Feminizing Hormone Replacement Therapy guide for the MtF transgender patient

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Hormone replacement therapy (HRT) is a medical treatment for the transgender, transsexual or non-binary gender patients with a diagnosis of gender dysphoria.

It is prescribed by the GP or by the specialist physician who is attending the patient with the aim of minimizing the secondary sexual characteristics which are typical to their gender assigned at birth and to develop the secondary sexual characteristics typical of the opposite gender thus reflecting their perceived gender which is known as gender identity. The goal of hormone replacement therapy is therefore to change the secondary sexual characteristics of the patient so that these will reflect their gender identity, with an improvement in their psychophysical condition and to help with their social inclusion and recognition in the society in their chosen gender role and gender identity.

In the case of MtF patients (Male to Female or M2F), which are individuals born as biological males, hormone replacement therapy will be defined as feminizing and demasculinizing as it will work towards stopping and reversing the development of the male sexual characters and induce the development of the female features.

The effects of hormone replacement therapy for the MtF transgender patient are subjective and depend upon multiple factors among which the number and the response of the estrogen receptors naturally occurring in the patient’s tissues and upon the time in life in which therapy is started. It is also subjective the aesthetic result that each patient wants to achieve, and which is not necessarily ultrafeminine in the case of the MtF transgender, but for instance it could be androgynous.

The patient with gender dysphoria doesn’t necessarily undergo medical and/or surgical procedures. It is up to each individual to decide what steps to take to solve the issues caused by the dysphoria. Facing and solving the feelings resulting from the incongruence between the sex assigned at birth and the gender identity, such as stress, anxiety and depression, are the aim of psychotherapy which is advised to better identify, discover and understand themself,  and to undertake the most appropriate path to reach their goals, first and foremost their psychophysical well-being. It is not up to the physician, to the psychotherapist or to the society to decide what is the path to undertake, from psychotherapy, to HRT, to surgeries; the healthcare professionals though, who are experts in the specific field of gender dysphoria, have to counsel and recommend what in their opinion is best for the patient basing their counseling on their studies, experience, the best available science, most recent publications, and international consensus; the patient can then chose freely what is best for theirself.

Physical effects of hormone replacement therapy (HRT) during MtF transitioning

As previously said, the effects from the feminizing HRT depend upon many factors, among which:

  • The age of the patient when they begin HRT. If the development of the secondary sexual characteristics is still ongoing, not yet started or has ended already.
  • The aesthgetic goal of the patient, which can vary from a mild demasculinization to achieve an androgynous result, to a marked feminization with total demasculinization.
  • The subjective response of the patient to the medications, depending upon their own physiology.

In general, the expected physical changes in the MtF transgender patients are the following (between brackets the expected start of noticeable changes and the achievement of the maximum result, again this is approximate and depending upon several factors):

  1. Body fat redistribution (3-6 months; 2-5 years). There will be a variation in the body fat deposition pattern. Abdominal fat will decrease, but it will increase in the glute and hips areas.
  2. Decrease in strength and muscular mass (3-6 months; 1-2 years).
  3. Skin thinning and reduced sebaceous gland activity (3-6 months; unknown). The skin will have the tendency to become thinner and the sebaceous glands will decrease their activity, resulting in dryer skin and possibly a reduction in the severity of acne if present.
  4. Libido reduction (1-3 months; 1-2 years).
  5. Reduction in spontaneous erections (1-3 months; 3-6 months).
  6. Sexual dysfunction (variable; variable)
  7. Breast development (3-6 months; 2-3 years). Thelarche or breast buds start being visible after 2-3 months from the beginning of the hormone replacement therapy. The extent of the development varies from subject to subject and depends upon the number of naturally occurring estrogen receptors in the breast tissue. The development seems to not be related to the treatment plan (dose and medication scheme). Most of the patients will undergo breast augmentation at a later time.
  8. Reduction in testicular volume (3-6 months; 2-3 years).
  9. Reduced sperm production (variable; variable). This, with the previous point, will lead to irreversible infertility, hence it is very important for doctors and patients to discuss this aspect of transitioning.
  10. Prostate volume reduction. The prostate will decrease its size by about 30%.
  11. Thinning and slower growth of facial and body hair (6-12 months; >3years). Beard, mustache, chest, abdomen, legs, arms, … all experience a progressive air thinning starting from about the 6th HRT in this case is not decisive and other treatments are often needed if the patient wants to get rid of hair, such as laser treatments, electrolysis, IPL or other permanent or temporary treatments depending upon the patient’s needs and goals.
  12. Stop of male pattern hair loss (1-3 months; 1-2 years). Male pattern hair loss or androgenic alopecia will stop within a couple of months. There is no regrowth of loss hair, but those which were thinning (going through the involution process) and not yet permanently lost will start growing back stronger, thicker and longer as “normal” hair.

There will also be a change in mood. Usually a lower aggressivity is observed, while being more prone to mood swings.

Side effects of feminizing hormone replacement therapy for MtF transgenders

As any other therapy, HRT carries risks and side effects.

There is a decrease in bone mineral density, with bones becoming similar to those of cisgender women, but therapy should not induce osteopenia nor osteoporosis. There might be also an increase in body weight due to the increase in body fat mass. There is also a 15% chance of experiencing hyperprolactinemia due to the development of lactotroph cell hyperplasia or prolactinomas.

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Medications and route of administration of feminizing hormone replacement therapy

Differently from FtM HRT where a single class of drugs is used (androgens, which means testosterone in one of the many forms, dosages and routes of administration available), feminizing HRT for the MtF patient utilizes a combination of different class of drugs, available in multiple forms and dosages.

Estrogens

Estrogens are available in different forms:

  • Oral route: such as estradiol or estradiol valerate with a daily dose of 2-6mg
  • Parenteral route (intramuscular): such as estradiol valerate with a weekly dose of 2-20mg or a fortnightly dose of 5-20mg
  • Transdermal route: such as estradiol patch 0,1-0,4mg/24h once or twice a week or estradiol hemihydrate gel 0,5-1,5mg/dose

Conjugated estrogens and ethinyl estradiol are not recommended due to the increased risk of cardiovascular pathologies such as deep vein thrombosis (DVT) and linked cardiovascular events.

Transdermal formulations seem to carry a lower risk of DVT as well as they seem not to raise triglycerides levels in the blood, whilst parenteral and oral estrogens seem to do so.

Anti-androgens

This is a class of drugs that reduce both the levels of endogenous testosterone and the effects caused by testosterone on the various organs and tissues of the body. Antiandrogens also lower the dose of estrogen needed and help in reversing the male features of the individuals.

  • Cyproterone acetate. A progestin medication with antiandrogen action, not approved in the USA, but cleared in other countries. Daily dose is 50-100mg through oral route and the drug might induce liver damage.
  • GnRH analogues. Gonadotropin Releasing Hormone analogues are pricey medications the totally block the release of hormones by the gonads so in the case of transgender women they suppress the production and release of testosterone. They are usually administered through the parenteral subcutaneous route. Some examples of such medications are Leuprolide Acetate 3,75mg/month or 11,25mg every three months; Triptorelin 3,75mg/month or 11,25 every three months; Goserelin Acetate 3,6mg/month or 10,8mg every three months.
  • Spironolactone. An antimineralocorticoid mainly used as hypertension medication. In HRT it has an antiandrogen effect due to decreasing the synthesis and the release of testosterone and inhibiting the bond between testosterone and androgen receptors. It requires careful monitoring of blood pressure and blood electrolytes such as potassium due to its pharmacodynamics. The medication is taken through the oral route with a dose of 100-200mg/day.
  • 5-alpha-reductase inhibitors (5-ARIs or DHT blockers). They block the conversion of testosterone into the more active and potent androgen dihydrotestosterone (DHT). They are effective in stopping and reversing male pattern hair loss, in reducing body hair growth and in reducing sebum production by sebaceous glands leading to a skin consistency more similar to the biologic female gender. The medication is taken through the oral route. Finasteride 2,5-5mg/day or Dutasteride 0,5mg/day.

Indications for estrogen HRT for the MtF transgender

There are some criteria to be met before having access to HRT as established by the international guidelines published in the Standards of Care 7th edition of the WPATH (World Professional Association for Transgender Health). These are clinical guidelines and may be modified by individual healthcare professionals based on the unique features of each patient.

  1. Persistent and well documented diagnosis of Gender Dysphoria by a mental health professional.
  2. In full possession of one’s faculties. Able to make a fully informed decision and to give consent for treatment.
  3. Age of majority in a given country.
  4. The absence of absolute medical contraindications (medical conditions which would make it too risky to start HRT).

If mental health conditions are present, they do not preclude access to HRT. Guidelines recommend managing those conditions before beginning therapy and for them to be reasonably well controlled.

Risks of feminizing hormone therapy (MtF) 

Before starting and while being on HRT it is very important to check and monitor several clinical parameters and to establish the risks associated with feminizing HRT. Among these there are the liver function and blood lipid profile.

The likely increased risks facing while on feminizing HRT for MtF transgenders are the increased risk of venous thromboembolic events, increased blood lipid levels, weight gain, gall stones and liver enzymes elevation.

In case of other concurrent risk factors, HRT could increase cardiovascular risk too.

Due to the increased risk of deep vein thrombosis it is recommended that all patients quit smoking.

The possibly increased risks are hyperprolactinemia, development of prolactinomas and hypertension.

In case of concurrent risk factors there could be an increased risk of type 2 diabetes.

Although HRT leads to changes in bone structure, there is no increased risk of osteoporosis. There is no clear conclusion on the degree of risk of developing breast cancer when comparing the MtF transgender women to that of biological females.

Patients over 50 years of age still should take into consideration the risk of developing benign prostate hyperplasia or a prostate tumor. Although HRT does not increase the risk of it, it’s always good to perform exams for early diagnosis.

Feminizing hormone replacement therapy as a criterion for surgical therapy in MTF transitioning

Some of the many available plastic, reconstructive and aesthetic surgeries for the treatment of gender dysphoria in the MtF patient have being on HRT as a prerequisite, according to international guidelines.

Although not being a prerequisite for augmentation mammaplasty (breast augmentation) by lipofilling or implants, HRT is highly recommended before this surgery takes place; the reason is that to have the best aesthetic result it is better to wait until the maximum physiological development of breast tissue is reached. Hence, 12 months on HRT are advised before undergoing the surgery.

For orchiectomy the criterion is being on HRT for 12 months. This gives the patient the chance of trying the suppression of testosterone and the introduction of estrogens in a reversible way, before going through an irreversible surgery.

Also, the vaginoplasty has the HRT criterion, paired with the one about living continuously for at least 12 months in the gender role that is congruent to their gender identity. Again, the international expert consensus bases this on the fact that this provides ample opportunity to experience and socially adjust in the patient’s desired gender role before undergoing irreversible surgery.

Risk Evaluation: absolute contraindication to feminizing hormone replacement therapy

As seen previously, the HRT for MtF transgender carries risks. In some cases, comorbidities can preclude HRT due to its absolute contraindication. This is because the risks for the patient are too high. Among these cases there are:

  • previous venous thrombotic events related to an underlying hypercoagulable condition
  • history of estrogen-sensitive neoplasm
  • end-stage chronic liver disease

Sources
  • World Professional Association for Transgender Health (WPATH) Standards of Care. 7th ed.
  • Transgender Medicine: A Multidisciplinary Approach.
    Leonid Poretsky, Wylie C. Hembree. Springer, 2019
  • Principles of Transgender Medicine and Surgery, second edition.
    Randi Ettner, Stan Monstrey, Eli Coleman. Routledge, 2016.
  • Management of Gender Dysphoria
    Carlo Trombetta, Giovanni Liguori, Michele Bertolotto. Springer, 2015

 

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