The Body, The Self
An otherwise healthy baby is born with a phallus that seems small for a penis but big for a clitoris. The labia are partially fused so that they resemble a scrotum.
A young girl complains of abdominal tenderness. An exam for a suspected inguinal hernia instead finds a pair of undescended testes.
A teen raised as a male comes to the doctor bleeding from his penis. An ultrasound reveals that a previously undetected uterus has shed its lining through the urethra: he’s experiencing his first period.
Each year, a portion of the population is born with biological characteristics—sex chromosomes, gonads, genitalia, hormones, or a combination—that don’t fit textbook definitions of male or female. Most differences present at birth. A minority are accompanied by significant, even life-threatening, medical concerns. Others pose little or no danger. In many cases, the physical and psychological risks are uncertain.
Since the 1990s, when patient advocacy groups gained a national platform, debates have churned about which differences indicate pathology and which represent a spectrum of human sex characteristics that deserve acceptance. Such questions have fueled disagreement over whether to refer to atypical sex characteristics as “disorders of sex development,” or DSDs, as they’ve been classified by the medical profession since 2006; as “differences of” or “diverse” sex development to avoid pathologizing language; as intersex traits or variations in sex characteristics; or to abandon umbrella categories and use only the names of specific conditions.
It isn’t clear how common DSDs are, in part because they encompass some forty to sixty conditions with an even greater number of causes. Estimates of incidence range from more than 1 in 100 to less than 1 in 5,000 births, suggesting a prevalence between 66,000 and 3.3 million people in the United States. For comparison, Down syndrome occurs in 1 in 800 births.
The relative rarity of cases, combined with anemic material in medical school curricula and significant research gaps, leaves many physicians, surgeons, mental health specialists, and others struggling to understand how best to care for these underserved people. Throw in conflicting pressures from professional, patient advocacy, and human rights groups, and the waters grow ever muddier.
Clinical and bioethical questions abound. What’s the best way to work with families to assign the “right” sex when babies are born with diverse genital presentations? When and how should health care teams recommend intervening? How do providers act responsibly without a definite diagnosis or long-term outcome data? How to balance safety with patient autonomy? How to uncouple medical necessity from societal pressures that call for people to conform to a sex binary?
It can be hard even to talk about it.
“I think these conditions get stigmatized and compartmentalized because they’re sexual,” says psychiatrist Vernon Rosario, PhD ’93 MD ’95. “We feel like we’re supposed to hide DSDs from patients, especially children.”
DSD care is “complicated medically, surgically, politically, and in other ways, and especially recently, it’s an area that’s been under attack,” says David Diamond, an HMS professor of surgery, the HMS Alan B. Retik Chair and Professor of Pediatric Surgery at Boston Children’s Hospital, and a member of the hospital’s Ethics Advisory Committee. “There aren’t a lot of colleagues who have the courage to discuss this.”
“A lot of clinicians have closed ranks,” says Jameson Garland, a Harvard Law School alumnus and researcher at Uppsala University in Sweden, who specializes in children’s rights in biomedicine. “They’re under incredible scrutiny, incredible pressure to not talk, and many of them struggle to have dialogue outside of their specialty and the medical profession in general.”
Generalists can expect to encounter a handful of patients with DSDs throughout their careers.
But avoiding conversation does a disservice to both patients and practitioners, not least because generalists can expect to encounter a handful of patients with DSDs throughout their careers.
“If you practice long enough, you’ll definitely come across it,” says Vincent Smith, a neonatologist and an HMS assistant professor of pediatrics at Boston Children’s. “It helps to think about it and talk about it before it becomes an issue directly related to you, so you don’t have to cope with it on the fly.”
If anything is clear, it’s that the hetereogeneity of DSDs reflects a diversity of patient identities and opinions and prevents one-size-fits-all health care decision-making.
Let’s talk about sex Sperm meets egg and chromosomes mix and match. Most embryos inherit two sex chromosomes, either XX or XY, which typically lead to bodies classified as female and male. But the story isn’t always so simple. Genetic mutations or variations on the sex chromosomes or elsewhere can create discrepancies between the classic karyotypes and physical characteristics. DSDs also can arise if embryos inherit unusual numbers of sex chromosomes, such as X or XXY, or develop different karyotypes in different cells, known as genetic mosaicism. Nongenetic factors contribute as well.
Early fetuses have a structure called the urogenital ridge that gives rise to the gonads, kidneys, and adrenal glands. This interconnectedness explains several DSDs, including why babies with changes in the Wilms’ tumor suppressor gene WT1 have a high risk of kidney failure and tumors in childhood along with underdeveloped gonads and genitourinary variations.
Rarely, gonads fail to develop altogether, leaving nonfunctional streaks of fibrous tissue with high cancer risk. Or, in the second most common cause of diverse genital presentation, embryos develop one mature gonad, usually a testis, and one streak gonad. In ovotesticular DSD, infants have a mix of gonadal tissue.
In some DSDs, the Wolffian ducts, which usually become the vas deferens, epididymis and seminal vesicles in males and disappear in females, or the Müllerian ducts, which usually become the Fallopian tubes and uterus in females and disappear in males, don’t develop as expected. Boys with persistent Müllerian duct syndrome have problems producing or detecting the hormone that normally suppresses maturation of female-associated structures. In girls with Mayer-Rokitansky-Küster-Hauser syndrome, the Müllerian ducts don’t form at all.
Many DSDs alter development of the external genitalia, which usually form as clitoris and labia unless exposed to testosterone from the testes.
People with XY chromosomes whose bodies can’t detect androgens appear female at birth, and at puberty they develop breasts as testosterone gets converted to estrogen, but they don’t produce sperm, have a uterus, or develop secondary male sex characteristics.
Inherited enzyme deficiencies can disrupt cortisol production by the adrenal glands, known as classic or severe congenital adrenal hyperplasia (CAH). The glands churn out excess androgens as they try to compensate. In fetuses that are genetically female, this androgen bath virilizes the genitals, sometimes to the extent that they’re presumed male at birth. In about 75 percent of cases, the adrenal glands also can’t produce hormones that balance salt and water in the kidneys, which, if not treated, can cause fatal complications in the weeks following birth. All fifty states screen newborns for classic CAH. Like insulin for type 1 diabetes, people with CAH need hormone supplements for life. CAH is the most common DSD for people with XX chromosomes.
If a genetic male has trouble converting testosterone to dihydrotestosterone, the urethra, initially located between scrotum and anus, may not reach its destination at the tip of the penis. Research suggests that this condition, hypospadias, affects about 0.4 percent of babies assigned male and is on the rise, likely because of environmental chemical exposure. Such exposure may also be triggering a rise in the incidence of undescended testes. Less commonly, failure of testosterone conversion can lead to diverse genital presentations in XY babies, who then develop male secondary sex characteristics at puberty when androgens surge.
Many more variations can arise from developmental byways. While effects vary, it’s common for people with DSDs to experience infertility or low fertility and to need hormone replacement to induce puberty or carry out other biological processes.
The weight of research For many infants who present with diverse genitalia, the precise etiology remains unknown. Without a definitive diagnosis, clinicians can’t rely on evidence or experience to guide care, says Rosario.
Researchers have unearthed dozens of genes and even more variants that contribute to DSDs. Still, the ever-expanding list explains a mere fraction of physical diversity. Sequencing techniques currently can detect a genetic cause for 20 percent to 45 percent of intersex babies.
Geneticists are trying to change that. At HMS and Boston Children’s, a team led by Joel Hirschhorn, MD ’95 PhD ’95, and Ingrid Holm is conducting whole-exome sequencing of infants with classic DSDs as well as infants with a broader range of variations to illuminate the genetics of sex development and assess how parents respond to test results.
“The person who has to live with this should have a voice when it’s appropriate. If there’s a medical indication to not wait, that trumps other things. But all else equal, it’s better for the person to contribute.”
International databases and multi-institutional research networks are making another dent in the unknown. The International DSD Registry hosts data from about 3,000 patients, ranging in age from infancy to 77 years, in thirty-four countries. The National Institutes of Health-funded DSD Translational Research Network, spanning twelve U.S. clinical sites, is examining genetic causes and participants’ physical and mental health.
By centralizing and standardizing data collection, such efforts have begun to identify new DSDs and biomarkers and track short- and long-term outcomes of DSDs and treatments, information that’s historically been in short supply, with the goal of improving diagnosis and care. The results also could clarify how often people with DSDs are assigned a sex at birth that they later do not identify with, a rate that studies estimate to be between 5 percent and 60 percent, depending on the condition.
Consensus statements from groups that include physicians, surgeons, bioethicists, lawyers, and patient advocates have attempted to synthesize the slim but growing body of research on DSDs and facilitate agreement on how to proceed. The first, known as the Chicago consensus, was published in 2006 and initiated many of the changes seen in intersex care, including the coining of “disorders of sex development” and a recommendation that patients be assessed by multidisciplinary teams in specialty centers. In 2016, a Global DSD Update revised the Chicago report. Still, gaps remain between recommendations and practice.
Intersex research funding is on the rise, though it has a long way to go. In fiscal year 2017, the NIH funded just eight projects related to DSDs, according to a portfolio analysis by the institutes’ Sexual and Gender Minority Research Office. It’s a morsel, and hunger is growing.
“When I attend sexual and gender minority research meetings, there are increasing numbers of research scientists interested in exploring this area,” says Jennifer E. Potter, MD ’87, an HMS professor of medicine at Beth Israel Deaconess Medical Center. “So that’s a real positive.”
No more simply pink or blue Medical and surgical practices are evolving as well, both in technique and philosophy. As times change and patients speak up, more practitioners question a tradition in intersex care that reinforces gender binaries and heterosexual norms.
For some people with DSDs, gender identity aligns with the sex they were assigned at birth; for some it does not. Some identify as male or female; some do not. Some are straight; some are not. For many, gender identity and sexuality are complicated.
“We’ve basically been thinking about sex development and gender identity all wrong for a very long time, and that has done a disservice to an entire population of people who do not fit our traditional expectations,” says Potter.
Another mid- to late-century trend now seen as a blunder was a tendency for practitioners and parents to hide DSD diagnoses.
In the 1950s and ’60s, influential but now discredited research argued that having “normal”-looking genitalia and a clear gender of rearing would lead to “stable male or female identity” and prevent same-sex attraction. The research intensified practices that had begun in the 1920s in which infants with variant or discordant sex characteristics were surgically altered to conform to certain male and female standards, and parents were encouraged to reinforce the assigned gender. Surgeons tended to prioritize fertility for those assigned female and sexual satisfaction for those assigned male. Vaginoplasty was recommended for female-assigned infants not only so those with a uterus could menstruate at puberty but also on the assumption that those with or without a uterus would later want to accommodate penile intercourse. Cosmetic outcomes frequently took precedence over future sexual function and sensation.
Another mid- to late-century trend now seen as a blunder was a tendency for practitioners and parents to hide DSD diagnoses. Patients sometimes didn’t discover they were intersex until well into adulthood. Many children weren’t told they’d undergone procedures or weren’t told why.
Documentation of psychological harm stemming from secrecy, legal requirements for informed consent, and other practical considerations—that patients will eventually grow up and see their medical records, that they will need to manage any related health issues—have led to greater transparency and shared decision-making between doctors and families. The American Psychological Association recommends explaining DSD diagnoses to children “throughout their lives in an age-appropriate manner.”
Along with openness has come an increasing emphasis on patient consent and autonomy. Many of the intersex people who have spoken publicly about their experiences express anger and anguish at not having been involved in major decisions about their bodies, especially when procedures resulted in infertility or in altered or “wrong” genitalia. Emotions have run even higher since research and patient testimonies revealed higher than expected rates of surgical complications such as pain, scarring, stenosis, poor sensation or sexual enjoyment, reduced sexual function, incontinence, and other dysfunctions.
Pause, consider Shifting to a consent-based model translates to postponing medically unnecessary interventions until patients are old enough to weigh in. A key question in intersex care then becomes what to consider unnecessary.
Sometimes distinctions are clear, as with salt-losing CAH, WT1 mutations, and other serious issues that may accompany diverse genitalia, such as an incomplete urethra or rectum, defects in the heart or other organs, microcephaly, joined fingers, epilepsy, or thalassemia. More often than not, however, the line isn’t so sharp.
“Some kids are born with significant midline malformations that require surgery just to survive,” says psychiatrist Rosario, who served on a multidisciplinary care team in a children’s DSD clinic at UCLA and sees patients through the Los Angeles County Department of Mental Health. “I don’t think even intersex activists would say you shouldn’t do that. The challenge then is determining what is lifesaving versus what’s more cosmetic. That is a gray area.”
It used to seem clear that surgeons should remove gonads because they carried high risk of becoming cancerous. Then researchers found that malignancy isn’t such a given. As studies narrow down gonadal cancer likelihood and timing for individual DSDs, recommendations have shifted toward active surveillance or watchful waiting to extend fertility and allow natural induction of puberty. Most people with DSDs can now safely retain well-developed gonads until puberty or later if desired, allowing them to participate in decision-making about risks and benefits. For those who do remove gonads because of cancer risk or to avoid initiating puberty in a gender they don’t identify with, doctors may be able to offer fertility preservation options.
Clinicians also are revisiting estimates of the likelihood that being born with a shared exit for the urethra and vagina leads to repeated urinary tract infections. If the risk proves lower than previously thought, surgeons may be able to delay procedures on this region until patients can have their say.
It’s been standard practice to surgically correct hypospadias. Stakeholders are now asking if the purpose is to allow urine and semen to exit the penis in a “normal” location, must it be done during infancy, or can it wait?
But the eye of the storm swirls around surgery primarily intended to make internal and external structures more definitively male or female.
A say in the matter Arguments in favor of performing nonurgent, so-called gender-normalizing operations in infancy range from the surgical to the social, including that children won’t remember the procedures, wound healing is faster and bleeding less, children won’t grow up “confused” about their sex or gender, and patients and families won’t be bullied or stigmatized for being different.
“With some of these anatomic disorders, it’s much easier technically to do a surgical procedure when a child is little,” says Diamond. “Usually when it’s easier for the surgeon it’s an easier recovery for the patient.”
Those in favor of waiting until patients can participate in decision-making emphasize bodily and reproductive autonomy and the risk of physical and psychological trauma. Surgical complications could overshadow the benefits, they argue. Construction or elimination of genitals could fail to align with the child’s ultimate gender identity. Children are denied the opportunity to say whether atypical genitalia bother them or are just fine.
“Sometimes we get it wrong, and the person who has to live with this should have a voice when it’s appropriate,” says neonatologist Smith. “If there’s a medical indication to not wait, that trumps other things. But all else equal, it’s better for the person to contribute.”
Without long-term outcome data, the risks of individual procedures can’t be quantified, nor can the advantages of waiting versus intervening early. It’s also unclear whether patients who’ve gone public reflect most intersex people’s experiences. Clinicians don’t know how much of the reported distress arises from outdated surgical techniques, nor do they know yet whether current procedures will prove any better.
Researchers are attempting to better gauge outcomes and satisfaction rates. A forthcoming European report will describe the opinions of more than one thousand intersex patients and their doctors regarding satisfaction with “anatomical and functional results of genital surgery,” according to a 2019 review article in the Journal of Pediatric Urology. Institutions are conducting other retrospective and prospective studies, such as a U.S. endeavor at multiple sites, including HMS.
Clinicians also are turning to transgender patients for insight. Teens and adults can provide immediate feedback on medical and surgical procedures and describe broad ranges of desired outcomes, which can then inform intersex care, says surgeon Diamond. The relationship seems fitting, since certain surgical interventions for transgender affirmation were informed by procedures developed for infants with DSDs.
But for many intersex advocates, the wait is too long for the results of such endeavors. Over the past decade, advocacy groups have led a global movement calling for a moratorium on genital and gonadal surgeries without patient consent. International health and human rights organizations, including the United Nations and the World Health Organization, have condemned the procedures, and several countries have restricted them. In February, the European Parliament urged member states to prohibit nonconsensual sex-normalizing surgeries “as soon as possible.” Some medical societies, consortia, and prominent figures such as a trio of former U.S. surgeons general have echoed the call. Several states, such as California, have considered bans.
This sea change has evoked an array of reactions, even among patients. People with CAH in particular say that an outright ban will do more harm than good by depriving families of the option to choose surgery. Appending an objection to a 2019 consensus paper by German academics that supported a ban, one CAH group said the majority of those with CAH who identify as female are satisfied with the results of their feminizing surgery and glad to have completed it in infancy.
The idea that the bodily autonomy of intersex children supersedes parents’ traditional roles as health care proxies remains a point of contention. National medical ethics councils in Finland, Germany, Sweden, and Switzerland say parents cannot authorize medically unnecessary surgery on genitals or gonads; the 2016 Global DSD Update says they can. Though the United States has not ruled on DSDs, its law and culture generally side with parents’ right to choose, say Garland and Diamond, and many clinicians continue to defer to them on intersex care.
“When we discuss the pros and cons of surgery with the family and they say, ‘We understand the different ways to go and this is what we think is best for our child,’ I accept that that is a responsible way to manage the child,” says Diamond.
Some clinicians fear losing the ability to use their medical expertise to guide families and make decisions based on individual cases. “It is not logical to impose mandatory restrictions on surgery in an area as complicated as this,” reads a 2017 joint statement from seven U.S. urology and endocrinology societies.
Rosario served as chair of the medical advisory board for the Intersex Society of North America from 2002 to 2006 before he joined the UCLA DSD clinic. Initially against infant genital-normalizing surgery, he found that “my opinion softened with actual clinical experience,” he says.
Arguments roil about where gender-normalizing surgery falls along the spectrum of acts performed on infant genitalia. All fifty U.S. states condemn female genital mutilation, some advocates point out, so why should intersex surgery be considered differently? Others make comparisons to male circumcision, yet that practice also has been questioned. Professional societies are increasingly supporting interventions for transgender patients, so why deny the choice to those with DSDs, people ask?
While individual clinicians may support restricting infant genital-normalizing surgery, Garland wonders whether the threat of malpractice litigation explains why the U.S. medical profession tends to emphasize following the standard of care rather than trying nonintervention. He adds that in countries where “the law requires scientific evidence and careful testing to establish the safety and efficacy of medical interventions, it’s been determined that these surgeries clearly don’t meet that standard.”
“As physicians and as a society, we’ve evolved, but we’re not to the point where we can routinely be comfortable with ambiguity. Some families can take that leap, but they are so uncommon.”
Pressure to change may come from peers, such as the Massachusetts Medical Society, which is debating a recommendation to delay surgeries on infants with DSDs “that are of a non-emergent status until the individual has the capacity to participate in the decision.” Doctors listen to other doctors, points out Smith, who serves on the LGBTQ committee that submitted the proposal.
Lawsuits also could influence U.S. medical practice. In a case that settled out of court in 2017, parents sued two South Carolina hospitals and a social services department for having performed feminizing surgery on a child they later adopted who grew up to identify as male.
Should DSD care shift, “we will need a new way of thinking about how to determine when a child is able to consent,” says Garland.
Those who worry about the lack of comparative data between early, delayed, and no intervention may take note as more nations and institutions restrict surgery on minors.
“We may have our control group developing in Europe,” says Diamond.
As more practitioners view forgoing surgery as an option, they turn to more flexible alternatives meant to support patients’ gender expression, such as hormone treatments. Surgeons also consider middle-ground procedures that preserve gender options as children grow.
In a 2018 case review in the Journal of Pediatric Urology, Diamond and colleagues described three infants with genetic mosaicism and complex urogenital and gonadal features whose parents all opted, among other procedures, to create vaginas but preserve the phalluses while they waited for their children to develop a gender. Two families were tentatively raising their children female; the other, gender neutral.
“I wouldn’t have thought that way at all ten years ago,” says Diamond, who estimates he sees one hundred DSD patients a year in the Behavioral Health, Endocrinology, Urology (BE-U) program at Boston Children’s. “My frame of mind would have been that the surgical options were more of a binary choice.”
To those who believe that refraining from intervention does the least harm, Diamond says, “You do your best, and you do it with a lot of humility because you know that no matter what you do, as much data as you have, you may be wrong.”
Mind and body Clinicians continue to learn how to avoid inadvertently making things worse for people with DSDs. Research studies and patient advocacy reports have documented the long-term psychological harm stemming from health care experiences such as repeated genital examinations and photography, depersonalization, and demeaning language.
That’s part of why psychologists and social workers have become essential members of DSD care teams over the past 20 years, although experts agree that psychosocial care still isn’t available to enough families.
“Surgeons and other specialists focus on their areas, particularly on the genitals, and they don’t pay as much attention to the rest of the person,” says Rosario. “My job is to ask, how are you doing in school, and how are you doing with friends?”
Although there is variation across conditions, initial research suggests that people with DSDs are more prone than the general population to mental health problems, including depression, anxiety, suicidal ideation, post-traumatic stress disorder, and trouble with intimacy. Such disparities may arise from treatment, culture, or the biology of the DSDs themselves.
“Maybe we should be trying to help parents, and by extension the people surrounding the parents—the extended family, the school system, all of these places—become more knowledgeable that there’s a spectrum of sex presentation.”
Other studies assess the frequency, severity, and nature of parental distress when children receive DSD diagnoses. Researchers at HMS and elsewhere have found that unexpected anatomical variations, the possibility of stigma, and lack of clarity about the child’s cancer risk, fertility, and future gender identity can cause significant anguish. Yet they also have found that caregivers of intersex children are no more depressed and, in fact, are less anxious than the general population.
Still more questions center on what should be done if the bulk of distress over DSDs arises from societal rather than medical issues.
Breaking away In an era of gender-reveal parties and bathroom access controversies, having a “perfectly happy” baby with DSD “can be like a crisis for families,” says Smith. “If there are no accompanying medical issues, then it becomes an entirely social-driven crisis.”
Clinicians and parents often cite the desire to protect children from social harm when they opt for gender-normalizing procedures. Why, critics ask, in a culture built around binary sex, is the standard solution to alter bodies that are nonbinary rather than broaden societal conceptions of sex and gender?
“It’s really fraught when a concerned parent or physician thinks that a child who is intersex, and maybe doesn’t present in a typical manner, is therefore going to have a harder time in the world,” says Potter. “That might be true, it might not be true, but in any event, trying to ‘fix’ it so that they look like people with binary bodies may make a big mess of things.”
“Maybe we should be trying to help parents, and by extension the people surrounding the parents—the extended family, the school system, all of these places—become more knowledgeable that there’s a spectrum of sex presentation,” she adds. “Instead of conforming a child to something, transform the world in which they live. Then life may not be so hard.”
“That’s where law can also play a significant role, stopping discrimination and encouraging increased support for parents and children,” says Garland.
While Garland, Potter, and others envision a more DSD-friendly future, they acknowledge that the systemic changes required will take time and effort. Meanwhile, others point out, clinicians, patients, and families must live in today’s cultural contexts.
Discomfort with atypical sex characteristics “is very much a societal problem, but we are caring for human beings who are brought up in our society to think in certain ways,” says Diamond. “As physicians and as a society, we’ve evolved a great deal, but we’re not at the point, I think, where we can routinely be comfortable with ambiguity. Some families can take that leap, but they are so uncommon.”
As our culture progresses, that balance may shift. The sharing of people’s preferred pronouns, encompassing a spectrum of identities beyond “he/his” and “she/hers,” is becoming more common. People with transgender, gender nonconforming, nonbinary, and intersex identities are increasingly out and proud.
“I’ve been very surprised and pleased to see how much has changed in the LGBT arena in the past twenty years,” says Garland. “It’s dramatic worldwide. Acceptance has increased of people with different sexualities and genders.”
If trends continue, then in another generation or two, the agitation around DSDs may calm. Doctors may deliver healthy intersex babies and simply say: “Congratulations.”
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