Estándares de Base de Datos

Introduction

In 1979 the World Professional Association for Transgender Health (WPATH)

established a standard of care for treatment of gender dysphoria. This standard of care focused on irreversible cross sex hormonal therapy and irreversible gender reassignment surgery. These treatments promote cross gender physical features but cannot undo the secondary characteristics that develop during puberty.9 _{In 2009 the Endocrine Society published guidelines that}

recommended treating adolescents with Gender Identity Dysphoria (GID) with reversible gonadotropin releasing hormones analogs (GnRHa). This lead to the release of the 7th _edition

updated guidelines from WPATH, which echoed the Endocrine Society’s recommendations and included GnRHa in the standard of care for adolescents with gender dysphoria.4

Both of these guidelines outline the criteria that must be met in order to begin hormonal therapy. Suppression of puberty with GnRHa can be started after the first signs of puberty, but no earlier than Tanner Stage 2.9 _{Tanner Staging is a classification systems based on the}

development of secondary sex characteristics of children during puberty. Tanner Stage 1 represents a pre-pubertal child with progression to Tanner Stage 5, a complete adult form.18

Suppression with GnRHa is a reversible therapy, allowing the patient more time to explore their identity without worrying about developing secondary sexual characteristics that do not match their identity. When patients turn 16 years old they can begin what have come to be called “gender affirming hormones”. For MTF these hormones include estrogen and spironolactone. For FTM these hormones include testosterone, and DHEA/DHEA-S/androstenedione.

62

Adolescents who present with gender dysphoria later in puberty (Tanner Stage 4 and 5) are started on gender affirming hormones and the dose is increased at a faster rate.9

WPATH and the Endocrine Society guidelines both emphasize close collaboration with mental health providers. Pediatric patients with gender dysphoria commonly experience

symptoms of depression, anxiety, social isolation, behavioral problems, substance abuse, school struggles, and suicidal ideation. Patients who are experiencing distress about their gender identity can be referred to a mental health (MH) professional who has training in providing care for transgender patients. MH professionals play a key role in providing gender affirmative counseling or therapy.10

Transgender youth are at a higher risk for poor health outcomes. They are more likely to participate in high risk health behaviors, and are at an increased risk for behavioral health issues. Family and societal disapproval, violence in school, and social stigma create stressors for

transgender youth that may increase the risk of experiencing mental illness, substance abuse, and sexual risk taking behavior.1 _{Transgender youth face significant rates of depression, suicidality,}

anxiety, body image distortion, substance abuse, and post-traumatic stress disorder.1

Current guidelines for providing care to children with gender dysphoria are based on expert opinion. These guidelines suggest that intervention leads to reductions of these poor health outcomes, improvement or elimination of mental health illness, and reductions in the amount of distress associated with gender dysphoria. However, there is insufficient quantities of evidence that show that hormonal therapy with or without psychological support results in the improvements described above.

63

Objectives

To perform a systematic review of literature on the effectiveness of hormonal therapy and psychological support, for transgender adolescents, towards the reduction of distress associated with gender dysphoria and the improvement of quality of life, overall well-being, psychological functioning, and social functioning.

Methods Inclusion and Exclusion Criteria

A set of eligibility criteria was developed to assess each study based on the PICTOSS outline, as seen in Table 8. Eligible studies focused on interventions in adolescents that are in the age window that meets the guidelines for starting hormonal therapy. WPATH and Endocrine Society guidelines state that the youngest age to start GnRHa is 12 years old. I wanted to focus on interventions that can be started during adolescence based on known guidelines and therefore I excluded surgical interventions. Since the standards of care for the management of transgender adolescents are a relatively new topic, I assumed that research would be relatively recent, but I wanted to capture all relevant literature in any case. For these reasons, I did not make publication date an eligibility criterion.

Table 8 about here Search Strategy

I conducted a systematic review of the PubMed and Cochrane databases for studies that were published in English. I did not search ClinicalTrails.gov because it would considered unethical to prevent adolescents from using hormonal therapy resulting in the development of irreversible secondary sexual characteristics. In addition, it would be unethical to assign adolescents to hormonal therapy. My last search in both databases was run on March 07, 2018. Within Cochrane my search terms included the following: transgender, children, hormones, and

64

psychological. Key search terms I used in the PubMed search included the following:

transgender, transsexualism, gender dysphoria, gender identity, gonadotropin-releasing hormone, depression, anxiety, quality of life, suicide, mental health, treatment outcome. A complete list of search terms for PubMed can be found in Table 9. Transgender recently became a term in 2012, therefore transsexualism, the term most often used before 2012, has to be included as well. Age limits includes the terms youth, children, or adolescent. When initial results were produced in PubMed they were filtered for age be selecting the “birth to 18 years old” filter.

Table 9 about here Study Selection

Citations of all records of potential relevance were uploaded into Covidence for study

assessment. Covidence is a component of Cochrane’s review production toolkit that is used to improve the production and use of systematic reviews. Covidence allows you to import citations, screen titles and abstract, upload references, screen full text, create extraction forms, populate risk of bias, and data extraction.19 _{I, the only investigator in this study, performed the eligibility}

assessment was independently in an unblended standardized manner. Each record was initially screened by reviewing the title and abstract of the study for relevance to the subject matter and for eligibility criteria.

Data Extraction

I developed a data extraction sheet with predefined data fields. This included the study

characteristics, participants’ characteristics, description of intervention, outcomes measured, and key discussion points. I extracted all data from the included studies. No variables were added after the review and extraction of data started.

65

Risk of bias

To ascertain the validity of the eligible studies, I assessed the risk of bias at the study level, in the following categories: selection bias, measurement bias, and potential for confounding. These biases were assessed on a scale of low, medium, and high. The impression of the overall risk of bias (internal validity) and the external validity were assessed on a scale of good, fair, and poor. My methods for gauging the risk of selection bias included looking at the method of recruiting, and the sample population. Methods that were used to gauge the risk of measurement bias included assessing if the study’s measures were equal, valid, and reliable. I gauged the risk of overall bias on the quality of the sampling, treatment of confounding factors, and taking into consideration the score that was given for the other types of biases previously described. One reviewer assesses risk of bias and confounding.

Results Study Selection

The combined search of PubMed and Cochrane produced 105 records of potential relevance (Refer to Figure 3). None of these records came from Cochrane. After the initial screening, 66 records were discarded because the studies did not meet the previously established eligibility criteria. The remaining 39 studies were then screened by assessing their full text for eligibility based on the criteria in Table 8. Articles were excluded as a result of ineligible study design (6), ineligible intervention (5), ineligible population (6), non-English studies (1), full text was not available (7), ineligible outcomes (8), a study was ongoing (1), only the title was present (1), duplication (1), and wrong indication (1). After the screening process was complete 2 studies were included in the qualitative and quantitative synthesis.

66

Study characteristics

A full descriptionof the data extracted from each study to be included in the qualitative analysis is summarized below in Table 10. The two studies were similar in their objectives/aims and research design. Interventions for each study included puberty suppression hormones and psychological support. Both studies have a similar length of follow up. Costa et al. conducted their research over the course of 18 months.12 _{De Vries et al. had an average time from start of}

GnRHa and CSH of 1.88 years.13 _{Lastly, these studies were similar in the results that were found.}

Both studies showed improvement in Children’s Global Assessment Scale (CGAS) after the intervention of puberty suppression and psychosocial functioning. De Vries et al also showed improvement in most of the other psychological functioning outcomes that they measured.13

These studies differed in the outcomes that were measured. Costa et al. outcomes

measurements included the Utrecht Gender Dysphoria Scale and CGAS.12 _{However, UGDS was}

only measured at baseline with no results described after the start of the intervention. The other study measured the same outcomes in addition to the following measurements:Child Behavior Checklist, Youth Self Report, Beck Depression Inventory, and the Trait Anger and Anxiety Scales of the State-Trait Personality Inventory.13

Difference arouse when observing the baseline characteristics of the population enrolled in each studies. The age at baseline (15.5 vs 13.6), the age starting GnRHa (16.48 vs 14.75), if the participants lived with both parents (41.5 vs. 62.9), and the timing of the study (2010-2014 vs 2000-2008) differed between the Costa et al. and de Vries et al studies respectively. Only one study reported on the participant’s level of social transition at baseline 12-13_.

The comparison between studies show that some clinical heterogeneity exist. I therefore hypothesized that this heterogeneity may results in some statistical heterogeneity.I hypothesized

67

that the magnitude of effect would not differ according to the methodological quality of the studies since both studies had the same study design and measurement techniques.

Table 10 about here Risk of bias

Overall I determined the overall risk of bias (internal validity) to be low for both studies. Common issues that arose when assessing the overall risk of bias was the increased potential for confounding. The observed baseline characteristics left out characteristics that could potentially affect participants’ global functioning throughout the study. De Vries et al. did not include gathering information on the level of social transition for the baseline characteristics. This includes, but is not limited to, wearing clothing, having hairstyles, and using a name that is congruent with their gender identity. The study mentions that participants were not consistently in their cross-gender role, but I felt they could have categorized this based on the level of transition of the participants. Neither study mentioned if participants had received prior

psychological support before beginning the study nor the length of time they had psychological support.

Another common issue was the external validity of the studies. In both studies participants were selected from one gender clinic that received referral from primary care physicians. Patients who present to a clinic may be substantially different from patients in the general transgender population, affecting the external validity of the study. Given the type of study design, maturation also contributed to the risk of bias. It is unknown if naturally occurring changes over time can be the underlying reasons for the results of the study or if it was actually due to the intervention. Reference Table 11 for a detailed description of the score assigned to each type of bias.

68

Table 11 about here Results of individual studies

Table 12 about here

The results of the studies are summarized in Table 12. The two studies measured the mean and standard deviation for each psychological and gender dysphoria outcome at different time points. De Vries et al. measured outcomes at baseline and then again shortly before patients started gender affirming hormones.13 _{Costa et al. measured outcomes at baseline, 6 months, 12}

months, and 18 months.12 _{T-test were performed comparing the various time points in each}

study. I calculated the mean differences to compare each time point by subtracting the mean for the higher time point from the second time point.

Both studies found significant improvement in the global functioning of transgender adolescent after starting GnRHa. Furthermore, both found no change in the amount of distress associated with gender dysphoria after starting GnRHa. Costa et al. showed that global

functioning increased with psychological support alone. The magnitude of improvement of global functioning was even greater when starting adolescents on GnRHa. This improvement continued to steadily increase at each evaluation throughout the 18 months of the study. When comparing the immediately eligible adolescents and delayed eligible (who only receive

psychological support), the immediately eligible adolescents had a significantly higher

psychosocial functioning after 12 months of GnRHa. After 12 months, the level of psychosocial functioning was comparable to a sample of adolescents without observed

psychological/psychiatric symptoms.12

In addition to improvement of global psychological functioning, the De Vries et al. study showed a reduction in behavioral problems, emotional problems, and depressive symptoms in

69

adolescents on puberty suppression hormones. The study found no significant change in Trait Anger nor the Trait Anxiety Scales of the Personality Inventory.13

Discussion Summary of Findings

The primary finding from this review is that puberty suppression hormones (GnRHa) and psychological support play key roles in the management of transgender adolescents. As

individual treatments, these treatments help to improve the psychological functioning of

transgender adolescent patients. When used in combination the beneficial effect is even larger. These findings will be relevant to the health care providers who are still skeptical about providing these treatment to their patients with gender dysphoria. With these studies, another element of education can be incorporated when discussing treatment options with transgender adolescents and their families. GnRHa not only improves psychological functioning but it gives adolescents the opportunity to reflect on their gender identity, gain real-life experience living as the other gender (social transition), and determine whether they desire the transition. These are all important opportunities from which transgender adolescents may be able to benefit without the distress of developing secondary sexual characteristics incongruent with their internal gender identity.

Limitations

Limitations of these studies include the study design, small sample size, and lack of long term follow up. In addition these studies only assessed psychological functioning outcomes and distress associated with gender dysphoria with participants taking GnRHa, and did not include patients taking cross sex hormones, which provide transgender adolescents with gender

70

match their self-perception, this intervention may result in further improvement of psychological functioning and improvement of gender dysphoria, the latter of which these studies were unable to show.

This provides implications for future research where study participants are followed from baseline through the completion of cross sex hormones. Outcomes can be measured before the transition from GnRHa to gender affirming hormones and then measured again at another time point after secondary sexual characteristics have developed. The WPATH estimates that most physical change occur over the course of two year.9 _{This potential future research can}

demonstrate if various psychological outcomes continue to improve after the use of gender affirming hormones and if the distress associated with gender dysphoria changes as a result of these hormones.

Another limitation of these studies is the external validity. As previously described participants were selected from one gender clinic that received referrals from primary care providers. Participants who present to clinic may be substantially different from the general transgender population. One key difference is that a population that goes to a transgender clinic has “come out” in some form. Furthermore, participants who were enrolled in the studies had strong family and social support which may not be as common within the general transgender population. This may have resulted in a higher psychological functioning at baseline because of this support. Lastly, throughout both studies participants received extensive psychological support, this frequency of support may not be possible in a real world setting. For all of these reasons, these studies are not applicable to all transgender adolescents. However, these studies are very applicable to transgender adolescents once they present to a transgender clinic.

71

Limitations at the review level include reporting bias, and incomplete retrieval of identified research. A key limitation is not having a second investigator, which could have reduced the possibility of rejecting a relevant report.

Conclusion

Despite the limitations of this review, the findings show that is evidence that supports the use of reversible puberty suppression hormones and psychological support in the management of care of transgender adolescent.

Funding