ANTI-ANDROGENS

The anti-androgens typically used at Sherbourne Health (Toronto, ON) are spironolactone or cyproterone acetate, with the former historically chosen preferentially as it was believed to have a superior safety profile. This practice has changed over time, as adequate anti-androgen effects and testosterone suppression into the female range are achievable at lower doses of cyproterone (i.e. 12.5 – 25mg daily) at which adverse effects are less likely (2). This is because cyproterone acetate is not only an androgen blocker but also works to reduce overall testosterone levels. However, cyproterone is often not given in the setting of moderate psychiatric or liver co-morbidities. Whereas spironolactone may be chosen because of the often wanted side-effect of gynecomastia. If spironolactone is chosen for androgen blockade, particular attention should be made to CAD/CHF, fluid status and hyperkalemia; electrolytes are generally repeated 2 weeks after starting this medication. A typical starting dose of spironolactone is 50mg po daily, with uptitration between 100-200mg po daily to help achieve androgen suppression.

The choice of anti-androgen should be made individually for each patient based on their medical history and preference regarding risk and side effect profiles. Following orchiectomy (+/- vaginoplasty), most transfeminine patients do not require androgen suppression. The androgen- blocker can be stopped immediately after surgery or tapered over the course of 4-6 weeks or more depending on individual factors (e.g., patients with hypertension or renal dysfunction on spironolactone should be tapered).

ESTROGENS

Estrogen acts directly on estrogen receptors to initiate feminization. Several forms and routes of administration of estrogen can be used for feminization. At Sherbourne Health (Toronto, ON), the most commonly used estrogen is oral 17-β estradiol (Estrace), which is covered by the Ontario Drug Benefits (ODB) program. While conjugated estrogens (e.g. Premarin) have historically been used, due to their accessibility/affordability and lower safety profiles for transwomen, they are no longer recommended (3).

Currently, there is no consensus on the best timing of the initiation of estrogens in relation to starting an anti-androgen. Common approaches have included initiation of an anti-androgen (usually 1-3 months) prior to the addition of estrogen, or alternatively, the simultaneous introduction and subsequent titration of both hormone therapies. In patients over 50 years old who have been on estrogen for several years, consideration may be given for dose reduction to mimic that of post-menopausal cis-women (e.g. starting/lower dose topical formulations).

Keep in mind: In adolescent patients, tanner stages are often used to aid in the initiation of estrogen therapy. Introducing estrogen too early during puberty (prior to the completion of skeletal growth) may lead to an earlier cessation of long bone growth and thus shorter adult height, an effect that would be irreversible. This may also be the desired effect. Complete epiphyseal fusion can occur as early as age 14 and as late as age 19 in assigned-male at birth individuals (4).

CONTRAINDICATIONS

• Unstable ischemic cardiovascular disease.

• Estrogen-dependent cancer.

• End-stage chronic liver disease.

• Psychiatric conditions limit the ability to provide informed consent.

• Hypersensitivity to one of the components of the formulation.

FORMULATIONS & RECOMMENDED DOSES OF ANTI-ANDROGENS & ESTROGEN

* Price quotes are provided by www.pharmacy.ca. The above prices are accurate as of May 2018 and represent the price for a 4-weeks supply of a generic brand of medication unless indicated otherwise (ranging from low dose to maximum dose). Prices include a usual and customary dispensing fee of $9.99, which may vary from pharmacy to pharmacy. Note: For patients on ODB, spironolactone, cyproterone, and oral estradiol are covered without the submission of an EAP form.

** Estradiol valerate IM must be prepared by a compounding pharmacy, price quote provided by Pace Pharmacy (including $10.99 dispensing fee)

a) rarely required or used. Maximal effect does not necessarily require maximal dosing. Use clinical judgement in selecting optimal individual dosing; b) Estradot® brand; c) Usual doses vary significantly between individuals. Use starting doses and titrate up based on patient response. Maximum doses are not often needed. Use clinical judgement in selecting optimal individual dosing; d) 200 mcg daily given as 2x100 mcg patches applied twice weekly (4 patches/week); e) Estragel

® brand f) Estradiol valerate IM must be prepared by a compounding pharmacy, commonly at the minimum concentration of 10mg/mL. Per updated Ontario guidelines, opened multi-use vials must be discarded after 28 days.

SAFETY

Transdermal estradiol (transdermal patch) seems to be less clot-forming (thrombogenic) than oral estradiol with fewer liver (hepatic) side effects and is thus recommended for patients over 40 or with risk factors for cardiovascular, thromboembolic, or liver disease (7).

PREVENTIVE CARE

Transfeminine patients maintained on feminizing hormone therapy have unique preventive care needs and recommendations. An adapted Preventive Care Checklist for transfeminine patients that can be used at the point of care can be found in the full Sherbourne Health Guidelines.

EFFECTS & EXPECTED TIME COURSE OF FEMINIZING HORMONES

The degree and rate of physical effects are largely dependent on age, genetics, body habitus and lifestyle, and to some extent, the dose and route used (chosen in accordance with a patient’s specific goals and risk profile) (8).

Keep in mind: Use patient preferred terminology. “Testicular” and “erections” may be upsetting to some but not all.

Physical changes related to androgen blockade and estrogen may take months to appear and are generally considered to be complete after 2-3 years on hormone therapy. Breast growth is an aspect of feminization to which many transfeminine patients assign great importance. The degree of breast development

is dependent on many factors, but most transfeminine patients experience modest breast development (average cup size <A, at a developmental Tanner stage of 2-3).9, 10 Feminizing therapy does not affect the pitch of the voice in transfeminine patients.

a) Estimates represent unpublished clinical and published observations 11,12,13

b) Significantly dependent on the amount of exercise;

c) Complete removal of facial hair requires electrolysis, laser treatment, or both.

MONITORING STRATEGIES & DOSE ADJUSTMENTS

• Standard monitoring of a feminizing hormone regimen should be employed at baseline, 3, 6, and 12 months; and yearly thereafter (creatinine and electrolytes should be checked 2-4 weeks after the initiation or dose increase of spironolactone).

• Some providers prefer to see patients monthly until an effective dose is established; most providers see patients on a q 3 monthly basis. Follow up visits should include a functional inquiry, targeted physical exam, bloodwork, and health promotion/disease prevention counselling as indicated.

• Dose titration of an anti-androgen and estrogen may be performed over the course of 3-6 months or more and will depend on patient goals, physical response, measured serum hormone levels, and other lab results.

• For many transfeminine patients, the goal will be to achieve the suppression of testosterone into the cis-female range. Hormone levels for those seeking a more androgynous appearance may intentionally be mid-range between male and female norms. These ranges are dependent on lab assays used. Try to have patients be consistent with their lab site or hospital site for which they perform blood work since reference ranges can differ.

• Measurement of total testosterone is adequate to assess the degree of androgen suppression, without the routine need for free testosterone levels. Be mindful that patients may have clinically relevant results without complete suppression of testosterone because of androgen blockade, which is not measurable.

• Serum estradiol levels should also be monitored. Most patients attain considerable feminization at estradiol levels between 200-500 pmol/L (in the mid-reference range of most labs).

  Keep in mind:

  Clinical effects are the goal of therapy, not specific lab values. If the sex marker associated with the patient’s health card has not been changed, the reported reference ranges will refer to the sex assigned at birth. Again, it is important to emphasize that reference ranges vary between laboratories - refer to reference ranges from the specific laboratory (often available online or by request from the lab).

HORMONE MONITORING SUMMARY FOR TRANSFEMININE PATIENTS

In this table, smaller and light blue checkmarks indicate parameters that are measured under particular circumstances.

NB: Individual parameters should be considered more frequently if concerns identified or existing risk factors are present.

Non-hormone labs:

• Hemoglobin/Hematocrit - use cis-female reference for the lower limit of normal and cis-male reference for the upper limit of normal.

• Creatinine - use cis-female reference for the upper limit of normal.

The decision to start hormone therapy is an individual one, based on the balance of risks and benefits for each person. In order to provide informed consent, it is important that you understand the expected feminizing changes as well as the possible risks and side effects. The use of feminizing hormone therapy (anti-androgen and estrogen) is based on many years of experience treating trans people. A growing body of research is providing us with more information, however, there are aspects of the medical effects and safety of feminizing hormone therapy that may not be fully understood.

It is possible that hormone therapy may not result in all of the changes that are hoped for.

Expected changes that are not permanent and are likely to reverse if hormones are stopped include:

• Loss of muscle mass and strength.

• Weight gain and/or redistribution of fat to the hips, buttocks, and thighs (some degree may be reversible)

• Softening of skin/decreased oiliness/change in body odour and amount of perspiration.

• Decreased sex drive, decreased strength of and/or ability to get erections, decreased volume and thinning of ejaculate.

• Thinning/slowing of body and facial hair growth.

• Scalp hair loss may slow or stop, but hair does not generally grow back.

Potential adverse effects of adding progestin to a feminizing hormone treatment may include, but are not limited to an increased risk of:

• Increased risk of:

  • Blood clots (deep vein thrombosis, pulmonary embolism, and stroke).

  • Increase in liver enzymes (often temporary).

  • Decrease in, or loss of, fertility (the ability to make healthy sperm is reduced and may be permanently affected by feminizing hormones, however, you still need to use birth control if you are having penetrative sex with a partner who could become pregnant).

  • Increased triglycerides, a type of fat in the blood.

  • Mood swings or depression (higher risk with cyproterone or progesterone).

  • Elevated levels of prolactin (a pituitary hormone), particularly in combination with cyproterone.

• Possible increased risk of:

  • Heart disease and stroke.

  • High blood pressure.

  • Diabetes.

  • Changes in cholesterol, which may increase the risk for heart attack or stroke.

  • Worsening of liver damage from other causes.

  • Gallbladder disease, gallstones, and need for gallbladder removal.

  • Pituitary tumours (tumour of small gland in the brain which makes prolactin).

  • Worsening of headaches or migraines.

  • Breast tumours/cancer (risk is lower than in cis women, but may be higher than in cis men).

• Other common side effects include:

  • Decreased sex drive and sexual functioning.

  • Fatigue.