gender reassignment hormone therapy female to male

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What is T therapy, and when can a person start it?

Female-to-male (FTM) testosterone therapy, or T therapy, is a treatment that some people may receive to induce “masculine” physical traits and suppress “feminine” ones.

Those who choose to undergo T therapy will receive the hormone testosterone to reduce estrogen production. Estrogen is a hormone associated with the development of typically feminine traits.

There are several potential benefits and risks associated with this therapy. Some people may experience changes within a few months, but certain changes may take a few years to take maximum effect.

This article will replace the term FTM testosterone therapy with the term T therapy. This is because FTM terminology is binary and exclusionary. Not everyone who uses testosterone-based hormone therapy is transitioning with the goal of presenting as a man.

This article will discuss T therapy, including the potential risks, the benefits, and what people can expect during and after treatment.

T therapy definition

T therapy is a treatment that induces typically masculine physical traits while suppressing typically feminine ones.

People undergoing T therapy receive the hormone testosterone. This helps decrease estrogen production and suppress menstrual cycles. It can also lead to physical changes, such as male-pattern hair growth and a deepening voice.

Changes due to treatment may be temporary or permanent.

Other names for T therapy may include masculinizing hormone therapy, cross-sex hormone therapy, testosterone-based hormone therapy, and gender affirming hormone therapy.

Why a person has it

A person may undergo T therapy if they have gender dysphoria . A person has gender dysphoria when they experience distress because their gender identity does not match their sex assigned at birth.

Testosterone treatment may reduce a person’s gender dysphoria and emotional distress and improve their quality of life. It may also promote the matching of a person’s gender identity and their body and allow them to experience gender congruence .

Undergoing T therapy during adolescence (around the age of 16 years and older) may stop the development of female secondary sex characteristics, such as breasts. It may also induce male secondary sex characteristics, such as facial hair.

Although research is ongoing, some people who wish to undergo T therapy may have difficulty receiving treatment or experience potential complications from it. This includes those who:

• are under 16 years of age
• have significant mental health complications that require treatment
• are pregnant or planning to become pregnant
• have or have had a hormone-sensitive cancer, such as breast cancer
• have a thromboembolic condition, such as deep vein thrombosis

Not everyone who experiences gender dysphoria will have T therapy. Although it may have benefits for some people, the treatment is not without risk.

The National Transgender Discrimination Survey Report on Health and Health Care reports that at least 80% of transgender people have either undergone gender affirming hormone therapy or wish to at some point.

How and when to take it

People may receive T therapy in a number of ways . These include:

• testosterone injections
• oral testosterone
• transdermal (through the skin) testosterone

In the United States, doctors prescribe the medication and provide guidelines on how to safely administer the therapy.

People typically receive T therapy as an injection, either into a muscle (intramuscular) or under the skin (subcutaneous). Most people will receive the injections weekly, though some people may require higher doses every 10–14 days .

Oral administration of testosterone undecanoate ( Jatenzo ) involves taking a pill twice daily. Transdermal options are available as a gel ( Androgel ) or a patch ( Androderm ). However, doctors are more likely to suggest these options to treat testosterone deficiency .

The age at which a person can access gender affirming hormone therapy varies across the world. For example, in Europe , many countries allow people between the ages of 14 and 18 years to access it, but in some countries, such as Holland, people can access it from the age of 12 years, as long as they have parental consent.

In some other European countries, access depends on the maturity of the person who wishes to receive the therapy.

In the U.S., most people can access T therapy at age 18 years, which is when they are capable of consent. At 17 years old, a person may have access, but they will require a parent or guardian to accompany them to appointments. At age 16 years or younger, additional paperwork is necessary for people to access such therapy.

Which changes may occur?

People may consider T therapy as a second puberty . Although some changes will occur quicker than others, it can take years for the full effect.

Changes may include :

Physical changes

Those undergoing T therapy may notice:

• thicker, oilier skin and larger pores
• acne, which may peak within the first year but then improve
• a more masculine facial appearance
• the growth of facial hair
• a deepening voice
• hair growth on the arms, back, and chest
• thinning hair on the head
• a reduction in fat around the hips and thighs
• an increase in stomach fat
• increased muscle in the arms and legs
• more prominent veins
• an increase in sweat production
• changes in the odors of sweat and urine

Some research also indicates that structural changes occur in the brains of those receiving continuous, high dose hormone therapy.

These changes could affect how a person interacts with others or their verbal and spatial abilities, for example.

Reproductive changes

T therapy will cause changes to the reproductive system, including:

• menstrual changes, such as lighter, shorter, or heavier periods before they stop completely
• difficulty releasing eggs from the ovaries
• a reduction in the ability to get pregnant

Emotional changes

Undergoing T therapy may lead to changes in a person’s emotional state. For example, a person may experience emotional shifts, or they may feel fewer emotions than they did previously. These changes may affect how the person relates to others or how they perceive things they once enjoyed.

When a person receives treatment for gender dysphoria, they may also begin to feel more like themselves and more comfortable in their own body. Some of these changes may settle down over time.

Sexual changes

T therapy will typically change a person’s libido as well as their genitals. Individuals may experience:

• an enlarged clitoris
• changes in orgasms
• changes in arousal
• changes in sexual interests and attractions

T therapy may reduce gender dysphoria and improve mood and quality of life. It may also allow a person to experience gender congruence, which can feel empowering and liberating.

Some research indicates that T therapy can bring about a number of desired effects in transgender men, including:

• the induction of masculine physical traits
• increased sexual desire
• cessation of menstruation
• reductions in gender dysphoria
• reductions in stress, anxiety, and depression

T therapy can involve a few risks, however, including:

• Acne: Acne is a common side effect of T therapy. It may peak during the first year of treatment before improving. Trying acne treatments and maintaining good skin care can often help people manage the condition.
• Fertility changes: Testosterone can reduce the ability to become pregnant, but it does not eliminate the chance. People should use birth control with any sexual partners who can produce sperm to prevent unintended pregnancy. Those who may want to get pregnant in the future should speak with a doctor about their options.
• Hair loss: Some people will experience hair thinning following T therapy. The extent to which this occurs may depend on their age and family history. Individuals can discuss treatment options for hair loss with a doctor if they so wish.
• Risks during pregnancy: Individuals undergoing T therapy should speak with a doctor immediately if they suspect that they are pregnant. Testosterone poses a risk to the health of the fetus.

Other complications of T therapy may include :

• abnormal levels of lipids in the blood (dyslipidemia)
• salt retention
• high blood pressure
• cardiovascular disease
• producing too many red blood cells (erythrocytosis)
• sleep apnea
• weight gain

Some effects are reversible once a person stops the treatment. However, some effects are unlikely to be reversible, including:

• clitoral growth
• facial hair growth
• male-pattern baldness
• voice changes

How to prepare

Before a person begins T therapy, a doctor will evaluate their health. They may take a complete personal and family medical history and perform a physical examination.

The doctor may also take blood tests and a pregnancy test, as well as any other age- and sex-related screenings they feel are necessary. They will discuss the potential risks associated with the treatment and discuss contraception and future fertility.

Some people may also undergo a mental health evaluation that explores their mental health, gender dysphoria, and use of alcohol and drugs.

People under 18 years of age may also see doctors with expertise in pediatric transgender health.

Some people may wish to see a mental health professional before beginning treatment to explore potential goals, challenges, and expectations of hormone therapy, as well as its effects. They may also wish to discuss the social supports available to them.

What to expect

During the visits, people will receive testosterone via an injection, patch, gel, or pill.

After starting the medication, physical changes may begin within a few weeks. Others may not appear for a few months , while some may take a few years for maximum effect.

Early changes tend to include oily skin, acne, and the cessation of menstrual periods. Later changes may include changes to facial appearance, hair growth, clitoral changes, and increased muscle mass.

People will have regular checkups with a doctor during treatment to monitor their progress and check for adverse effects. Doctors will also recommend screenings, such as breast cancer and cervical screenings, based on age-appropriate recommendations.

The results of hormone therapy can vary. They depend on factors such as genetics, overall health, and the age of the person undergoing treatment.

Starting treatment in one’s 40s or 50s, for example, can bring about less dramatic changes than those that would occur in adolescents or young adults who receive T therapy.

Once a person is within the normal range of testosterone levels for men, receiving higher doses does not typically result in more dramatic effects. However, higher doses can cause complications.

T therapy is a treatment option for those who experience gender dysphoria. It causes the development of typically masculine traits, such as facial hair growth, increased muscle mass, and a deeper voice.

This treatment may improve mental health and quality of life in those who experience gender dysphoria. It does carry some risks, however. These include hair loss, fertility changes, high blood pressure, and weight gain.

Results will vary depending on several factors, including when the person begins treatment. Individuals who wish to learn more about T therapy can speak with a doctor.

Last medically reviewed on March 18, 2021

How we reviewed this article:

• Access to transgender hormone therapy. (n.d.). https://fra.europa.eu/en/publication/2017/mapping-minimum-age-requirements/transgender-hormone-therapy
• A guide for young trans people in the UK. (2007). http://cdn0.genderedintelligence.co.uk/2012/11/17/17-15-02-A-Guide-For-Young-People.pdf
• Androderm (testosterone transdermal system), for topical use CIII. (2011). https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020489s025lbl.pdf
• Costa, R., et al . (2016). The effect of cross-sex hormonal treatment on gender dysphoria individuals’ mental health: A systematic review. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977075/
• Food and Drug Administration. (2019). FDA approves new oral testosterone capsule for treatment of men with certain forms of hypogonadism [Press release]. https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-testosterone-capsule-treatment-men-certain-forms-hypogonadism
• Garg, G., et al . (2020). Gender dysphoria. https://www.ncbi.nlm.nih.gov/books/NBK532313/
• Gender affirming hormone therapy. (n.d.). https://www.plannedparenthood.org/planned-parenthood-southwest-central-florida/medical-services/transgender-hormone-services
• Information on testosterone hormone therapy. (2020). https://transcare.ucsf.edu/article/information-testosterone-hormone-therapy
• Irwig, M. S. (2017). Testosterone therapy for transgender men [Abstract]. https://pubmed.ncbi.nlm.nih.gov/27084565/
• Medical management of FTM. (n.d.). http://transcaremoncton.craigchisholm.me/index.php/ftm/
• Medication guide: Androgel. (2014). https://www.fda.gov/media/77988/download
• Nguyen, H. B., et al . (2019). What has sex got to do with it? The role of hormones in the transgender brain. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235900/
• Practical guidelines for transgender hormone treatment. (n.d.). https://www.bumc.bu.edu/endo/clinics/transgender-medicine/guidelines/
• Understanding gender. (n.d.). https://genderspectrum.org/articles/understanding-gender
• Unger, C. A. (2016). Hormone therapy for transgender patients. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182227/
• What is gender dysphoria? (2020). https://www.psychiatry.org/patients-families/gender-dysphoria/what-is-gender-dysphoria

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• Dtsch Arztebl Int
• v.117(43); 2020 Oct

Hormonal Gender Reassignment Treatment for Gender Dysphoria

Gesine meyer.

1 Medical Clinic I: Gastroenterology and Hepatology, Pneumology and Allergology, Endocrinology and Diabetology, Nutritional Medicine, University Hospital Frankfurt, Frankfurt, Germany

Jörg Bojunga

No data are available at present on the prevalence of gender dysphoria (trans-identity) in Germany. On the basis of estimates from the Netherlands, it can be calculated that approximately 15 000 to 25 000 persons in Germany are affected. Persons suffering from gender dysphoria often experience significant distress and have a strong desire for gender reassignment treatment.

This review is based on pertinent publications retrieved by a selective search in the PubMed database employing the searching terms “transsexualism,” “transgender,” “gender incongruence,” “gender identity disorder,” “gender-affirming hormone therapy,” and “gender dysphoria.”

In view of its far-reaching consequences, some of which are irreversible, hormonal gender reassignment treatment should only be initiated after meticulous individual consideration, with the approval of the treating psychiatrist/psychotherapist and after extensive information of the patient by an experienced endocrinologist. Before the treatment is begun, the patient must be extensively screened for risk factors. The contraindications include severe preexisting thromboembolic diseases (mainly if untreated), hormone-sensitive tumors, and uncontrolled preexisting chronic diseases such as arterial hypertension and epilepsy. Finding an appropriate individual solution is the main objective even if contraindications are present. Male-to-female treatment is carried out with 17β-estradiol or 17β-estradiol valerate in combination with cyproterone acetate or spironolactone as an antiandrogen, female-to-male treatment with transdermal or intramuscular testosterone preparations. The treatment must be monitored permanently with clinical and laboratory follow-up as well as with gynecological and urological early-detection screening studies. Prospective studies and a meta-analysis (based on low-level evidence) have documented an improvement in the quality of life after gender reassignment treatment. Female-to-male gender-incongruent persons often have difficulty being accepted in a gynecological practice as a male patient.

Further prospective studies for the quantification of the risks and benefits of hormonal treatment would be desirable. Potential interactions of the hormone preparations with other medications must always be considered.

Gender dysphoria—or gender incongruence or transsexuality–is characterized by a mismatch between the biological sex and the inner sense of gender (gender identity). A transgender woman is a biologically male person with female gender identity; correspondingly, a transgender man is a biologically female person with male gender identity. In the Netherlands, the prevalence of gender dysphoria is estimated to be 0.02–0.03% ( 1 ). For Germany, no estimates have yet been published. Based on the above figures, it can be assumed that approximately 15 000 to 25 000 people are affected. While earlier studies ( 1 , e1 , e2 ) reported a gender ratio of transgender women to transgender men of approximately 2 : 1, more recent studies found increasingly similar proportions ( e3 ) or even a reversal of this ratio ( 2 ).

This article has been certified by the North Rhine Academy for Continuing Medical Education. The CME questions on this article can be found at http://daebl.de/RY95 . Answers must be submitted by 22 October 2021.

Participation is possible at cme.aerztebatt.de

With the onset of puberty, transgender persons typically experience significant psychological distress (gender dysphoria) and consequently seek gender-affirming—or gender reassignment—treatment ( e4 ). With 9% to 11% and 1.5% to 2%, the rates of suicide attempts ( 3 ) and committed suicides ( 4 ), respectively, are increased among people with gender dysphoria compared to the general population. In 2010, a meta-analysis found a decrease in mental and physical complaints as well as an increase in quality of life after the start of gender-affirming hormone therapy (GAHT) ( 5 ), but the data quality of this study was limited. However, later prospective studies confirmed these findings ( 6 , e5 ). The two-year follow-up after GAHT revealed the following differences compared to the pre-treatment status:

• Decrease in depressive symptoms (Beck Depression Inventory [BDI] II scores: transgender women -1.41, p<0.001; transgender men -1.31, p<0.001)
• Reduction in body uneasiness (Body Uneasiness Test [BUT] index: transgender women -0.24, p<0.001; transgender men -0.24, p = 0.001)
• Decrease in gender dysphoria (GIDYQ AA score: transgender women -0.06, p<0.001; transgender men -0.05, p = 0.001) ( 6 ).

For persons with gender dysphoria, treatment with cross-sex hormones delivers a sense of identity. However, since gender-affirming hormone therapy has a significant effect on a person’s hormonal balance, it is associated with a risk of adverse effects which is particularly high in the event of unsupervised treatment or overdosing.

Using treatment data from a large Dutch gender identity clinic collected in the period from 1980 to 2015, Wiepjes et al. demonstrated a 20-fold increase in newly started GAHT ( 1 ). Similarly, many treatment providers in Germany have observed an increase in the number of affected persons in recent years (personal communication from colleagues of other institutes). Factors potentially contributing to this trend include growing societal acceptance and a significant increase in public attention and media coverage ( e6 – e10 ). Nevertheless, in Germany, too, those affected do frequently not receive optimal care ( 7 , 8 , e4 , e11 ).

The aim of this article is to provide up-to-date insights into and recommendations for gender-affirming hormone therapy (GAHT) as well as information about special aspects that should be taken into account by general practitioners and specialists involved in the care of transgender persons.

Overall, the evidence from studies on the effects and risks of GAHT—which also forms the basis of the guidelines of the Endocrine Society which were initially created under US and European co-authorship in 2009 and then updated in 2017 ( 9 )—is weak. Most studies are retrospective data analyses, frequently based on comparatively few cases. Prospective studies are scarce. There are no randomized controlled trials and, ultimately, it is difficult to imagine that studies designed will ever be conducted, not least for ethical reasons. A German or European guideline on GAHT has not yet been created.

This review is based on a selective search of the PubMed database for original publications and review articles up to December 2019. The following search terms were used: “transsexualism”, “transgender”, “gender incongruence“, “gender identity disorder“, “gender affirming hormone therapy“, “gender dysphoria”.

Requirements

Treatment with GAHT quickly causes marked and partly irreversible changes. Thus, prior to the start of treatment, it is critical to confirm the diagnosis and to ensure that a clear, written indication for GAHT is established by a psychotherapist or psychiatrist ( 9 – 11 , e12 ). There are no strict requirements for the duration of preceding psychotherapy and, given the very different circumstances and needs of the affected individuals, any such requirement may not be helpful after all.

GAHT can be started at about age 16 years, provided a written, documented informed consent is obtained from the adolescent’s parents or guardian and the adolescent is mature enough to make this decision. In gender-dysphoric younger children and adolescents, a reversible puberty-suppressing therapy with gonadotropin-releasing hormone (GnRH) analogs can be initiated with the onset of puberty ( 9 ). In minors, confirmation of the indication by an independent second therapist should be required ( 9 ). Prior to the initiation of treatment, the patient must be informed in detail about the treatment effects, their course over time, the limitations of the treatment and potential adverse effects ( 9 , 10 ).

Medical diagnostic work-up prior to treatment initiation

A comprehensive pre-treatment risk screening, including thorough medical history, family history and physical examination as well as clinical chemistry testing of relevant parameters is required to identify potential contraindications and risk factors. This screening also helps to adapt the planned treatment to a patient’s individual risk profile ( box ).

Recommendations for pre-treatment screening und possible contraindications (according to [9, 10])

• Cardiovascular disease
• Thromboembolic disorders
• Hormone-sensitive cancers (endometrial, breast, cervical, prostate)
• Dyslipidemia
• Medical examination, including weight, blood pressure
• Secondary sexual characteristics (breast, genitals, body hair pattern)
• Biological women: Gynecological screening, including at least transabdominal ultrasound of the internal genitalia
• Biological men >40 years: urological screening
• Liver function tests
• Blood count
• HbA1c, if required fasting glucose levels
• Lipid profile
• Hormonal status (TSH, LH, FSH, estradiol, testosterone, prolactin; in biological women in addition DHEAS, androstenedione)
• In biological men: PSA
• Coagulation status (INR, PTT)
• Thrombophilia screening in patients with a positive personal or family history
• Uncontrolled pre-existing chronic conditions (diabetes mellitus, arterial hypertension, epilepsy)
• Severe thromboembolic pre-existing condition
• Ischemic cardiovascular or cerebrovascular pre-existing condition
• Refractory migraine
• Hepatic insufficiency, liver cirrhosis
• Severe psychiatric disorder (e.g. acute psychosis) influencing the decision or treatment
• Current alcohol or drug abuse
• Non-adherence
• Desire to have children

DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone;

HbA 1c , hemoglobin A 1C ; INR, international normalized ratio; LH, luteinizing hormone;

PSA, prostate-specific antigen; PTT, partial thromboplastin time;

TSH, thyroid-stimulating hormone

Many healthcare payers require that a somatic variation of sex development is ruled out before treatment is started ( e13 ). These differential diagnostic conditions, such as Klinefelter syndrome and complete androgen resistance syndrome, are rare and can be excluded based on the medical history, physical examination and measuring of basal hormone levels. Only in the presence of major clinical abnormalities and grossly abnormal laboratory findings, further diagnostic work-up, including chromosomal analysis, should be performed.

Pre-existing conditions, such as arterial hypertension, diabetes, dyslipidemia, and HIV, require adequate treatment. Adequately controlled, they are not considered absolute contraindications. In the presence of elevated liver enzyme levels, a pre-existing hepatic condition should be ruled out. Further diagnostic testing may be required.

GAHT is so essential for patients with gender dysphoria that priority even over contraindications can be given to this treatment on an individual basis after detailed discussion of associated risks. The decision to provide the treatment should also be broadly supported by all clinicians involved in the patient’s care. Absolute contraindications are very rare. Unsupervised self-medication is associated with high risks. Thus, instead of withholding therapeutically controlled hormone treatment in patients with contraindications, ideally an experienced endocrinologist should carefully evaluate each case individually to find a personalized solution.

Male-to-female gender dysphoria

Treatment recommendations.

GAHT of male-to-female transsexuals is based on the oral or transdermal administration of 17ß-estradiol or 17ß-estradiol valerate ( 9 ). Because of the significantly more unfavorable risk profile, treatment with ethinyl estradiol is obsolete ( 12 – 14 ). Since thromboembolic complications are more common with oral estradiol treatment ( 15 ), preference is given to the transdermal route of application if additional risk factors, such as overweight, older age and smoking, are present.

Since reducing androgen levels is another important requirement for the desired feminization of the body ( 16 , e14 ), patients also receive supplementary anti-androgen therapy. Here, the standard treatment is the administration of cyproterone acetate ( 17 ). Alternatively, treatment with spironolactone may be considered. Administration of a GnRH analog is another treatment option, but the significantly higher costs of this approach need to be taken into consideration. Anti-androgen treatment is discontinued, at the latest, once orchiectomy has been performed as part of the gender-affirming surgical procedure. An additional benefit on breast development by supplemental progesterone treatment has not yet been confirmed ( 18 , 19 ). There is a lack of randomized controlled trials evaluating this aspect. Given the increased risk of breast cancer and thromboembolic events associated with hormone replacement therapy in postmenopausal women ( e15 ), additional administration of progesterone in transgender women is currently not recommended ( 9 ). Information about the medications used for GAHT and their standard dosing schedules is provided in Table 1 .

GnRH, gonadotropin-releasing hormone; IM, intramuscular; PO, per os; SC, subcutaneous

Course and limitations of treatment

Table 2 gives an overview of the course of treatment over time and its limitations. GAHT cannot alter the size and shape of the male larynx and consequently the pitch of the voice. While body and facial hear growth are diminished, they usually do not stop completely; consequently, epilation treatment is required in most cases.

Adverse reactions and risks

Table 3 gives an overview of adverse reactions and risks. The development of venous thromboembolism (VTE) is a relevant risk. Older, retrospective data from the time when ethinyl estradiol (today considered obsolete) was still commonly used show a significant increase in the risk of thromboembolism with the occurrence of a VTE in 5.5% to 6.3% of ethinyl estradiol-treated patients ( 12 , 20 ). With the advent of modern treatment regimens, the prevalence of VTEs has declined to about 0.6% to 2% ( 21 , 22 ). To date, no studies evaluating the perioperative risk of thromboembolism have been conducted in patients receiving feminizing hormone therapy. Studies investigating this risk in postmenopausal women receiving hormone replacement therapy found heterogeneous results ( e16 – e18 ). Transdermal estradiol therapy without co-administration of progestin appears to be no significant additive risk factor in this patient population. The potential negative effect of temporarily discontinuing GAHT on mind and body, the risk profile and the treatment used have to be taken into consideration when making recommendations on the perioperativen management of GAHT ( 23 ). Most treating clinicians currently recommend to discontinue the hormone therapy for two weeks prior to scheduled surgical interventions ( 24 ).

* 1 Potential side effects of estradiol

* 2 Potential side effects of cyproterone acetate

Occasionally, weight gain of 3 to 4 kg, on average, is observed ( 25 , 26 ). In addition, older studies showed an increase in triglycerides ( 26 , 27 ) from 76 mg/dL to 128 mg/dL, on average, (p<0.001) and in 11% of cases a maximum increase in liver enzyme levels to the 2.5-fold of the upper limit of normal (ULN) ( 12 ). When transdermal estradiol formulations are used, unfavorable changes in these laboratory parameters are significantly less common ( 27 ) or levels even decrease to the female reference range ( 17 ).

Long-term data on cardiovascular risk are scarce. However, a recent study found an increased occurrence of cerebral ischemia in transgender individuals receiving GAHT compared to age-matched women (2.4-fold risk increase) and men (1.8-fold risk increase) ( 28 ). The rate of myocardial infarction was higher compared to biological women but comparable with the rate in age-matched men ( 28 , 29 ). From about age 50 years onwards, it is recommended to reduce the estradiol dose, mimicking the normal age-related hormonal changes ( 30 ). Nevertheless, it may be useful to continue treatment with a low maintenance dose beyond the statistical age of menopause to preserve bone density ( 31 ). If additional risk factors for osteoporosis are present and especially in the rare cases where GAHT is not continued after orchiectomy, e.g. because of contraindications, it is recommended to measure bone density using dual-energy X-ray absorptiometry (DXA) ( 9 ). However, the costs of DXA for this indication are not covered by German statutory health insurance funds.

While, especially in patients receiving high doses of estradiol, mild increases in prolactin levels are common and considered acceptable, relevant increases of prolactin levels >2x ULN may require an adjustment of the estradiol dose, once functional causes of hyperprolactinemia (e.g. preceding palpation of the breast) have been ruled out. If elevated levels persist, magnetic resonance imaging (MRI) of the pituitary gland should be performed since isolated cases of prolactinoma have been reported among patients receiving long-term high-dose estradiol therapy ( 32 ). In a recent Dear Doctor letter (“Rote-Hand-Brief”), a dose-dependent increase in the risk of meningioma occurrence has been described for patients treated with cyproterone acetate.

GAHT leads to testicular atrophy and over the course of treatment potentially to irreversible infertility ( 33 ). Information about theses consequences of the therapy and the options for preserving fertility ( ebox ) should be an integral part of the informed consent discussion.

Options for preserving fertility

Both feminizing and virilizing hormone therapy have a negative effect on fertility. The extent to which fertility is impaired varies widely between individuals and at what point in the course of treatment these limitations will occur is unpredictable; furthermore, patients may develop irreversible infertility. Thus, prior to the start of GAHT, patients must be informed in detail about the available fertility-preserving options. The discussion should also address the legal limitations existing in Germany and the costs patients have to cover themselves: depending on the type and duration of treatment, these can be far in the five-digit euro range.

For transgender women, there is the option of cryopreservation of sperm, ideally prior to the start of treatment. To achieve pregnancy, insemination or IVF/ICSI treatment (IVF, in vitro fertilization; ICSI, intracytoplasmatic sperm injection) with egg cells of the female partner may be required, depending on the quality and amount of the available cryopreserved material. In Germany, it is legal to provide treatment for legally same-sex lesbian couples desiring to have children; however, not all centers offer this service.

In transsexual men, fertility can be maintained by cryopreservation of egg cells or ovarian tissue. If no gender-affirming surgery with hysterectomy and salpingo-oophorectomy has been performed, a spontaneous pregnancy can be achieved after discontinuation of GAHT. Since egg cell donation is prohibited by law in Germany, only the transsexual man himself can carry out the pregnancy—after having discontinued GAHT.

The costs of cryopreservation and later assisted reproduction are not covered by the statutory health insurance funds and must be borne by the patients themselves. Under German legislation, the transsexual woman whose sperm has fathered a child and the transsexual man who gives birth to a child remain registered as the father and mother, respectively, of the child even after their legal sex status has changed ( 10 , e20 ).

Female-to-male gender dysphoria

Gender-affirming hormone therapy of female-to-male transsexual persons is based on testosterone administered as a transdermal gel or intramuscular depot preparation. A progestin can be added temporarily to the regimen to suppress menstruation until adequate suppression of the gonadotropic axis is achieved by testosterone ( 9 ). Progestin preparations need to be taken very regularly to ensure reliable menstrual suppression. Typically, treatment is started with a low dose taken once daily. If this is not successful, the dose can be increased to twice daily or, alternatively, a GnRH analog may be used. Further information about the preparations used and the recommended doses is presented in Table 1 .

Table 2 gives an overview of the course of treatment over time and its limitations.

Adverse reactions and risks are listed in Table 3 . Acne is the most common adverse reaction of testosterone therapy ( 17 , 34 ). Depending on the severity and form of acne, topical retinoids, benzoyl peroxide, adapalene, azelaic acid, or clindamycin are used. Systemic treatment with retinoids or antibiotics is reserved for severe forms of acne ( e19 ). Combination oral contraceptives with anti-androgenic progestin component are not suitable for the treatment of transgender men ( 35 ). In transgender men receiving retinoid treatment who are sexually active with biological men, reliable contraception has to be ensured because of the teratogenicity of the drug.

In the experience of the authors, an increase in aggressive behavior is occasionally reported. This issue should already be addressed prior to the start of treatment and regularly discussed over the course of therapy.

Because of the effect of testosterone on erythropoiesis, up to 11% to 17% of these patients develop erythrocytosis. This risk increases with increasing duration of the hormone therapy and the size of the testosterone dose, but essentially even patients with normal testosterone levels are at risk ( 17 , 36 ). If side effects occur, the dose of testosterone should be reduced or the injection interval extended. Currently there is no reliable answer to the question whether erythrocytosis in transgender men increases the risk of thrombosis to an extent which is similar to that seen in patients with myeloproliferative disorders ( 24 ).

Body weight can increase by 2 kg to 4 kg on average ( 25 , 26 ); however, an increase in muscle mass is also noted. While some studies indicated an unfavorable effect on lipid metabolism (increase in LDL cholesterol and decrease in HDL cholesterol) ( 25 , 26 ), other studies found that blood lipid levels rather tend to align with the male reference range ( 17 ). Overall, there is some evidence indicating a somewhat increased risk of cardiovascular events ( 28 , 29 ). It appears that if modern, guideline-based treatment regimens are used, relevant increases in liver enzyme levels occur significantly less frequently ( 17 , 27 ) compared to the rates reported in earlier studies ( 12 ).

Contraception/fertility

Testosterone therapy alone does not provide adequate contraception before gonadectomy is performed. Safe contraceptive options which can be used in combination with GAHT include barrier methods, oral progestins as well as hormone-free or progestin-releasing intrauterine devices ( 37 ). In the informed consent discussion, the issue of contraception as well as the options for preserving fertility ( ebox ) must be addressed.

Follow-up examinations

After the initiation of treatment, a regular clinical and laboratory follow-up of the patients is required ( 9 ). During the first year, checks at three-month intervals are useful; in the long term, checks should be performed every 6 to 12 months and be continued even after the patient underwent gender-affirming surgery. It is useful to measure serum sex hormone levels to assess the required dosing and, above all, to prevent overtreatment. In transgender women, the goal should be to achieve estradiol levels in the middle of the reference range for premenopausal women (<200 pg/mL) and testosterone levels within the reference range for women (< 55 ng/dL). The development of a female breast shows marked interindividual differences, occurs mainly during the first one to two years of hormone therapy and frequently remains incomplete at puberty level. Several studies have shown that breast development does not correlate with the estradiol levels measured ( 17 , 18 , 38 ). Increasing the estradiol dose beyond the normal limit does not result in further growth of the breast, but increases the risk of adverse long-term effects of the hormone therapy.

In transgender men, the goal is to achieve a testosterone level within the male reference range (approx. 250–840 ng/dL). Hemoglobin and hematocrit are important markers of the effect of testosterone ( 17 , 36 ) and should be regularly monitored over the course of treatment because of the risk of erythrocytosis, among others.

In addition, patients should be screened for potential adverse reactions and risks on a regular basis. During screening, patients should be asked about risk factors and possible co-medications. Furthermore, body weight, blood pressure, liver enzyme levels, lipid status, blood count, and, in patients receiving feminizing treatment, also prolactin levels should be checked ( 9 ).

Gynecological and urological care

In a retrospective analysis of more than 2000 transgender women receiving feminizing GAHT, a recent study from the Netherlands has shown a 46-fold increase in breast cancer risk among transgender women compared to men. However, with a standardized incidence ratio of 0.3, the incidence of breast cancer in transgender women remains below the incidence observed in biological women ( 39 ). It is recommended that transgender women attend the standard gynecological screening program ( 9 ).

Since the prostate gland is not removed during genital gender-affirming surgery but remains in situ and sporadic cases of benign prostatic hyperplasia ( 40 ) and prostate cancer ( e21 ) have been reported in transgender women receiving hormone therapy, annual checks of prostate-specific antigen (PSA) levels and clinical examinations of the prostate gland are recommended ( 9 ).

Since testosterone is aromatized to estradiol, patients receiving GAHT are in principle still at risk for hormone-dependent cancers. While related data are scarce, overall hysterectomy with bilateral salpingo-oophorectomy is recommended. It is also recommended that until patients have undergone this procedure, or as an alternative if no surgery is performed, they should attend regular gynecological screening examinations ( 9 ).

Despite their importance, these screening examinations are frequently not or only irregularly attended. The psychological barrier for transgender men to undergo a gynecological examination is often high. Reports of transgender men finding it very difficult to be accepted by a gynecologist’s practice are not uncommon ( 7 ). It is critical that transgender men have access to gynecological care—even after their legal sex status has been changed and their registered gender is male.

Treatment of pre-existing chronic conditions and intercurrent diseases

Attention should be paid to a few peculiarities and potential drug interactions ( table 4 ).

DOAC, direct oral anticoagulants

Key Messages

• Since gender-affirming hormone therapy (GAHT) quickly leads to significant and partly irreversible changes, it is crucial to ensure that the treatment is clearly indicated.
• Prior to initiation of GAHT, risk factors (especially substance abuse, overweight, age, personal or family history positive for thrombophilia or hormone-sensitive cancer) and pre-existing chronic conditions (e.g. arterial hypertension, diabetes, dyslipidemia, chronic hepatitis B and C, HIV) should be identified and adequately treated.
• As recommended in the available guidelines, 17ß-estradiol (valerate) in combination with an anti-androgen is used for feminizing therapy. The use of ethinyl estradiol is obsolete due to the significantly worse side effect profile. For virilizing GAHT, transdermal or intramuscular testosterone preparations are used.
• After the initiation of therapy, clinical and laboratory checks should be performed at regular intervals.
• For persons with gender dysphoria, access to regular gynecological/urological care has to be ensured—even after their legal sex status has changed.

Questions regarding the article in issue 43/2020:

The submission deadline is 22 October 2021. Only one answer is possible per question. Please select the answer that is most appropriate

In Germany, how many people are estimated to be affected by gender dysphoria?

• 1000 to  1500
• 3000 to  6000
• 5000 to 10 000
• 5 000 to 25 000
• 50 000 to 75 000

Which of the following is a contraindication for gender-affirming hormone therapy?

• Disposition to develop allergies/atopy
• Cerebrovascular and severe thromboembolic pre-existing conditions
• Overweight (BMI: 25–29.9) or obesity (BMI >30)
• History of fractures
• Depressive symptoms

Which medication (and route of administration) is the standard treatment used in male-to-female hormone therapy?

• 17β-estradiol intravenously and cyproterone acetate
• Oral or transdermal ethinyl estradiol and intravenous 17β-estradiol
• Oral progesterone and ethinyl estradiol
• Oral or transdermal 17β-estradiol and cyproterone acetate
• Progesterone and 17β estradiol intravenously

Which medication is the standard treatment used in female-to-male gender-affirming hormone therapy?

• Transdermal dehydroepiandrosterone (DHEA)
• Testosterone, transdermal or intramuscular depot formulation
• Testosterone, oral administration or as a suppository
• Oral or intramuscular progesterone
• Oral dehydroepiandrosterone (DHEA)

Which effect of feminizing hormone therapy is typically the first to manifest?

• Decrease in body and facial hair
• Reduction of muscle mass and strength
• Reduction of libido and spontaneous erections
• Fat redistribution
• Softening of the skin

Acne is a common side effect of virilizing hormone therapy. What treatment should be offered to patients suffering from acne?

• Prescription of oral contraceptives with anti-androgenic effect
• Topical treatment with anti-androgenic agents
• Discontinuation of hormone therapy until the acne has cleared
• Topical treatment with retinoids, benzoyl peroxide or clindamycin
• Systemic treatment with benzoyl peroxide over a period of four weeks

With regard to contraception, which statement applies to patients receiving female-to-male gender-affirming hormone therapy (GAHT)?

• Testosterone therapy provides sufficient contraception after a period of about three months; therefore, no further measures are required.
• Progestin-releasing intrauterine devices must not be implanted.
• With the start of testosterone treatment, a contraceptive effect is guaranteed.
• In this situation, medications with estrogen as the sole active ingredient can be prescribed.
• During GAHT, mechanical contraception and oral progestins can be used.

With regard to co-medication, what needs to be considered in patients receiving estradiol as part of GAHT?

• Anticonvulsants and anti-infectives may reduce the effect of estradiol; adjustment of the estradiol dose may be required.
• The induction or cytochrom-P450 enzymes by various co-medications increases the effect of estradiol.
• Because of significant drug interactions with estradiol, anticoagulants should ideally not be used as co-medication.
• The effect of metoprolol and imipramine is reduced by estradiol; therefore, the doses of these substances may need to be increased.
• Anticoagulants as co-medication with estradiol have an increased effect; a reduction of the anticoagulant dose is indicated.

Which of the following risks is significantly increased in patients receiving virilizing hormone therapy?

• Risk of ovarian cancer
• Risk of depressive symptoms
• Risk of cervical cancer
• Risk of erythrocytosis
• Risk of meningioma

Question 10

Which of the following risks is increased in patients receiving feminizing hormone therapy compared to age-matched women or men?

• Risk of aggressive behavior
• Risk of cerebral ischemia
• Risk of basal cell carcinoma
• Risk of prostate cancer
• Risk of bipolar disorder

Acknowledgments

Translated from the original German by Ralf Thoene, MD.

In memory of Dr. Sophinette Becker, 1950–2019, former Head of the Sexual Medicine Outpatient Clinic of the Frankfurt University Hospital, longstanding co-publisher of the “Zeitschrift für Sexualforschung“ and co-founder of the Rhein-Main Working Group on Transidentity.

Conflict of interest

The authors declare no conflict of interest.

• Patient Care & Health Information
• Tests & Procedures
• Feminizing hormone therapy

Feminizing hormone therapy typically is used by transgender women and nonbinary people to produce physical changes in the body that are caused by female hormones during puberty. Those changes are called secondary sex characteristics. This hormone therapy helps better align the body with a person's gender identity. Feminizing hormone therapy also is called gender-affirming hormone therapy.

Feminizing hormone therapy involves taking medicine to block the action of the hormone testosterone. It also includes taking the hormone estrogen. Estrogen lowers the amount of testosterone the body makes. It also triggers the development of feminine secondary sex characteristics. Feminizing hormone therapy can be done alone or along with feminizing surgery.

Not everybody chooses to have feminizing hormone therapy. It can affect fertility and sexual function, and it might lead to health problems. Talk with your health care provider about the risks and benefits for you.

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Why it's done

Feminizing hormone therapy is used to change the body's hormone levels. Those hormone changes trigger physical changes that help better align the body with a person's gender identity.

In some cases, people seeking feminizing hormone therapy experience discomfort or distress because their gender identity differs from their sex assigned at birth or from their sex-related physical characteristics. This condition is called gender dysphoria.

Feminizing hormone therapy can:

• Improve psychological and social well-being.
• Ease psychological and emotional distress related to gender.
• Improve satisfaction with sex.
• Improve quality of life.

Your health care provider might advise against feminizing hormone therapy if you:

• Have a hormone-sensitive cancer, such as prostate cancer.
• Have problems with blood clots, such as when a blood clot forms in a deep vein, a condition called deep vein thrombosis, or a there's a blockage in one of the pulmonary arteries of the lungs, called a pulmonary embolism.
• Have significant medical conditions that haven't been addressed.
• Have behavioral health conditions that haven't been addressed.
• Have a condition that limits your ability to give your informed consent.

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Research has found that feminizing hormone therapy can be safe and effective when delivered by a health care provider with expertise in transgender care. Talk to your health care provider about questions or concerns you have regarding the changes that will happen in your body as a result of feminizing hormone therapy.

Complications can include:

• Blood clots in a deep vein or in the lungs
• Heart problems
• High levels of triglycerides, a type of fat, in the blood
• High levels of potassium in the blood
• High levels of the hormone prolactin in the blood
• Nipple discharge
• Weight gain
• Infertility
• High blood pressure
• Type 2 diabetes

Evidence suggests that people who take feminizing hormone therapy may have an increased risk of breast cancer when compared to cisgender men — men whose gender identity aligns with societal norms related to their sex assigned at birth. But the risk is not greater than that of cisgender women.

To minimize risk, the goal for people taking feminizing hormone therapy is to keep hormone levels in the range that's typical for cisgender women.

Feminizing hormone therapy might limit your fertility. If possible, it's best to make decisions about fertility before starting treatment. The risk of permanent infertility increases with long-term use of hormones. That is particularly true for those who start hormone therapy before puberty begins. Even after stopping hormone therapy, your testicles might not recover enough to ensure conception without infertility treatment.

If you want to have biological children, talk to your health care provider about freezing your sperm before you start feminizing hormone therapy. That procedure is called sperm cryopreservation.

How you prepare

Before you start feminizing hormone therapy, your health care provider assesses your health. This helps address any medical conditions that might affect your treatment. The evaluation may include:

• A review of your personal and family medical history.
• A physical exam.
• A review of your vaccinations.
• Screening tests for some conditions and diseases.
• Identification and management, if needed, of tobacco use, drug use, alcohol use disorder, HIV or other sexually transmitted infections.
• Discussion about sperm freezing and fertility.

You also might have a behavioral health evaluation by a provider with expertise in transgender health. The evaluation may assess:

• Gender identity.
• Gender dysphoria.
• Mental health concerns.
• Sexual health concerns.
• The impact of gender identity at work, at school, at home and in social settings.
• Risky behaviors, such as substance use or use of unapproved silicone injections, hormone therapy or supplements.
• Support from family, friends and caregivers.
• Your goals and expectations of treatment.
• Care planning and follow-up care.

People younger than age 18, along with a parent or guardian, should see a medical care provider and a behavioral health provider with expertise in pediatric transgender health to discuss the risks and benefits of hormone therapy and gender transitioning in that age group.

What you can expect

You should start feminizing hormone therapy only after you've had a discussion of the risks and benefits as well as treatment alternatives with a health care provider who has expertise in transgender care. Make sure you understand what will happen and get answers to any questions you may have before you begin hormone therapy.

Feminizing hormone therapy typically begins by taking the medicine spironolactone (Aldactone). It blocks male sex hormone receptors — also called androgen receptors. This lowers the amount of testosterone the body makes.

About 4 to 8 weeks after you start taking spironolactone, you begin taking estrogen. This also lowers the amount of testosterone the body makes. And it triggers physical changes in the body that are caused by female hormones during puberty.

Estrogen can be taken several ways. They include a pill and a shot. There also are several forms of estrogen that are applied to the skin, including a cream, gel, spray and patch.

It is best not to take estrogen as a pill if you have a personal or family history of blood clots in a deep vein or in the lungs, a condition called venous thrombosis.

Another choice for feminizing hormone therapy is to take gonadotropin-releasing hormone (Gn-RH) analogs. They lower the amount of testosterone your body makes and might allow you to take lower doses of estrogen without the use of spironolactone. The disadvantage is that Gn-RH analogs usually are more expensive.

After you begin feminizing hormone therapy, you'll notice the following changes in your body over time:

• Fewer erections and a decrease in ejaculation. This will begin 1 to 3 months after treatment starts. The full effect will happen within 3 to 6 months.
• Less interest in sex. This also is called decreased libido. It will begin 1 to 3 months after you start treatment. You'll see the full effect within 1 to 2 years.
• Slower scalp hair loss. This will begin 1 to 3 months after treatment begins. The full effect will happen within 1 to 2 years.
• Breast development. This begins 3 to 6 months after treatment starts. The full effect happens within 2 to 3 years.
• Softer, less oily skin. This will begin 3 to 6 months after treatment starts. That's also when the full effect will happen.
• Smaller testicles. This also is called testicular atrophy. It begins 3 to 6 months after the start of treatment. You'll see the full effect within 2 to 3 years.
• Less muscle mass. This will begin 3 to 6 months after treatment starts. You'll see the full effect within 1 to 2 years.
• More body fat. This will begin 3 to 6 months after treatment starts. The full effect will happen within 2 to 5 years.
• Less facial and body hair growth. This will begin 6 to 12 months after treatment starts. The full effect happens within three years.

Some of the physical changes caused by feminizing hormone therapy can be reversed if you stop taking it. Others, such as breast development, cannot be reversed.

While on feminizing hormone therapy, you meet regularly with your health care provider to:

• Keep track of your physical changes.
• Monitor your hormone levels. Over time, your hormone dose may need to change to ensure you are taking the lowest dose necessary to get the physical effects that you want.
• Have blood tests to check for changes in your cholesterol, blood sugar, blood count, liver enzymes and electrolytes that could be caused by hormone therapy.
• Monitor your behavioral health.

You also need routine preventive care. Depending on your situation, this may include:

• Breast cancer screening. This should be done according to breast cancer screening recommendations for cisgender women your age.
• Prostate cancer screening. This should be done according to prostate cancer screening recommendations for cisgender men your age.
• Monitoring bone health. You should have bone density assessment according to the recommendations for cisgender women your age. You may need to take calcium and vitamin D supplements for bone health.

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Feminizing hormone therapy care at Mayo Clinic

• Tangpricha V, et al. Transgender women: Evaluation and management. https://www.uptodate.com/contents/search. Accessed Oct. 10, 2022.
• Erickson-Schroth L, ed. Medical transition. In: Trans Bodies, Trans Selves: A Resource by and for Transgender Communities. 2nd ed. Kindle edition. Oxford University Press; 2022. Accessed Oct. 10, 2022.
• Coleman E, et al. Standards of care for the health of transgender and gender diverse people, version 8. International Journal of Transgender Health. 2022; doi:10.1080/26895269.2022.2100644.
• AskMayoExpert. Gender-affirming hormone therapy (adult). Mayo Clinic; 2022.
• Nippoldt TB (expert opinion). Mayo Clinic. Sept. 29, 2022.
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Hormone therapy in female-to-male transgender patients: searching for a lifelong balance

Affiliations.

• 1 Department Interdisciplinary Medicine, Unit of Obstetrics and Gynecology, University of Bari "Aldo Moro", Bari, Italy.
• 2 Interdisciplinary Department of Medicine, Gynecology and Ostetrics Clinic, University of Bary, Bari, Italy. [email protected].
• 3 Department of Obstetrics and Gynaecology, ASTT Lecco, Ospedale Leopoldo Mandic, Merate, Italy.
• 4 Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, CNR, Bari, Italy.
• PMID: 33026609
• DOI: 10.1007/s42000-020-00238-2

Background: Reassignment of a female-to-male (FtM) person requires gender-affirming, androgenic hormonal treatment that is planned to induce appropriate structural changes. This therapy must be prolonged long term, even after the sex reassignment surgery (SRS). The purpose of this study is to evaluate the effects of hormone therapy with testosterone in FtM subjects during a 24-month follow-up in order to highlight the occasional need for early decompensation and to make adequate hormone therapy modulations.

Methods: Fifteen out of 23 FtM persons had been previously treated with SRS, while eight were still awaiting surgery. During hormone therapy, both groups were followed for 24 months, with evaluation of desired changes, adverse effects, and functional or metabolic indicators.

Results: In the group of operated FtM subjects (15/23), a significant increase of total testosterone (total T) and free testosterone (free T) was found after 24 months. Luteinizing hormone (LH) maintained a low level, decreasing after ovariectomy, while FSH increased. Voice deepening, facial and body hair variation, male-pattern balding, and body mass index (BMI) increase are all physical changes due to androgenization. In both groups of patients who have been closely monitored, the side effects and thromboembolic, metabolic, and cardiovascular risks of androgen therapy, even in the long term, appear to be irrelevant.

Conclusion: Total T, free T, and LH dosages are shown to be reliable markers of correct androgenization. Strict monitoring of lipid profile, evaluation of BMI and hematocrit, avoidance of self-initiated therapeutic modifications, adherence to a healthy lifestyle, and avoidance of excessive daily calorie intake can limit risks linked to long-term testosterone administration.

Trial registration: Retrospectively registered.

Keywords: Health; Long-term therapy; Testosterone; Transgender.

• Androgens / administration & dosage
• Androgens / pharmacology*
• Testosterone / administration & dosage
• Testosterone / pharmacology*
• Transgender Persons*
• Testosterone

Practical Guidelines for Transgender Hormone Treatment

Adapted from:  Gardner,   Ivy  and  Safer, Joshua D . 2013   Progress on the road to better medical care for transgender patients. Current Opinion in Endocrinology, Diabetes and Obesity 20(6): 553-558.

• In order to improve transgender individuals’ access to health care, the approach to transgender medicine needs to be generalized and accessible to physicians in multiple specialties.
• A practical target for hormone therapy for transgender men (FTM) is to increase testosterone levels to the normal male physiological range (300–1000 ng/dl) by administering testosterone.
• A practical target for hormone therapy for transgender women (MTF) is to decrease testosterone levels to the normal female range (30–100 ng/dl) without supra- physiological levels of estradiol (<200 pg/ml) by administering an antiandrogen and estrogen.
• Transgender adolescents usually have stable gender identities and can be given GnRH analogs to suppress puberty until they can proceed with hormone therapy as early as age 16.

Hormone regimes for transgender men (female to men, FTM)

    1. Oral

• Testosterone undecanoate*      160–240mg/day

   2. Parenterally (i.m. or subcutaneous)

• Testosterone enanthate or cypionate      50–200mg/week or 100–200mg/2 weeks
• Testosterone undecanoate      1000 mg/12 weeks

   3. Transdermal

• Testosterone 1% gel      2.5 – 10 g/day
• Testosterone patch      2.5 – 7.5 mg/day 

i.m., intramuscular. *Not available in the USA.

Monitoring for transgender men (FTM) on hormone therapy:

• Monitor for virilizing and adverse effects every 3 months for first year and then every 6 – 12 months.
• Monitor serum testosterone at follow-up visits with a practical target in the male range (300 – 1000 ng/dl). Peak levels for patients taking parenteral testosterone can be measured 24 – 48 h after injection. Trough levels can be measured immediately before injection.
• Monitor hematocrit and lipid profile before starting hormones and at follow-up visits.
• Bone mineral density (BMD) screening before starting hormones for patients at risk for osteo- porosis. Otherwise, screening can start at age 60 or earlier if sex hormone levels are consistently low.
• FTM patients with cervixes or breasts should be screened appropriately.

Hormone regimes for transgender women (male to women, MTF)  

     1. Anti-androgen

• Spironolactone    100 – 200 mg/day (up to 400 mg)
• Cyproterone acetatea    50–100mg/day
• GnRH agonists    3.75 mg subcutaneous monthly

    2. Oral estrogen

• Oral conjugated estrogens    2.5–7.5mg/day
• Oral 17-beta estradiol    2–6mg/day

    3. Parenteral estrogen

• Estradiol valerate   5–20mg i.m./2 weeks   or cypionate   2–10mg i.m./week

    4. Transdermal estrogen

• Estradiol patch     0.1–0.4mg/2X week

i.m., Intramuscular; MTF, male to female. aNot available in the USA.

Monitoring for transgender women (MTF) on hormone therapy:

• Monitor for feminizing and adverse effects every 3 months for first year and then every 6– 12 months.
• Monitor serum testosterone and estradiol at follow-up visits with a practical target in the female range (testosterone 30 – 100 ng/dl; E2 <200 pg/ml).
• Monitor prolactin and triglycerides before start- ing hormones and at follow-up visits.
• Monitor potassium levels if the patient is taking spironolactone.
• BMD screening before starting hormones for patients at risk for osteoporosis. Otherwise, start screening at age 60 or earlier if sex hormone levels are consistently low.
• MTF patients should be screened for breast and prostate cancer appropriately.

3. Leinung MC, Urizar MF, Patel N, Sood SC. Endocrine treatment of transsexual  * persons: extensive personal experience. Endocr Pract 2013; 19:644 – 650.

4. Gorin-Lazard A, Baumstarck K, Boyer L, et al. Is hormonal therapy associated *with better quality of life in transsexuals? A cross-sectional study. J Sex Med 2012; 9:531–541.

5. Obedin-Maliver J, Goldsmith ES, Stewart L, et al. Lesbian, gay, bisexual, and transgender-related content in undergraduate medical education. J Am Med Assoc 2011; 306:971 – 977.

6. Safer JD, Tangpricha V. Out of the shadows: it is time to mainstream treatment for transgender patients. Endocrine Pract 2008; 14:248 – 250.

7. Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 2004; 350:333 – 341.

8. Meyer-Bahlburg HFL. Gender identity outcome in female-raised 46,XY per- sons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav 2005; 34:423 – 438.

9. Zhou J-N, Hofman MA, Gooren LJG, Swaab DF. A sex difference in the human brain and its relation to transsexuality. Nature 1995; 378:68 – 70.

10. Kruijver FP, Zhou JN, Pool CW, et al. Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab 2000; 85:2034 – 204z

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12. Rametti G, Carrillo B, Go ́mez-Gil E, et al. White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study. J Psychiatr Res 2011; 45:199 – 204.

13. RamettiG,CarrilloB,Go ́mez-GilE,etal.Themicrostructureofwhitematterin male to female transsexuals before cross-sex hormonal treatment. A DTI study. J Psychiatr Res 2011; 45:949–954.

14. GreenR,NewmanL,StollerR.Treatmentofboyhood‘transsexualism’.Arch Gen Psychiatry 1972; 26:213–217.

15. Liao L-M, Audi L, Magritte E, et al. Determinant factors of gender identity: a commentary. J Pediatr Urol 2012; 8:597–601.

16. World Professional Association for Transgender Health. Standards of care for the health of transsexual, transgender, and gender nonconforming people. 7th ed.; 2011. http://www.wpath.org/documents/Standards%20of%20Care% 20V7%20-%202011%20WPATH.pdf (Accessed on 24 December 2012)

17. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endo- crine treatment of transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2009; 94:3132 – 3154.

18. Gooren LJ. Care of transsexual persons. N Engl J Med 2011; 364:2559– 2560.

19. BhasinS,SaferJ,TangprichaV.Thehormonefoundation’spatientguideto the endocrine treatment of transsexual persons. J Clin Endocrinol Metab 2009; 94:.

20. Bockting WO, Miner MH, Swinburne Romine RE, et al. Stigma, mental health, *  and resilience in an online sample of the US transgender population. Am J Public Health 2013; 103:943 – 951.

21. Olshan JS, Spack NP, Eimicke T, et al. Evaluation of the efficacy of sub-cutaneous administration of testosterone in female to male transexuals and hypogonadal males. Endocr Rev 2013; 34:(03_MeetingAbstracts): MON- 594.

22. Nagarajan V, Chamsi-Pasha M, Tang WHW. The role of aldosterone receptor antagonists in the management of heart failure: an update. Cleve Clin J Med 2012; 79:631 – 639.

23. Asscheman H, Giltay EJ, Megens JAJ, et al. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol 2011; 164:635 – 642.

24. Wierckx K, Mueller S, Weyers S, et al. Long-term evaluation of cross-sex * hormone treatment in transsexual persons. J Sex Med 2012; 9:2641–2651.

25. Wallien MSC, Cohen-Kettenis PT. Psychosexual outcome of gender-dysphoric children. J Am Acad Child Adolesc Psychiatry 2008; 47:1413 – 1423. 26. Cohen-Kettenis PT, Delemarre-van de Waal HA, Gooren LJG. The treatment of adolescent transsexuals: changing insights. J Sex Med 2008; 5:1892–1897.

27. De Vries ALC, Steensma TD, Doreleijers TAH, Cohen-Kettenis PT. Puberty suppression in adolescents with gender identity disorder: a prospective follow-up study. J Sex Med 2011; 8:2276 – 2283.

28. Safer JD, Pearce EN. A simple curriculum content change increased medical & student comfort with transgender medicine. Endocrine Pract 2013; 33:39–44.

Transgender Hormone Therapy

As a trans woman, trans man, or nonbinary person, you may want your body to look and feel differently. You may hope to look as female or male as possible. Or you might just want less obvious sex characteristics. Whatever your goal, we’ll work with you to find the right transgender hormone therapy for you.

Ready to begin hormones? Unsure? Either way, we’re here to help. You don’t need a referral to see us.

What Does Transgender Hormone Therapy Do?

Starting hormone therapy is like going through a second puberty. You’ll experience changes that are:

• Reproductive

Transgender Hormone Therapy at UVA

If you have gender dysphoria, you may want more obvious or less obvious sex characteristics. At UVA, we work to find you the right transgender hormone therapy. Christine Eagleson, MD, walks us through the process. View hormone therapy transcript.

Physical Effects 

Sex hormones create physical changes in your body. The speed and amount of the changes will vary from person to person.

MTF Hormone Changes

Physically, if you’re taking female hormones, you can expect to:

• Grow breasts
• Lose muscle tone
• Have the hair on your face and chest thin
• Experience fewer and smaller erections
• Have your testicles shrink
• Possibly stop creating sperm
• Have fat move to your face and thicken around your hips and thighs

FTM Hormone Changes

If you’re taking testosterone, you can expect:

• Your skin to become thicker and more oily
• To sweat more
• Development or worsening of acne
• Fat moving away from hips and thighs
• More muscle definition in your arms and legs
• A more angular look to your face
• Voice changes
• Thicker and fast-growing hair in different places
• Libido and sexuality changes
• Shorter periods that eventually stop

How Long Will These Changes Take?

The effects of hormone therapy vary from person to person. How quickly the changes happen will depend on a range of factors. Some new body features may affect you almost right away. Others may take from two to five years to develop.

You might want to wait for a while after starting hormones before surgery. You won't know what procedures you want or need until you know what effects hormones will have.

Emotional Changes

Everyone going through hormone therapy should prepare to have emotional shifts. Your feelings, interests, and sexuality could all fluctuate. It can feel like a rollercoaster.

If you can, get a support system in place as you start this journey. Having a therapist, friends, or family who knows what you’re going through can really help.

If you’re overwhelmed by changes in your mood, like feeling depression or anxiety, let us know. We’ll work with you on finding ways to address problems. Finding someone to talk to or tweaking your dose could make you feel better.

Fertility & Birth Control

You may think that you’ve stopped making sperm or eggs. But you may still have the ability to get pregnant or get someone else pregnant. Depending on the type of sex you have, you may still need to use birth control to prevent pregnancy.

Taking transgender hormones can change your reproductive system and make it hard to have your own baby. We can work with you on your options for saving your sperm or eggs.

Getting Started with Hormones

Many people ask: How soon can I start hormones?

We know the urgency you can feel. But we also want to make sure to keep you healthy and safe.

Creating Your Hormone Therapy Plan

We’ll need to look at several factors, including:

• Your goals – how much you hope to change
• Your age and medical history

A blood test happens first. This will give us a baseline to compare against after you start hormones.

Analyzing your blood also helps us see if taking hormones could cause side effects. And we’ll continue to monitor your blood levels during therapy to make sure you’re OK.

We usually get lab results back in a couple of days. If we don’t see any issues, usually then your transgender hormone therapy can start.

Pills, Gels, Patches, or Shots

You have options with how to take your hormones. Typically, gender hormones include:

• Testosterone comes as a gel, patch, or injection.
• Estrogen, and sometimes progesterone, come as a pill, patch, or injection.
• Spironolactone, which blocks testosterone, is taken as a pill.

Your insurer may cover certain types of hormones and not others.

Hormones at home? Yes, we can teach you how to give yourself a hormone injection at home. 

Hormone Therapy Risks & Side Effects 

Any kind of hormone treatment can cause mood changes. You’ll also want to watch for other symptoms, depending on what you’re taking. We will talk about a lot of possible side effects at your appointment, but here are some of the more serious ones.

Testosterone Side Effects

In addition to worsening any acne, if you’re taking testosterone, we’ll need to watch your red blood cell count. Testosterone can cause your body to make more red blood cells than you need. Other conditions can also cause this increase. So we’ll figure out the cause and what we can do to even things out.

Estrogen & Spironolactone Risks

If you’re taking estrogen, you’ll need to watch for signs of:

• Blood clots

These risks are more serious if you smoke. So tend to want a plan to help you quit tobacco before you start estrogen.

Spironolactone can put you at risk for:

• Dehydration
• High potassium
• Needing to pee more than normal

• Vol 5, No 6 (December 18, 2016) /

Hormone therapy for transgender patients

Cécile A. Unger

Center for Urogynecology & Pelvic Reconstructive Surgery, Center for LGBT Care, Department of Obstetrics & Gynecology, Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA

Abstract: Many transgender men and women seek hormone therapy as part of the transition process. Exogenous testosterone is used in transgender men to induce virilization and suppress feminizing characteristics. In transgender women, exogenous estrogen is used to help feminize patients, and anti-androgens are used as adjuncts to help suppress masculinizing features. Guidelines exist to help providers choose appropriate candidates for hormone therapy, and act as a framework for choosing treatment regimens and managing surveillance in these patients. Cross-sex hormone therapy has been shown to have positive physical and psychological effects on the transitioning individual and is considered a mainstay treatment for many patients. Bone and cardiovascular health are important considerations in transgender patients on long-term hormones, and care should be taken to monitor certain metabolic indices while patients are on cross-sex hormone therapy.

Keywords: Hormone therapy; transgender; gender dysphoria; cross-sex hormones

Submitted Jul 23, 2016. Accepted for publication Jul 26, 2016.

doi: 10.21037/tau.2016.09.04

Introduction

Transgender individuals experience discord between their self-identified gender and biological sex. Transgender men are individuals who were assigned female at birth but identify as men, and transgender women are individuals who were assigned male at birth but identify as women. While research in this area is sparse, the current evidence points toward a biologic etiology for transgenderism. These data come from studies examining children with congenital genitourinary anomalies who were assigned gender at birth ( 1 , 2 ), as well as postmortem cadaveric studies ( 3 ). Estimation of prevalence of transgenderism has historically been challenging. The most recent estimates in the United States have been reported from survey studies, and range from 0.3–0.5% ( 4 , 5 ).

The number of transgender individuals seeking cross-sex hormone therapy has risen over the years ( 6 ). The administration of exogenous virilizing hormones is considered medically necessary for many transgender individuals ( 7 ). Many transgender men seek therapy for virilization and the mainstay treatment is exogenous testosterone. Transgender women desire suppression of androgenic effects and often use anti-androgen therapy with feminizing exogenous estrogens.

The purpose of this review is to present updates on the current hormonal regimens used by transgender patients, to discuss the safety and efficacy of these treatments, and to provide a summary of the current data that exist on both their short- and long-term effects.

Both the World Professional Association for Transgender Health (WPATH) and the Endocrine Society have created transgender-specific guidelines to help serve as a framework for providers caring for gender minority patients. These guidelines are mostly based on clinical experience from experts in the field. Guidelines for hormone therapy in transgender men are mostly extrapolations from recommendations that currently exist for the treatment of hypogonadal natal men and estrogen therapy for transgender women is loosely based on treatments used for postmenopausal women.

In the past, the guidelines for hormone therapy initiation recommended that all patients undergo a “real life test” prior to starting medical therapy. This test required patients to live full-time as their self-affirmed gender for a predetermined period of time (usually 12 months) before starting cross-sex hormones. The recommendation was intended to help patients transition socially. However, both above-mentioned societies have recognized that this step is unreasonable for many patients as social transition can be very challenging if there is incongruence between an individual’s self-affirmed gender and their physical appearance. As a result, the updated guidelines do not require this step, and instead, the societies recommend that patients transition socially and with medical therapy at the same time ( 7 , 8 ).

WPATH recommends that hormone therapy should be initiated once psychosocial assessment has been completed, the patient has been determined to be an appropriate candidate for therapy, and informed consent reviewing the risks and benefits of starting therapy has been obtained. Per WPATH, a referral is required by a qualified mental health professional, unless the prescribing provider is qualified in this type of assessment. The criteria for therapy include: (I) persistent well-documented gender dysphoria (a condition of feeling one’s emotional and psychological identity as male or female to be opposite to one’s biological sex) diagnosed by a mental health professional well versed in the field; (II) capacity to make a fully informed decision and to consent for treatment; (III) age of majority; and (IV) good control of significant medical and/or mental comorbid conditions.

This fourth criterion can sometimes be the most challenging to interpret. Many patients may have concurrent mood disorders related to their gender dysphoria, and experienced providers may have success alleviating the severity of these symptoms by allowing the patient to begin the medical transition process. Later in this review I discuss the effects hormones have on quality of life and perception of personal well-being. This is a key concept and should be considered when patients are being evaluated for hormone therapy initiation. Patients with comorbid psychiatric conditions should be closely monitored and mental health support remains paramount for these patients.

Testosterone

Testosterone therapy is used to suppress female secondary sex characteristics and masculinize transgender men. The therapy used resembles hormone replacement regimens used to treat natal men with hypogonadism and most of the preparations are testosterone esters.

Current formulations for testosterone are presented in Table 1 . Oral formulations such as testosterone undecanoate (Andriol ® ) are used in Europe but continue to not be available in the United States due to concerns about first-pass metabolic effects from the drug. The most commonly used formulations in the United States are those that are administered via the intramuscular or subcutaneous route, and include testosterone enanthate (Delatestryl ® ) and cypionate (Depo ® -Testosterone). These are usually administered weekly, but if higher doses are needed to reach adequate physiologic levels, the dosing interval can be extended to every 10 to 14 days. Testosterone undecanoate (Aveed ® ) is a long-acting testosterone that can be administered every 12 weeks and was approved by the FDA in 2014 for treatment of male hypogonadism, and it can be used off-label to treat gender dysphoria in transgender men. Transdermal options (Androgel ® , Androderm ® ) are also good alternatives for some patients.

Before a patient is started on testosterone, a baseline hematocrit and lipid profile should be obtained, as these indices will change over time. In addition, if a patient is at significant risk for osteoporosis, a baseline bone mineral density should be obtained ( 9 ). Most providers start testosterone therapy with half the anticipated dose needed to reach maximum virilization in a patient. Goal testosterone levels (male physiologic range) are 300–1,000 ng/dL, and testosterone dosages can be quickly titrated to reach adequate levels. Studies exist looking at dose-response with regard to virilization once testosterone is initiated. Nakamura et al. ( 10 ) showed that early onset of treatment effects of testosterone therapy is dose-dependent, but within six months of initiating therapy, higher doses are no more effective than lower doses. Therefore, while higher doses may achieve desirable effects sooner, the risks associated with fast titration need to be assessed, and patients should be aware that testosterone effects eventually become the same over the intermediate-term.

Testopel ® are FDA-approved testosterone pellets that are implanted subcutaneously. Once implanted, the pellets slowly release testosterone for a long-acting androgenic effect. They are approved for the treatment of primary hypogonadism and hypogonadotropic hypogonadism. Our group recommends that patients first be started on an alternative form of testosterone until maximum virilization is achieved and maintenance dosing is then necessary. Patients may then be transitioned to the implanted pellets. The number of pellets to be implanted depends upon the minimal daily requirements of testosterone needed to reach physiologic levels. Each pellet is cylindrical in shape and contains 75 mg of testosterone and six pellets may be implanted with each pass of the insertion device that is provided with the kits. Two pellets should be inserted for every 25 mg of parenteral testosterone needed weekly. The pellets are placed in a fatty area under the skin. Most commonly, the upper gluteal region or hip is used as a site for implantation. Approximately 1/3 of the pellets become absorbed in the first month, 1/4 in the second month and 1/6 in the third month. The effects of the pellets may last up to 6 months, but most patients require re-implantation every 3 to 4 months.

Hormone therapy for transgender women is intended to feminize patients by changing fat distribution, inducing breast formation, and reducing male pattern hair growth ( 11 ). Estrogens are the mainstay therapy for trans female patients. Through a negative feedback loop, exogenous therapy suppresses gonadotropin secretion from the pituitary gland, leading to a reduction in androgen production ( 12 ). Estrogen alone is often not enough to achieve desirable androgen suppression, and adjunctive anti-androgenic therapy is also usually necessary.

Ethinyl estradiol used to be the mainstay of most estrogen-directed therapies. This is no longer the case, as clinical evidence has showed a strong relationship between ethinyl estradiol and the incidence of deep venous thrombosis ( 13 ). As a result, there are strong recommendations against the use of ethinyl estradiol in transgender patients ( 8 ). Oral (Estrace ® , Gynodiol ® ) and transdermal (Alora ® , Climera ® , Esclim ® , Estraderm ® , Vivelle ® ) estradiol and parenteral estradiol valerate (Delestrogen ® ) are currently the preferred formulations of estrogen. See Table 2 for dosing recommendations. No studies have examined the efficacy of the different formulations specific to transgender hormone management. After the age of 40, transdermal formulations are recommended as they bypass first pass metabolism and seem to be associated with better metabolic profiles ( 14 ).

There are no unanimous recommendations for the use of anti-androgens. Options are also listed in Table 2 . Spironolactone is one of the most common medications used to suppress endogenous testosterone in trans female patients. The biggest risk associated with spironolactone is hyperkalemia, and this should be closely monitored. Other options include 5α-reductase inhibitors such as finasteride, but these can be associated with liver toxicity and may not be as effective as spironolactone ( 8 ). GnRH agonists can be very expensive, and are not always a good option for patients. Progestins are used by some providers, but should be used with caution as there is a theoretical risk of breast cancer associated with long-term exogenous progesterone use ( 15 ).

Effects of testosterone and estrogen

Many trans men seek maximum virilization, while others desire suppression of their natal secondary sex characteristics only. As a result, hormone therapy can be tailored to a patient’s transition goals, but must also take into account their medical comorbidities and the risks associated with hormone use.

Within three months of initiating testosterone therapy, the following can be expected: cessation of menses (amenorrhea), increased facial and body hair, skin changes and increased acne, changes in fat distribution and increases in muscle mass, and increased libido ( 11 , 16 ). Later effects include deepening of the voice, atrophy of the vaginal epithelium, and increased clitoral size. Male pattern hair loss also can occur over time as a result of androgenic interaction with pilosebaceous units in the skin ( 17 ). Some patients find this favorable as it may be considered masculinizing. For those who do not find it favorable, 5α-reductase inhibitors can be used as adjuncts to combat alopecia. However, patients should be made aware of the potential side effects on sexual functioning that can be associated with these medications, and they should be counseled that no data exist on the use of these medications in transgender men ( 18 ). In most female-to-male patients (unless testosterone is administered during the peri-pubertal period), there is some degree of feminization that has taken place that cannot be reversed with exogenous testosterone. As a result, many transgender men are shorter, have some degree of feminine subcutaneous fat distribution, and often have broader hips than biologic males ( 19 ).

The following changes are expected after estrogen is initiated: breast growth, increased body fat, slowed growth of body and facial hair, decreased testicular size and erectile function. The extent of these changes and the time interval for maximum change varies across patients and may take up to 18 to 24 months to occur. Use of anti-androgenic therapy as an adjunct helps to achieve maximum change.

Hormone therapy improves transgender patients’ quality of life ( 20 ). Longitudinal studies also show positive effects on sexual function and mood ( 16 , 18 ). There is biologic evidence that may explain this. Kranz et al. ( 21 ) have looked at the acute and chronic effects of estrogen and testosterone on serotonin reuptake transporter (SERT) binding in trans men and women. SERT expression has been shown to be reduced in individuals with major depression ( 22 ). Kranz et al. found that androgen treatment in transmen increased SERT binding in several places in the brain and anti-androgen and estrogen therapy led to decreases in regional SERT binding in trans women. These types of data are preliminary, but do point to the important role of hormone therapy in patients who suffer from gender dysphoria.

Hormone therapy may even have a positive effect on physiologic stress as well. Colizzi et al. ( 23 ) looked at 70 transgender patients on hormone therapy and measured their cortisol levels as well as their perceived stress before and 12 months after starting hormone therapy. They found that after starting cross-sex hormones, both perceived stress and cortisol were significantly reduced. This finding also has important implications for treatment.

Surveillance

Surveillance recommendations for cross-sex hormone therapy are listed in Tables 3 and 4 . Patients on testosterone should be monitored every 3 months for one year and then every 6 to 12 months thereafter. Tables 3 and 4 display surveillance recommendations for trans men and women. Hormones should be carefully monitored to avoid a prolonged hypogonadal state if dosing is too low, which can lead to significant losses in bone mineral density; and to avoid exposures to supraphysiologic levels, which could have significant physiologic and metabolic effects ( 24 ).

Sex steroids—testosterone and estradiol—are necessary to maintain bone health in men and women, respectively. They are responsible for bone growth and turnover, and hypogonadal states in both males and females can result in clinically significant bone loss. Testosterone has a direct role in bone health maintenance, but the steroid is also aromatized peripherally to estradiol, which has a very important role as well ( 25 ). Testosterone also has an important role in increasing muscle mass, which further helps with bone health preservation. Studies have looked at bone health in transgender men on long-term testosterone therapy. Exogenous testosterone appears to have an anabolic effect on cortical bone and when dosed at physiologic levels, is adequate enough to avoid issues with bone demineralization in transgender patients ( 26 ). Transgender women may be at higher risk for bone loss despite estrogen use ( 27 ). This is likely a result of anti-androgen use, and therefore, providers should consider stopping anti-androgen therapy if and when patients undergo orchiectomy with or without genital confirmation surgery. Screening for bone loss should be performed per the guidelines for the general population, unless a patient has baseline low bone mineral density, or is at risk for osteoporosis (tobacco use, alcohol abuse, previous fractures, eating disorder, family history of osteoporosis). Patients at risk should be screened sooner and more regularly.

It is not clear whether use of exogenous testosterone increases the risk of cardiovascular disease in transgender men. Some studies have shown that testosterone has a negative effect on indices that may increase the risk of cardiovascular events. For instance, Gooren and Giltay ( 28 ) showed that long-term testosterone use reduced high-density lipoprotein cholesterol and increased triglycerides as well as inflammatory markers. Other studies have found similar changes. Wierckx et al. ( 16 ) looked at 50 patients on testosterone for a mean time of 10 years and found that many patients had elevated cholesterol and serum triglycerides while several had elevated blood pressure. Despite these metabolic changes, and negative impact on potential risk factors for cardiovascular disease, no studies have found an increase in the occurrence of cardiovascular events such as myocardial infarction, deep vein thrombosis, and cerebrovascular events ( 16 , 29 , 30 ).

Studies looking at the effects of estrogen on cardiovascular disease in transgender women are not very conclusive, but do show that there may be a trend toward an increased risk of heart disease, which should be further studied. Use of oral ethinyl estradiol appears to be strongly associated with cardiovascular events ( 30 ) and should therefore be avoided as a mainstay therapy for patients ( 31 ). In addition, diabetes is a significant risk factor for cardiovascular disease and may have an important role in raising the risk of cardiovascular morbidity in trans women on estrogen, as this comorbidity has been found to be prevalent among the transgender population ( 32 ).

Large-scale prospective studies are lacking. Many of the studies that currently exist have small patient numbers as well as short or medium-term follow-up, and very few of the patients studied are over the age of 65. Furthermore, no head-to-head comparisons of hormone regimens have been published. It is therefore, not possible to draw definitive conclusions about the adverse effects of long-term cross-sex hormone use.

Special considerations

Routine laboratory monitoring of patients on cross-sex hormone therapy can be challenging because results are often reported using gender-specific reference intervals, which are not all appropriate for transgender patients. With the exception of cholesterol, triglycerides, hemoglobin and hematocrit, there are few published data on reference ranges for cardiovascular and metabolic measurements that may be important in the diagnosis and management of other diseases in transgender patients. Roberts et al. ( 33 ) looked at metabolic indices in male-to-female patients on hormone therapy in order to determine appropriate reference ranges. They found that hemoglobin, hematocrit and low-density lipoprotein resembled biologic female ranges. However, alkaline phosphatase, potassium, and creatinine levels were similar to male reference levels. And, importantly, triglyceride levels were higher than both biologic male and female reference ranges. From their study, the authors concluded that it is not possible to predict reference ranges for transgender women based only on what is already known about postmenopausal women on estrogen therapy, and that new reference ranges must be studied and validated to avoid diagnostic errors in this patient population.

Adolescents also seek hormone therapy for treatment of gender dysphoria. The purpose of this review was to cover guidelines and management for adult patients, but it is important to mention special considerations that must be taken when treating adolescent patients. Cross-sex hormones are usually recommended at the age of sixteen ( 7 ). However, in some situations when delay of therapy may lead to psychologic and cognitive trauma in a child, it may be appropriate to commence therapy earlier ( 34 ). In these cases, and most adolescent cases, it is important to have a multi-disciplinary approach to treatment and management, and parental support is imperative. In youth who have reached Tanner Stage 2 development, GnRH agonists are used to suppress endogenous hormones to avoid full pubertal development and cross-sex hormone therapy is initiated by or at age sixteen. There are many ethical issues to address in the care of the adolescent transgender patient, and the care of this patient population should be left to specialists who are well versed in this type of care.

It is not uncommon for patients to seek hormone therapy from alternative sources ( 35 ). In a recently published cross-sectional analysis, Mepham et al. ( 36 ) found that one in four trans women self-prescribe cross-sex hormones, most commonly through the Internet. In another study looking at 314 trans women in San Francisco, 49% were found to be taking hormones not prescribed by a clinician ( 37 ). Over the years, as more medical providers are gaining better experience prescribing hormones, patients are less likely to acquire hormones from these outside sources. It is important to screen patients for outside use, and to educate them about the risks associated with this. Patients sometimes feel that road blocks are placed in front of them when hormones are not prescribed right away, especially if they are being asked to seek further psychiatric care before initiating hormones. Some patients do require additional mental health care, but the time should be taken to explain to patients that the provider who intends to prescribe hormones to patients is not trying to “gate keep” the patient away from this type of therapy, but rather, he or she is ensuring that the patient has a positive outcome on the therapy. This again speaks to the importance of a multi-disciplinary approach to the care of these patients.

Conclusions

Many transgender individuals seek cross-sex hormone therapy for treatment of gender dysphoria. Hormone therapy plays an integral role in the transition process for patients. Guidelines exist to help providers prescribe and monitor therapy. Hormone therapy has been shown to be associated with positive outcomes for patients, but there are important metabolic implications of therapy that must be carefully considered when treating patients.

Acknowledgements

Conflicts of Interest : The author has no conflicts of interest to declare.

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