Transgender hormone therapy, the administration of the sex hormones of the non-natal sex, is effective, therapeutic, and safe for most individuals. In general, trans women take estrogen and antiandrogens. Trans men take testosterone. Family physicians and other primary care providers should be capable of providing and monitoring hormone therapy for the majority of their patients.
The goals of therapy are to help the patient achieve a more feminine or masculine appearance and countenance. The patient is likely to benefit not only from the hormone-induced changes, but from the knowledge he or she now has the "correct" hormones. There may be practical benefits, such as improved "passability" and reduced social stigma, in addition to improved psychological functioning.
Estrogen is typically combined with an androgen-blocking drug to achieve optimal feminization. A progestin may or may not be added depending on the patient and provider.
Estrogen may be given through a pill, transdermal patch, or injection. Oral estrogen is typically in the form of 17ß estradiol or conjugated equine estrogens (eg Premarin). Generally, 2-8 mg qd of estradiol are prescribed, or 1.25-2.5 mg qd of the more potent Premarin is used. The transdermal patch also contains 17ß estradiol, and usually 100 mcg patches are used twice a week. With injections, 100 mg of estradiol may be given every two weeks.
Each form of estrogen has its advantages and treatment must be tailored to the patient. Oral estrogen is convenient and easy to use. Injectable estrogen produces higher serum levels of estrogen and may increase the risk of prolactinoma. However, many patients suggest it achieves better results than the oral formulation. Transdermal estrogen lowers the risk of thromboembolism, which is useful for older patients or anyone with other risk factors. Injectables and patches both avoid the "first-pass" effect of hepatic metabolism.
These drugs work exactly like our endogenous estrogen. They bind to the intracellular estrogen receptor, which then dissociates from heat shock proteins and dimerizes before binding to a hormone-response element in the nucleus. As a result, transcription of estrogen-dependent genes is altered.
Estrogen also reduces endogenous testosterone synthesis. Exogenous sex hormones deliver negative feedback to the hypothalamus and pituitary, which decreases release of GnRH, LH and FSH. This leads to decreased synthesis of gonadal androgens. Also, exogenous estrogen increases hepatic synthesis of sex hormone binding globulin (SHBG), which preferentially binds to androgens and prevents their activity. However, not all androgens will be suppressed and use of an anti-androgen is indicated.
Estradiol is converted to estriol, a less active metabolite. Estradiol undergoes sulfate and glucuronide conjugation in the liver and is excreted through the kidneys. Inhibitors of the CYP3 enzymes such as certain antiretrovirals and antibiotics can raise concentrations of estradiol in the blood to dangerous levels.
Spironolactone, which blocks the androgen receptor, is often used as an anti-androgen, and trans women generally take 100-200 mg daily. Spironolactone is better known as a potassium-sparing diuretic that blocks aldosterone receptors in the collecting duct of the nephron. This results in decreased sodium and water reabsorption, affecting electrolytes and blood pressure. It has historically been used to treat heart failure, ascites and hypokalemia. You may recall seeing gynacomastia listed as a side-effect. In this case, one person's side-effect is another's persons intended outcome!
The use of a progestin as the third component of hormone therapy is contested. Medroxyprogesterone or micronized progesterone may be used to increase breast development. Critics say that progestins increase the risk of breast cancer and cardiovascular disease with little benefit (Gooren, 2007).
Therapeutic Effects of Estrogen
What doesn't change: voice, size of hands, feet and facial features, height, thyroid cartilage
- Breast development (After two years of therapy, no further growth is expected; patients with large-breasted female relatives and younger patients typically have the most development; most patients only reach Tanner Stage III or IV)
- Expansion of the nipple-areolar complex
- Redistribution of body fat from the abdomen to hips and thighs
- Testicular atrophy (due to lack of FSH, LH stimulation)
- Prostate atrophy (lowering the risk of prostate cancer, especially in persons <50 years of age)
- Decreased spontaneous erections
- Change in body and urine odor
- Softening of the skin
- Decreased acne
- Reduction in unwanted body hair
- Prevention of male-pattern baldness
- Calming effects and "inner peace"
Usually, testosterone alone results in sufficient masculinization of the natal female. Typically, 150-250 mg of testosterone esters are given intramuscularly every two weeks. Half the dose may be taken every week to provide a more consistent level of hormone. The patient may be provided with syringes and inject at home. Transdermal testosterone is also available, and 5 mg per day is commonly used.
Testosterone works similarly to estrogen. The lipophilic steroid crosses the plasma membrane and binds to the androgen receptor. The receptor undergoes a conformational change and translocates to the nucleus, where it binds to hormone repsonse elements in the DNA and alters the transcription of androgen-dependent genes.
Testosterone can be converted by 5alpha-reductase to dihydrotestosterone (DHT), a more potent metabolite that binds five times as strongly to the androgen receptor. DHT cannot be aromatized to estradiol. Also, testosterone will similarly depress the hypothalmic-pituitary-gonadal axis through negative feedback on GnRH and the gonadotropins.
Androgens are inactivated in the liver where they undergo conversion to an excretable hydrophilic form. Specifically, they undergo sulphate or glucuronide conjugation and are excreted by the kidneys. As with estrogen, the CYP3 family of enzymes is involved and certain drugs may induce or inhibit testosterone metabolism.
Therapeutic Effects of Testosterone
What doesn't change: breast size, pelvic structure, height
- Lowering of the voice
- Decreased or absent periods
- Redistribution of body fat from hips and thighs to the abdomen
- Increased lean body/muscle mass
- Increased libido
- Increased body and facial hair
- Coursening of the skin
- Urine and body odor changes
- Thickening of the laryngeal prominence
- Thickening of the bones in the face
- Increased energy
- Positive mood
Estrogen therapy is generally considered safe for young, healthy patients, but the risks increase with age and certain medical problems. You should be on alert for any of the following side-effects:
More serious potential complications include:
- nausea and vomiting
- changes to nevi
- spider angioma
- decreased libido
Given the potential for serious adverse effects, clinicians adjust dosing of hormone therapy for patients with known risk factors for these diseases. For example, patients who are older, obese or smokers should receive lower doses of estrogen or transdermal estrogen. Patients with a history of stroke, MI, DVT, hyperlipidemia, liver disease or other relevant health problems should also receive lower doses. It is very important to monitor patients on hormone therapy for indicators of disease.
- Prolactinoma (prolactin-secreting adenoma of the pituitary gland) growth or induction
- Venous thrombus formation (estrogen increases transcription of certain clotting factors while decreasing levels of anticoagulation factors; one study [van Kesteren, et al, 1997] estimated 20-fold increase in DVT)
- Pulmonary embolism
- Liver damage
- Breast cancer (risk of breast cancer remains much lower than for natal women. Risk is affected by the age at onset and dosing of estrogen therapy)
- Type 2 diabetes (decreased sensitivity to insulin)
- New-onset or worsening of depression
- Hypotension, hyperkalemia, hyponatremia (secondary to spironolactone)
The patient taking testosterone may experience adverse effects. These can include
More serious potential complications include:
- oily skin
- male-pattern baldness
- weight gain
- polycystic changes to the ovaries
- menstrual bleeding
*Men develop heart disease on average 10 years earlier than women. Sex hormones certainly play a role in this difference. Testosterone is known to increase arterial stiffness and impair vascular reactivity (McCredie, et al, 1998; Emi, et al, 2008). The effects of exogenous hormone therapy on cardiovascular disease risk are not well known.
- liver disease (metabolic cholestasis and hepatocellular adenoma; parenteral forms of testosterone decrease risk)
- cardiovascular disease (increased TG and decreased HDL)*
- diabetes melllitus type II (decreased insulin sensitivity)
- breast cancer (testosterone may be aromatized to estrogen)
- endometrial cancer
- ovarian cancer
- sleep apnea
Do not give testosterone to anyone who is pregnant or may become pregnant.
Side Effects and Contraindications
Initiation and Monitoring of Hormones
A patient asks to take hormones for gender transition. What do you do? First, you should decide if hormone therapy is appropriate, independent of the potential complications. You may feel comfortable making your own assessment of the patient's gender dysphoria, or you may first refer the patient to a mental health professional to make the initial evaluation.
If you decide to proceed with treatment, you should first perform a full history and physical, including a urogenital exam to look for abnormalities such as cryptorchidism. Blood tests should be used to look for endocrine abnormalities such as polycystic ovary syndrome. Karyotyping is not indicated unless you expect Klinefelter's Syndrome for other reasons. Also look for underlying disease or risk factors for disease that may be exacerbated by estrogen or testosterone. Make sure you discourage smoking and the use of illicit hormones (obtained from friends, "the street," or the Internet).
Routine Monitoring and Lab Work
It is important to monitor patients taking sex hormones. In general, persons should be evaluated at 3 months, 6 months, 1 year, and every year thereafter. Additional evaluation may be indicated in the setting of chronic disease. Begin with a low dose of hormones and gradually increase the dose if no problems are detected. For women, you might start with 0.5 mg estradiol and 50 mg spironolactone per day, doubling the dose every 3-6 months until you reach the adult dose of 2-8 mg estradiol and 200 mg spironolactone per day. For men, you might start with 50 mg testosterone every other week, increasing the dose every 3-6 months until you reach 200 mg every other week. The goal is to increase the dose until target serum levels of estrogen and testosterone are reached and the patient achieves the expected level of feminization or masculinization, as long as it is safe to do so. People vary in their ability to metabolize sex hormones.
Appropriate monitoring includes much more than just lab tests. Hormonal transition is a stressful time for many people. Find out how the patient is coping. Ask about the changes that have occurred. Are they happy, frustrated or regretful? Do they have adequate social support? Men and women should be screened for depression given the social stigma they may face, but estrogen in particular is associated with a worsening of mood.
3 Month Follow-Up
Women: Check estrogen and testosterone levels to assess suppression of endogenous testosterone production and patient adherence. Increase the dose as appropriate. Assess electrolytes, lipids (triglycerides, HDL, LDL, VLDL, total cholesterol) and liver enzymes (prothrombin time, AST, ALT, bilirubin, albumin). Assess thyroid function if indicated. Assess breast development.
Men: Check serum testosterone and increase the dose as appropriate. Serum estrogen levels are not as important. Obtain a complete blood count. Elevated hematocrit may indicate polycythemia. Check liver enzymes, lipids, fasting glucose, creatinine and BUN.
6 Month Follow-Up
Women: Recheck serum testosterone and estrogen levels. Assess electrolytes, lipids and liver enzymes. Assess breast development. Adjust the dose if necessary. Patients may take up to 2-8 mg estradiol or 1.25-2.5 mg premarin and 200 mg spironolactone per day.
Men: Recheck serum testosterone. Adjust the dose if necessary. You may eventually prescribe up to 250 mg testosterone every other week, or 125 mg testosterone weekly. As above, assess liver enzymes, lipids, fasting glucose, creatinine and BUN.
History and Culture
Biology of Gender Identity
Links and Resources
About the Author
Initiation and Monitoring
Effects of Hormone Therapy
Side-Effects and Contraindications
Standards of Care (WPATH)
Writing a Support Letter
Clinical Best Practices
Mechanism of a typical steroid hormone and the hypothalamic-pituitary-gonadal (HPG) axis