to obtain enough data to find what we already pretty much know to be the fact -- that morbidity associated with these medications is low."

The issue isn't whether or not HRT is safe enough for trans people to use. Medical experts agree that it is. And even if there are negative side effects, that's OK. This treatment is necessary, but transgender people, like all people, deserve thorough research into medication that is crucial to their health.

This is particularly obvious to Shane. He deals with a number of health conditions, including an autoimmune disease, that require pharmaceutical intervention. Rather than harming him, Shane says, testosterone has improved his health. His bone density is up, as is his red blood cell count, which was low before because of anemia. But the lack of clarity about testosterone's unknown and long-term effects is worrying to him. "I know every drug interaction to every drug I've ever taken," he says. "I know every long-term implication. I've had to take chemotherapy before, and I know that has harmful effects. But I have no choice about taking that, because I need it to save my life. The difference is, with that drug, they've researched it. I know exactly what type of screenings I should get for possible damage."

This isn't the case for his HRT.

Transgender people shouldn't have to piece together their health care from bits of information they heard on the street or learned online. These are young people accessing lifesaving treatment. Though more social infrastructure supporting and affirming their lives exists today than ever before in American history, there are also wide expanses of darkness in trans medicine. They need to be illuminated so that trans people today and in future generations can thrive.

"Your life doesn't stop after transition," says Shane. "The whole reason people do it is so they can live a full, happy, authentic life."

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