Hormone replacement therapy (HRT) is a medical treatment for the transgender, transsexual or non-binary gender patients with a diagnosis of gender dysphoria.
Its goal is to relieve the dysphoria and lead to psychological well-being by minimizing the secondary sexual characteristics of the gender assigned at birth (biological gender) and by inducing the development of the secondary sexual characteristics of the opposite gender or gender identity.
In the case of the FtM patients (Female to Male or F2M) which are the transgender individuals who were assigned the female gender at birth, hormonal therapy will be masculinizing and its goal will be to minimize female features and induce the development of male features, to reflect the patient’s gender identity. In the specific FtM case, the changes induced are often clear and satisfactory.
The effects of hormone replacement therapy are subjective, meaning that they vary based on the subjective physiological response of each individual. Different are also the expectation of each person with gender dysphoria: some might look for a mild de-feminization to achieve an androgynous result, others might want a strong masculinization with total defeminization.
It is also important to remind that having a gender identity which is different from the gender assigned at birth does not imply resorting to medical therapies, such as HRT, or surgical therapies, such as sex reassignment surgery; it is up to each individual to decide what path to follow based on their own expectations and personal characteristics, with the help and advice from the experts in the field. It is not up to the society, to the physicians or to the psychologists to impose anything. It is up to them though to evaluate specific risks and advise or discourage certain therapies or procedures.
The physical effects of hormone replacement therapy for the FtM transgender
As previously stated, the effects vary based on each individual physiologic response. In general, we can expect:
- Lowering of the voice pitch
- Growth, thickening and darkening of facial and body hair
- Cessation of menstruation
- Increased volume of the clitoris
- Breast and vaginal atrophy
- Increase of libido
- Decrease of fat mass with change in its storage pattern
- Increase in muscle mass and strength
Other effects not desired but possible:
- Increase in sebum secretion and skin more prone to acne
- Onset of androgenetic alopecia (male pattern hair loss in the frontal-temporal region)
- Behavioral and mood changes
- Sleep apnea
- Weight gain and increase in abdominal visceral fat
Most of these changes start after 1-12 months from the beginning of HRT and the maximum results are expected after 1-5 years. The period is expected to stop early, between 2-6 months from the beginning of HRT and it is usually a highly satisfactory event for the patients.
Side effects of hormone replacement therapy for the FtM transgender
HRT like any other therapy carries risks and it is possible to experience side effects:
- Polycythemia, which is an increase in RBC number in the blood resulting in an increased hematocrit.
- Hyperlipidemia, which means an elevated level of lipids in the blood
- Water retention with appearance of edemas
For this reason it is always recommended to be under the care of an expert endocrinologist. Regular doctor’s appointments and blood tests every three months during the first year of HRT and every 6-12 months from the second year on.
Medications available and administration route for masculinizing hormone replacement therapy
HRT for the FtM transgender utilizes almost exclusively testosterone, which is available in multiple forms, doses and routes of administration.
Oral testosterone (testosterone undecanoate, brand name Andriol® or Jatenzo®) is not advised as it has lower efficacy when compared to other routes of administration because of lower serum testosterone levels; moreover it has limited efficacy in suppressing menses, it has potential liver toxicity and can increase the risk of hepatic cancer. It needs to be taken 2 to 3 times per day.
Parenteral testosterone (intramuscular) is available in a diverse range of formulations containing testosterone esters (cypionate or enanthate) with brand name Sustanon® or Testoviron® in 250ng vials; esters are molecules that allow for an extended release of the drug, although not linear. This determines the need for an injection every 2-4 weeks, depending upon the individual response, goals and expectations. Nonlinear release means that the blood level of testosterone between one injection and the following will vary: the first days following an injection the testosterone levels will be higher, with possible side effects such as aggressivity and excessive libido, while the final days before the next injection they will be lower than needed, with possible sides such as irritability and tiredness. To avoid or limit such issues it is possible to increase the number of injections using a lower dose of medication. Since 2007 and approved in 2019 by the FDA in the USA, testosterone undecanoate for intramuscular use is available (brand name Nebid® in 1000mg vials); this formulation is able to keep testosterone blood levels stable for about 12 weeks.
Third and last administration route available is the transdermal one, by applying a gel containing the drug to the skin. The most common brand names are Androgel® and Testogel® available in single use 50mg sachets, Testim® available in single use 50mg tubes and Tostrex® 2% in multidose 60g tubes. Transdermal formulations are usually prescribed and advised as maintenance long-term therapy or post-surgery (ovariectomy).
In any case, supraphysiological levels of testosterone are to be avoided and should only be sought levels in the normal range of biological males. For this reason, the endocrinologist will prescribe regular blood tests, often in the days prior the next injection (when levels should be at the lowest), to avoid too high or insufficient levels of testosterone during the entire duration of the treatment.
Other medications used as hormone replacement therapy for the FtM transitioning are progestins, such as medroxyprogesterone, or GnRH-agonists (gonadotropin releasing hormone agonist). They are both used only in some cases and only as a short term treatment to induce menstrual cessation early in HRT.
Increased risk associated with HRT in FtM transgenders
Increased risk linked to masculinizing hormone replacement therapy are divided into three categories:
- Likely increased
- Possibly increased
- Inconclusive / not increased
As any medication or medical procedure there are links between the probability of an adverse event and the therapy taken. These risks depend upon many factors: age, comorbidities and anamnesis, dosage, route of administration, period of administration, …
Among the likely and possible risks there are polycythemia, weight gain and increase in visceral fat, lowering of HDL cholesterol and modification of the lipid profile (LDL, HDL, triglycerides), liver enzymes elevation and exacerbation of underlying psychiatric disorders (especially with supraphysiologic blood levels of testosterone).
The endocrinologist will take care of prescribing all the exams and collect all the information needed to inform you of possible risks and minimize their chance and to keep you informed on your specific situation. Among the many, the osteoporotic, cardiovascular and neoplastic risk will be evaluated.
Indications of masculinizing hormone replacement therapy
The criteria to access HRT with testosterone for FtM transgender patients are defined by the Standards of Care 7th edition of the WPATH (World Professional Association for Transgender Health).
- Persistent and well documented diagnosis of Gender Dysphoria by a mental health professional.
- In full possession of one’s faculties. Able to make a fully informed decision and to give consent for treatment.
- Age of majority in a given country.
- The absence of absolute medical contraindications (medical conditions which would make it too risky to start HRT).
Masculinizing hormone replacement therapy as a criterion for surgical therapy in FtM transitioning
Some of the many available plastic, reconstructive and aesthetic surgeries for the treatment of gender dysphoria in the FtM patient have being on HRT with testosterone as a prerequisite, according to international guidelines.
For ovariectomy and hysterectomy the criterion is being on HRT for at least 12 continuous months; this is due to the fact that it is better for the patient to experiment with a partially reversible transition before undergoing irreversible surgery. For the same reason, HRT is also a pre-requisite to metoidioplasty or phalloplasty with 12 months of continuous therapy and 12 months of continuous living in the gender role congruent with the patient’s gender identity; again this is based on expert clinical consensus that this experience provides ample opportunity for patients to socially adjust in their desired gender role, before undergoing irreversible surgery.
For the mastectomy no pre-requisite is set.
Before undergoing any surgery, HRT is paused during the 2 weeks prior to the surgery, due to the fact that testosterone increases the risk of thromboembolic events. Therapy is then restarted a few days after surgery, when prescribed by the surgeon responsible for the patient’s health and wellbeing.
Risk assessment: absolute contraindication to hormone replacement therapy
Hormone replacement therapy with testosterone carries risks as we have previously seen. In some cases, some comorbidities might represent absolute contraindication to the prescription of HRT and thus to its start. This is because the risk of negative events for the patient would be too high. Among these cases there are:
- Pregnancy, during which the risk would not only be for the transgender patient, but also for the developing embryo or fetus.
- Unstable coronary artery disease
- Untreated polycythemia with a hematocrit of 55% or higher
- The presence of risk factors for the development of cancer, especially the estrogen-dependent ones, as testosterone may also be converted into estradiol by an enzyme called aromatase. Elevated levels of estrogen can raise the risk of some cancers such as breast and ovary tumors. An oncologic screening and consultation are thus advised.
- Cardiovascular and cerebrovascular diseases require a specialist evaluation by a cardiologist, with special focus on the possibility of worsening of such conditions due to HRT.
- Polycystic ovarian syndrome (PCOS) if present needs to be evaluated before starting HRT. This is because PCOS is linked to an higher chance of developing diabetes, cardiovascular disease, hypertension and endometrial and ovarian cancers.
Is hormone replacement therapy capable of modifying the bone structure?
The changes in bone structure that happen during puberty and adolescence can’t be modified at a later time by HRT. If hormone replacement therapy is started during or before puberty it can stop and prevent such changes to happen. Some of the bone structures might undergo slight modifications also in adults, such as hands, feet and mandible, but most of the scheleton won’t undergo obvious modifications.
Is HRT sufficient for contraception?
Testosterone therapy greatly reduces the chances of getting pregnant but does not totally eliminate the risk of it. The FtM transgender patients who are still sexually active with male cisgender partners before SRS are advised to use contraceptive methods to avoid pregnancies.
Does hormone replacement therapy cause infertility?
HRT alone, without sex reassignment surgery like hysterectomy and ovariectomy, causes difficulty in conceiving and in some cases causes irreversible infertility. The patients interested in conceiving should discuss this with their treating physician. It will be necessary to pause HRT with testosterone and some assisted reproductive technologies might be needed, such as in-vitro fertilization (IVF) due to the modifications in the reproductive system from taking testosterone. Freezing of oocytes is an option to consider before starting HRT for the patients who have doubts or express interest regarding conceiving a child.
Does HRT reduce breast size?
Although testosterone therapy stops breast development, when it is still in its developing stage, and reduces its dimensions according to some FtM patients, there should be no obvious modifications in breast size with HRT alone. Some changes are possible and are likely due to the reduction of body fat mass and the changes in the pattern of fat storage as fat contributes to breast size.
Does increasing the testosterone dose lead to a quicker transition?
No, on the contrary the excess of testosterone might lead to elevated estrogen levels due to the aromatase enzyme, which converts testosterone into estradiol. This could lead to the opposite result, which is a slower transition and slower changes to the body. Moreover, supraphysiological levels of testosterone are not advised as they increase the risks of adverse events for the patient.
Is HRT a lifelong treatment?
HRT is generally a lifelong treatment, both for the psycho-physical wellbeing of the patient and to avoid the return of some female features, unless prescribed by the endocrinologist or treating physician due to the risks for the patient’s health. Maintenance therapy after SRS or after having obtained satisfactory results with testosterone requires lower doses compared to the initial stages of transitioning.
- Feldman, J. (2005, April). Masculinizing hormone therapy with testosterone 1% topical gel. Paper presented at the 19th Biennial Symposium of the Harry Benjamin International Gender Dysphoria Association, Bologna, Italy.
- Moore, E., Wisniewski, A., & Dobs, A. (2003). Endocrine treatment of transsexual people: A review of treatment regimens, outcomes, and adverse effects. Journal of Clinical Endocrinology & Metabolism, 88(8), 3467– 3473. doi:10.1210/jc.2002–021967
- World Professional Association for Transgender Health Standards of Care. 7th
- 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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