Clinical pearls: Gender-affirming hormone therapy

July 05, 2021
 

Written by Abdi Kadir

This article is part of a series appearing in 
Interactions, our biweekly newsletter, written and researched by CSHP's students. We've created this series as a valuable learning activity for pharmacy students undertaking rotations at CSHP. Crafting these pieces not only helps students gain in-depth knowledge of specific conditions, treatments, and resources, it also helps them hone their skills in research, critical appraisal, evaluation, synthesis, and writing – all of which will serve them well in clinical practice. The Professional Practice Team works with the students to select hot topics that are of interest and utility to both the students and to you, the reader. We hope you enjoy this piece by one of our future colleagues! Let us know what you think: If you would like to provide any comments or constructive feedback for our students, please email us at practice@cshp.ca.


Background

Compared to the general population, transgender patients suffer significant health disparities. Trans patients report that the single largest component inhibiting their access to care is a lack of provider expertise in transgender healthcare.1 One study found that 63% of trans patients who had a regular family doctor had to provide education to their doctor about trans issues.2

There is a clear opportunity for healthcare providers to better educate ourselves on the topic of transgender healthcare to help narrow health outcome disparities, to facilitate access to medication, and to combat stigma. In this article, we will focus on gender-affirming hormone therapy (GAHT) and drug dosing considerations in this population.  

For a quick overview of relevant terminology, click here.

Hormone therapy for gender transition

GAHT aims to reduce endogenous sex hormone levels, thus reducing the secondary sex characteristics of the individual’s gender assigned at birth. GAHT replaces endogenous sex hormones to levels consistent with the individual’s gender identity by using the principles of hormone replacement treatment of hypogonadal patients. Doses are variable and can be tailored to patient-specific factors and goals.3  

Transmasculine patients may receive androgen preparations to induce masculinization of secondary sex characteristics. This results in physiological changes, including increased muscle mass, decreased fat mass, increased facial and body hair, acne, male pattern baldness in genetically predisposed individuals, and cessation of menses.4

Transfeminine patients may be given estrogen preparations to induce feminization of secondary sex characteristics.  Physiological doses of estrogen alone are insufficient to suppress testosterone levels into the cis female range in transfeminine patients who have not undergone gonadectomy; therefore, adjunct medication with androgen-suppressing agents is needed to supress testosterone further in transfeminine patients with gonads. Physiological changes in trans women can include redistribution of facial and body subcutaneous fats, breast development, reduction in muscle mass and body hair, change in sweat and odor patterns, and possible arrest or reversal of scalp and hair loss.

GAHT may impact fertility. Masculinizing and feminizing hormones regimens have variable temporary and long-term impacts. Therefore, there is a need for clinicians and patients to discuss birth control and the possibility of fertility preservation prior to the initiation of hormone therapy.5

Note that medications may differ in coverage depending on provincial drug plans.  


Masculinizing hormone therapy

Testosterone 

Endocrinologic masculinization of patients is achieved through use of testosterone to induce male physical characteristics. Testosterone works primarily by direct stimulation of androgen receptors in target tissues. Clinical effects correlate to elevation of serum testosterone level to a cis male reference range, rather than decreasing serum estradiol. All testosterone preparations are chemically equivalent to endogenous testosterone secreted from human testis. Testosterone is available in several injected and topical preparations. Testosterone enanthate or testosterone cypionate are the most used injections. Dosing can be done weekly or biweekly depending on patient-specific factors and goals. Both products can be used intramuscularly or subcutaneously; however, weekly injections are preferred to reduce peak/trough variation. Intramuscular therapy is associated with greater side effects, as it causes high peaks and low troughs.5,6 Topical testosterone can be used, however masculinizing effects are slower due to a longer time needed to reach cis male range physiological concentrations. The transdermal patch is changed daily. The gel is less commonly used due to the impracticality of applying daily, worry of washing it off, and the potential of transferring it to others through contact. Patients require monitoring of levels to reach individual targets based on physiologic cis male range. Supraphysiological levels may cause adverse effects such as erythrocytosis, sleep apnea, hypertension, excessive weight gain, salt retention, and lipid changes. Lab test monitoring is done every 3 months in the first year, then once or twice every year. Generally, a mid-cycle level is sufficient, but if the patient is experiencing cyclic symptoms such as migraines, pelvic cramping, or mood swings, peaks (1-2 days post-injection) and trough (1 hour before new dose) levels can be taken to determine wide fluctuation in hormone levels.

Post-gonadectomy, patients are recommended to receive the same dose of testosterone prior to surgery. This is because the removal of female gonads has no influence on testosterone production. Therefore, the testosterone target remains the same. Some patients may choose to reduce their dose, which is appropriate as long as dosing maintains bone density.4

 

Feminizing hormone therapy

Estrogen 

Estrogens are the sex hormone used in the feminizing protocol. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. They function through direct activation of estrogen receptors found in the body. Specifically,17-beta estradiol (estradiol) is given to patients over synthetic ethinyl estradiol (EE) and conjugated estrogens found in hormonal contraceptives, due to a smaller risk of Venous Thromboembolism (VTE).7 VTE remains a serious adverse event of feminizing hormone therapy in transfeminine patients, especially in individuals with additional risk factors like older age, obesity, and smoking. Estradiol serum concentration can also be monitored through blood analysis (unlike with EE), allowing clinicians to target physiological estrogen ranges found in cis women. This minimizes the likelihood of side effects and simplifies dose optimization.8  

Estradiol is offered in multiple formulations including oral and sublingual forms, intramuscular injection (IM), a transdermal patch, and a transdermal gel. Oral estradiol is subject to the first pass effect which, according to the first pass hypothesis, contributes to negative hepatic and prothrombotic effects. Sublingual estradiol provides rapid absorption followed by a rapid fall in serum levels over the first 6 hours of dosing. Experts postulate that this more closely mimics physiological estradiol. Serum levels reach higher peaks than oral formulation and have a larger area under the curve over 24 hours. This may translate into a greater physiological effect. Some individuals may appreciate this theoretical benefit, but the rapid peaks and increased periodicity may make monitoring of serum levels more difficult.5 IM has similar peaks and increased periodicity; however, it is not routinely used as it takes a long time to reach steady state and has a high potential for abuse and overdose.8 Topical estradiol formulations do not go through the first pass effect, therefore there are less prothrombotic risks and relatively steady serum levels. It is preferred in patients who are over 40 or who have risk factors for cardiovascular and thromboembolic disease. Most commonly, patients receive the transdermal patch (EstradotTM). Other topical formulations include a cream manufactured through compounding pharmacies and a gel (EstragelTM). The area of the skin needed for adequate absorption of the gel is large and can be inconvenient for patients. Further, it is difficult to achieve target serum concentrations with the cream and gel formulations. They are good alternatives for the patch if an individual experiences a skin reaction as a result of wearing the patch.4,5,8 Adverse effects of hormonal estrogen therapy include cardiovascular disease, hypertriglyceridemia, liver or gallbladder dysfunction, migraines, mood swings, hot flashes, and weight gain.3  

Venous Thromboembolism (VTE) 

Historically, studies on transfeminine patients have revealed a significant increase in thromboembolic events with estrogen administration at the highest risk during the first year of treatment. However, many of the patients in the original studies evaluating thromboembolic risk were taking ethinyl estradiol, which is known to be significantly more thrombogenic than estradiol.9 Current studies make it difficult to infer a conclusion on thromboembolic risk in transgender women due to the heterogeneity of the populations studied. Significant confounders such as smoking, obesity, and age – all of which are known risk factors for developing VTE -- make it difficult to assess estradiol’s influence.8,9 While our current knowledge is somewhat limited, as clinicians we can promote smoking cessation and an active lifestyle. 

Hormone cessation perioperatively 

It is a common practice to stop estrogen 2 to 4 weeks prior to surgical procedures due to the increased risk of VTE.8 A 2019 systematic review on the surgical risk of VTE for transgender patients receiving exogenous hormones suggests that there is no evidence to support routine discontinuation of all hormone therapy prior to surgery. The authors state that most of the risk was associated with oral estrogen, which is not routinely used in transgender patients. Even with oral formulations, the reports of VTE are conflicting. More research is needed to confirm the safety of continuing hormone treatment and to identify the risks of short-term discontinuation.10 

Antiandrogens  

Antiandrogens are utilized to suppress testosterone production and block its effects to minimize male secondary sex characteristics. However, many secondary sex characteristics are permanent upon completion of natal puberty and are irreversible. Antiandrogens have a secondary effect of allowing the use of lower levels of 17-beta estradiol (estradiol) and therefore a reduction in estrogen-related side effects.

  1. Spironolactone is a potassium sparing diuretic but is commonly used as an androgen blocker in feminizing regimens. At high doses (100-400mg/day), spironolactone blocks androgen receptors and supresses testosterone synthesis. Hyperkalemia remains the most serious risk, but it is very uncommon in patients with no contraindications (ACEi, ARBs) and adequate renal function. Monitoring blood pressure and electrolytes should be done frequently. Additionally, due to the diuretic effect of spironolactone, patients may experience polyuria, polydipsia and orthostasis.4 
  2. Oral Cyproterone is a synthetic steroid with progestin-like activity. It blocks androgen receptors similar to spironolactone, but it has secondary effects of inhibiting 5-alpha reductase and inhibiting luteinizing hormone (LH) secretion, thus leading to decreased testosterone production.5,6,11 Cyproterone can cause liver enzyme elevation, hepatotoxicity, anemia, thrombocytosis, and prolactinoma, especially when paired with estrogen. This drug is two-thirds excreted in the feces and one-third cleared in the urine, therefore it is contraindicated in active liver disease and severe renal insufficiency.  
  3. 5-alpha reductase inhibitors, including finasteride and dutasteride, are used less commonly, but are nevertheless antiandrogen options. Finasteride and dutasteride block 5-alpha reductase mediated conversion of testosterone to more potent androgen variants. However, since they are not directly blocking testosterone activity or affecting its synthesis, the antiandrogen affect is lessened. 5-alpha reductase inhibitors are a good choice if spironolactone is contraindicated or for patients seeking partial feminization. They may also be an appropriate choice for adjunct therapy to complete androgen blockade or orchiectomy (surgical removal of one or both testicles).4 

Generally, following gonadectomy, most transfeminine patients will not need androgen suppression, however estrogen supplementation is needed long-term to avoid hypogonadism and to preserve bone mineral density.8 Reducing estrogen dosing is not required post-operatively, but some patients may find that a lower dose suffices to maintain feminization in the absence of any endogenous estrogen.5 

Changes in Hemoglobin and Hematocrit (H&H) 

The use of antiandrogen agents in feminizing hormonal regiments causes lower testosterone availability and activity. This translates to a decrease in erythropoiesis, leading to a decrease in H&H. Therefore, for H&H in trans women, it may be reasonable to reference lower limit ranges congruent with gender identity. For the H&H upper limit, it may be reasonable to use cis male ranges: trans women do not menstruate, and if the patient still retains gonads, there is a pulsatile release of testosterone that may positively influence H&H.4 

Testosterone increases erythropoiesis and stops menses in trans men, leading to an overall increase in H&H. Therefore, it is reasonable to use cis male ranges as the upper limit of normal and, if patients are amenorrheic, to use cis male lower limits for H&H.4 

Adolescent treatment

Young adolescents with gender dysphoria or gender incongruence can experience psychological harm, including suicidal ideations and depression. Psychological interventions may be useful and sufficient for some, but others perceive the physical changes of puberty as highly discomforting and unbearable. Medical interventions can prevent psychological harm. There are dedicated clinics in each province (such as SickKids and CHEO Gender Diversity Clinic) that are able to supress puberty in young adults with medication. Pubertal suppression is fully reversible and can enable adolescents to live in their experienced gender before deciding to proceed with gender-affirming sex hormone treatment and surgery.3 Pubertal suppression also allows time for adolescents to attain the cognitive ability and maturity to consent to gender-affirming therapy.12 

Pubertal development and gonadal function are suppressed most effectively via gonadotropin suppression using GnRH analogs. GnRH analogs are long-acting agonists that suppress gonadotropins by GnRH receptor desensitization after an initial increase of gonadotropins.3 The agent used is leuprolide acetate which is dosed by weight and is injected muscularly every 4 weeks. Bone density is a concern when suppressing puberty in individuals, therefore calcium and vitamin D is supplemented. Further bone density scans should be evaluated every 6-12 months.12 In female-assigned patients, breast tissue will become atrophic, and menses will stop. In male-assigned patients, virilization will stop and testicular volume may decrease. Some other side effects include hot flashes, fatigue, and mood alterations.

Dosing considerations in transgender patients

A recent review assessed the implications of GAHT on medication dosing. Specifically, the paper reviewed current literature for effects on serum creatinine and lean body mass. Four studies reported on biometric laboratory values. Three studies reported that after hormone therapy, values of transgender patients more closely resembled the standard values of their gender identity as opposed to their assigned sex at birth. One study reported a range that more closely resembled those associated with their assigned sex at birth. As a result of these findings, the authors recommend that creatinine clearance (CrCl) and ideal body weight should be calculated based on patient’s gender identity after a patient has been on hormone therapy for 6 months or longer.13 However, this in itself may not be ideal as the difficulty in estimating creatinine clearance is compounded by a patient’s sex, age, weight, height, and muscle mass. Therefore, it may be best to determine creatinine clearance through a 24-hour urine collection, which is independent of a patient’s sex, weight, or height. This method may be inconvenient for the patient, however accurate creatinine clearance is necessary for dosing.13


Click here for references.