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Transgender Hormonal Treatment
Introduction
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Gender identity is biological.
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Transgender individuals have gender identities that differ from the sex recorded at birth.
Gender identity is a person’s intrinsic sense of being male, female, neither, or a combination of both. , Transgender is an umbrella term that refers to individuals whose gender identities differ from the sex recorded at birth, usually based on external genitalia, whereas cisgender describes individuals whose gender identities align with their recorded sex at birth. , Trans and gender incongruent are terms similar in definition to transgender. Along with gender nonbinary, gender diverse, and genderqueer, these terms are adjectives for people with a gender identity that is not aligned with visible anatomy at birth. Terminology that was used regularly in the past may develop pejorative connotations over time. For example, the term transsexual is an older, nonpreferred, term for transgender individuals who have changed their bodies in order to align with their gender identities, usually through hormonal therapy and/or gender affirming surgeries. , Studies estimate that 0.6% of adults or approximately 1.4 million individuals identify as transgender in the United States ( Table 31.1 ).
Table 31.1a
Monitoring for Transgender Men (FTM) on Hormone Therapy
Adapted from Gardner I, Safer J. Progress on the road to better medical care for transgender patients. Curr Opin Endocrinol Diabetes Obes . 2013;20(6):55308.
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Table 31.1b
Hormone Regimes for Transgender Men
Adapted from Gardner I, Safer J. Progress on the road to better medical care for transgender patients. Curr Opin Endocrinol Diabetes Obes . 2013;20(6):55308.
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i.m., intramuscular.
Table 31.1c
Adverse Effects: Androgen Supplementation
Adapted from World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People . 7th ed. 2011.
| Likely Increased Risk: |
|---|
| Polycythemia |
| Weight gain |
| Acne |
| Androgenic alopecia (balding) |
| Sleep apnea |
| Possible Increased Risk: |
| Hyperlipidemia |
| Possible Increased Risk with Presence of Additional Risk Factors: |
| Destabilization of psychiatric disorders with manic or psychotic symptoms (bipolar, schizoaffective disorder) |
| Cardiovascular disease |
| Hypertension |
| Type 2 diabetes mellitus |
| No Increased Risk or Inconclusive: |
| Loss of bone density |
| Breast cancer |
| Cervical Cancer |
| Ovarian Cancer |
| Uterine Cancer |
Historically, transgender health determination and management was considered to fall within the behavioral health sphere. The DSM V defines gender dysphoria as a transgender identity that is “associated with clinically significant distress or impairment in social, occupational, or other important areas of functioning.” However, it is important to note that not every transgender or gender nonbinary (TGNB) individual experiences gender dysphoria. In other words, with the changing culture and the progress in medicine, only some TGNB individuals experience significant gender dysphoria at some point in their lifetimes. Thus, the International Classification of Diseases , 11th edition (ICD-11) will remove the term “gender dysphoria” and add the term “gender incongruence” to a new sexual health section to match our current understanding that an individual’s TGNB gender identity is not inherently a mental health concern.
Strong evidence from twin studies, studies of differences in sexual differentiation (DSDs), and studies of sexual dimorphism in neurologic structures now point to gender identity as a biological phenomenon. Both individuals in a pair of identical twins are more likely to be transgender than in fraternal twins. In one study of 14 genetically XY children with cloacal exstrophy who were assigned female at birth, investigators found that all eight of the children who were aware of their XY chromosome pattern identified as male including four who reported male gender identity even prior to learning about their chromosomal status. Two additional children assigned as male continued to identify as male. In a larger study of 46 XY children with penile agenesis, cloacal exstrophy, and penile ablation, investigators found that 15 of the 72 children assigned female at birth identified as male, and an additional 10 of the 72 children who continued to identify as female reported significant gender dysphoria. All of the children assigned male at birth continued to identify as male, except that one male child reported gender dysphoria.
In addition, studies of the brains of transgender individuals suggest a physical manifestation of gender identity. A postmortem study of six transgender women (male-to-female, MTF) found that the size of the bed nucleus of the stria terminalis (BST) in the hypothalamus was within the female range. Examination of a transgender woman who did not undergo hormonal treatment also showed BST immunocytochemistry staining of somatostatin neurons within the female range. In addition, examination of one transgender man (female-to-male, FTM) revealed a BST within the male range. These differences in BST staining were independent of sexual orientation and sex hormone treatment. , Attempts to extend the cadaver finding with radiology include a positron emission tomography (PET) study measuring changes in regional cerebral blood flow using OH 2 O that found hormonally treated transgender women exhibited a pattern of hypothalamic activation intermediate between male and female when smelling certain steroids. Diffusion tensor imaging studies showed that hormonally untreated transgender men exhibited white matter microstructure more typically male than female, and untreated transgender women exhibited white matter microstructure intermediate between nontransgender male and female individuals used as controls. ,
Gender identity is durable, meaning that it does not change over time. There is no convincing literature that demonstrates an ability to externally change a person’s gender identity. Attempts to change gender identity rely on pressure to conform to sex norms, and demonstrably result in poor psychosocial outcomes.
Diagnosis
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Gender incongruence must be diagnosed before moving forward with medical therapy.
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Other medical and mental health disorders must be addressed before proceeding with treatment.
Gender incongruence is typically self-reported by the patient and does not necessarily need to be confirmed by a mental health professional. In the absence of confounding circumstances, such as the presence of untreated psychosis, the diagnosis of gender incongruence can be made by a qualified medical provider based on existing World Professional Association for Transgender Health (WPATH) or Endocrine Society guidelines. , Assessments of a patient’s readiness for treatment should center on assessing the patient’s ability to provide informed consent. Complicating medical and mental health disorders should be addressed before treatment.
| Criteria for Hormone Therapy |
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Hormonal Treatment for Transgender Individuals
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Exogenous testosterone is given to increase testosterone levels to the male range for transgender men.
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Estrogens and adjunctive antiandrogens are given to reduce testosterone to the female range for transgender women.
The current broad strategy for hormone therapy for transgender patients includes (1) androgens to virilize transgender men and (2) estrogens, in addition to adjunctive antiandrogens, to reduce testosterone levels to the conventional female range for transgender women while avoiding supra-physiological levels (> 200 pg/mL). ,
Mental health support is key to a good transgender health program. Patients should be screened for confounding mental health issues along with the patient’s ability to undergo hormone therapy. Although transgender individuals have a high incidence of mental health distress, it is often a result of social stigma, not gender incongruence.
Hormone Therapy for Transgender Men (FTM)
The hormonal treatment for transgender men is very similar to hormone replacement therapy for hypogonadal cisgender men. , Testosterone is administered to achieve a goal testosterone level in the typical normal cisgender male physiological range (300–1000 ng/dL). Patients can anticipate increased facial/body hair, male-pattern balding, increased acne, increased libido, increased muscle mass, clitoromegaly, deepening of the voice, and redistribution of fat within the first 3 to 12 months of testosterone therapy. Menstrual cessation occurs in the majority of individuals after six months of treatment. The exact effects and time course of testosterone will vary from patient to patient.
When a transgender man begins hormone treatment, he can be started with half the dose used for a typical 70 kg man and then titrated quickly to achieve typical male physiological serum levels (300–1000 ng/dL). There is no indication for antiestrogens. Some patients, including some who identify as nonbinary, may choose to be treated with smaller doses of testosterone. Although some circulating sex steroid is needed for good bone health, there is no other known health reason to prefer a typically male hormone profile, a typically female hormone profile, or something in between. The main caution is to counsel patients that even low-dose hormone regimens can have dramatic physical consequences for some people and patients should find that acceptable before embarking on treatment.
Testosterone can be administered orally, transdermally, or parenterally ( Tables 31.2 a, b, and c). Testosterone enanthate or cypionate 50 to 200 mg weekly can be administered intramuscularly (i.m.) or subcutaneously (s.q.). Higher doses (100–200 mg) can be administered every 2 weeks but may result in more significant periodicity in testosterone levels. Transdermal preparations such as testosterone gel (2.5–10 g/day) or testosterone patch (2.5–7.5 mg/day) will achieve the same virilizing effects as intramuscular testosterone, but the patch may cause skin irritation. Although not widely used, oral testosterone undecanoate (160–240 mg/day) was approved for use in the United States in 2019.
Table 31.2a
Monitoring for Transgender Women (MTF) on Hormone Therapy
Adapted from Gardner I, Safer J. Progress on the road to better medical care for transgender patients. Curr Opin Endocrinol Diabetes Obes . 2013;20(6):55308.
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Table 31.2b
Hormone Regimes for Transgender Women
Adapted from Gardner I, Safer J. Progress on the road to better medical care for transgender patients. Curr Opin Endocrinol Diabetes Obes. 2013;20(6):55308.
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Table 31.2c
Adverse Effects: Antiandrogen and Estrogen Supplementation
Adapted from World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People . 7th ed. 2011.
| Likely Increased Risk: |
|---|
| Venous thromboembolic disease |
| Gallstones |
| Weight gain |
| Hypertriglyceridemia |
| Likely Increased Risk with Presence of Additional Risk Factors: |
| Cardiovascular disease |
| Possible Increased Risk: |
| Hypertension |
| Hyperprolactinema |
| Possible Increased Risk with Presence of Additional Risk Factors: |
| Type 2 diabetes mellitus |
| No Increased Risk or Inconclusive: |
| Breast cancer |
Patients taking testosterone should be monitored for both virilizing and adverse effects every 3 months for the first year and then every 6 to 12 months ( Tables 31.2 a, b, and c).
Serum testosterone levels should be monitored until stability is achieved within the male range. Patients taking testosterone enanthate or cypionate intramuscularly or subcutaneously can have testosterone peak levels measured 24 to 48 hours after injections and occasional trough levels measured immediately prior to injections. Patients taking testosterone transdermally can have levels sampled at any time after 1 week. Androgen-sensitive indices such as hematocrit (or hemoglobin) and lipid profile should be monitored at follow-up visits. Because adequate levels of sex hormones are required to maintain bone mass, patients should avoid hypogonadism, notably if they have undergone oophorectomy. Otherwise, BMD screening can be initiated at age 60 or if testosterone levels are consistently low. Transgender men with cervixes or breast tissue should undergo age-appropriate cancer screening.
Testosterone therapy should not be initiated in patients who are pregnant, have unstable coronary artery disease, or have untreated polycythemia (hematocrit at or above 55%). Testosterone therapy may unmask polycythemia and hyperlipidemia, which should be treated appropriately. It is unknown if testosterone therapy puts transgender men at an increased risk for uterine or ovarian cancer. To date, there is insufficient evidence to recommend routine hysterectomy and/or oophorectomy in transgender men for the purpose of malignancy prevention.
Testosterone is known to stimulate erythropoiesis; therefore monitoring to ensure that hematocrit levels are less than 55% is necessary for transgender men. , Although current data support the safety of transgender hormone therapy, more long-term studies are needed in this area.
Hormone Therapy for Transgender Women (MTF)
The goal of hormone therapy for transgender women is to decrease testosterone to the female range (<50 ng/dL) without supraphysiological levels of estradiol (<200 pg/mL). These targets are typically achieved with a treatment regimen consisting of estrogen in combination with an adjunctive antiandrogen. While the effects and time course of estrogen and adjunctive antiandrogen therapy vary, patients can expect decreased facial/body hair, decreased libido, decreased spontaneous erections, decreased skin oiliness, decreased muscle mass, redistribution of fat, and breast development within the first 3 to 12 months. Breast growth will usually peak after 2 years of hormone therapy. Like transgender men, some patients, including some who identify as nonbinary, may choose to be treated with lower dose regimens. Although some circulating sex steroid is needed for good bone health, there is no other known health reason to prefer a typically male hormone profile, a typically female hormone profile, or something in between. The main caution is to counsel patients that even low-dose hormone regimens can have dramatic physical consequences for some people and patients should find that acceptable before embarking on treatment.
Treatment with estradiol in and of itself will suppress testosterone levels in transgender women. However, incorporating an adjunctive antiandrogen into the paradigm for trans women allows for lower doses of estrogen, thus limiting dose-related adverse effects ( Table 31.3 ). Spironolactone is the most commonly prescribed and least costly antiandrogen used in the United States. It is an aldosterone receptor antagonist that has been shown to decrease mortality in patients with New York Heart Association class 3 and greater congestive heart failure. Spironolactone also inhibits the secretion and activity of testosterone (although the mechanism is not known).
Table 31.3
List of Common Gender Affirming Surgeries
Adapted from Non-Surgical Services, Center For Transgender Medicine And Surgery. https://www.bmc.org/center-transgender-medicine-and-surgery/clinical-services .
| For Transgender Women: | |
| Chest Reconstruction Surgery | This procedure involves using breast implants to fulfill the desire for fuller breasts (breast enlargement). |
| Facial Feminization Surgery | Facial feminization surgery (FFS) involves a group of surgical procedures that alter the face to increase its femininity. During facial feminization surgery, masculine markers are removed from the face in order to feminize and beautify the face. |
| Genital Surgery | Male to female genital reconstruction surgery includes an orchiectomy (removal of the testicles) and neovaginoplasty (surgical construction of a vagina). |
| For Transgender Men: | |
| Chest Reconstruction Surgery (mastectomy) | A surgical procedure to remove the breasts. |
| Hysterectomy | A surgical procedure to remove all or parts of the uterus. |
| Oophorectomy | A surgical procedure to remove one or both ovaries. |
| Genital Surgery | Female to male genital reconstruction surgery includes phalloplasty (construction of a phallus and neourethra) and metoidioplasty (lengthening of the clitoris). |
Spironolactone can be administered in doses of 100 to 200 mg daily; up to 400 mg may be administered if tolerated. Doses can be divided, but patients should be aware that the weak diuretic properties of spironolactone may become more apparent at higher doses, making evening dosing less favored. Gonadotropin-releasing hormone (GnRH) agonists (3.75 mg subcutaneously monthly), such as leuprolide, inhibit the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and therefore testosterone but are often expensive and must be given by injection. Although GnRH agonists have been used to treat children with precocious puberty along with adolescent transgender individuals and appear well-tolerated, there are no studies demonstrating safety with very long-term use. Cyproterone acetate is often used in Europe but is not available in the United States. Cyproterone acetate has been associated with elevated prolactin levels, worsening lipid profiles, and rare meningioma formation.
Estrogen can be administered orally, transdermally, or parenterally ( Table 31.3 ). Oral conjugated estrogens 2.5 to 7.5 mg and oral 17-beta estradiol 2 to 6 mg daily are popular because they are easy to use and readily available. With conjugated estrogens, some metabolites are missed on serum estradiol tests and so estradiol is more commonly prescribed. Ethinyl estradiol has been associated with an increased risk of venous thromboembolism (VTE). Estradiol and spironolactone can be started at lower doses (e.g., 1/4 strength) and increased until serum testosterone levels are within the female range (<50 ng/dL). Some propose that the hepatic first pass for oral estrogen increases thrombosis risk and that a transdermal estradiol patch (0.1–0.4 mg twice weekly) should be used in transgender women who are at increased risk for thromboembolic disease. Data do show fewer thrombotic events in patients using transdermal patches but it is not known whether the association relates to a “first pass” effect, a lower delivered dose, or some other factor. Estradiol can be administered parenterally with estradiol valerate or cypionate 5 to 20 mg i.m. every 2 weeks or 2 to 10 mg i.m. every week, but levels are harder to monitor.
Transgender women on hormone therapy can be monitored for feminizing and adverse effects every 3 months for the first year and then every 6 to 12 months ( Table 31.3 ). Hormone therapy is titrated to achieve goal hormone levels rather than a specific physical endpoint (like breast size) or subjective sense of feminization.
Serum testosterone and estradiol levels should be monitored until they stabilize within the female range (testosterone <50 ng/dL; estradiol <200 pg/mL). Spironolactone is a potassium-sparing diuretic and can cause hyperkalemia in rare individuals with renal dysfunction, so it is vital to monitor potassium for patients taking spironolactone. Estrogen-sensitive indices such as prolactin and triglycerides are often monitored. However, prolactin elevations have only been noted in patients using adjunct cyproterone acetate, not in patients using other adjunct treatments or patients using estrogens alone. , Patients should be warned of the potential for VTE. Adequate levels of sex hormones are required to maintain bone mass; patients should avoid hypogonadism, particularly those who have undergone orchiectomy or vaginoplasty. BMD screening should be initiated at age 60 but may be performed earlier if sex hormone levels are consistently low. Transgender women should be screened for breast and prostate cancer per current guidelines. ,
Surgical Treatment for Transgender Individuals
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Surgeries available for transgender men (FTM) include chest reconstruction, vaginectomy, hysterectomy, oophorectomy, metoidioplasty, and/or phalloplasty.
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Surgeries available for transgender women (MTF) include breast augmentation, laryngeal or vocal feminization surgery, reduction of thyroid chondroplasty, penectomy, inversion vaginoplasty, and/or intestinal vaginoplasty.
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Not all transgender patients desire surgery, or all surgical options available to them.
The goal of medical therapy for some transgender individuals is to match the body to gender identity. Many transgender individuals find hormone therapy alone successful in expressing their gender identity. However, some transgender individuals will pursue surgery. Gender affirmation surgery may be limited due to the small number of qualified medical facilities. Patients may opt for one or more of the available surgical options ( Table 31.4 ).
Table 31.4
Terms Used to Describe Various Aspects of Gender and Sexuality
Adapted from UpToDate, Terms used to describe various aspects of gender and sexuality. https://www.uptodate.com/contents/transgender-men-evaluation-and-management?search=transgender% 20men&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
| Gender Identity | The Innate Sense of One’s Own Sex, Male, Female, Neither, or a Combination of Both |
|---|---|
| Sex Recorded at Birth | Typically recorded according to external genitalia |
| Gender Expression | How gender identity is presented either to oneself or to the outside world (i.e., feminine, masculine, androgynous); gender expression does not necessarily correlate with sex recorded at birth or gender identity |
| Gender Nonconformity | Variation from the cultural norm in gender expression or gender role behavior (i.e., in choices of toys, playmates, etc.) |
| Transgender, Trans, Gender Incongruent | Umbrella terms to describe individuals whose gender identity is different from their sex recorded at birth. Notably, the terms are adjectives (“transgender people”), not nouns (“transgenders”) |
| Gender Dysphoria | Distress or discomfort that may occur when gender identity and sex recorded at birth are not completely congruent |
| Transsexual | Older clinical term that has fallen out of favor; historically, it was used to refer to transgender people who sought medical or surgical interventions for gender affirmation |
| Sexual Orientation | An individual’s pattern of physical and emotional arousal (including fantasies, activities, and behaviors) and the sex of persons to whom an individual is physically or sexually attracted (gay/lesbian, straight, bisexual). The sexual orientation of transgender people is based upon gender identity (i.e., a transgender man who is attracted to other men might identify as a gay man; a transgender woman who is attracted to other women might identify as a lesbian) |
| Sexual Behaviors | Specific behaviors involving sexual activities that are useful for screening and risk assessment; many youth reject traditional labeling (homosexual, heterosexual, bisexual) but still have same-sex partners |
| Transgender Man/Transman | Person with a masculine gender identity whose sex recorded at birth was female |
| Transgender Woman/Transwoman | Person with a feminine gender identity whose sex recorded at birth was male |
| Genderqueer, or Nonbinary | Person of any sex recorded at birth who has a gender identity that is neither masculine nor feminine, is some combination of the two, or is fluid |
Surgeries for Transgender Men (FTM)
Chest Reconstruction Surgery
Frequently referred to as “top surgery,” chest reconstruction surgery can consist of multiple steps, as deemed necessary by the patient. These include subcutaneous mastectomies, reduction and repositioning of the nipple-areola complex, and chest contouring with liposuction. Depending on the volume of parenchyma, position of the nipple-areola complex, and degree of skin elasticity, either a periareolar or inframammary surgical approach with free nipple grafts may be performed.
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