While individuals have demonstrated gender diversity throughout history, the use of medication and/or surgery to bring a person’s physical sex characteristics into alignment with their gender identity is relatively recent, with origins in the first half of the 20th century. Adolescent gender-affirming care, however, did not emerge until the late 20th century and has been built upon pioneering work from the Netherlands, first published in 1998. Since that time, evolving protocols for gender-diverse adolescents have been incorporated into clinical practice guidelines and standards of care published by the Endocrine Society and World Professional Association for Transgender Health, respectively, and have been endorsed by major medical and mental health professional societies around the world. In addition, in recent decades, evidence has continued to emerge supporting the concept that gender identity is not simply a psychosocial construct but likely reflects a complex interplay of biological, environmental, and cultural factors. Notably, however, while there has been increased acceptance of gender diversity in some parts of the world, transgender adolescents and those who provide them with gender-affirming medical care, particularly in the USA, have been caught in the crosshairs of a culture war, with the risk of preventing access to care that published studies have indicated may be lifesaving. Despite such challenges and barriers to care, currently available evidence supports the benefits of an interdisciplinary model of gender-affirming medical care for transgender/gender-diverse adolescents. Further long-term safety and efficacy studies are needed to optimize such care.
The relatively recent recognition of diversity of “gender identity” – one’s inner sense of self as male or female or somewhere on the gender spectrum – in the current culture belies its long-standing presence in cultures diverse and ancient. “Transgender” (sometimes referred to as “gender incongruence”) is defined as a marked and persistent incongruence between an individual’s experienced gender and their sex designated at birth. Transgender is often used as an umbrella term to encompass all gender identities that are not the same as the birth-assigned gender (typically based on the sex designated at birth) but may also be used specifically for a binary gender identification.
As our understanding of gender has been evolving over time, so has the language used to describe gender. Throughout this manuscript, the authors have primarily used the terminology of the present day, though historical descriptions will contain language that is clearly outdated. We have chosen to use these terms only to maintain the historical perspective in this context.
The Historic and Cultural Diversity of Gender
Though it may seem that transgender as a concept is a recent phenomenon, there are both ancient and diverse examples that underscore the understanding that humans have experienced gender as beyond the set of cultural norms assigned to them based on their genitals. In Greek and Roman mythology, there are legends of deities who defy traditional concepts of gender; the most famous may be Hermaphroditus, a son born of Hermes and Aphrodite. When the nymph Salmacis fell in love with him, their forms became merged, with the god depicted as having male genitalia with breasts and a more feminine body shape [1, 2]. Norse mythology gives us the notorious shape and sex shifting Loki, who was known for his trickery, appearing at times in a female form when it suited his purpose . Several Indigenous North American tribes have long-standing recognition and language for gender and/or sexual minority-identified individuals that often signified a third gender, or a combination of male and female. Though the designation and roles varied among tribes, the term “two-spirit” was coined in 1990 during the international LGBT Native American Gathering and attributed to Elder Maya Laramee [3, 4]. This term is not specific to any one tribe or any one group of individuals but encompasses any indigenous member with gender-diverse identification or same-sex attraction.
Biological Underpinnings of Gender Identity
John Money, a New Zealand psychologist and faculty member in pediatrics at Johns Hopkins University beginning in the early 1950s, and co-founder of the Gender Identity Clinic at that university, promoted the concept that gender identity was influenced by “social learning and memory” in conjunction with biological factors . However, a widely publicized case described in a book by John Colapinto published in 2000 lends strong support to the concept that gender identity is not primarily learned . This book focused on a failed circumcision in an 8-month-old male resulting in loss of the penis, leading Money to advise the family to castrate the infant and raise him as a girl . The child never accepted a female gender identity, became severely depressed, and changed gender to male during adolescence. He later committed suicide . In subsequent years, evidence in support of biological underpinnings to gender identity development has continued to emerge, derived primarily from three biomedical disciplines: genetics, endocrinology, and neurobiology .
Starting in the late 1970s, heritability of being transgender was suggested from studies describing concordance of gender identity in monozygotic twin pairs and in father-son and brother-sister pairs [8, 9]. In the largest twin study evaluating gender identity, in which at least one member of a twin pair was transgender, there was a much greater likelihood that the other member of the twin pair was also transgender if they were identical versus nonidentical (but same sex) twins . Attempts to identify polymorphisms in candidate genes that might be more prevalent in transgender versus cisgender individuals have been inconsistent. In particular, a 2009 study from Japan did not find any significant associations of transsexualism with polymorphisms in five candidate genes (encoding the androgen receptor, CYP19, ER-alpha, ER-beta, and the progesterone receptor) . However, a 2019 study in 380 transgender women and 344 cisgender male controls demonstrated an over-representation of several allele combinations involving the androgen receptor in transgender women . A subsequent study using whole-exome sequencing in a relatively small number of transgender males (n = 13) and transgender females (n = 17) demonstrated 21 variants in 19 genes that were associated with previously described estrogen receptor-activated pathways of sexually dimorphic brain development . An association between polymorphisms in the estrogen receptor alpha gene promoter and a transgender male identity has also been reported .
The vast majority of transgender individuals do not have an intersex condition or any associated abnormality in sex steroid production or responsiveness . However, studies in a variety of intersex conditions have informed our understanding of the potential role of hormones, particularly prenatal and early postnatal androgens, in gender identity development . For example, several studies of 46,XX individuals with virilizing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency demonstrated a greater prevalence of a transgender identity outcome (female to male) compared to the general population [15-17]. One such study published in 2006 demonstrated a relationship between severity of congenital adrenal hyperplasia and gender identity outcome, where 7% of patients with the severe salt-wasting form had gender dysphoria or a male gender identity, while no gender dysphoria was seen in any of the less severely affected individuals . Studies in a variety of other hormonal and nonhormonal intersex conditions support a role of prenatal and/or postnatal androgens in gender identity development . However, in 2011, a case report in a 46,XY individual with complete androgen insensitivity and a male gender identity challenged the concept that androgen receptor signaling is required for male gender identity development .
Neuroimaging studies that aim to understand the neurobiology of gender identity indicate that some sexually dimorphic brain structures are more closely aligned with gender identity than with physical sex characteristics in transgender adults prior to treatment with gender-affirming hormones [19-21]. A similar trend was reported in studies of gray matter in youth with gender dysphoria . In 2021, an MRI study in transgender adults, also prior to treatment with gender-affirming sex hormones, found that transgender people have a unique brain phenotype “rather than being merely shifted towards either end of the male-female spectrum” . Notably, in both transgender adolescents and adults, several functional brain studies looking at responses to odorous compounds or mental rotation tasks demonstrated that patterns typically observed to be sexually dimorphic were more closely aligned with gender identity than with physical sex characteristics, even before treatment with gender-affirming sex hormones [24-26].
History of Modern Gender-Affirming Medical Treatment
Though individuals have demonstrated gender diversity throughout history, the use of medication and/or surgery is relatively recent with origins in Germany in the first half of the 20th century and is credited to the pioneering work of Magnus Hirschfeld. The institution he founded, “Institut für Sexualwissenschaft (the Institute for Sexual Science)” in Berlin (1922), paved the way for the use of hormones and surgery . In Hirschfeld’s study of what he named “sexual intermediaries,” he recognized that people may be born with a nature contrary to their assigned gender. In cases where the desire to live as the opposite sex was strong, he thought science ought to provide a means of transition. Innovative for his time, he argued that a person may be born with characteristics that did not fit into heterosexual or binary categories and supported the idea that a “third sex” existed naturally . The first documented case of genital surgery was performed at the institute on Dorchen Richter in 1922 with orchiectomy and then 1931 with penectomy and vaginoplasty [27, 28]. Notable patients, including Lili Elbe (born Einar Wegener), the patient on whom the movie “The Danish Girl” is based, underwent a series of operations including transplant of both ovaries and a uterus .
This clinic would be a century old if it had not fallen victim to Nazi ideology and Hitler’s mission to rid Germany of Lebensunwertes Leben, or “lives unworthy of living.” What began as a sterilization program ultimately led to the extermination of millions of Jews, Gypsies, Soviet, and Polish citizens, as well as homosexuals and transgender people. When the Nazis came for the institute in 1933, Hirschfeld had fled to France. Troops swarmed the building and created a bonfire that engulfed more than 20,000 of his books, some of them rare copies that had helped provide a history for transgender people .
In the 1950s, German-American physician Harry Benjamin (1885–1986) introduced the term “transsexuality,” defining a “transsexual” person as someone who identifies in opposition to their “biological sex” . Harry Benjamin graduated cum laude from medical school in Tübingen, Germany, in 1912. He moved to New York City in 1914 to study tuberculosis, but over time, he became known as a geriatrician, endocrinologist, and sexologist . He did not treat his first transgender patient until he was in his 60s, and his colleagues described him as follows: “Being a true physician, Benjamin treated all these patients as people and by respectfully listening to each individual voice, he learned from them what gender dysphoria was about” . Notably, he did not describe “transsexualism” as a psychological problem, but as a biological condition that could be treated with hormone or surgical therapy . He treated over 1,500 patients, and in 1966, he published the first medical textbook in this field, “The Transsexual Phenomenon” . His work was very influential, and he became known as “The Father of Transsexualism” [31, 32].
Following World War II, gender-affirming treatment in the USA was limited to wealthy patients who could afford to travel to Europe, though they did so at great risk given the laws in several states outlawing “cross-dressing” . Christine Jorgensen (1926–1989) brought visibility to transgender patients, having undergone medical and surgical transition in Europe after she had served time in the US military as a male .
Influenced by Dr. Benjamin Harris’ “The Transsexual Phenomenon” , Johns Hopkins Hospital in Baltimore became the first academic institution in the USA to offer gender-affirming surgery . Soon after, at least another 8 academic institutions opened transgender programs throughout the 1960–1970s (University of Minnesota, University of Washington, Northwestern/Cook County Health in Chicago, Stanford University, Cleveland Clinic, University of Colorado, Baptist Medical Center in Oklahoma City, and Washington University in St. Louis) .
Toward the end of the 1970s, however, most transgender programs closed access to new patients. These closures were done quietly out of public view, and the causes were often not disclosed . At Johns Hopkins Hospital, Paul McHugh became the Chair of Psychiatry in 1975. From the moment he was hired, McHugh openly stated he intended to stop gender-affirming surgery at this hospital . Under his leadership, another Johns Hopkins psychiatrist, Dr. Jon Meyer, published a study of 50 patients which concluded that gender-affirming surgery did not provide “objective” benefit for transgender individuals . This publication led to the sudden closure of the clinic in 1979 . Interestingly, John Money, who believed that gender could be learned and who co-founded the Johns Hopkins gender clinic, publicly expressed opposition to Meyer’s conclusions of his study .
The program at the Baptist Medical Center in Oklahoma City had been functioning since 1973. However, in 1977, its existence was brought to the attention of the Board of Directors of the Baptist General Convention of Oklahoma. This led to a 54-2 vote by the Board of Directors at the Baptist Medical Center to close the program. Physicians who passionately advocated to continue this practice issued a joint statement saying, “If Jesus Christ were alive today, undoubtedly he would render help and comfort to the transsexual” .
It is thought that publicity around the Meyer paper  from Johns Hopkins played a role in an escalation of closure of other clinics . Despite these closures, academic interest in the field led to the foundation of the Harry Benjamin Gender Dysphoria Association in 1979 . This association had the goal of organizing professionals who were interested in the “study and care of transsexualism and gender dysphoria.” It has since been renamed the World Professional Association for Transgender Health (WPATH) and has evolved into a large international multidisciplinary organization that provides Standards of Care for the treatment of transgender/gender-diverse (TGD) adolescents and adults .
In 1980, “transsexualism” and “gender identity disorder of childhood” were both recognized as illnesses in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders . In 2013, the term “gender identity disorder” was replaced by “gender dysphoria in children” and “gender dysphoria in adolescents and adults” to diagnose and treat those transgender individuals who felt distress at the mismatch between their gender identities and their bodies, with the American Psychiatric Association stating that “it is important to note that gender nonconformity is not in itself a mental disorder” .
In 2019, the World Health Organization International Classification of Diseases version 11 replaced International Classification of Diseases-10’s “transsexualism” and “gender identity disorder of children” with “gender incongruence of adolescence and adulthood” and “gender incongruence of childhood,” respectively . Gender incongruence was moved out of the “Mental and behavioral disorders” chapter into a new chapter, entitled “Conditions related to sexual health” . This reflects current perspective that TGD identities are not mental health illnesses and that classifying them as such can cause significant stigma.
History of Gender-Affirming Medical Treatment in Adolescents
Providers in the Netherlands recognized the importance of preventing progression of a gender incongruent puberty by using a gonadotropin hormone-releasing hormone analog (GnRHa) followed by treatment with either testosterone or estrogen to bring physical characteristics into alignment with a patient’s gender identity [45, 46]. This approach was first published by Drs. Cohen-Kettenis and van Goozen in 1998 in a case report of an adolescent treated with GnRHa by Dr. Henriette A. Delemarre-van de Waal (though not named in the publication) (Dr. Sabine E. Hannema, personal communication) . Under the direction of Dr. Peggy Cohen-Kettenis, the first program geared to treating adolescents with gender dysphoria was established in the Netherlands . Initially based on the guidelines of adult transgender treatment established by the Harry Benjamin Society and adapted to adolescents, patients first underwent comprehensive psychological assessment to establish a diagnosis of gender dysphoria (then called “gender identity disorder”) and then initiated treatment with GnRH agonists (GnRHa) typically at Tanner 2–3 to pause pubertal development [45, 46]. The time spent under pubertal suppression would be used to further explore gender identity prior to committing to either estrogen or testosterone and their physical effects. This intervention with a GnRHa would also be somewhat of a diagnostic aid in that if it eased the distress; it was reasonable to correlate the distress with gender dysphoria as a primary cause. This was followed by hormone therapy around age of 16 years and then gender-affirming genital surgery at 18 years or later [45, 46, 48]. The “Dutch Protocol”  was adapted by practitioners internationally, though it was not until pediatric endocrinologist and adolescent medicine pediatrician Dr. Norman Spack, having traveled to Amsterdam to observe the clinic there, established the first formal US program geared specifically to transgender adolescents at Boston Children’s Hospital: the Gender Management (subsequently replaced with Multispecialty) Service program in 2007 . It should be noted that adolescents there and elsewhere across the USA had been treated outside of a structured program . Clinical protocols at Gender Management Service were derived from direct observation, adaptation of the Dutch program, and a May 2005 consensus meeting (the Gender Identity Research and Education Society) and expanded upon previous guidelines from the Standards of Care of the WPATH and those from the Royal College of Psychiatrists [46, 51, 52].
The Endocrine Society guidelines, with input from the Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, the European Society for Endocrinology, and WPATH, were first published in 2009 and recommended the use of GnRHa as a treatment for selected adolescents . Pubertal suppression could be initiated when the individual reached Tanner 2 or 3, followed by gender-affirming hormones at age of 16 years. Subsequent standards of care and clinical practice guidelines published by WPATH (SOC 8 in 2022) , the University of California San Francisco in 2016 , and the Endocrine Society (updated in 2017)  continued to recommend treatment for adolescents starting with pubertal suppression at Tanner 2 and 3, with consideration of gender-affirming sex hormones in some adolescents younger than 16 years old (on a case-by-case basis) who had demonstrated strong and persistent gender dysphoria. Of note, the WPATH SOC 8 does not list minimum age requirements for gender-affirming medical care .
In 2014, a published resource guide providing contact information showed that there were 32 US and 2 Canadian programs available to treat TGD adolescents . As of March 2022, there were about 60 recognized pediatric/adolescent multidisciplinary gender programs in the USA, though smaller programs and individual offices probably also provide care . Some programs have been closed for political reasons with potentially dire consequences for both patients and practitioners .
Changing Prevalence of Trans Identities and the Rise of Nonbinary Identification
Worldwide, the prevalence of people declaring a gender identity that is different from that assigned at birth has risen sharply as the recognition of gender diversity, and its social acceptance has increased. Early estimates of prevalence for those seeking hormonal treatment are notable for relatively low prevalence and a heavy predominance of birth-assigned males. In 1968, two authors published estimates demonstrating this trend. In the USA, Pauly cited 1:100,000 birth-assigned males and 1:400,000 birth-assigned females . In Sweden, the estimate again favored the birth-assigned males at 1:37,000 and birth-assigned females at 1:103,000 . By the mid-80s, numbers had risen with a similar ratio of birth-assigned males at 1:18,000 and birth-assigned females at 1:54,000 . The same year, authors in Singapore reported much higher numbers of 1:2,900 and 1:8,300 birth-assigned males and females, respectively . The Williams Institute of the University of California Los Angeles School of Law has tracked prevalence of transgender identification in the USA. A report from 2022 (based on data from 2017, 2019, and 2020) revealed that the prevalence of adults in the USA who identified as transgender has remained stable at around 0.5% of the population, or 1.3 million adults. However, the percentage of trans-identified youth (ages 13–17) had notably increased in recent years from 0.7% to 1.4% of the population . Recent reports have also noted a rise in nonbinary gender identification and a reversal in the sex ratio of adolescents presenting for gender-affirming care from a predominance of those designated male at birth to a predominance of individuals designated female at birth. In 2017, a large adolescent multidisciplinary survey noted that 63% of the presenting patients were birth-assigned females .
Legislative and Social Dynamics
Since 2016, many US states and European countries have introduced laws that restrict transgender youth from accessing gender-affirming care, team sports, and restrooms that are consistent with their gender identity . Simultaneously, numerous reputable national and international academic medical societies have openly and repeatedly stated their opposition to these laws. This includes the Pediatric Endocrine Society [66, 67], the Endocrine Society [68, 69], the American Academy of Pediatrics , the American Medical Association , the United States Professional Association for Transgender Health , the American Association for Child and Adolescent Psychiatry , and in a united statement, also the American Psychiatric Association, the American College of Obstetricians and Gynecologists, the American Academy of Family Physicians, and the American Osteopathic Association .These societies have stated that these bills are discriminatory and cause harm to the mental health of transgender youth. Despite this, some bills have passed successfully .
While there is a long-standing history acknowledging the existence of human gender diversity, the history of gender-affirming medical care for adolescents, in particular, is relatively brief. Evolving protocols for gender-diverse adolescents, first pioneered in the Netherlands, have been incorporated into clinical practice guidelines and standards of care published by the Endocrine Society and WPATH, respectively, and have been endorsed by major medical and mental health professional societies around the world. Notably, however, while there has been increased acceptance of gender diversity in some parts of the world, transgender adolescents and those who provide them with gender-affirming medical care, particularly in the USA, have been caught in the crosshairs of a culture war, with the risk of preventing access to care that published studies have indicated may be lifesaving. Despite such challenges and barriers to care, currently available evidence supports the benefits of an interdisciplinary model of gender-affirming medical care for transgender adolescents. Further long-term safety and efficacy studies are needed to optimize such care.
Statement of Ethics
Not applicable as this is a historical report and not a report of research.
Conflict of Interest Statement
Jeremi M. Carswell, Ximena Lopez, and Stephen M. Rosenthal declare no conflicts of interest.
This work has not received any funding or financial support.
Jeremi M. Carswell, Ximena Lopez, and Stephen M. Rosenthal contributed equally to the writing of the manuscript. Jeremi Carswell and Ximena Lopez are the co-first authors, and Stephen M. Rosenthal is the senior and corresponding author.
Data Availability Statement
There were no data generated for this report.