GAHT in transgender adolescents

GAHT in Transgender Adolescents

Induction of secondary sex characteristics with estradiol in male-to-female transgender adolescents

Oral Estradiol Treatment

Usage of estradiol (17β-estradiol), the most highly secreted hormone from native ovarian tissue in women of reproductive age, is recommended. It is available in both oral and transdermal forms. The dosage of 17β-estradiol should be gradually increased every six months to ensure that the physical transition is most similar to natural puberty. Such induction of secondary sex characteristics may take a few years from initiation of therapy. 17β-estradiol products currently available on the market are primarily certified internationally and by the Thai Food and Drug Administration for hormone replacement therapy indications in post-menopausal women. However, 17β-estradiol has been safely used for GAHT in transgender women as an extended indication.

Examples of pubertal induction protocol with oral estradiol for male-to-female transgenders

Start with 5 μg 17β-estradiol/ kg body weight/day for six months, followed by 10 μg /kg of body weight/day for six months, followed by
15 μg /kg of body weight/day for six months, followed by
20 μg /kg of body weight/day for six months.
Then, adjust the final dosage to 2-6 mg per day based on blood estradiol levels, targeted at 100-200 pg estradiol per ml.

Transdermal Estradiol Treatment

Because oral 17β-estradiol only comes in 1 mg tablet in Thailand, it is not easy to gradually increase the dose as suggested above. As a result, transdermal treatment may be the easier drug administration option because healthcare providers can easily adjust the dose. Moreover, it does not interfere with liver function (unlike oral hormones, which have first-pass hepatic effects). In addition, transdermal estradiol can maintain blood hormone levels better than oral estradiol. Currently, two forms of transdermal estradiol are available in Thailand: transdermal patch and gel.

17β-estradiol patch

The patch can be placed on any exposed skin, such as the lower abdomen or buttocks. Do not place it on the breast or areas that rub against clothes, such as areas around the hips, hairy areas, or areas with creases. Replace the patch every 3.5 days (twice a week) to maintain targeted blood levels. Adjust the dosage every six months like with oral estradiol.

Examples of pubertal induction protocol with transdermal estradiol for male-to-female transgenders

(For 17β-estradiol transdermal patches (50 μg/24 hours))
Start 17β-estradiol at 6.25-12.5 μg/24 hours (cut the patch into 1/8 - 1/4) for six months. Then, increase
the dosage to 25 μg/24 hours (cut into 1/2 patches) for six months, followed by 37.5 μg/24 hours (cut into 3/4 patches) for six months.
The final dose to 50-200 μg/24 hours (one - four patches) based on blood estradiol levels, targeted at 100-200 pg/ml.

GAHT in Transgender Adults

Oral Estradiol

Either 17β-estradiol hemihydrate or estradiol valerate can be used. After ingestion, estradiol valerate is rapidly metabolized to 17β-estradiol in the intestine and liver. The recommended dosage of estradiol is 2-6 mg/day for both estradiol valerate and 17β-estradiol hemihydrate.

The estrogen in contraceptive pills (Ethinyl estradiol) is not recommended for male-to- female transgender individuals. This is because of increased risks of complications, such as a significantly higher risk of deep vein thrombosis compared to 17β-estradiol, especially in male-to-female transgender individuals aged over 40.

Conjugated equine estrogens and conjugated estrogens should be used with caution because they may carry a greater risk of deep vein thrombosis than 17β-estradiol, especially in male-to-female transgender individuals aged over 40 (Thailand no longer distributes conjugated equine estrogen manufactured from the urine of pregnant mares, but plant-based conjugated estrogens are still available on the market. However, this latter is not widely used because few clinical studies support its use).

Transdermal Estradiol (patch and gel)

Recommended dosages of 17β-estradiol patches are 25 -200 μg/24 hours (half to four patches). Patches should be replaced every 3.5 days (twice a week). For 0.06% 17β-estradiol gels, 2.5-10 g/day should be used and applied to the skin once a day.

Injectable Estradiol (Estradiol Valerate or Cypionate)

The recommended dosage is 5-30 mg every two weeks or 2-10 mg every week. The clinical practice of using injectable estradiol is somewhat different from usage of injectable testosterone. Injectable testosterone is widely used, available in most healthcare facilities to treat men with abnormally low hormone levels, and certified by the Food and Drug Administration. On the other hand, injectable estradiol is rarely used in postmenopausal women and is unavailable in public healthcare facilities. Moreover, injectable estradiol therapy may have some disadvantages, including pain at the injection site in some cases and supraphysiologic levels of estradiol immediately after injection, especially when incorrectly administered.8 Consequently, injectable estradiol is provisionally not widely used as GAHT for male-to-female transgender individuals and its prescription must be done with caution with careful monitoring of dose-response. Regardless of estradiol formulation, dosage is adjusted based on blood estradiol levels, targeted at 100-200 pg/ml.

Monitoring male-to-female Transgender Adults on Estradiol Therapy

Implement quarterly assessment in the first year and every six to twelve months thereafter to monitor the feminization progress and potential side effects.
Measure blood estradiol and testosterone levels quarterly. Aim for 100-200 pg/ml estradiol levels and total testosterone levels below 50 ng/dl.
If on spironolactone treatment, patients should also have their blood potassium levels checked to monitor for hyperkalemia. This should be done quarterly in the first year and once a year thereafter.
Patients should undergo cancer screening in a manner corresponding to their biologic sex, as native tissues such as the prostate gland are still in place.
Consider obtaining a baseline bone mineral density (BMD). Retesting should be done for transgender patients with a low risk of osteoporosis at the age 60, or for those with irregular compliance to hormonal therapy.
Due to reports that male-to-female transgender patients on estrogen therapy have higher blood prolactin levels (up to 20%) than normal – which may be due to estrogen stimulation of the pituitary cells or concurrent use of the antiandrogen cyproterone acetate – baseline prolactin levels should be measured and then rechecked every 1-2 years for patients on high doses of estrogen.

Progesterone

Some male-to-female transgender individuals take progesterone in combination with estrogen believing that breast development would more closely resemble that of natural puberty compared to taking estrogen alone. Progesterone is also believed to have positive effects on mood and sexuality. However, current studies are inadequate to confirm the definitive benefits and risks of progesterone in male-to-female transgender individuals. Therefore, it is not considered a standard GAHT regimen for male-to-female transgender individuals.

Antiandrogens

One major difference between GAHT in male-to-female transgender individuals and GAHT in female-to-male transgender individuals is that male-to-female transgender individuals who have not undergone orchiectomy will need antiandrogen therapy. On the other hand, female-to-male transgender individuals will not need estrogen suppression for hormones produced by the ovaries. Two types of antiandrogens, spironolactone and cyproterone acetate, are recommended for male-to-female transgender individuals in Thailand (Cyproterone acetate is not available in some countries like the United States) with the following dosages:

Spironolactone: 100 – 300 mg/day
Cyproterone acetate: 25 – 50 mg/day

Additionally, 3.75 mg of GnRH agonist can be injected monthly or 11.25 mg injected every 3 months to suppress androgen. However, this is not widely used because it is expensive and overly suppresses sex hormones. It can be used instead in cases where spironolactone or cyproterone acetate cannot be given.

5α-reductase inhibitors are not recommended as antiandrogen therapy for male-to-female transgender GAHT because they do not suppress blood testosterone levels and have serious side effects.

The goal antiandrogen therapy for testes hormonal inhibition is to lower total testosterone levels to less than 50 ng/dl. Male-to-female transgender individuals who have not undergone orchiectomy should use estradiol in conjunction with antiandrogen drugs. If they already had an orchiectomy, male-to-female transgender individuals may stop taking antiandrogens and take only estradiol.

Healthcare providers should monitor the usage of estradiol in combination with antiandrogens by aiming for blood total testosterone levels below 50 ng/dl and a satisfactory physical transition for the transgender women. This is because antiandrogens work at the cellular receptor level and is unable to be accurately measured by testing blood levels. Hormone level measurements, including protocols and equipment used, vary by laboratory, and present another limitation to accurate testing.

Refer: Gender-Affirming Hormone Treatment in Transgender People - The Thai Handbook of Transgender Healthcare Services, Center of Excellence in Transgender Health, Chulalongkorn University

REFERENCES

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