Puberty Blocking Therapies (PBT)

By Stephen Kramer, MD, Attending, Department of Psychiatry

There continues to be controversy regarding transgender children and adolescents, with vestiges of the earlier debates surrounding the cultural acceptance, medical management and classification of gender identity conditions in adults.

The scientific dissention has spilled over to the public domain, sometimes creating a toxic atmosphere of political and cultural divisiveness. For example, last year in Arkansas it was deemed unlawful for doctors to provide transgender medical care to children and adolescents. Similarly, culture wars are periodically ignited regarding trans childrens’ use of restrooms and participation in sports. Bioethicists continue to debate the boundaries of medical therapies/standard of care for trans adolescents. Puberty blocking treatments (PBT) have long been proposed as a viable option since they are considered “reversible.” After receiving PBT, sex hormones and genital surgeries are also discussed and have been utilized in some countries.

There are several key components of the argument against puberty blocking drugs as a reasonable “middle ground” in adolescent gender transition, a “safe” interim measure to give children time to explore their internalized gender. First, these drugs are experimental in the treatment of transgender incongruence, still unapproved by regulatory agencies for that purpose, a condition that is in many ways still poorly understood. Second, the processes of puberty and adolescence have been increasingly uncoupled and the delay of puberty artificially in the treatment of gender incongruence is likely leading to an asynchrony in overall development, the full impact of which is still unknown. Third, the complex multi-layered psychosocial and psychiatric aspects and complications of gender identity development and “diagnosing” gender incongruence have largely been shelved in the political/culture wars.

Background of Puberty Blocking Drugs

Puberty suppression is affected using gonadotropin releasing hormone analogs (agonists). These drugs paradoxically through repeated stimulation of the pituitary cause a desensitization to gonadotropins. The drugs were developed initially to treat precocious puberty in the 1970s and 1980s. They have also been used in other medical conditions such as “ Puberty suppression is affected using gonadotropin releasing hormone analogs (agonists). These drugs paradoxically through repeated stimulation of the pituitary cause a desensitization to gonadotropins.” prostate cancer. They mostly include long-acting preparations of the drug leuprorelin, which over time decreases the release of testosterone and estrogen.

The paradigm for adolescent transition, developed mainly by a small group of Dutch researchers operating out of a clinic in Amsterdam beginning in the 1980s, was to use puberty suppressing drugs beginning in early puberty, usually around age 12, through the age of 16 (usually after a period of living behaviorally and socially as the congruent gender). This followed using cross hormone therapy to initiate puberty at around that time. Genital and other surgeries could follow at around age 18 (sometimes before).

Over the past 10 years, the use of puberty suppression in gender transitioning adolescents has been endorsed by such organizations as the World Professional Association for Transgender Health (WPATH), the Endocrine Society/ American Association of Clinical Endocrinologists and other international endocrinology groups.

The five criteria for undergoing medical puberty suppression developed by the WPATH are:

Evidence of gender dysphoria from early childhood onwards;
An increase in the intensity of gender dysphoria after the first pubertal changes
No signs of psychiatric comorbidity;
Provision of adequate psychological and social support during the treatment;
Demonstration of knowledge and understanding of the effects of puberty suppression by the patient.

An Unapproved Treatment for a Vaguely Defined Condition

Despite the qualified endorsement of puberty suppression as a viable treatment for gender dysphoria by several mainstream medical groups, including the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics, several ethicists and researchers have pointed out that the treatment remains experimental, off-label and additional study is indicated, particularly randomized controlled trials. A few of the documented side effects of puberty suppression that have been noted in some studies include decreases in bone mineral density, impairments in cognitive functioning such as spatial ability, and damage to reproductive functioning. Hruz et al., in 2017 noted that while the “Dutch group” found that there were no side effects in their cohort of subjects who underwent puberty suppression and then cross hormone therapy, it remains unclear whether transgender adolescents who would undergo puberty suppression and then choose not to proceed to cross hormone therapy and remain as their natal gender, would go on to have normal development without complications.

Hruz’s group’s comprehensive review of the issue of PBT in The New Atlantic further posits that puberty suppression is a minimally studied treatment for a condition that is still poorly understood in terms of causation. Di Ceglie (2000) summarizes some of the potential etiologies of gender dysphoria. Hormonal factors in the fetal period have been investigated, and genetics have also been studied with no clear findings at present. Differences in the size of certain brain regions, such as the third interstitial nucleus of the anterior hypothalamus, have been demonstrated but mainly in the homosexual male population (not transgender correlates).

De Ceglie cites Robert Stoller’s work which suggested certain psychodynamic factors – such as overly close relationships between boys and their mothers and distant relationships with their fathers – may be connected to the development of transgender identity; for girls, he posits a background of a depressed mother and absent father. Di Ceglie also cites the work of other clinically based researchers that highlight early maternal influences, inability to mourn attachment figures in early childhood, and one parent’s wish for a child of the opposite gender. Of course, the main concern regarding the ongoing uncertainty regarding the cause of gender incongruence is to adopt as the standard of care a still unproven medical therapy that may have deleterious effects later in life.

A secondary controversy regarding puberty suppression in transgender adolescents has been the issue of informed consent. As part of the Dutch protocol, consent and thorough knowledge of the subject is required for the therapy to proceed. Bioethicists have vigorously debated the issue of informed consent in transgender adolescents, with one contingent asserting that 12-year-olds should be able to override their parents and that if parents do not agree with the puberty suppression protocol, this is a form of neglect or emotional abuse necessitating child protective services involvement. Priest (2019) expands the notion of “psychological harm” and states “transgender adolescents have a fundamental right to PBT even if their parents disapprove.” The line between parental concern around a still unproven medical treatment, and lack of support for their child’s transition, is effectively blurred. To expect 12-year-olds to be able to adequately understand, process, reason and appreciate the implications of using a still unapproved experimental treatment, is concerning.

Puberty and Adolescence: Two Distinct but Overlapping Processes

Sisk et al., (2005) review the research on the interaction between steroid hormones and the adolescent brain (human and mammalian subjects). A clear distinction is made between puberty and adolescence; puberty is a gonadal hormone event, while adolescence is a more protracted period of overall development lasting a decade. Some of the brain changes in adolescence appear to be dependent on the steroid hormones, others are not and occur independently. For example, three areas of the brain: the anteroventral periventricular nucleus, the locus coeruleus and the visual cortex, undergo profound cellular changes during adolescence, some of which are gonadal hormone driven, and some which are not. Synaptic remodeling in various areas of the brain has also been shown to be differentially impacted by the steroid hormones. Some of the additional research cited includes evidence that there may be a “window of opportunity” of adolescent brain development/ sensitivity to the steroid hormones, which once closed, cannot be reversed. Some cognitive abilities such as spatial ability and psychosocial development are a few of the domains that may be affected. These are some of the concerns in artificially delaying the gonadal hormone event of puberty.

In considering gender identity development, it may be helpful to place it in the larger context of overall adolescent development. In addition to the physical changes associated with puberty, there are social and emotional developmental changes in separation from parental figures, personal identity, the importance of peer group relationships, and the beginning of the exploration of romantic attachments. Cognitively, there are changes in capacity for abstract thinking, improved impulse control, mastery of risk/reward situations, improvements in working memory, language and regulation of emotional states. Moral developmental tasks of adolescence include a move from “preconventional” to “conventional” stage of conception of the individual’s relationship to society (Kohlberg’s theory of moral development), increasing capacity for empathy, shift from rule-based thinking to role-based thinking, and the questioning of parental and societal values (Hazen et al, 2008).

If puberty is delayed as it is with the puberty blocking hormones, ostensibly to provide the transgender individual more time to “live in” a less genderdifferentiated body, there will be some asynchrony between sexual body characteristics and some or all the above developmental processes. Notably there will be delay and some discordance between sexual maturity anatomically and the capacity for sexual and romantic attachment. Suleiman et al., (2016) summarize the limited research in adolescent brain development in relation to the readiness for attachment and relationships.

Puberty sets in motion an extremely complex interplay of brain and endocrine processes. These result in complicated feedback loops that facilitate development not just of mating behavior, but the capacity for romantic attachment that have lifelong implications. The individual’s sense of themselves as a sexual being is developed and solidified. The authors state that research findings “highlight the difficulty in disentangling the biologically-mediated effects of gonadal hormones from the socially-mediated effects of bodily changes.” These concerns regarding the capacity for healthy relationships are compounded by recent research substantiating the enormous challenges, for many reasons, that transgender adults have in maintaining stable romantic attachment (Marshall, et al., 2020).

In addition to the limited understanding of the relationship of puberty to other developmental stages of adolescence, there is a paucity of data regarding the impact of artificial alterations to the occurrence of puberty (delaying puberty due to precocious puberty which is how the use of the puberty blockers began), and any potential correlation with psychopathology. Sisk et al., (2005) review the connection between eating disorders, depression and early puberty. Females with early puberty have a higher incidence of bulimia and other eating disordered behavior. There is also an association between depression and precocious puberty, also seen mainly in females.

Conclusion

In summary, puberty blocking drugs have been advanced as the “standard of care”/ “middle ground” for adolescents with gender dysphoria/incongruence, since the late 1990s. This movement was primarily based on the work of a small group of researchers in the Netherlands working with transgender adolescents in a specialty clinic, one of the first of its kind. This group and their work eventually developed a devoted following in the transgender community, in social activist and medical circles. The increased acceptance of gender identity conditions in general, several prominent celebrities “coming out” as transgender, along with the progressive advance in LGBTQ rights over the past 20 years, hastened the politicization of the scientific body of knowledge of transgender conditions. It seems important, particularly for health care providers who may deal directly with trans youth and adults, to stay grounded in the reality that puberty blocking treatment is not a “middle ground” in the care of transgender adolescents as sometimes proposed, but a yet unproven experimental treatment that requires further study.