Introduction

This program will specifically focus on various aspects of gender affirming hormone therapy (GAHT), including medical and mental health issues, as well as legislative issues potentially impacting the prescribers’ care of the transgender community. Studies have shown that GAHT is important in the treatment of gender dysphoria and these therapies have consistently shown improvements in the social and psychological well-being of the transgender community (1).

Definition

Gender affirming hormone therapy (GAHT) is defined as the medical treatment sought by persons included in the transgender umbrella. This therapy allows the secondary sex characteristics to be more aligned with the person’s gender identity. Gender affirming hormone therapy can be used as a stand-alone treatment for persons not interested in pursuing gender affirming surgery; it may also be used before surgery to improve surgical outcomes.

Overview of Prescribing of GAHT

At present, approximately 1.5 million people in the United States alone currently identify as transgender, and the numbers continue to increase. The use of GAHT is considered to be an integral part of the routine health care offered to transgendered patients. GAHT can be used to induce either feminizing or masculinizing changes in a transgender person, in addition to various other medical and/or surgical options that all focus on aligning physical characteristics with gender identity. (2)

Clinical criteria for prescribing GAHT are multifaceted.

The World Professional Association for Transgender Health advises that medical treatment should only occur after a thorough psychosocial assessment has been undertaken by a clinician experienced in the field. (3)

Per state guidelines, informed consent must be obtained from the patient/ parental consent when applicable.

A multidisciplinary team specialized in the treatment of young people is best. General Practitioners (GPs) and Pediatricians play an important supporting role for the child and their family. Treatment varies according to the child’s stage of puberty.

Legal Issues on Use of GAHT

It is important to know your state guidelines. As licensed healthcare providers, you are responsible for understanding the laws in place in your specific state of residence and practice. Many states have specific transgender medical guidelines for treatment; you must adhere to your specific state guidelines to avoid criminal charges and sanctions against your licensure. (4)

There is varying oversight in different states, including:

• Sanctuary states that protect access to gender-affirming care for residents of that state, as well as act as a safe haven for transgender persons from other states.
• States without restrictions on gender-affirming care.
• States that restrict access to gender-affirming care for minors.
• States that restrict access to gender affirming care for both minors and adults.

Almost half of the state legislatures in the country recently passed laws restricting or banning such care. Some states have even criminalized providing minors with gender-affirming care. Some states are removing minors from their parents’ care if they allow the child to receive gender-affirming care, while others are requiring medical professionals to end any gender affirming care for minors (forced de-transitioning).

Other states have placed restrictions on the use of Medicare funds to pay for GATH. Finally, some states have threatened felony charges and loss of medical licenses to those healthcare providers who deliver gender affirming care for minor children.

For more information on your specific state and its laws regarding GAHT, click on the following link: https://www.findlaw.com/lgbtq-law/state-laws-on-gender-affirming-care.html

Indications of Use

Gender affirming hormone therapy (GAHT) is an important component of care for many trans people. These hormone therapies are medical forms of gender affirmation. Studies have shown that transgender persons are at high risk for both mental and physical health issues when denied access to gender affirming healthcare.

While the trans community welcomes GAHT, it is not without risk. GAHT has been linked with ongoing clinical changes and challenges in lipid metabolism and insulin resistance, thus increasing the risk for chronic disease. Ongoing lifestyle, medical, and psychological therapies must be a part of any GAHT treatment plan. (5)

Transgender youths who have not completed puberty can receive a class of medication called “puberty blockers,” which suppresses the release of sex hormones (testosterone and estrogen).

These medications would suppress the growth of facial and body hair and prevent the usual voice deepening associated with male puberty. For females, puberty blockers would stop normal breast development and interrupt normal menstruation. If the puberty blockers are stopped at any point in the puberty growth cycle, normal hormone function returns. The goal in using puberty blockers is thought to allow a person time to further determine their true gender identity before the emergence of permanent sex characteristics.

These medications are also used in this younger population before the start of long-term hormone therapy, as part of the entire gender affirmation therapy cycle. After puberty blocker therapy, adults usually go on to receive hormone therapy aimed at increasing levels of either estrogen or testosterone to aid in the development of sex characteristics more aligned with their chosen gender identity. (6)

According to the National Transgender Discrimination Survey, 95% of transgender people and 49% of nonbinary people were interested in hormone therapy. (7)

Puberty Blockers

As stated previously, the use of puberty blockers is aimed at delaying the changes that generally occur in puberty. By doing so, the transgendered youth is allowed critical time to explore gender identity issues and feelings of gender dysphoria. Oftentimes, the use of puberty blockers is found to improve mental health and well-being, lowering levels of depression and thoughts of self-harm.

The medications most often used as puberty blockers are called gonadotropin-releasing hormone analogues (GnRH). Puberty blockers do not cause permanent physical changes; the physical changes associated with puberty resume once the medication is discontinued (8).

Puberty blockers are usually administered as subcutaneous implants or as a 1-3 month “depot” (slow release) medication injection. This therapy halts the production of gonadal sex steroids (both testosterone and estrogen) by persistently activating and desensitizing the gonadotropin-releasing hormone receptor, which causes suppression of hormones that are generally released by the anterior pituitary gland.

These medications are fully reversible and allow puberty-related changes to resume after their discontinuation. (9)

Common medications used as puberty blockers include the following (11):

• Goserelin (Zoladex)- also used in the treatment of breast and prostate cancer, as well as endometriosis
• Histrelin (Supprelin LA)- also used in the treatment of advanced prostate cancer
• Leuprolide (Lupron, Fensolvi)- also used in the treatment of endometriosis and prostate cancer
• Triptorelin (Trelstar)- also used in the treatment of advanced prostate cancer.

The following dosing recommendations for puberty blockers refer to the treatment of precocious puberty (the intentional suppression of early puberty). In terms of the transgender community, early puberty suppression becomes gender affirming care:

• Goserelin: 3.6mg every 4 weeks as a depot injection
• Histrelin:  medicated implant inserted under the skin; removed yearly and reimplanted if desired; implant dose is 50mg; dose released is approximately 65 mcg/day
• Leuprolide: intramuscular injection (weight-based dosing); usual injected dose is 45mg every 6 months, or 22.5mg every 3 months
• Triptorelin: intramuscular injection every 6 months (weight-based dosing); total dose should not exceed 22.5mg injectable.

Puberty blockers were approved by the Food and Drug Administration in 1993. They are currently used “off-label” in the treatment of gender dysphoria; they were initially approved for the treatment of precocious puberty (early onset puberty). (12)

Side Effects

Despite being fully reversible, the use of puberty blockers is not without risk. These medications may affect standard physical growth patterns and decrease bone density in the patient, heightening the risk of bone fractures in the future. (10)

In addition, these medications may cause the following side effects:

• Changes in weight (weight gain)
• Changes in mood
• Headaches
• Hot flashes

Masculinizing Hormone Therapy

Masculinizing hormone therapy uses various types of testosterone to promote masculinizing changes in both binary and non-binary individuals. Testosterone is most often given as an injection, but other forms are available, including pills and creams.

The use of masculinizing testosterone therapy has been shown to cause any/all of the following effects:

• Body hair/facial hair growth
• Increased muscle mass
• Increased sex drive
• Body fat and facial fat redistribution
• Hairline recession, “male pattern baldness”
• Changes in emotion
• Growth of the clitoris
• Interruption/cessation of normal menstruation
• Deepening of voice

Drug Class

Testosterone is in the drug class known as androgenic hormones, as well as an anabolic steroid. It is the primary male sex hormone and a naturally occurring anabolic steroid.

Testosterone cypionate is the most common form of injectable testosterone.

Side effects may include the following:

• Enlargement of male breasts
• Acne
• Localized pain at the injection site
• Changes in frequency and duration of erections
• Increase in facial and body hair.
• Changes in sex drive and a lowering of sperm count
• Feelings of anxiety, depression

Testosterone enanthate is an alternative testosterone used for persons with known allergy to testosterone cypionate. This medication is used as a testosterone replacement and is also used in the treatment of breast cancer.

Common side effects include the following:

• Enlargement of male breasts
• Acne
• Localized pain at the injection site.

In a female patient, the use of testosterone would cause the following effects:

• Deepening of the voice
• Absence of menstrual periods

Other side effects include the following:

• Elevated serum calcium
• Elevated serum cholesterol
• Elevated red blood cell counts

Mechanism of Action

The dosing of testosterone is titrated to achieve what is considered the physiological concentrations of the preferred gender. For that reason, dosing is individualized, based on body composition (height/weight and desired outcomes). Testosterone titrating aims to achieve maximal effectiveness with minimal harmful side effects. (13)

Different forms of testosterone

• Topicals – includes patches, lotions, and gels, applied daily (topical testosterone, 50 mg/5 g sachet initial dose)
• Intramuscular injections – every 1 to 4 weeks (testosterone undecanoate 1000 mg every 10–12 weeks)
• “Pellet” implants – inserted under the skin every few months via a minor in-office procedure (testopel pellets-> 75mg/pellet)

*Dosing is dependent on BMI, body fat, patient compliance, age, etc. (14)

Side Effects

Several physical, mental, and emotional changes are possible with testosterone therapy, such as:

• Redistribution of weight from thighs and hips to the abdomen
• Increased muscle mass
• Changes in facial features (such as the appearance of a more angled jawline)
• Deepened voice, vocal pitch
• Increased libido
• A different range of emotions
• Changes in clitoral size and length
• Shortened or absent menstruation

Alternatives

If GAHT alone does not achieve its desired goals, surgical intervention may be considered. For those individuals requesting body changes without masculinization, breast augmentation and low estrogen doses may be an additional option. Additionally, some transgender individuals may request partial feminization or partial masculinization without affecting actual sexual function. (15)

Feminizing Hormone Therapy 

Feminizing hormone therapy, or estrogen hormone therapy, is a treatment protocol that is used to induce the female or feminine physical traits while also suppressing the masculine physical characteristics. Feminizing hormone therapy, conversely, uses a combination of estrogen and a testosterone blocker.

This estrogen hormone therapy has also been referred to as “male-to-female” (MTF) hormone therapy. Used correctly, estrogen hormone therapy offers the transgender patient the benefits of an improved quality of life by reducing gender dysphoria and increasing gender congruence. (16)

The additional use of a testosterone blocker in this case is because testosterone is stronger in its effects on the body than estrogen. Various forms of estrogen may be used for gender affirming hormone therapy, including oral tablets, transdermal patches, or injectables.

The use of feminizing estrogen in combination with testosterone blocker therapy has been shown to cause any/all of the following effects:

• Breast growth and development
• Body fat redistribution
• Reduction of facial and body hair
• Muscle mass reduction
• Testicular size reduction
• Reduction in erectile function

Drug Class 

The primary form of estrogen used is estradiol.

In estrogen-based GAHT, bioidentical estrogen (17-beta estradiol) is used. The term “bioidentical” describes hormone therapies chemically similar to the hormones our bodies produce. (17).

Dosing and Mechanism of Action

The time interval for maximal benefits varies throughout the transgender population, with an average of 18-24 months of therapy to achieve desired results. Initial changes such as chest development and nipple area tenderness may occur as early as 3-6 months after initiation of treatment.

It is possible that an individual taking GAHT, even at maximal dosing, may not achieve their desired testosterone suppression; hence, surgical interventions may be considered.

The initial prescribing doses of estrogen (estradiol) hormone therapy are as follows:

• Oral estradiol (valerate) is available at 2.0-6.0 mg daily.
• Transdermal estradiol patches are available in doses of 25- 200ug (new patch placement usually every 3-5 days)
• Parenteral estradiol valerate is available as an intramuscular injection of 5-30mg IM every 2 weeks or 2-10mg IM every week.

Starting doses, titrating doses, and medication availability are driven by patient preference, provider input and guidance, insurance plan formulary coverage, and pharmacy medication availability. (18)

Contraindications for Estrogen Therapy:

• Previous history of VTE (Venous thromboembolism)
• History of estrogen-sensitive neoplasm
• Advanced stages of chronic liver disease
• Hypertriglyceridemia (relative contraindication) (19)

Alternatives

Feminizing GAHT uses a form of estrogen, known as estradiol, to suppress the body’s production of testosterone. This medication regimen may also include progesterone and possibly another medication (“anti-androgen”) to suppress male hormone production further. (20)

The desired effects of these feminizing medications include the following:

• The development of breast tissue and female pattern fat distribution
• A decrease in testicle size
• A decrease in facial and body hair

Potential side effects of this medication include the following (21):

• Blood clot development
• Elevated levels of serum triglycerides
• Changes in mood, affect, and potential worsening of pre-existing mental health illnesses.
• Increased risk of breast tissue tumors and other hormone-sensitive cancers (such as prostate and pituitary cancers)
• Changes in fertility (decreased ability to produce sperm)

Warnings and Special Considerations

• The use of GAHT elevates the risk of blood clot formation, including deep vein thrombosis and pulmonary embolism.
• The risk of elevated triglyceride levels predisposes a patient to a heightened risk of stroke, heart disease, hypertension, and osteoporosis.
• The risk of heightened mental health issues is elevated with the use of GAHT and may lead to worsening depression and heightened suicidal tendencies.

Testosterone Blockers or Androgen Blocker Therapy

As you may recall, testosterone is a type of androgen sex hormone naturally produced. Medications used to block testosterone intentionally are referred to as testosterone (T-blockers) or androgen blockers.

Testosterone blockers “block” testosterone receptors, which are the proteins that testosterone interacts with. Additionally, they block the conversion of testosterone to dihydrotestosterone (DHT), a stronger form of testosterone.

It is important to note that estrogen, not testosterone blockers, is primarily involved in lowering testosterone levels.

The most commonly used T-Blockers in GAHT are spironolactone and DHT blockers, finasteride and dutasteride.

• Spironolactone (Aldactone) is a direct androgen receptor blocker, which is used off-label in conjunction with estrogen.
• Finasteride (Proscar) and dutasteride (Avodart) are 5-alpha reductase inhibitors; they block the conversion of testosterone to DHT (dihydrotestosterone), the stronger form of testosterone. (22)

Initial dosing and side effects 

Spironolactone (Aldactone) is a direct androgen receptor blocker used off-label as an estrogen supplement. The starting dose is 50mg tablets, taken once daily. As a diuretic, this medication causes increased urination and may lower blood pressure. It may also cause elevated potassium levels.

DHT has been linked to scalp hair loss. DHT blockers finasteride and dutasteride have been used to treat hair loss and are approved for the treatment of male pattern baldness. This medication may be of benefit to transgender women experiencing male pattern hair loss.

• Finasteride (Proscar) has a starting dose of 1-5mg tablet daily.
• Dutasteride (Avodart) has a starting dose that is usually 0.5mg daily.

Progesterone therapy

Progesterone is another hormone that may be used as part of an estrogen-based GAHT plan of care. Bioidentical progesterone (Prometrium) is sometimes used in GAHT (although there are not many studies available confirming the medication’s effects in this off-label usage), as it is believed that it “may” help with breast development, improvement in libido, and fullness in the hip area.

Treatment plans must be individualized and based on the individuals’ objectives, the risk-benefit analysis of the medications used, preexisting comorbidities, and socio-economic factors. The desired physical changes have no definite timeline regarding appearance. Some features may occur within a month of using GAHT, while other changes can take up to six or more months, if not years, for peak drug effect (23).

Risks

As with the use of any medication, there are certain risks associated with the use of these hormone therapies.

In general, these classes of medications heighten the risk for the following:

• High blood pressure/ cardiovascular disease
• Blood clot formation/ thromboembolism/pulmonary embolism
• High cholesterol/ dyslipidemia
• Heart disease
• Type 2 diabetes
• Weight gain
• Certain types of cancers (primarily breast and prostate cancer)
• Infertility/Interfertility
• Hepatic toxicity

Contraindications

As with any use of long-term hormonal therapy and associated treatments, a screening process should be in place to ascertain if the patient is appropriate for GAHT. Some areas of consideration have led to the following contraindications for GAHT usage. As always, the final determination is patient-specific and taken on a case-by-case basis.

Listed among absolute contraindications were the following (in no specific order):

• History of hormone-sensitive cancer (to include endometrial, breast, cervical, and prostate cancer)
• Current alcohol or drug use/abuse
• Liver insufficiency or cirrhosis
• Uncontrolled preexisting chronic medical conditions (including diabetes and hypertension)
• Preexisting history of ischemic cardiovascular or cerebrovascular conditions
• Severe psychiatric disorders influencing decision-making capacity
• Known noncompliance with previous medical treatment therapy

Nursing Considerations

The following nursing considerations are not ranked/ordered in any specific order; they are all significant areas in the care of transgender patients undergoing GAHT.

• Assess the patient’s literacy level when overseeing GAHT. Many of these hormones affect both medical and mental health, and patients should fully understand the risk factors and side effects associated with their usage.
  • Full informed consent should be obtained before beginning treatment and with additional medical therapies. (25)
• Obtain a thorough patient history regarding medical and medication compliance. All patients should be evaluated for their ability to comply with medication usage and their history regarding previous medical care and follow-up.
• GAHT use is a long-term process, and the patient must be willing to comply with the rules and regulations associated with it.
• Assess for pre-existing medical conditions. Comorbid health conditions may directly influence (prevent) the use of certain GAHT or heighten the risk of side effects.
  • Routine follow-up care and preventive health screenings are a high priority in the care of the transgender patient undergoing GAHT.
• Evaluate accessibility and affordability. Many insurance companies do not cover GAHT or limit the medications covered by their plan. The patient must understand these potential limitations, be aware of alternative coverage or alternative medications, and be aware of the associated risk of de-transitioning if the current medication regimen is no longer covered.

A multidisciplinary approach is significant in the care of a patient using GAHT. Many patients begin using GAHT to treat gender dysphoria or gender incongruence. Others may use GAHT before surgical transition.

These patients’ medical and mental health may be affected in the long term, so all patients should benefit from a multidisciplinary team to assess holistic needs throughout the transition period.

As advanced practice nurses, you should have complete transparency in the care of the transgender patient. Accept your limitations, biases, and scope of practice in knowing how to serve your patient best and when it is everyone’s best interest to be referred to other medical practitioners. The care of the transgendered patient is multifaceted and will often require professional partnerships or referrals outside your level of knowledge.

Routine care and follow-up  

All transgender patients should receive routine healthcare screenings—annual examinations, routine height, weight, and vital sign checks, and mental health screenings. They should receive the same standard of care that all patients receive in your practice setting, including annual immunizations, routine physical examinations, and (comorbid) disease-specific laboratory studies. Consideration should be given to whether your transgender patient is pre-operative or post-operative in their transition period; additional routine studies may be indicated. (26)

Preventive care   

All transgender patients should receive preventive screenings, such as annual vital signs/ weights/ blood pressure screenings, depression screenings, and skin cancer checks. In addition, due to the risk of dyslipidemia and cardiovascular side effects from some hormonal therapies, preventive screenings may also include annual lipid studies, breast self-examination, prostate and pelvic/ PAP smear examinations, counseling on sexual practices and assessment of risk factors, as well as any hormone level checks (as indicated by types of medications in use).

Ongoing counseling 

All transgender patients should be routinely screened for depression and gender dysphoria/gender identity issues.  Outside referrals to mental health professionals may be required if findings are outside your scope of practice. Additionally, alignment with group support services may be of benefit. Many transgender persons have reported significant levels of depression, anxiety, social isolation, and even suicidal ideation. Ongoing mental health therapies throughout the transgender transition lifetime are an important aspect of holistic care.

Resources (Legal, Social, Community, Surgical)

All transgender patients should be educated on the variety of services available to them within their community, as well as at the state and national levels. They may need services such as legal guidance (name changes), community resources (support groups, medication financing, employment services), and possible outside referrals for surgical intervention to complete the transition process.

Caring for the transgender population requires an interdisciplinary approach, as all healthcare professionals are highly encouraged to align themselves with a variety of services best suited for the individual patient.

Micro-dosing

Transgender patients seeking gradual and more subtle physical changes may elect to use microdosing of their GAHT (28). The effects of micro-dosing, which involves taking lower doses of hormones intentionally, allow the patient to achieve a gradual change in their body without experiencing any drastic adjustments.

The use of micro-dosing in the GAHT also affords the transgender patient some financial benefits if the full dose GAHT pricing is causing financial difficulties. Finally, micro-dosing with GAHT lowers the risk of aggravating any preexisting medical conditions that may be negatively affected by full-strength therapies.

Micro-dosing may be utilized in a variety of medications used in GAHT. Whether the transgender patient is being treated by injectables, topical gels, topical creams, or patches, the current prescribed dose may be reduced for the reasons mentioned above. For example, an injectable medication dose may be reduced from 50mg to 20mg; a patch delivery medication may be ordered at a lower dose (from 4mg to 1-2mg). Topical gel and cream-based medications may be prescribed in lower percentage concentrations.

Patients choosing micro-dose medications must be fully informed of the medication effects/side effects/ and the “anticipated” effects of this “off-label” dosing regimen.

Conclusion

The World Professional Association for Transgender Health (wpath.org) aims “to promote evidence-based care, education, research, public policy, and respect in transgender health”. As healthcare professionals, we should also strive to promote the delivery of quality care to the transgender community and ensure that they have equal access to all necessary medical, surgical, and mental health services required for their safety and well-being.

Gender affirming healthcare is a patient’s right, and the transgender community needs the support and understanding of healthcare professionals to ensure their access is not compromised. (29)