Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline

This Endocrine Society Clinical Practice Guideline systematically reviewed existing evidence to establish best practices for the endocrine treatment of individuals experiencing gender dysphoria or gender incongruence. The primary "intervention" tested across the synthesized studies was gender-affirming hormone therapy (GAHT), which includes:

• For transgender females (assigned male at birth): Estrogen therapy, often combined with anti-androgens, to suppress endogenous testosterone and induce feminizing physical changes.
• For transgender males (assigned female at birth): Testosterone therapy to suppress endogenous estrogen and induce masculinizing physical changes.
• For adolescents (post-pubertal): Gonadotropin-releasing hormone (GnRH) agonists, commonly known as "puberty blockers," to temporarily halt endogenous pubertal development.

The "comparators" were not typically direct placebo controls, as hormone therapy is a desired medical intervention for gender affirmation. Instead, comparisons were often implicit against the natural progression of natal puberty or against different hormone regimens, doses, or routes of administration.

The "outcome measures" investigated across the reviewed literature included:

• Physical changes: Development of secondary sex characteristics aligned with the affirmed gender (e.g., breast development, fat redistribution, skin softening for transwomen; voice deepening, facial/body hair growth, muscle mass increase for transmen).
• Hormone levels: Achieving and maintaining sex hormone levels (e.g., estradiol, testosterone, prolactin, LH, FSH) within the normal physiological range for the affirmed gender, while effectively suppressing endogenous natal hormones.
• Safety and adverse effects: Monitoring for potential risks and complications associated with long-term hormone use, such as cardiovascular disease, venous thromboembolism (VTE), bone mineral density (BMD) changes, liver dysfunction, and specific cancer risks (e.g., breast, prostate, reproductive organ cancers).
• Psychological well-being: Although not directly measured by the guideline itself, the underlying studies often assessed improvements in gender dysphoria, mental health, and overall quality of life following hormone therapy.
• Fertility preservation: The guideline also addressed the importance of discussing and offering options for fertility preservation prior to initiating hormone treatments, which can impact reproductive capacity.
• Diagnostic and treatment criteria: The guideline also established criteria for diagnosing gender dysphoria/incongruence and for initiating and continuing endocrine treatment, emphasizing the role of mental health professionals and multidisciplinary care teams.

In essence, the guideline aimed to provide a comprehensive framework for clinicians to safely and effectively manage the endocrine aspects of gender affirmation, focusing on achieving desired physical changes while minimizing health risks.

This guideline is a systematic review and clinical practice guideline, meaning it synthesizes evidence from numerous studies rather than conducting a new one. Therefore, "who was studied" refers to the populations included in the underlying research that informed these recommendations.

The guideline focuses on gender-dysphoric/gender-incongruent persons across different age groups:

• Adolescents: Specifically, those who have entered puberty (Tanner Stage G2/B2 or beyond). The guideline recommends against hormone treatment for prepubertal children. For adolescents, the initial focus is on puberty suppression, followed by gender-affirming hormones. It notes that while most adolescents have the capacity for informed consent by age 16, there may be compelling reasons to initiate sex hormone treatment prior to this, though published experience before 13.5 to 14 years of age is minimal.
• Adults: Individuals aged 18 years and older seeking gender-affirming hormone therapy.

The guideline does not specify exact sample sizes, health statuses, or settings for the individuals in the underlying studies, as it draws from a broad range of research. However, the recommendations are generally applicable to individuals diagnosed with gender dysphoria or gender incongruence who are seeking medical transition. The guideline also implicitly excludes individuals with conditions that might mimic gender dysphoria (e.g., body dysmorphic disorder) or those for whom hormone treatment would be medically contraindicated without careful evaluation. The recommendations are intended for individuals receiving care from medical and mental health professionals, typically in clinical settings.

As a clinical practice guideline based on a systematic review, the "how they measured it" refers to the methods employed in the original studies that were reviewed, as well as the methodology used by the guideline task force to synthesize this evidence.

In the underlying studies, common measurement instruments and methods included:

• Hormone Levels:
  • Blood tests: Used to measure circulating levels of sex hormones (e.g., estradiol, total testosterone, free testosterone, dihydrotestosterone (DHT)), pituitary hormones (e.g., luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin), and other relevant markers. These are typically measured using standardized laboratory assays (e.g., immunoassays, liquid chromatography-tandem mass spectrometry). The goal is to suppress natal hormones and achieve target levels for the affirmed gender.
• Physical Changes:
  • Clinical examination: Regular physical assessments by endocrinologists or other medical professionals to monitor the development of secondary sex characteristics (e.g., breast budding and growth, fat redistribution, skin texture changes for transwomen; voice deepening, facial/body hair growth, clitoral enlargement, muscle mass changes for transmen). These are often assessed qualitatively or using standardized scales (e.g., Tanner stages for pubertal development, Ferriman-Gallwey score for hirsutism).
  • Anthropometric measurements: Body weight, height, body mass index (BMI), and body composition (e.g., using DEXA scans or bioelectrical impedance analysis) to track changes in muscle and fat distribution.
  • Voice analysis: Objective measures of voice pitch (fundamental frequency) and range for transmen.
• Bone Mineral Density (BMD):
  • Dual-energy X-ray absorptiometry (DEXA) scans: Used to measure bone density, particularly in individuals with risk factors for osteoporosis or those who have undergone gonadectomy and may be at risk for bone loss if hormone levels are not adequately maintained.
• Cardiovascular Risk Factors:
  • Blood tests: Fasting lipid profiles (total cholesterol, LDL, HDL, triglycerides) and glucose screening (fasting glucose, HbA1c) to monitor for changes in cardiovascular and metabolic health.
  • Blood pressure measurements: Routine monitoring of blood pressure.
• Psychological Well-being and Diagnosis:
  • Clinical interviews and psychological assessments: Conducted by trained mental health professionals (MHPs) using diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM) (e.g., DSM-5 for Gender Dysphoria) or the International Statistical Classification of Diseases and Related Health Problems (ICD) to diagnose gender dysphoria/