The Ethics of Navigating Teen Gender Transitions
Transgender teen Theo Zachariah began identifying as trans at age 13, and now at 16, takes testosterone.
At first, Miriam Zachariah's teenage nephew Theo, who was born female, came out as gay. But he "presented as very gender fluid," she says, which suggested that he hadn't made "a clear choice one way or another."
Families, physicians, and psychologists have pondered whether it's better, neutral, or worse to postpone gender transitions until adulthood.
Zachariah decided to ask her nephew, "Do you think you might be trans?" While he answered "no," the question "broke something open for him," she recalls.
A month later, at age 13, he began identifying as trans. And at 14 1/2, he started undergoing gender transition with an endocrine-blocking injection. More recently, at age 16, he added testosterone injections, and soon he won't need the endocrine blocker any longer.
"His voice is deepening, and his muscle mass is growing," says Zachariah, a principal of two elementary schools in Toronto who became her nephew's legal guardian while he was starting to transition.
There are many medical and bioethical aspects associated with the transition to one's self-identified gender, especially when the process involves children and adolescents. Families, physicians, and psychologists have pondered whether it's better, neutral, or worse to postpone the transition until adulthood, while remaining cognizant of the potential consequences to puberty suppression with cross-sex hormones and the irreversibility of transgender surgeries.
Studies have found a higher prevalence of mental health issues among transgender and gender nonconforming youth, particularly if they are unable to express themselves in the self-identified gender. Research also has shown that transgender adults in the process of transitioning initially experienced worse mental health problems than their adolescent counterparts.
The Endocrine Society, a professional medical organization that provides recommendations for clinical practice, stipulates in its guidelines that the diagnosis of gender identity be limited to qualified mental health professionals for those under age 18. This is important because children are still evolving in their thought processes and capacity to articulate themselves, says endocrinologist Joshua Safer, inaugural executive director of the Center for Transgender Medicine and Surgery at the Icahn School of Medicine at Mount Sinai in New York.
A transition can begin safely in gradations, by allowing young children to experiment with haircuts and clothes of either gender before puberty. "If it just ends up being a stage of life, we haven't done anything permanent," says Safer, who is president of the United States Professional Association for Transgender Health as well as steering committee co-chair of TransNet, the international transgender research consortium.
After changes in appearance, the next step would be to try puberty blockers. Also used to halt precocious puberty, the injections are "a reasonably established intervention" for transgender youth, although there are some concerns that the drugs could interfere with bone health in the future, he says.
From a mental health standpoint, "hormones for youth who qualify for them have offered a tremendous boost in well-being and also a reduction in anxiety, depression, and suicidality that often plague transgender youth when they experience their bodies as totally discordant with their self-knowledge of their authentic gender," says psychologist Diane Ehrensaft, director of mental health in the Child and Adolescent Gender Center at Benioff Children's Hospital of the University of California at San Francisco.
Many of these youth have either known about or have been living in their authentic gender since early childhood; others discovered their true identities in adolescence, often with the onset of puberty, says Ehrensaft, associate professor of pediatrics. The effects of gender-affirming hormone treatments are at least partially reversible, she adds, whereas surgical procedures are irreversible. Regardless of reversibility, best practices include careful consideration of all interventions to ensure they are in a youth's best interests in promoting gender health and general well-being.
When a child exhibits signs of gender dysphoria, parents and guardians should at a minimum take these feelings seriously.
In determining readiness for a transgender operation, an assessment of maturity is as important as chronological age, says Loren Schechter, plastic surgeon and director of the Center for Gender Confirmation Surgery at Weiss Memorial Hospital in Chicago. With the consent of a parent or guardian, he commonly performs mastectomies on adolescents at age 17 and sometimes earlier, based on the clinical circumstances and along with a multidisciplinary team that includes a primary care provider and a mental health professional.
"Typically, before surgery, people have had the opportunity and time to consider their options," Schechter says, observing that "the incidence of regret or changing one's mind is extremely low." Others may opt to transition socially but not surgically. "We recognize that gender is not binary," he explains. Some individuals may not "discreetly fit into male or female" in how they perceive themselves.
When a child exhibits signs of gender dysphoria, parents and guardians should at a minimum take these feelings seriously, not dismiss them. They may want to enlist the assistance of a gender identity clinic to address the social environment and guide the child in exploring activities with the self-identified gender, says Kelly McBride Folkers, research associate in the Division of Medical Ethics at New York University School of Medicine.
At one end of the spectrum, some parents and guardians are overzealous in supporting their child's gender-identity pursuits while the youngster is still in an early phase of decision-making. On the flipside, other parents and guardians are not at all supportive, leaving the child at risk for long-term psychological effects, says Folkers, who is also associate director of the High School Bioethics Project at NYU, an educational program that aids teachers and students in examining ethical and conceptual concepts across various areas, one of which is gender.
"It's important to help children navigate through this process early, so that they have all of the social and familial support they need if and when they choose to seek medical options for gender affirmation later," she says.
There are various reasons why children and adolescents want to explore the opposite gender when they reach puberty. "It's a small percentage who will persist and insist and be consistent with that opposite gender identity," says Nicole Mihalopoulos, adolescent medicine physician and associate professor of pediatrics at the University of Utah School of Medicine in Salt Lake City.
Turning to a social work support system can help bring clarity for teens, parents, and guardians.
For those youth, it's appropriate to start the conversation about a medication to block puberty, but without actually promoting a hormonal transition to the opposite gender, in order for the child to further explore living as the opposite gender. "Children need to start at puberty because we need to know that their bodies are physiologically normal," Mihalopoulos says.
A lack of breast development in girls or a lack of testicular development in boys could point to an abnormality in the hypothalamus, pituitary gland, or ovaries/testicles. "That needs to be identified and corrected first," she explains, "before I would say, 'Let's start on the medical transition path of the alternate gender.' "
For parents and guardians, says Theo Zachariah's aunt Miriam, it's very tempting to misinterpret a child's struggling attempts to articulate being trans as an adolescent identity crisis. That's when turning to a social work support system can bring clarity. A youth mental health agency with experience in trans issues made a positive impact on Theo's family through one-on-one counseling and in groups for teens and parents.
"The dialogue they were able to engage in with my nephew, his mom and us," she says, was very instrumental "in helping us all figure out what to do and how to navigate the change."
Questions remain about new drug for hot flashes
In May, a new drug, Fezolinetant, was approved by the FDA to treat hot flashes associated with menopause.
Vascomotor symptoms (VMS) is the medical term for hot flashes associated with menopause. You are going to hear a lot more about it because a company has a new drug to sell. Here is what you need to know.
Menopause marks the end of a woman’s reproductive capacity. Normal hormonal production associated with that monthly cycle becomes erratic and finally ceases. For some women the transition can be relatively brief with only modest symptoms, while for others the body's “thermostat” in the brain is disrupted and they experience hot flashes and other symptoms that can disrupt daily activity. Lifestyle modification and drugs such as hormone therapy can provide some relief, but women at risk for cancer are advised not to use them and other women choose not to do so.
Fezolinetant, sold by Astellas Pharma Inc. under the product name Veozah™, was approved by the Food and Drug Administration (FDA) on May 12 to treat hot flashes associated with menopause. It is the first in a new class of drugs called neurokinin 3 receptor antagonists, which block specific neurons in the brain “thermostat” that trigger VMS. It does not appear to affect other symptoms of menopause. As with many drugs targeting a brain cell receptor, it must be taken continuously for a few days to build up a good therapeutic response, rather than working as a rescue product such as an asthma inhaler to immediately treat that condition.
Hot flashes vary greatly and naturally get better or resolve completely with time. That contributes to a placebo effect and makes it more difficult to judge the outcome of any intervention. Early this year, a meta analysis of 17 studies of drug trials for hot flashes found an unusually large placebo response in those types of studies; the placebo groups had an average of 5.44 fewer hot flashes and a 36 percent reduction in their severity.
In studies of fezolinetant, the drug recently approved by the FDA, the placebo benefit was strong and persistent. The drug group bested the placebo response to a statistically significant degree but, “If people have gone from 11 hot flashes a day to eight or seven in the placebo group and down to a couple fewer ones in the drug groups, how meaningful is that? Having six hot flashes a day is still pretty unpleasant,” says Diana Zuckerman, president of the National Center for Health Research (NCHR), a health oriented think tank.
“Is a reduction compared to placebo of 2-3 hot flashes per day, in a population of women experiencing 10-11 moderate to severe hot flashes daily, enough relief to be clinically meaningful?” Andrea LaCroix asked a commentary published in Nature Medicine. She is an epidemiologist at the University of California San Diego and a leader of the MsFlash network that has conducted a handful of NIH-funded studies on menopause.
Questions Remain
LaCroix and others have raised questions about how Astellas, the company that makes the new drug, handled missing data from patients who dropped out of the clinical trials. “The lack of detailed information about important parameters such as adherence and missing data raises concerns that the reported benefits of fezolinetant very likely overestimate those that will be observed in clinical practice," LaCroix wrote.
In response to this concern, Anna Criddle, director of global portfolio communications at Astellas, wrote in an email to Leaps.org: “…a full analysis of data, including adherence data and any impact of missing data, was submitted for assessment by [the FDA].”
The company ran the studies at more than 300 sites around the world. Curiously, none appear to have been at academic medical centers, which are known for higher quality research. Zuckerman says, "When somebody is paid to do a study, if they want to get paid to do another study by the same company, they will try to make sure that the results are the results that the company wants.”
Criddle said that Astellas picked the sites “that would allow us to reach a diverse population of women, including race and ethnicity.”
A trial of a lower dose of the drug was conducted in Asia. In March 2022, Astellas issued a press release saying it had failed to prove effectiveness. No further data has been released. Astellas still plans to submit the data, according to Criddle. Results from clinical trials funded by the U.S. goverment must be reported on clinicaltrials.gov within one year of the study's completion - a deadline that, in this case, has expired.
The measurement scale for hot flashes used in the studies, mild-moderate-severe, also came in for criticism. “It is really not good scale, there probably isn’t a broad enough range of things going on or descriptors,” says David Rind. He is chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit authority on new drugs. It conducted a thorough review and analysis of fezolinestant using then existing data gathered from conference abstracts, posters and presentations and included a public stakeholder meeting in December. A 252-page report was published in January, finding “considerable uncertainty about the comparative net health benefits of fezolinetant” versus hormone therapy.
Questions surrounding some of these issues might have been answered if the FDA had chosen to hold a public advisory committee meeting on fezolinetant, which it regularly does for first in class medicines. But the agency decided such a meeting was unnecessary.
Cost
There was little surprise when Astellas announced a list price for fezolinetant of $550 a month ($6000 annually) and a program of patient assistance to ease out of pocket expenses. The company had already incurred large expenses.
In 2017 Astellas purchased the company that originally developed fezolinetant for $534 million plus several hundred million in potential royalties. The drug company ran a "disease awareness” ad, Heat on the Street, hat aired during the Super Bowl in February, where 30 second ads cost about $7 million. Industry analysts have projected sales to be $1.9 billion by 2028.
ICER’s pre-approval evaluation said fezolinetant might "be considered cost-effective if priced around $2,000 annually. ... [It]will depend upon its price and whether it is considered an alternative to MHT [menopause hormone treatment] for all women or whether it will primarily be used by women who cannot or will not take MHT."
Criddle wrote that Astellas set the price based on the novelty of the science, the quality of evidence for the drug and its uniqueness compared to the rest of the market. She noted that an individual’s payment will depend on how much their insurance company decides to cover. “[W]e expect insurance coverage to increase over the course of the year and to achieve widespread coverage in the U.S. over time.”
Leaps.org wrote to and followed up with nine of the largest health insurers/providers asking basic questions about their coverage of fezolinetant. Only two responded. Jennifer Martin, the deputy chief consultant for pharmacy benefits management at the Department of Veterans Affairs, said the agency “covers all drugs from the date that they are launched.” Decisions on whether it will be included in the drug formulary and what if any copays might be required are under review.
“[Fezolinetant] will go through our standard P&T Committee [patient and treatment] review process in the next few months, including a review of available efficacy data, safety data, clinical practice guidelines, and comparison with other agents used for vasomotor symptoms of menopause," said Phil Blando, executive director of corporate communications for CVS Health.
Other insurers likely are going through a similar process to decide issues such as limiting coverage to women who are advised not to use hormones, how much copay will be required, and whether women will be required to first try other options or obtain approvals before getting a prescription.
Rind wants to see a few years of use before he prescribes fezolinetant broadly, and believes most doctors share his view. Nor will they be eager to fill out the additional paperwork required for women to participate in the Astellas patient assistance program, he added.
Safety
Astellas is marketing its drug by pointing out risks of hormone therapy, such as a recent paper in The BMJ, which noted that women who took hormones for even a short period of time had a 24 percent increased risk of dementia. While the percentage was scary, the combined number of women both on and off hormones who developed dementia was small. And it is unclear whether hormones are causing dementia or if more severe hot flashes are a marker for higher risk of developing dementia. This information is emerging only after 80 years of hundreds of millions of women using hormones.
In contrast, the label for fezolinetant prohibits “concomitant use with CYP1A2 inhibitors” and requires testing for liver and kidney function prior to initiating the drug and every three months thereafter. There is no human or animal data on use in a geriatric population, defined as 65 or older, a group that is likely to use the drug. Only a few thousand women have ever taken fezolinetant and most have used it for just a few months.
Options
A woman seeking relief from symptoms of menopause would like to see how fezolintant compares with other available treatment options. But Astellas did not conduct such a study and Andrea LaCroix says it is unlikely that anyone ever will.
ICER has come the closest, with a side-by-side analysis of evidence-based treatments and found that fezolinetant performed quite similarly and modestly as the others in providing relief from hot flashes. Some treatments also help with other symptoms of menopause, which fezolinetant does not.
There are many coping strategies that women can adopt to deal with hot flashes; one of the most common is dressing in layers (such as a sleeveless blouse with a sweater) that can be added or subtracted as conditions require. Avoiding caffeine, hot liquids, and spicy foods is another common strategy. “I stopped drinking hot caffeinated drinks…for several years, and you get out of the habit of drinking them,” says Zuckerman.
LaCroix curates those options at My Meno Plan, which includes a search function where you can enter your symptoms and identify which treatments might work best for you. It also links to published research papers. She says the goal is to empower women with information to make informed decisions about menopause.
A company in England has made a test that picks out the compounds from breath that reveal if people have liver disease.
Every year, around two million people worldwide die of liver disease. While some people inherit the disease, it’s most commonly caused by hepatitis, obesity and alcoholism. These underlying conditions kill liver cells, causing scar tissue to form until eventually the liver cannot function properly. Since 1979, deaths due to liver disease have increased by 400 percent.
The sooner the disease is detected, the more effective treatment can be. But once symptoms appear, the liver is already damaged. Around 50 percent of cases are diagnosed only after the disease has reached the final stages, when treatment is largely ineffective.
To address this problem, Owlstone Medical, a biotech company in England, has developed a breath test that can detect liver disease earlier than conventional approaches. Human breath contains volatile organic compounds (VOCs) that change in the first stages of liver disease. Owlstone’s breath test can reliably collect, store and detect VOCs, while picking out the specific compounds that reveal liver disease.
“There’s a need to screen more broadly for people with early-stage liver disease,” says Owlstone’s CEO Billy Boyle. “Equally important is having a test that's non-invasive, cost effective and can be deployed in a primary care setting.”
The standard tool for detection is a biopsy. It is invasive and expensive, making it impractical to use for people who aren't yet symptomatic. Meanwhile, blood tests are less invasive, but they can be inaccurate and can’t discriminate between different stages of the disease.
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
The team is testing patients in the early stages of advanced liver disease, or cirrhosis, to identify and detect these biomarkers. In an initial study, Owlstone’s breathalyzer was able to pick out patients who had early cirrhosis with 83 percent sensitivity.
Boyle’s work is personally motivated. His wife died of colorectal cancer after she was diagnosed with a progressed form of the disease. “That was a big impetus for me to see if this technology could work in early detection,” he says. “As a company, Owlstone is interested in early detection across a range of diseases because we think that's a way to save lives and a way to save costs.”
How it works
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
Study participants breathe into a mouthpiece attached to a breath sampler developed by Owlstone. It has cartridges are designed and optimized to collect gases. The sampler specifically targets VOCs, extracting them from atmospheric gases in breath, to ensure that even low levels of these compounds are captured.
The sampler can store compounds stably before they are assessed through a method called mass spectrometry, in which compounds are converted into charged atoms, before electromagnetic fields filter and identify even the tiniest amounts of charged atoms according to their weight and charge.
The top four compounds in our breath
In an initial study, Owlstone captured VOCs in breath to see which ones could help them tell the difference between people with and without liver disease. They tested the breath of 46 patients with liver disease - most of them in the earlier stages of cirrhosis - and 42 healthy people. Using this data, they were able to create a diagnostic model. Individually, compounds like 2-Pentanone and limonene performed well as markers for liver disease. Owlstone achieved even better performance by examining the levels of the top four compounds together, distinguishing between liver disease cases and controls with 95 percent accuracy.
“It was a good proof of principle since it looks like there are breath biomarkers that can discriminate between diseases,” Boyle says. “That was a bit of a stepping stone for us to say, taking those identified, let’s try and dose with specific concentrations of probes. It's part of building the evidence and steering the clinical trials to get to liver disease sensitivity.”
Sabine Szunerits, a professor of chemistry in Institute of Electronics at the University of Lille, sees the potential of Owlstone’s technology.
“Breath analysis is showing real promise as a clinical diagnostic tool,” says Szunerits, who has no ties with the company. “Owlstone Medical’s technology is extremely effective in collecting small volatile organic biomarkers in the breath. In combination with pattern recognition it can give an answer on liver disease severity. I see it as a very promising way to give patients novel chances to be cured.”
Improving the breath sampling process
Challenges remain. With more than one thousand VOCs found in the breath, it can be difficult to identify markers for liver disease that are consistent across many patients.
Julian Gardner is a professor of electrical engineering at Warwick University who researches electronic sensing devices. “Everyone’s breath has different levels of VOCs and different ones according to gender, diet, age etc,” Gardner says. “It is indeed very challenging to selectively detect the biomarkers in the breath for liver disease.”
So Owlstone is putting chemicals in the body that they know interact differently with patients with liver disease, and then using the breath sampler to measure these specific VOCs. The chemicals they administer are called Exogenous Volatile Organic Compound) probes, or EVOCs.
Most recently, they used limonene as an EVOC probe, testing 29 patients with early cirrhosis and 29 controls. They gave the limonene to subjects at specific doses to measure how its concentrations change in breath. The aim was to try and see what was happening in their livers.
“They are proposing to use drugs to enhance the signal as they are concerned about the sensitivity and selectivity of their method,” Gardner says. “The approach of EVOC probes is probably necessary as you can then eliminate the person-to-person variation that will be considerable in the soup of VOCs in our breath.”
Through these probes, Owlstone could identify patients with liver disease with 83 percent sensitivity. By targeting what they knew was a disease mechanism, they were able to amplify the signal. The company is starting a larger clinical trial, and the plan is to eventually use a panel of EVOC probes to make sure they can see diverging VOCs more clearly.
“I think the approach of using probes to amplify the VOC signal will ultimately increase the specificity of any VOC breath tests, and improve their practical usability,” says Roger Yazbek, who leads the South Australian Breath Analysis Research (SABAR) laboratory in Flinders University. “Whilst the findings are interesting, it still is only a small cohort of patients in one location.”
The future of breath diagnosis
Owlstone wants to partner with pharmaceutical companies looking to learn if their drugs have an effect on liver disease. They’ve also developed a microchip, a miniaturized version of mass spectrometry instruments, that can be used with the breathalyzer. It is less sensitive but will enable faster detection.
Boyle says the company's mission is for their tests to save 100,000 lives. "There are lots of risks and lots of challenges. I think there's an opportunity to really establish breath as a new diagnostic class.”