Fall 2024 - Vol. 19, No. 3 INTRODUCTION
People who are transgender, gender diverse, or gender non-conforming have a gender identity that differs from their sex assigned at their birth. A recent study done by the Pew Research Center shows that 1.6% of American adults identify as transgender or nonbinary, and among young adults 18-29 years of age, it is even more common, at 5.1%.¹

Gender-diverse people have high rates of health disparities, including higher rates of human immunodeficiency virus (HIV), substance use, mental health disorders, and victimization, much of which is attributable to minority stress; as opposed to stress that is experienced by everyone, minority stress has its roots in stigma and prejudice.² Suicide risk is high in gender-diverse populations: between 22% and 43% of transgender people have attempted suicide in their lifetime.³ Importantly, good social support mitigates some of this risk — in one study of trans youth 16-24 years of age, the risk of suicide attempt in individuals with strongly supportive parents was 4% compared to 57% in those with somewhat supportive to not-at-all supportive parents.⁴

In addition, gender-diverse individuals face significant discrimination in medical settings. According to a study performed in 2022 by the Center for American Progress, 16% of transgender respondents reported that their provider used harsh/abusive language and 10% reported providers refusing to see them. There are challenges outside of discrimination, as well — a lack of training in gender-affirming care means that 30% of transgender respondents reported having to teach their provider about their gender so they receive appropriate medical (not even necessarily gender-affirming) care.⁵

Ample evidence shows that gender-affirming hormone therapy (GAHT) improves mental health outcomes for appropriate patients.^6,7

How does a provider assess whether an adult patient is a good candidate for GAHT? 
According to the World Professional Association for Transgender Health (WPATH) Standards of Care, the following are needed to begin gender-affirming hormone therapy in adults 18 years of age and older: 

1. Patients should have marked and sustained gender incongruence — typically defined as being at least six months in duration. 
2. Patients should have the ability to consent to starting hormone therapy and understand the potential impact on reproductive options. 
3. Patients should have appropriate co-management of mental health conditions and physical health conditions that could negatively impact the outcome of treatments.^8-10

In addition, a comprehensive medical, behavioral, social, gender, and sexual history should be obtained (see Table 1). Relevant physical exam steps should be completed; a genital exam is generally not necessary prior to initiating treatment.



In this article, we will review two fictionalized patient cases to introduce providers to prescribing gender-affirming hormone therapy for adults. Both patients meet WPATH criteria for initiating GAHT. Prescription of GAHT for adolescents is beyond the scope of this article. These cases in no way encompass the wide variety of experiences and identities lived by gender-diverse persons but seek to teach some basic principles. Every patient may have different goals. It is worth noting that for some persons who may not want a drastic change in their physical appearance, hormone therapy should be started at a low dose and titrated slowly. 

CASE 1: AH
AH is a 28-year-old patient who presents as a new patient to a primary care office to discuss gender-affirming hormone therapy. AH identifies as a transgender (or “trans”) woman and uses she/her pronouns. She had a male sex assigned at birth.

AH has known since early childhood that something was different about how she felt in her body. As a young child, she had more traditionally “feminine” interests and got along better with other young girls. She would frequently ask her parents if she could become a girl, but stopped when it was clear this was upsetting her parents.

During puberty, she experienced extreme distress at her pubertal changes. She started to experience severe depression in her adolescent years, culminating in a suicide attempt and psychiatric hospitalization at age 16 years.

She first identified as trans at age 18 years, after learning about the trans community and realizing that the concept of being transgender finally explained how she had been feeling. She started identifying as a woman at that time to supportive friends but was not “out” to her family due to concerns about her safety while living at home. In her mid-20s, with the help of a supportive gender-affirming therapist, she started living independently and had improvement in her depression. She started identifying as a woman to those around her, growing out her scalp hair, doing laser removal of her facial and body hair, and experimenting with more “feminine” clothes.

She has developed a strong support system with friends, a long-term partner, and a few supportive family members. She presents at this time to discuss gender-affirming hormone therapy. She strongly desires the development of breasts, a more “feminine” body shape, a more “feminine” voice, and the reduction of facial and body hair. She does not want biological children.

What medications would you use for gender-affirming hormone therapy for AH? 
The most common medications used would be estradiol and an antiandrogen. A common starting dosage would be estradiol oral 2 mg daily and spironolactone oral 50 mg daily.^9,10

The goals of these medications are to further develop “feminine” secondary sex characteristics and suppress or minimize “masculine” secondary sex characteristics.^9,10 The expected effects and timeline of secondary sex characteristic development are listed in Tables 2 and 3.



Patients should be informed that it may take months to start seeing the effects of GAHT and that maximal effect can take three to five years. Providers should review the expected effects of the medication, timeline to effect, and potential adverse effects with patients before initiating therapy. Of note: most of the potential side effects from estrogen and antiandrogen therapies are similar to the potential health risks seen in cisgender women — that is, a woman whose gender matches their sex assigned at birth.

Providers should ensure special attention is paid to discussing fertility effects — gender-affirming hormone therapy may cause potentially permanent infertility. Anyone desiring future fertility should be referred to a fertility specialist prior to starting GAHT.

Oral estradiol is the most commonly used formulation of estradiol due to cost and ease of use (see Table 4).



The preferred estrogen formulation is 17-beta estradiol rather than ethinyl estradiol (commonly used in oral contraceptives) or conjugated estrogens (often used to treat menopausal symptoms); the latter two would impose a higher thrombotic risk. Providers should consider use of transdermal estradiol for patients who have risk factors for atherosclerotic cardiovascular disease or venous thromboembolism as it confers a lower thrombotic risk than oral or injectable formulations.

Spironolactone is the most commonly used antiandrogen as it has a stronger antiandrogenic effect than the 5-alpha reductase inhibitors. 5-alpha reductase inhibitors may be more effective for patients with significant alopecia or patients who cannot tolerate spironolactone. The 5-alpha reductase inhibitors block the conversion of testosterone to its more potent form, dihydrotestosterone (DHT).

GAHT is not an effective contraceptive on its own. Patients who are sexually active with someone who can get pregnant should ensure contraception is used.

What lab testing should be done prior to starting GAHT? 
A comprehensive metabolic panel should be completed prior to starting spironolactone.

What lab testing should be done to monitor efficacy of GAHT in this patient? 
Typically, total testosterone, estradiol, and a basic metabolic panel should be checked every three months while titrating therapy and then yearly thereafter. A pregnancy test is not necessary.

Goal estradiol levels for patients seeking full feminizing effect are typically in the natal female range of 100-200 pg/ml. Goal testosterone levels are typically less than 55 ng/dl. If patients are on injectable therapy, levels should be checked mid-cycle.^9,10

CASE 2: PW 
PW is a 22-year-old patient seeking gender-affirming hormone therapy. He identifies as transmasculine and uses he/they pronouns. He had a female sex assigned at birth.

PW states that they never felt “right” in their body ever since early childhood. He was always quite sporty, called a “tomboy,” but never felt like that label fit correctly. His parents remember that he was extremely distressed when he had to wear dresses growing up and when people described him and his sisters as “the girls of the family.” Starting in early adolescence, he was able to identify that he did not feel like a girl inside.

He started puberty at an early age and started menstruating at age 11. He felt severe dysphoria related to breast growth and menstruation. He had significant depression in early adolescence and was later diagnosed with bipolar 2 disorder at age 16. He was started on lamotrigine, and his mood has been stable on this medication since then.

He has a generally supportive family and came out as gender fluid at age 14 to friends and family, meaning he had a gender identity that was not fixed. As he then explored his gender identity further, he came out as transmasculine around age 18, meaning he identified as masculine, although not necessarily male. He tends to dress in more androgynous clothes and binds his breasts daily.

He has been doing voice training online to try to develop a more “masculine” voice. He is interested in gender-affirming hormone therapy, with the goal of developing a more “masculine” body shape, stopping menstruation/monthly bleeding, and developing body/facial hair growth. He thinks he is interested in top surgery in the future. He does not think he wants biological children but would like to talk to a fertility specialist to discuss options before deciding, and he is referred to a fertility specialist before initiation of GAHT.

What medication would you start for gender-affirming hormone therapy for this patient? 
The most commonly used medication in this setting is testosterone, which is most often administered via injection. A typical starting dose may be testosterone cypionate 50 mg subcutaneous once weekly.^9,10

The goal of androgenizing therapies is to develop more “masculine” secondary sex characteristics and to suppress or minimize “feminine” secondary sex characteristics. The expected effects and timeline of development on secondary sex characteristics are listed in Tables 5 and 6.



Patients should be informed that it may take months to start seeing the effects of GAHT and that maximal effect can take three to five years to develop. Providers should review the expected effects of the medication, timeline to effect, and potential adverse effects with patients before initiating therapy. Of note: most of the potential side effects from testosterone are similar to potential health risks seen in cisgender men. Providers should discuss the potentially permanent fertility effects of these medications.

Several formulations are available and effective (see Table 7).



The most commonly used formulation for testosterone administration is injectable testosterone, which has a low cost and increases testosterone quickly and efficiently. Transdermal testosterone is also commonly used and may produce a steadier state of hormone levels but a slightly more gradual physical change.

Androgenizing therapy is not reliable contraception for individuals capable of pregnancy; therefore, pregnancy testing should always be a consideration as needed, and counseling regarding pregnancy and contraception is essential. No forms of birth control are absolutely contraindicated; however, combined estrogen-progesterone forms of birth control might interfere with androgenizing therapy.

What testing should be done at baseline for PW? 
Baseline testing should include hematocrit and pregnancy testing if pregnancy is possible. 

What follow-up testing should be done for this patient? 
Typically, total testosterone and hematocrit should be assessed every three months while titrating therapy and then yearly. Pregnancy status should be checked as indicated. Goal total testosterone levels for patients seeking full masculinizing effect are typically in the upper end of the normal cisgender male range, 650-1,000 ng/dl. If patients are on injectable therapy, the level should be checked mid-cycle.^9,10

At follow-up visits for patients on GAHT, providers should assess adherence, barriers to getting medications, and side effects. Providers should discuss physical changes and satisfaction to goals, as well as mental health, sexual health, relationships and intimate partner violence, and pregnancy prevention. Providers should also inquire about the patient’s social transition and plans for medical or non-medical gender-affirming treatments.

CONCLUSION 
Gender-diverse people experience high levels of discrimination and health disparities, and special attention should be paid to ensuring that clinical environments are affirming for these populations. GAHT can help achieve significant improvement in mental health for gender-diverse patients and is within the purview of primary care providers.
  1. Brown A. About 5% of young adults in the U.S. say their gender is different from their sex assigned at birth. Pew Research Center. June 7, 2022. Accessed August 5, 2024. https://www.pewresearch.org/short.reads/2022/06/07/about-5-of-young-adults-in-the-u-s-say-their-gender-is-different-from-their-sex-assigned-at-birth/
2. Frost DM, Meyer IH. Minority stress theory: application, critique, and continued relevance. Curr Opin Psychol. 2023;51:101579. 
3. Bauer GR, Scheim AI, Pyne J, Travers R, Hammond R. Intervenable factors associated with suicide risk in transgender persons: a respondent driven sampling study in Ontario, Canada. BMC Public Health. 2015;15:525. 
4. Travers R, Bauer G, Pyne J, et al. Impacts of strong parental support for trans youth: a report prepared for Children’s Aid Society of Toronto and Delisle Youth Services. Trans PULSE Project. October 2, 2012. Accessed August 5, 2024. https://transpulseproject.ca/wp-content/uploads/2012/10/Impacts-of-Strong-Parental-Support-for-Trans-Youth-vFINAL.pdf
5. Medina C, Mahowald L. Discrimination and barriers to well-being: the state of the LGBTQI+ community in 2022. The Center for American Progress. January 12, 2023. Accessed August 5, 2024. https://www.americanprogress.org/article/discrimination-and-barriers-to-well-being-the-state-of-the-lgbtqi-community-in-2022/
6. D’hoore L, T’Sjoen G. Gender-affirming hormone therapy: an updated literature review with an eye on the future. J Intern Med. 2022;291(5):574-592. 
7. Tordoff DM, Wanta JW, Collin A, Stepney C, Inwards-Breland DJ, Ahrens K. Mental health outcomes in transgender and nonbinary youths receiving gender-affirming care [published correction appears in JAMA Netw Open. 2022 Jul 1;5(7):e2229031]. JAMA Netw Open. 2022;5(2):e220978. 
8. Coleman E, Radix A, Bouman W, et al. Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgend Health. 2022;23(Suppl 1):S1-S259. 
9. Thompson J, Hopwood RA, deNormand S, Cavanaugh R. Medical Care of Trans and Gender Diverse Adults. Fenway Health; 2021. Accessed August 5, 2024. https://fenwayhealth.org/wp-content/uploads/Medical-Care-of-Trans-and-Gender-Diverse-Adults-Spring-2021-1.pdf 
10. UCSF Gender Affirming Health Program. Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People. 2nd ed. Deutsch MB, ed. University of California San Francisco; 2016.