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What Is Gender-Affirming Hormone Therapy?

• How to Get Started
• Masculinizing Therapy
• Feminizing Therapy
• What to Expect
• Access to Treatment

Gender-affirming hormone therapy helps transgender and other gender-nonconforming people align their bodies with their gender identity . Not all transgender (trans) people are interested in hormone therapy. However, many transgender people, particularly binary transgender people, turn to hormones to affirm their gender.

Gender-affirming hormone therapy is comprised of masculizing hormone therapy used in trans men and feminizing hormone therapy used in trans women.

This article describes the goals of gender-affirming hormone therapy, how the treatment is administered, and the different types of hormones used. It also explains what to expect when undergoing gender-affirming hormone therapy and the possible risks.

Verywell / Brianna Gilmartin

Definitions

The term "gender affirmation" is preferred over "gender confirmation" because a transgender person does not need to confirm their gender to anyone. The word "confirm" suggests proof, while "affirm" means to assert strongly.

Who Is Gender-Affirming Hormone Therapy For?

Gender-affirming hormone therapy is the primary medical treatment sought by transgender people. It allows their secondary sex characteristics to be more aligned with their individual gender identity.

Gender-affirming hormone therapy comes in two types:

• Masculinizing hormone therapy used to develop typically male sex characteristics
• Feminizing hormone therapy used to develop typically female sex characteristics

Hormone therapy can be used on its own for people who have no interest in pursuing gender-affirming surgery . It can also be used in advance of surgery (usually for six months to one year) to improve the outcomes of surgery, such as breast augmentation.

According to the National Transgender Discrimination Survey, 95% of transgender people and 49% of non-binary people were interested in hormone therapy.

Hormone Therapy vs. Puberty Blockers

Puberty blockers are used to delay the onset of puberty in young, gender-diverse people prior to the start of hormone therapy. They are considered to be a distinct but complementary component of gender-affirmation therapy.

How to Get Started 

Gender affirmation is a process in which hormones only play a part. It typically starts with social gender affirmation in which you alter your appearance, wardrobe, and manner of grooming while updating your name, pronouns, and legal documentation.

Medical gender affirmation is typically the next step in which you work with a healthcare provider to identify your personal goals and which type of types of treatments are needed to achieve those goals.

Hormone therapy is typically overseen by a specialist in the endocrine (hormonal) system called an endocrinologist . Other healthcare providers trained in gender-affirming medical care may be equally qualified to administer treatment.

Depending on state law and other factors, healthcare providers may be able to dispense treatment on the same day. No letter from a mental health provider may be needed. Call Planned Parenthood or your local LGBTI organization to learn about the laws in your state.

To receive authorization for insurance coverage, many insurers require a diagnosis of gender dysphoria . To do so, a therapist or mental health professional must confirm that there is a mismatch between a person's expressed or experienced gender and the gender they were assigned at birth for a period of at least six months.

How to Choose the Right Provider

Not every endocrinologist is equally well-suited to administer gender-affirming hormone therapy. Those who have undergone a comprehensive, multidisciplinary gender-affirmation training program are generally preferred.

Do not hesitate to ask about a healthcare provider's experience and qualifications in administering gender-affirming care.

Masculinizing Hormone Therapy

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

There has been growing interest in the use of subcutaneous pellets for testosterone treatment, as they only need to be inserted two to four times a year. However, they are not always available or covered by insurance.

Changes that can be induced by masculinizing hormone therapy include:

• Facial and body hair growth
• Increased muscle mass
• Lowering of the pitch of the voice
• Increased sex drive
• Growth of the glans clitoris
• Interruption of menstruation
• Vaginal dryness
• Facial and body fat redistribution
• Sweat- and odor-pattern changes
• Hairline recession; possibly male pattern baldness
• Possible changes in emotions or interests

Masculinizing hormone therapy cannot reverse all of the changes associated with female puberty. If transmasculine individuals have experienced breast growth that makes them uncomfortable, they may need to address that with binding or top surgery .

Testosterone will also not significantly increase height unless it is started reasonably early. Finally, testosterone should not be considered an effective form of contraception, even if menses have stopped.

Feminizing Hormone Therapy

Feminizing hormone therapy uses a combination of estrogen and a testosterone blocker. The testosterone blocker is needed because testosterone has stronger effects on the body than estrogen.

The blocker most commonly used in the United States is spironolactone , a medication also used for heart disease. The medication used as a puberty blocker, called Supprelin LA (histerline), can also be used to block testosterone.

Various forms of estrogen can be used for feminizing hormone therapy. In general, injectable or topical forms are preferred as they tend to have fewer side effects than oral estrogens. However, some trans women prefer oral estrogens.

Changes that can be induced by feminizing hormone therapy include:

• Breast growth
• Softening of the skin
• Fat redistribution
• Reduction in face and body hair (but not elimination)
• Reduced hair loss/balding
• Muscle-mass reduction
• Decrease in erectile function
• Testicular size reduction

Estrogen cannot reverse all changes associated with having undergone testosterone-driven puberty. It cannot eliminate facial or body hair or reverse shoulder width, jaw size, vocal pitch, or facial structure. Many of these can be addressed with aesthetic or surgical treatments.

What to Expect During Treatment

Some hormones used for gender-affirming hormone therapy are self-administered or given by someone you know. Others need to be administered by a healthcare provider.

Thereafter, regular follow-ups are needed to evaluate the effects of treatment and possible side effects. Most healthcare providers recommend visiting every 3 months for the first year and every 6 to 12 months thereafter.

Effects of Therapy

It can take three to five years for your body to show the full effects of gender-affirming hormone therapy. Some changes can occur within the first six months, such as the development of larger breasts. Others, like changes in facial structure, can take years.

In addition to physical changes, hormone therapy can cause emotional changes. If you are sexually active, it may improve sexual satisfaction as well as your overall sense of well-being. Hormone therapy can also help to ease the stress associated with gender dysphoria.

If you discontinue therapy, some changes may be reversible. Others like changes in bone structure may be permanent.

Possible Risks

As beneficial as gender-affirming hormone therapy can be, it also carries certain risks depending on which hormone you are taking.

Possible risks of feminizing hormone therapy include:

• High blood pressure
• Blood clots
• Heart disease
• Type 2 diabetes
• Weight gain
• Infertility
• Breast and prostate cancer

Risks of masculinizing hormone therapy:

• Male pattern baldness
• High cholesterol
• Pelvic pain
• Sleep apnea
• Interfertility

Access to Gender-Affirming Hormone Therapy

Until relatively recently, access to gender-affirming hormone therapy was largely managed through gatekeeping models that required gender-diverse people to undergo a psychological assessment before they could access hormone treatment.

However, there has been a growing movement toward the use of an informed consent model to better reflect access to other types of medical care. This change has been reflected in the standards of care for transgender health produced by the World Professional Association of Transgender Health (WPATH).

Gender-affirming hormone therapy is considered to be a medically necessary treatment for gender dysphoria. It should be covered by most insurers in the United States after legal changes that occurred as part of the passage of the Affordable Care Act.

However, state laws vary substantially in terms of transgender protections, and some states do allow policies to exclude various aspects of transgender health care, including gender-affirming hormone therapy.

Access to hormone therapy can be prohibitively expensive for many people if they need to pay out of pocket, which may lead some people to try to get these medications from friends or other unlicensed sources.

In addition, individuals who are involved with carceral systems such as immigrant detention may be denied access to hormones. This can have significant negative physical and psychological effects.

Gender-affirming hormone therapy is the primary form of treatment for transgender people. Masculizing hormone therapy involving testosterone is used to develop secondary male sex characteristics like larger muscles. Feminizing hormone therapy involving estrogen and a testosterone blocker is used to develop secondary female sex characteristics like breasts.

Some masculinizing and feminizing effects can occur within months, while others may take years. If you stop treatment, many of the effects will reverse while some will be permanent. Regular follow-up care is needed to avoid potential side effects and long-term complications.

Gardner I, Safer JD. Progress on the road to better medical care for transgender patients . Curr Opin Endocrinol Diabetes Obesity . 2013 20(6):553-8. doi:10.1097/01.med.0000436188.95351.4d

James SE, Herman JL, Rankin S, Keisling M, Mottet M, Anafi M. The Report of the 2015 U.S. Transgender Survey . Washington, DC: National Center for Transgender Equality. 2016.

Planned Parenthood. Gender-affirming hormone therapy: what to expect on your first visit and beyond .

Boskey ER, Taghinia AH, Ganor O. Association of surgical risk with exogenous hormone use in transgender patients: A systematic review . JAMA Surg . 2019;154(2):159-169. doi:10.1001/jamasurg.2018.4598

Almazan AN, Benson TA, Boskey ER, Ganor O. Associations between transgender exclusion prohibitions and insurance coverage of gender-affirming surgery. LGBT Health . 2020;7(5). doi:10.1089/lgbt.2019.0212

White Hughto JM, Reisner SL. A systematic review of the effects of hormone therapy on psychological functioning and quality of life in transgender individuals . Transgender Health . 2016;1(1),21–31. doi:10.1089/trgh.2015.0008

Cavanaugh T, Hopwood R, Lambert C. Informed consent in the medical care of transgender and gender-nonconforming patients . AMA Journal of Ethics . 2016;18(11),1147–1155. doi:10.1001/journalofethics.2016.18.11.sect1-161

World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People (7th Version) . WPATH. 2011.

By Elizabeth Boskey, PhD Boskey has a doctorate in biophysics and master's degrees in public health and social work, with expertise in transgender and sexual health.

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What to Know About Gender-Affirming Hormone Therapy

Aug 24, 2021

Alto Pharmacy

For many transgender men and women, hormone replacement therapy is an important component of their transitioning process, allowing them to develop physical traits aligned with their gender identity. Taking this step to feel more comfortable in your body is a big decision, and there are many factors to consider as you determine if gender-affirming hormone replacement therapy is right for you. 

Below is an overview of hormone replacement therapy medications and side effects to help you learn more about the process.

Hormone replacement therapy for transgender women

Estrogen and testosterone-blocking medications help transgender women develop a more feminized appearance in line with their gender identity while transitioning. It reduces the discomfort of gender dysphoria , the distress caused by having a gender identity that differs from the sex you were assigned at birth. Many transgender women experience less emotional distress, improved personal relationships, and a better overall quality of life as a result of hormone replacement therapy .

Feminizing hormone replacement therapy causes a variety of physical changes like breast development and facial and body hair reduction. You may also experience a loss of muscle tone and changes in your body shape as the body redistributes fat cells.

Feminizing hormone replacement therapy medication and timing

While your healthcare provider will help you develop an individualized treatment plan, feminizing hormone therapy often begins by taking 100 to 200 milligrams daily of a diuretic called spironolactone to begin blocking male hormone receptors and suppress testosterone production. Some individuals begin taking estrogen immediately, in tandem with spironolactone, to further reduce testosterone production and develop more feminine characteristics. In other cases, estrogen is introduced after several weeks of spironolactone use. Your doctor will recommend the best plan for your needs.

There are various methods for administering estrogen, including orally, by injection, or as a cream, gel, spray, or patch. Commonly used forms of estrogen during a male-to-female transition include:

Oral: Estradiol tablets . Note that your doctor may advise you to let the tablets dissolve under your tongue rather than swallowing them. This is called sublingual administration , which may lower your risk for blood clots since it bypasses the liver.

Injections: Estradiol valerate (branded options include Delestrogen®) and estradiol cypionate (branded options include DEPO®-Estradiol)

Patches: 17B-Estradiol patch

Feminizing hormone replacement therapy side effects

You may experience one or more of the following hormone replacement therapy side effects . Your doctor can advise you about the potential risks and benefits prior to starting hormones.

A blood clot in a deep vein (also known as deep vein thrombosis ) or in your lungs

High levels of triglycerides , a type of fat found in the blood

Weight gain

High potassium levels

High blood pressure

Reduced libido

Feminizing hormone replacement therapy may also increase your risk for some chronic health conditions. Since estrogen affects how your body responds to insulin, it can lead to changes in your blood sugar levels and a greater risk for type 2 diabetes . Research into the impact of estrogen on your cardiovascular system is ongoing, and some studies have found a connection between estrogen therapy and a greater risk for heart disease and stroke. You may also face a greater risk of breast cancer after starting hormone replacement therapy.

Certain underlying health conditions may increase your risk of health complications related to the use of estrogen and testosterone-blocking hormones. It’s important to share your full medical history with your doctor, especially if you’ve had a hormone-related cancer, like prostate cancer, or a history of blood clots.

Feminizing hormone therapy and fertility

Gender-affirming hormone replacement therapy may affect your fertility , as it impacts sperm production. While some transgender women can produce sperm again after stopping hormone treatment, research indicates that this may not be the case universally, and there is a risk of permanent infertility with long-term use of hormones. If you would like to have biological children, ask your doctor about your options with freezing your sperm before starting hormones.

Hormone replacement therapy for transgender men

Hormone replacement therapy for transgender men during a female-to-male transition also combats gender dysphoria , leading to reduced emotional discomfort and better overall mental health.

During the process, you will take testosterone , which decreases estrogen production and suppresses menstruation. Testosterone is typically administered by injection (branded options include Delatestryl® and Tesamone®) or as a gel applied to the skin (branded options include AndroGel®, Testim®, Fortesta®, and Axiron®). In some cases, it may be applied as a patch or pellets positioned under the skin. If you have a persistent menstrual flow, your doctor might recommend taking progesterone to control it.

You may observe some of the following physical changes within several months of starting hormones, though individual responses to treatment varies:

Deepening of the voice

Facial and body hair growth

Body fat redistribution

Increased muscle mass and strength

Masculinizing hormone replacement therapy side effects

There are several potential side effects that transgender men may experience as a result of hormone replacement therapy, including the following:

Overproduction of red blood cells

Blood clot in a deep vein or lung

Pelvic pain

Sleep apnea

Abnormal cholesterol levels

Masculinizing hormone replacement therapy may also increase your risk for type 2 diabetes and cardiovascular disease .

You are more likely to experience one or more of these health complications if you have had breast cancer or have a history of blood clots. It may be unsafe to continue with hormone treatment if you are pregnant or breastfeeding. Be sure to discuss the potential risks and benefits of hormone replacement therapy with your doctor, and make sure they are aware of your full medical history.

Masculinizing hormone therapy and fertility

While some transgender men have sucessfully undergone egg freezing or IVF after starting hormone therapy, long-term use of hormones may lead to permanent infertility. If you want to leave open the possibility of starting a family by having children biologically , consult your doctor about your options for egg freezing before starting treatment.

Given that individual responses to testosterone treatment vary, you have a chance of becoming pregnant even while taking hormones. Your doctor can advise you about your options for birth control.

Baseline and follow-up testing for hormone replacement therapy

Before you begin hormone replacement therapy, your doctor will order tests to measure your baseline lipid, blood sugar, liver enzyme, and electrolyte levels, which may change throughout the course of your treatment. Your doctor will also evaluate your medical history to identify any health conditions that may affect treatment. This is also a good opportunity to discuss reproductive health and fertility considerations, including potential contraception options if you are a transgender man.

Throughout hormone therapy, you will have regular follow-up appointments with your healthcare provider to document physical changes in your appearance and monitor the impact of hormones on your lipids, blood sugar, and liver enzymes.

Hormone replacement therapy affects you emotionally as well as physically. In the long term, gender-affirming treatment, including both hormone therapy and surgery, can lead to better mental health, reducing the need for depression and anxiety-related treatment .

Your doctor will likely ask questions related to your mental health during your initial consultation — including any symptoms of gender dysphoria that you have experienced and how they impact you at work, school, or home — and continue the conversation throughout your treatment.

It’s important to be honest with your doctor about how you are feeling — your mental health matters as much as your physical health. Don’t be afraid to ask for mental health-related resources if you need extra support, and remember that your doctor is here to help you without judgment.

View the National Institute of Mental Health’s suggestions for finding mental health treatment, and the Human Rights Campaign’s list of LGBTQ mental health resources.

A pharmacy partner you can rely on

Alto is here to support your journey with hormone replacement therapy. Our team of patient care pharmacists has experience working with the LGBTQ+ community and is available to answer any questions you have about the process.

We also make it as simple as possible to stay on top of your medications, with same-day delivery and mediation management tools like reminders and auto refills in our app. Reach out any time to get started by phone at 1-800-874-5881 or download the app for secure messaging with our care team.

This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition.

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Treatment - Gender dysphoria

Treatment for gender dysphoria aims to help people live the way they want to, in their preferred gender identity or as non-binary.

What this means will vary from person to person, and is different for children, young people and adults. Waiting times for referral and treatment are currently long.

Treatment for children and young people

If your child may have gender dysphoria, they'll usually be referred to one of the NHS Children and Young People's Gender Services .

Your child or teenager will be seen by a multidisciplinary team including a:

• clinical psychologist
• child psychotherapist
• child and adolescent psychiatrist
• family therapist
• social worker

The team will carry out a detailed assessment, usually over 3 to 6 appointments over a period of several months.

Depending on the results of the assessment, options for children and teenagers include:

• family therapy
• individual child psychotherapy
• parental support or counselling
• group work for young people and their parents
• regular reviews to monitor gender identity development
• referral to a local Children and Young People's Mental Health Service (CYPMHS) for more serious emotional issues

Most treatments offered at this stage are psychological rather than medical. This is because in many cases gender variant behaviour or feelings disappear as children reach puberty.

Hormone therapy in children and young people

Some young people with lasting signs of gender dysphoria who meet strict criteria may be referred to a hormone specialist (consultant endocrinologist). This is in addition to psychological support.

Puberty blockers and gender-affirming hormones

Puberty blockers (gonadotrophin-releasing hormone analogues) are not available to children and young people for gender incongruence or gender dysphoria because there is not enough evidence of safety and clinical effectiveness.

From around the age of 16, young people with a diagnosis of gender incongruence or gender dysphoria who meet various clinical criteria may be given gender-affirming hormones alongside psychosocial and psychological support.

These hormones cause some irreversible changes, such as:

• breast development (caused by taking oestrogen)
• breaking or deepening of the voice (caused by taking testosterone)

Long-term gender-affirming hormone treatment may cause temporary or even permanent infertility.

However, as gender-affirming hormones affect people differently, they should not be considered a reliable form of contraception.

There is some uncertainty about the risks of long-term gender-affirming hormone treatment.

Children, young people and their families are strongly discouraged from getting puberty blockers or gender-affirming hormones from unregulated sources or online providers that are not regulated by UK regulatory bodies.

Transition to adult gender identity services

Young people aged 17 or older may be seen in an adult gender identity clinic or be referred to one from a children and young people's gender service.

By this age, a teenager and the clinic team may be more confident about confirming a diagnosis of gender dysphoria. If desired, steps can be taken to more permanent treatments that fit with the chosen gender identity or as non-binary.

Treatment for adults

Adults who think they may have gender dysphoria should be referred to a gender dysphoria clinic (GDC).

Find an NHS gender dysphoria clinic in England .

GDCs have a multidisciplinary team of healthcare professionals, who offer ongoing assessments, treatments, support and advice, including:

• psychological support, such as counselling
• cross-sex hormone therapy
• speech and language therapy (voice therapy) to help you sound more typical of your gender identity

For some people, support and advice from the clinic are all they need to feel comfortable with their gender identity. Others will need more extensive treatment.

Hormone therapy for adults

The aim of hormone therapy is to make you more comfortable with yourself, both in terms of physical appearance and how you feel. The hormones usually need to be taken for the rest of your life, even if you have gender surgery.

It's important to remember that hormone therapy is only one of the treatments for gender dysphoria. Others include voice therapy and psychological support. The decision to have hormone therapy will be taken after a discussion between you and your clinic team.

In general, people wanting masculinisation usually take testosterone and people after feminisation usually take oestrogen.

Both usually have the additional effect of suppressing the release of "unwanted" hormones from the testes or ovaries.

Whatever hormone therapy is used, it can take several months for hormone therapy to be effective, which can be frustrating.

It's also important to remember what it cannot change, such as your height or how wide or narrow your shoulders are.

The effectiveness of hormone therapy is also limited by factors unique to the individual (such as genetic factors) that cannot be overcome simply by adjusting the dose.

Find out how to save money on prescriptions for hormone therapy medicines with a prescription prepayment certificate .

Risks of hormone therapy

There is some uncertainty about the risks of long-term cross-sex hormone treatment. The clinic will discuss these with you and the importance of regular monitoring blood tests with your GP.

The most common risks or side effects include:

• blood clots
• weight gain
• dyslipidaemia (abnormal levels of fat in the blood)
• elevated liver enzymes
• polycythaemia (high concentration of red blood cells)
• hair loss or balding (androgenic alopecia)

There are other risks if you're taking hormones bought over the internet or from unregulated sources. It's strongly recommended you avoid these.

Long-term cross-sex hormone treatment may also lead, eventually, to infertility, even if treatment is stopped.

The GP can help you with advice about gamete storage. This is the harvesting and storing of eggs or sperm for your future use.

Gamete storage is sometimes available on the NHS. It cannot be provided by the gender dysphoria clinic.

Read more about fertility preservation on the HFEA website.

Surgery for adults

Some people may decide to have surgery to permanently alter body parts associated with their biological sex.

Based on the recommendations of doctors at the gender dysphoria clinic, you will be referred to a surgeon outside the clinic who is an expert in this type of surgery.

In addition to you having socially transitioned to your preferred gender identity for at least a year before a referral is made for gender surgery, it is also advisable to:

• lose weight if you are overweight (BMI of 25 or over)
• have taken cross-sex hormones for some surgical procedures

It's also important that any long-term conditions, such as diabetes or high blood pressure, are well controlled.

Surgery for trans men

Common chest procedures for trans men (trans-masculine people) include:

• removal of both breasts (bilateral mastectomy) and associated chest reconstruction
• nipple repositioning
• dermal implant and tattoo

Gender surgery for trans men includes:

• construction of a penis (phalloplasty or metoidioplasty)
• construction of a scrotum (scrotoplasty) and testicular implants
• a penile implant

Removal of the womb (hysterectomy) and the ovaries and fallopian tubes (salpingo-oophorectomy) may also be considered.

Surgery for trans women

Gender surgery for trans women includes:

• removal of the testes (orchidectomy)
• removal of the penis (penectomy)
• construction of a vagina (vaginoplasty)
• construction of a vulva (vulvoplasty)
• construction of a clitoris (clitoroplasty)

Breast implants for trans women (trans-feminine people) are not routinely available on the NHS.

Facial feminisation surgery and hair transplants are not routinely available on the NHS.

As with all surgical procedures there can be complications. Your surgeon should discuss the risks and limitations of surgery with you before you consent to the procedure.

Life after transition

Whether you've had hormone therapy alone or combined with surgery, the aim is that you no longer have gender dysphoria and feel at ease with your identity.

Your health needs are the same as anyone else's with a few exceptions:

• you'll need lifelong monitoring of your hormone levels by your GP
• you'll still need contraception if you are sexually active and have not yet had any gender surgery
• you'll need to let your optician and dentist know if you're on hormone therapy as this may affect your treatment
• you may not be called for screening tests as you've changed your name on medical records – ask your GP to notify you for cervical and breast screening if you're a trans man with a cervix or breast tissue
• trans-feminine people with breast tissue (and registered with a GP as female) are routinely invited for breast screening from the ages of 50 up to 71

Find out more about screening for trans and non-binary people on GOV.UK.

NHS guidelines for gender dysphoria

NHS England has published what are known as service specifications that describe how clinical and medical care is offered to people with gender dysphoria:

• Non-surgical interventions for adults
• Surgical interventions for adults
• Interim service specification for specialist gender incongruence services for children and young people

Review of gender identity services

NHS England has commissioned an independent review of gender identity services for children and young people. The review will advise on any changes needed to the service specifications for children and young people.

Page last reviewed: 28 May 2020 Next review due: 28 May 2023

May 12, 2022

What the Science on Gender-Affirming Care for Transgender Kids Really Shows

Laws that ban gender-affirming treatment ignore the wealth of research demonstrating its benefits for trans people’s health

By Heather Boerner

As attacks against transgender kids increase in the U.S., Minnesotans hold a rally at the state’s capitol in Saint Paul in March 2022 to support trans kids in Minnesota and Texas and around the country.

Michael Siluk/UCG/Universal Images Group via Getty Images

Editor’s Note (3/30/23): This article from May 2022 is being republished to highlight the ways that ongoing anti-trans legislation is harmful and unscientific.

For the first 40 years of their life, Texas resident Kelly Fleming spent a portion of most years in a deep depression. As an adult, Fleming—who uses they/them pronouns and who asked to use a pseudonym to protect their safety—would shave their face in the shower with the lights off so neither they nor their wife would have to confront the reality of their body.

What Fleming was experiencing, although they did not know it at the time, was gender dysphoria : the acute and chronic distress of living in a body that does not reflect one’s gender and the desire to have bodily characteristics of that gender. While in therapy, Fleming discovered research linking access to gender-affirming hormone therapy with reduced depression in transgender people. They started a very low dose of estradiol, and the depression episodes became shorter, less frequent and less intense. Now they look at their body with joy.

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So when Fleming sees what authorities in Texas , Alabama , Florida and other states are doing to bar transgender teens and children from receiving gender-affirming medical care, it infuriates them. And they are worried for their children, ages 12 and 14, both of whom are agender—a identity on the transgender spectrum that is neither masculine nor feminine.

“I’m just so excited to see them being able to present themselves in a way that makes them happy,” Fleming says. “They are living their best life regardless of what others think, and that’s a privilege that I did not get to have as a younger person.”

Laws Based on “Completely Wrong” Information

Currently more than a dozen state legislatures  or administrations are considering—or have already passed—laws banning health care for transgender young people. On April 20 the Florida Department of Health issued guidance to withhold such gender-affirming care. This includes social gender transitioning—acknowledging that a young person is trans, using their correct pronouns and name, and supporting their desire to live publicly as the gender of their experience rather than their sex assigned at birth. This comes nearly two months after Texas Governor Greg Abbott issued an order for the Texas Department of Family and Protective Services to investigate for child abuse parents who allow their transgender preteens and teenagers to receive medical care. Alabama recently passed SB 184 , which would make it a felony to provide gender-affirming medical care to transgender minors. In Alabama, a “minor” is defined as anyone 19 or younger.

If such laws go ahead, 58,200 teens in the U.S. could lose access to or never receive gender-affirming care, according to the Williams Institute at the University of California, Los Angeles. A decade of research shows such treatment reduces depression, suicidality and other devastating consequences of trans preteens and teens being forced to undergo puberty in the sex they were assigned at birth).

The bills are based on “information that’s completely wrong,” says Michelle Forcier, a pediatrician and professor of pediatrics at Brown University. Forcier literally helped write the book on how to provide evidence-based gender care to young people. She is also an assistant dean of admissions at the Warren Alpert Medical School of Brown University. Those laws “are absolutely, absolutely incorrect” about the science of gender-affirming care for young people, she says. “[Inaccurate information] is there to create drama. It’s there to make people take a side.”

The truth is that data from more than a dozen studies of more than 30,000 transgender and gender-diverse young people consistently show that access to gender-affirming care is associated with better mental health outcomes—and that lack of access to such care is associated with higher rates of suicidality, depression and self-harming behavior. (Gender diversity refers to the extent to which a person’s gendered behaviors, appearance and identities are culturally incongruent with the sex they were assigned at birth. Gender-diverse people can identify along the transgender spectrum, but not all do.) Major medical organizations, including the American Academy of Pediatrics (AAP) , the American Academy of Child and Adolescent Psychiatry , the Endocrine Society , the American Medical Association , the American Psychological Association and the American Psychiatric Association , have published policy statements and guidelines on how to provide age-appropriate gender-affirming care. All of those medical societies find such care to be evidence-based and medically necessary.

AAP and Endocrine Society guidelines call for developmentally appropriate care, and that means no puberty blockers or hormones until young people are already undergoing puberty for their sex assigned at birth. For one thing, “there are no hormonal differences among prepubertal children,” says Joshua Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery in New York City and co-author of the Endocrine Society’s guidelines. Those guidelines provide the option of gonadotropin-releasing hormone analogues (GnRHas), which block the release of sex hormones, once young people are already into the second of five puberty stages—marked by breast budding and pubic hair. These are offered only if a teen is not ready to make decisions about puberty. Access to gender-affirming hormones and potential access to gender-affirming surgery is available at age 16—and then, in the case of transmasculine youth, only mastectomy, also known as top surgery. The Endocrine Society does not recommend genital surgery for minors.

Before puberty, gender-affirming care is about supporting the process of gender development rather than directing children through a specific course of gender transition or maintenance of cisgender presentation, says Jason Rafferty, co-author of AAP’s policy statement on gender-affirming care and a pediatrician and psychiatrist at Hasbro Children’s Hospital in Rhode Island. “The current research suggests that, rather than predicting or preventing who a child might become, it’s better to value them for who they are now—even at a young age,” Rafferty says.

A Safe Environment to Explore Gender

A 2021 systematic review of 44 peer-reviewed studies found that parent connectedness, measured by a six-question scale asking about such things as how safe young people feel confiding in their guardians or how cared for they feel in the family, is associated with greater resilience among teens and young adults who are transgender or gender-diverse. Rafferty says he sees his role with regard to prepubertal children as offering a safe environment for the child to explore their gender and for parents to ask questions. “The gender-affirming approach is not some railroad of people to hormones and surgery,” Safer says. “It is talking and watching and being conservative.”

Only once children are older, and if the incongruence between the sex assigned to them at birth and their experienced gender has persisted, does discussion of medical transition occur. First a gender therapist has to diagnose the young person with gender dysphoria .

After a gender dysphoria diagnosis—and only if earlier conversations suggest that hormones are indicated—guidelines call for discussion of fertility, puberty suppression and hormones. Puberty-suppressing medications have been used for decades for cisgender children who start puberty early, but they are not meant to be used indefinitely. The Endocrine Society guidelines recommend a maximum of two years on GnRHa therapy to allow more time for children to form their gender identity before undergoing puberty for their sex assigned at birth, the effects of which are irreversible.

“[Puberty blockers] are part of the process of ‘do no harm,’” Forcier says, referencing a popular phrase that describes the Hippocratic Oath, which many physicians recite a version of before they begin to practice.

Hormone blocker treatment may have side effects. A 2015 longitudinal observational cohort study of 34 transgender young people found that, by the time the participants were 22 years old, trans women experienced a decrease in bone mineral density. A 2020 study of puberty suppression in gender-diverse and transgender young people found that those who started puberty blockers in early puberty had lower bone mineral density before the start of treatment than the public at large. This suggests, the authors wrote, that GnRHa use may not be the cause of low bone mineral density for these young people. Instead they found that lack of exercise was a primary factor in low bone-mineral density, especially among transgender girls.

Other side effects of GnRHa therapy include weight gain, hot flashes and mood swings. But studies have found that these side effects—and puberty delay itself—are reversible , Safer says.

Gender-affirming hormone therapy often involves taking an androgen blocker (a chemical that blocks the release of testosterone and other androgenic hormones) and estrogen in transfeminine teens, and testosterone supplementation in transmasculine teens. Such hormones may be associated with some physiological changes for adult transgender people. For instance, transfeminine people taking estrogen see their so-called “good” cholesterol increase. By contrast, transmasculine people taking testosterone see their good cholesterol decrease. Some studies have hinted at effects on bone mineral density, but these are complicated and also depend on personal, family history, exercise, and many other factors in addition to hormones.”

And while some critics point to decade-old study and older studies suggesting very few young people persist in transgender identity into late adolescence and adulthood, Forcier says the data are “misleading and not accurate.” A recent review detailed methodological problems with some of these studies . New research in 17,151 people who had ever socially transitioned found that 86.9 percent persisted in their gender identity. Of the 2,242 people who reported that they reverted to living as the gender associated with the sex they were assigned at birth, just 15.9 percent said they did so because of internal factors such as questioning their experienced gender but also because of fear, mental health issues and suicide attempts. The rest reported the cause was social, economic and familial stigma and discrimination. A third reported that they ceased living openly as a trans person because doing so was “just too hard for me.”

The Harms of Denying Care

Data suggest the effects of denying that care are worse than whatever side effects result from delaying sex-assigned-at-birth puberty. And medical society guidelines conclude that the benefits of gender-affirming care outweigh the risks. Without gender-affirming hormone therapy, cisgender hormones take over, forcing body changes that can be permanent and distressing.

A 2020 study of 300 gender-incongruent young people found that mental distress—including self-harm, suicidal thoughts and depression— increased as the children were made to proceed with puberty according to their assigned sex. By the time 184 older teens (with a median age of 16) reached the stage in which transgender boys began their periods and grew breasts and transgender girls’ voice dropped and facial hair began to appear, 46 percent had been diagnosed with depression, 40 percent had self-harmed, 52 percent had considered suicide, and 17 percent had attempted it—rates significantly higher than those of gender-incongruent children who were a median of 13.9 years old or of cisgender kids their own age.

Conversely, access to gender-affirming hormones in adolescence appears to have a protective effect. In one study, researchers followed 104 teens and young adults for a year and asked them about their depression, anxiety and suicidality at the time they started receiving hormones or puberty blockers and again at the three-month, six-month and one-year mark. At the beginning of the study, which was published in JAMA Network Open in February 2022, more than half of the respondents reported moderate to severe depression, half reported moderate to severe anxiety, and 43.3 percent reported thoughts of self-harm or suicide in the past two weeks.

But when the researchers analyzed the results based on the kind of gender-affirming care the teens had received, they found that those who had access to puberty blockers or gender-affirming hormones were 60 percent less likely to experience moderate to severe depression. And those with access to the medical treatments were 73 percent less likely to contemplate self-harm or suicide.

“Delays in prescribing puberty blockers and hormones may in fact worsen mental health symptoms for trans youth,” says Diana Tordoff, an epidemiology graduate student at the University of Washington and co-author of the study.

That effect may be lifelong. A 2022 study of more than 21,000 transgender adults showed that just 41 percent of adults who wanted hormone therapy received it, and just 2.3 percent had access to it in adolescence. When researchers looked at rates of suicidal thinking over the past year in these same adults, they found that access to hormone therapy in early adolescence was associated with a 60 percent reduction in suicidality in the past year and that access in late adolescence was associated with a 50 percent reduction.

For Fleming’s kids in Texas, gender-affirming hormones are not currently part of the discussion; not all trans people desire hormones or surgery to feel affirmed in their gender. But Fleming is already looking at jobs in other states to protect their children’s access to such care, should they change their mind. “Getting your body closer to the gender [you] identify with—that is what helps the dysphoria,” Fleming says. “And not giving people the opportunity to do that, making it harder for them to do that, is what has made the suicide rate among transgender people so high. We just—trans people are just trying to survive.”

IF YOU NEED HELP If you or someone you know is struggling or having thoughts of suicide, help is available. Call the National Suicide Prevention Lifeline at 1-800-273-8255 (TALK), use the online Lifeline Chat or contact the Crisis Text Line by texting TALK to 741741.

Australian Journal of General Practice

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Hormone therapy for trans and gender diverse patients in the general practice setting

In recent years there has been a significant increase in the number of trans, gender diverse and non-binary (TGDNB) people accessing healthcare. For many of these individuals the first port of call will be to their local general practitioner (GP). The TGDNB community is a high-priority population with the highest suicide rates of any population group in Australia. There is evidence that mental health outcomes improve significantly when individuals are able to access gender-affirming hormones.

The aim of this article is to provide GPs working in Australia with a practical guide to prescribe gender-affirming hormone therapy to TGDNB patients.

GPs are ideally placed to provide care for TGDNB patients in the primary care setting. Gender incongruence is no longer viewed as a mental health disorder. In recent years there has been a move away from mandatory psychiatric assessment to more contemporary patient-centred models of care.

General practitioners (GPs) throughout Australia are highly likely to encounter trans, gender diverse and non-binary (TGDNB) patients in their daily practice. The World Health Organization estimates that up to 0.5% of the global population identify as transgender or gender diverse. 1 In Australia, 2.3% of students in years 10–12 identified as trans and gender diverse in a national sexual health survey in 2018. 2

In recent years there have been many advances in the field of transgender health. These include:

• a recognition that gender diversity is not a mental health disorder 3,4
• a move away from mandatory psychiatric assessment to more contemporary patient-centred models of care 5
• an understanding of a diverse range of gender identities including identities outside of the binary. 6,7

TGDNB patients may present to their GPs requesting gender-affirming care, and this may include a request for gender-affirming hormones. It has become clear that reducing barriers to healthcare and providing earlier access to gender-affirming hormones improves the health outcomes and wellbeing of TGDNB people. 8,9 However, significant numbers of people within the TGDNB community find themselves unable to access appropriate and timely medical services. In a recent national survey of TGDNB individuals, over half of the respondents reported their access to gender-affirming care as either ‘ok’, ‘poor’ or ‘non-existent’. 10

GPs throughout Australia are ideally placed to provide gender-affirming care to TGDNB patients. Gender-affirming hormones can be prescribed and monitored in a primary care setting in most cases. Several local resources have been developed to assist GPs to prescribe hormone therapies. Training and professional development activities are available, and mentoring by a colleague with experience working in the field is recommended.

General principles of prescribing gender-affirming hormones

The general principles of prescribing gender-affirming hormones can be summarised as follows.

• The goal of gender-affirming hormone therapy is to align physical appearance with gender identity to reduce distress and improve wellbeing.
• Hormone therapy should be individualised – there is no ‘one size fits all’.
• When prescribing hormone therapy, it is important to start with low doses and titrate up gradually.
• Gender-affirming hormone therapy is usually, but not always, lifelong. Some patients choose to cease hormones once the desired changes have occurred.

Informed consent model of care

In 2017 the Equinox Gender Diverse Health Centre in Melbourne (Thorne Harbour Health) produced the first Australian guideline for an ‘informed consent’ model of care, Protocols for the initiation of hormone therapy for trans and gender diverse patients . 5 The guideline is based on a similar protocol that was successfully implemented in the USA. 11 The guideline is endorsed by the Australian Professional Association for Transgender Health (AusPATH) and the Gender Clinic, Monash Health, Victoria. Under an informed consent model of care, the treating GP is the main care provider. There is an emphasis on self-determination, patient-centred care and mental health support. Mental health support can be provided by a counsellor, GP, psychologist, psychiatrist or peer worker depending on the patient’s needs. If the patient is unable to give informed consent or has severe unstable mental health concerns such as active psychosis, a psychiatry review is recommended prior to initiation of gender-affirming hormones. Depression and anxiety are common in the TGDNB population and are not a contraindication to the commencement of gender-affirming hormones.

Before initiating gender-affirming hormones, it is important to confirm a history of gender incongruence. This is self-determined by the patient. A patient will typically describe a persistent incongruence between their gender identity and their birth-assigned gender. It is important to spend time counselling the patient about hormone therapies and exploring their psychosocial situation and supports. This may be covered in a relatively short time or may require several consultations. The length of time required depends on the level of experience of the treating GP and the complexity of the presentation.

Pre-commencement visits provide an invaluable opportunity to provide preventive care, sexual health screening and general health checks. A suggested checklist for use prior to commencing gender-affirming hormones follows.

• Confirm history of gender incongruence (self-determined by the patient).
• Take a comprehensive medical history and family history to exclude contraindications to hormone therapies.
• Perform a mental health assessment and offer referral for counselling or peer support.
• What are their goals?
• Do they have any concerns?
• What are their expectations? Are they realistic?
• Discuss expected changes resulting from hormone use and an expected timeline for changes.
• Discuss potential complications and side effects of gender-affirming hormones.
• Check baseline blood pressure and body mass index.
• Organise baseline blood tests including follicle-stimulating hormone, luteinising hormone, oestradiol, total testosterone, full blood examination, urea and electrolytes, and liver function tests. Consider glycated haemoglobin and fasting lipids if the patient is aged >40 years or if additional cardiovascular risk factors are present.
• Offer referral for sperm-cryopreservation prior to commencement of feminising hormones.
• Assess and document capacity to give informed consent.

Regular clinical review is essential after commencement of gender-affirming hormones. Visits should include a mental health review, blood tests, blood pressure, body mass index, counselling and advice.

Feminising hormones

The most commonly prescribed feminising hormone for TGDNB people in Australia is oestradiol valerate. 12 Typical doses are outlined in Table 1. Ethinylestradiol is no longer the preferred option because of concerns it may confer a higher thrombotic risk. 13,14 Transdermal oestradiol is another option and is preferred over oral oestradiol for patients aged >40 years and those with risk factors for thromboembolic disease. Oestradiol subcutaneous implants are preferred by many patients; however, these products can be difficult to access in Australia and can be financially prohibitive as they are not available on the Pharmaceutical Benefits Scheme (PBS). Patients should be counselled that physical changes with oestrogen are likely to be slow and will vary between individuals.

Early changes with oestrogen include:

• calmer mood
• softer skin
• reduction in libido
• erectile dysfunction.

Changes that occur over the following six-to-twelve months include:

• body fat redistribution (a more curvy body shape)
• decreased muscle mass
• decreased testicular volume
• breast development (can take up to three years).

Oestrogen does not alter the voice. If their voice is causing distress, the patient can be offered a referral to a speech pathologist for voice feminisation therapy.

Side effects

Side effects of oestradiol are similar to those of the oral contraceptive pill. Nausea and weight gain may occur. More serious side effects include deep vein thrombosis, gallstones, infertility and liver impairment. Fertility is reduced soon after commencing oestrogen because of reduced spermatogenesis and atrophy of seminiferous tubules. 15 Sperm cryopreservation should be discussed prior to commencement of gender-affirming hormones. Smokers should be warned of the cumulative risk of smoking on thrombosis risk, and supported to quit.

Blood tests should be organised on a three-monthly basis during the first year, then six-to-twelve–monthly in the longer term to check oestradiol and testosterone levels, liver function, urea and electrolytes and full blood examination. There is ongoing debate about the optimum range for oestradiol levels in this setting. As a general guide, an oestradiol level in the cisfemale (non-transgender female) range of 300–800 pmol/L is reasonable. There can be considerable variability between oestradiol levels, and it is important not to become too fixated on ‘the levels’. If the patient is happy with how their transition is progressing, the dose does not necessarily need to be adjusted. It is important to ensure oestradiol levels are not too high (>1000 pmol/L) as this may predispose the patient to a higher risk of adverse effects. Non-binary patients may prefer a target oestradiol level between the male and female range.

Oestrogen therapy will usually suppress testosterone levels but often not to the desired level. In this case, the GP can consider prescribing an anti-androgen.

Anti-androgens

Anti-androgens are usually prescribed alongside oestradiol to reduce testosterone levels. The most commonly prescribed anti-androgens for gender transition in Australia are spironolactone and cyproterone acetate. 12

Typical doses are outlined in Table 2. Cyproterone acetate is a more potent anti-androgen than spironolactone 16 and has progestogenic properties. An Australian study is currently underway to ascertain the optimum cyproterone acetate dose in this setting (Dr J Dean, ‘GoLoCypro: Titrating the lowest effective dose of cyproterone acetate for treatment of trans and gender diverse people who request feminizing hormones [2019–2021]’, The University of Queensland).

Some people choose not to take an anti-androgen, including those who wish to preserve erectile function.

Patients taking anti-androgens should be counselled that physical changes are likely to be slow and will vary between individuals.

Effects of anti-androgens include:

• slower growth of body hair
• reduction of acne

Facial hair usually persists. Laser or electrolysis treatments may be indicated.

Patients often report feeling tired following commencement of anti-androgens. Spironolactone is usually well tolerated but can cause hyperkalaemia, postural hypotension and diuresis. Cyproterone acetate may exacerbate depression. Hepatotoxicity and meningioma 17 have been reported with high doses of cyproterone.

For people desiring cisfemale hormone levels, hormone therapy should aim for a total testosterone level of <2 nmol/L. It is important to monitor electrolytes and liver function tests on a six-monthly basis. Spironolactone blocks peripheral testosterone receptors and therefore may be clinically effective even in the setting of a measured serum testosterone level above target. It is important to treat the patient according to their goals and not get too caught up in ‘the levels’.

Some TGDNB patients choose to undertake orchidectomy to avoid the need for anti-androgens. In this instance, it is important to continue oestradiol for bone protection.

Progesterone

Progesterone was routinely prescribed to transfeminine patients in past years when combined oral contraceptives were the standard of care. In recent years oestradiol has become the preferred option, and progesterone is less frequently prescribed. There is a lack of evidence of the efficacy of progesterone in this setting. Anecdotally, many patients report breast growth with progesterone, particularly when taken during the first two years of gender transition. If prescribing progesterone, a micronised product such as prometrium 100 mg orally daily could be considered. This is likely to have less adverse metabolic effects than synthetic progesterone. There is no need to cycle the progesterone. Patients should be warned of possible sedation with this product and advised to take it at night-time on an empty stomach.

Masculinising hormones

The most commonly prescribed masculinising hormone for gender affirmation in Australia is testosterone undecanoate. 12 Other options include fortnightly depot testosterone injections and transdermal preparations, outlined in Table 3. Fortnightly injections have become less popular in recent years because of the resultant peaks and troughs of testosterone levels and the potential for mood lability. Transdermal testosterone is a good option for patients who are needle phobic or prefer the convenience of a topical product. The gels tend to be sticky and can take several minutes to absorb.

In contrast to feminising hormones, testosterone can cause physical changes relatively quickly, and patients should be counselled to this effect. Within six months of commencement of masculinising hormones, the patient’s appearance will usually be much changed.

Early changes with testosterone include:

• increased libido
• increase in clitoral size.
• amenorrhoea
• body fat redistribution
• muscle growth
• increase in body and facial hair
• voice deepening.

Side effects of testosterone include weight gain, androgenic alopecia, sleep apnoea and polycythaemia. Acne is common, particularly during the first two years after initiation of testosterone. 18 The usual treatment measures can be used for acne in this context, including topical therapies, tetracyclines or referral for isotretinoin.

Voice deepening with testosterone is usually irreversible. Some patients report ‘vocal fatigue’ with testosterone, 19 which is a tiring and hoarseness of the voice that worsens throughout the day. This is particularly relevant in occupations where voice projection is required, and speech pathology referral may be considered.

Vaginal irritation due to atrophic vaginitis is commonly encountered. A twice-weekly 10 μg vaginal oestradiol pessary may be acceptable to the patient and will often reduce symptoms.

As a result of concerns about fertility, TGDNB patients are often advised to freeze oocytes prior to gender transition. This is probably unnecessary as ovulation and menstruation typically resume on cessation of testosterone. 15,20 Many transmasculine people cease testosterone temporarily in order to start a family, either by harvesting and donating eggs or by carrying a biological child. 15

It is recommended that full blood examination, liver function and testosterone levels are checked six-monthly. After initiation of testosterone, haemoglobin and haematocrit levels will usually increase. 21 If the haematocrit level exceeds 0.5 (50%), the patient may be at an increased risk of a thrombotic event. Strategies to lower haematocrit level include extending the interval between injections, reducing the dose or switching to an alternative testosterone product. If polycythaemia persists, referral to a haematologist for therapeutic venesection is recommended.

For patients desiring testosterone levels in the cismale (non-transgender male) range, hormone therapy should aim for a trough total testosterone level of 10–15 nmol/L. Levels are usually checked just prior to a testosterone injection or 24 hours after application of a transdermal preparation. There is a lack of data regarding long-term effects of testosterone in the TGDNB setting. Patients should be advised to cease smoking, exercise regularly and optimise body mass index. It is important to monitor lipids, particularly if other cardiovascular risk factors are present.

If mood irritability or fatigue is experienced towards the end of the injection interval, consideration can be given to reducing the injection interval.

Testosterone should not be relied on for contraception as breakthrough ovulation may occur. However, contraceptives containing oestrogen should generally be avoided for transmasculine patients. A useful statement outlining contraception choices for TGDNB people is available from the Faculty of Sexual and Reproductive Healthcare, UK. 22

Children and adolescents

For patients <16 years of age, consideration of puberty blockers and gender-affirming hormones generally occurs in a tertiary setting. Australian standards of care and treatment guidelines for trans and gender diverse children and adolescents are available. 23 Long waiting times are usually encountered. GPs can assist these patients by providing a safe, inclusive and welcoming practice environment and offering mental health support. For patients with dysphoria relating to menstruation, a prescription of norethisterone 5 mg orally twice daily may provide temporary amenorrhoea and reduce distress.

There have been many advances in the field of transgender health. Gender diversity is no longer considered a mental health disorder, and new pathways of care have been developed. GPs are ideally placed to provide gender-affirming care in the primary care setting.

• GPs are likely to encounter TGDNB patients in their daily practice.
• GPs can initiate gender-affirming hormones for adults under an ‘informed consent model of care’ in most cases.
• Several resources exist to assist GPs to upskill in the prescription and monitoring of gender-affirming hormones.
• Cheung AS, Wynne K, Erasmus J, Murray S, Zajac JD. Position statement on the hormonal management of adult transgender and gender diverse individuals. Med J Aust 2019;211(3):127–33. doi: 10.5694/mja2.50259. www.mja.com.au/journal/2019/211/3/position-statement-hormonal-management-adult-transgender-and-gender-diverse
• Equinox Gender Diverse Health Centre – Protocols for the initiation of hormone therapy for trans and gender diverse patients, https://equinoxdotorgdotau.files.wordpress.com/2018/08/equinox-informed-consent-guidelines.pdf
• Equinox Gender Diverse Health Centre – Hormone replacement therapy prescribing guide for general practitioners, https://equinoxdotorgdotau.files.wordpress.com/2019/09/equinox-hrt-prescribing-guide-for-gps-2019.pdf
• Northwest Melbourne Primary Health network – Primary health care for trans, gender diverse & non-binary people (online training module), https://aelp.smartsparrow.com/v/open/f3xc2ipc
• Australian Professional Association for Transgender Health, https://auspath.org

Acknowledgements

Did you know you can now log your CPD with a click of a button?

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• Bretherton I, Thrower E, Grossmann M, Zajac JD, Cheung AS. Cross-sex hormone therapy in Australia: The prescription patterns of clinicians experienced in adult transgender healthcare. Intern Med J 2019;49(2):182–88. doi: 10.1111/imj.14035. Search PubMed
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• Asscheman H, T’Sjoen G, Lemaire A, et al. Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: A review. Andrologia 2014;46(7):791–95. doi: 10.1111/and.12150. Search PubMed
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• Gil M, Oliva B, Timoner J, Maciá MA, Bryant V, de Abajo FJ. Risk of meningioma among users of high doses of cyproterone acetate as compared with the general population: Evidence from a population-based cohort study. Br J Clin Pharmacol 2011;72(6):965–68. doi: 10.1111/j.1365-2125.2011.04031.x. Search PubMed
• Motosko CC, Zakhem GA, Pomeranz MK, Hazen A. Acne: A side-effect of masculinizing hormonal therapy in transgender patients. Br J Dermatol 2019;180(1):26–30. doi: 10.1111/bjd.17083. Search PubMed
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Long term hormonal treatment for transgender people

• Related content
• Peer review
• Martin den Heijer , professor of endocrinology 1 2 ,
• Alex Bakker , transgender man with 20 years of experience taking hormonal treatment ,
• Louis Gooren , emeritus professor in transgender medicine 2
• 1 Department of internal medicine, VU Medical Center, Amsterdam, Netherlands
• 2 Center of expertise on gender dysphoria, VU Medical Center, Amsterdam, Netherlands
• Correspondence to M den Heijer m.denheijer{at}vumc.nl

What you need to know

Transgender people using hormone treatment need lifelong medical support and care. Hormonal treatment for gender dysphoria resembles hormone replacement therapy for people with hypogonadism.

Hormone treatment in transgender people is accepted to be safe and increases overall wellbeing in most people. The most common (though rare) side effects are venous thrombosis in trans women due to oestrogens and polycythaemia caused by androgens in trans men.

Some trans women will not have had their prostate removed and some trans men keep their ovaries. Be aware of the risk of cancer in these sites and think about the added risk of hormone supplementation.

The aim of hormone treatment in transgender people is to adjust their secondary sex characteristics to be more congruent with their experienced gender. Hormone treatment for transgender people is usually initiated by specialist gender clinics, but some people start hormone treatment of their own accord without a prescription. With growing numbers of transgender people presenting to healthcare services (estimated as 9.2 per 100 000 1 ), general practitioners, general endocrinologists, and other doctors will become increasingly involved in their long term care, the prescription of hormones, and consideration of potential side effects. Several guidelines are available on the start of hormonal treatment 2 3 4 5 6 7 ; the focus of this article is the long term hormonal care for transgender people who might no longer attend a specialist clinic. It is aimed at a more general readership of physicians occasionally seeing adult transgender people.

Transgender terminology

Language and terminology are sensitive. Some terms used in the past are no longer appropriate because they might have negative connotations.

The term gender has historically been used to refer to psychological, behavioural, and sociological characteristics, and their categorisation by society as “masculine” or “feminine.” The term sex has historically been used to refer to biological characteristics similarly categorised. Transgender people stress the importance of proper language that respects their identity. Terms like male-to-female transgender or cross-sex hormonal therapy might therefore not be appropriate because they suppose a binary view. Even the distinction between gender and sex might be perceived as an oversimplification. Be sensitive to a person’s own use of terminology and interpretation of their identity. If in doubt, ask your patient what language they prefer.

Trans woman

A woman who was assigned male at birth.

A man who was assigned female at birth.

In this article we use these terms also for people who identify as non-binary transgender and wish for partial changes. Attending physicians should be aware of possible medical problems resulting from biological aspects of the sex at birth. For example, prostate cancer in a trans woman.

Non-binary/Gender-queer

The terms “non-binary” and “gender-queer” are used by people who do not exclusively identify as man or woman, masculine or feminine, male or female.

Anti-androgens

Agents antagonising testosterone action.

Anti-gonadotropics

Agents that inhibit secretion of luteinising and follicle stimulating hormones from the pituitary.

Hormone treatment in transgender people

Many transgender people seek to adjust their physique to be more congruent with their experienced gender by using hormone treatments and/or undergoing surgical interventions. The broad aims of hormone treatment in adult transgender people are to eliminate as far as desired the earlier hormonal effects of the sex steroids of their sex at birth and to induce the desired secondary sex characteristics of the experienced gender.

Hormone preparations that are used in transgender medicine for gender dysphoria are the same that are used in gonadal endocrinology, although they are usually not licensed for treating gender dysphoria in itself. Table 1 lists these preparations.

Hormones used in transgender persons with typical doses in adults (20-50 years)

• View inline

Hormones induce more than one effect. Oestrogens, for example, influence breast growth, bone density, skin, and the clotting system. Generally, it is not possible to selectively stimulate one effect and inhibit another. The effects of gonadal hormones can differ between persons because of the individual properties of the hormone receptors. Some people show a clear change in fat distribution pattern but little breast development, while in others the opposite occurs. In general, regular hormone treatment is needed for two to three years to reach its effect. 3

Hormone treatment for trans women

The key element in treating trans women is the administration of oestrogens. Guidelines recommend using the natural form 17 β-oestradiol because ethinyloestrogen (common in oral contraceptives) has been associated with a strong increase in the risk of venous thrombosis and cardiovascular disease. 8 Progestogens cause no additional feminisation effect when prescribed alongside oestrogens.

Anti-androgen

In some people, oestrogen administration only suppresses testosterone below the upper level of cis (ie, persons for whom their gender identity matches their sex at birth). To achieve full suppression in all people, most guidelines recommend the use of oestrogen in combination with a testosterone suppressing agent. 3 7 Testosterone suppressing agents (or anti-androgens) of several pharmacological classes are available ( table 1 ). GnRH agonists are effective but more expensive (€100-150 per month). They are first line treatment in the UK. Cyproterone acetate combines anti-androgenic and anti-gonadotropic effects and is widely used in continental Europe. Spironolactone is an aldosterone antagonist with anti-androgenic properties and is used as anti-androgen primarily in the US. A recent study showed comparable effect of GnRH analogues instead of cyproterone acetate in suppressing testosterone levels. 9 If trans women have undergone orchidectomy (as part of the surgical reassignment), anti-testosterone treatment could be stopped.

Clinical effect

Important effects of combined oestrogen and anti-testosterone treatment include breast development, softer skin, loss of sexual hair growth, increase in fat mass, broader hips, a decrease of lean body mass, and a decrease or change in libido with clinically relevant mood changes. 7 Not all effects are as strong in every person. Sometimes, additional measures are needed to achieve the desired effects, such as laser and electrolysis to remove unwanted hair, or breast augmentation to achieve sufficient breast volume.

Hormone treatment for trans men

Testosterone.

In trans men, testosterone is the key hormone administered and no anti-oestrogens are needed. 6 Testosterone is converted to oestradiol (by aromatase activity in fat cells) in men and women and oestradiol plays an important role in bone physiology in cis men and trans men. 10

Important effects of testosterone are an increase in lean body mass and muscle strength, body and hair growth in a male pattern, and lowering of the voice. Testosterone supplementation given in the doses in table 1 leads to cessation of monthly periods. If uterine bleeding persists, a GnRH agonist or progestin (lynestrenol 5 mg daily or medroxyprogesterone 10 mg three times daily or another progestin) could be added to stop uterine bleeding.

Principles of dosing

Most guidelines state that dosing of hormones should be guided by blood levels of oestradiol and testosterone, based on mean levels of the desired gender. These levels are often achieved with the dosages mentioned above; however, hormone levels are not a goal in themselves. The primary goals are usually a degree of feminisation or masculinisation as specified by the patient, which are achieved with their fullest effects after two to five years, similar to the temporal pattern of hormonal puberty. After this period, the goal for hormonal treatment—especially if in the meantime the gonads have been removed—might be to avoid signs and symptoms of hypogonadism such as mood changes, fatigue, osteoporosis, and muscle weakness. While dosage advice and target levels are an aid to avoiding underdosing and overdosing, one should be aware that, due to hormone receptor properties, similar levels can have different biological effects in different individuals, and different individuals can have different ideas about the desired outcome. In other words: the clinical effects and wellbeing of the trans person are paramount, not the hormone levels themselves. This applies also to persons who do not fit in the male/female distinction (non-binary or gender queer). It is possible to achieve hormone levels that are in between male and female reference ranges for both testosterone and oestradiol, but it is important to avoid hypogonadism in patients that already have gonadectomy in order to prevent bone loss and other consequences of hypogonadism.

How well does it work and how safe is it?

It has been shown that hormone treatment in transgender people with gender dysphoria increases wellbeing in most people. 11 12 13 From a medical point of view, hormonal treatment seems to be acceptably safe. 14 15

Oestrogens increases the risk of venous thrombosis, but a study in trans women showed that long term treatment with oestrogen yields only a low thrombotic risk (one event in 1,286 person years). 16 Oral oestradiol supplementation has a more prothrombotic effect than parenteral oestradiol supplementation; therefore it might be recommended to use parenteral supplementation in people with a higher risk for venous thrombosis (ie, family history of thrombosis or age over 50). 17

Testosterone-blockers can have their own side effects, such as hyperprolactinaemia 18 and an increased risk for meningioma with cyproterone acetate (although still very rare), 19 and high potassium levels with spironolactone.

Testosterone supplementation increases the haematocrit into the male reference range and can sometimes lead to polycythaemia 20 ; therefore monitoring haematocrit is recommended every three months in the first year and them one to two times per year. 3 Liver toxicity of testosterone has been described but is rare, and no liver function tests are recommended. 3

Bone and cardiovascular disease

Bone density can be affected, but both testosterone and oestrogen in recommended dosages lead to an increase in bone density. 21 22 In general, oestradiol for trans women has a beneficial effect on cardiovascular risk factors, while testosterone for trans men has a detrimental effect. 23 But limited experience points in the opposite direction for cardiovascular disease itself: an increase in cardiovascular disease in oestrogen users (particularly ethinyl oestradiol) and decrease in testosterone users. 24 No clear explanations for this paradoxical finding are available yet.

Malignancies

Cases of cancer of the prostate and breast have been reported but recent studies showed no increased overall risk, although the estimated breast cancer risk in trans women is 33 times higher compared with cis men. 25 26 27 28

However, much of what we know about the effects of hormone treatment in transgender people is from relatively small studies ( table 2 ). Large, well designed studies, particularly in ageing subjects, are urgently needed to collect reliable estimates on effects and side effects.

Possible areas of concern in the long term follow-up of transgender persons on hormonal treatment and practical recommendations

Long term follow-up

Hormone supplementation is in principle lifelong, and people benefit from regular (yearly or two yearly) supervision by a doctor with an understanding of transgender health and hormone prescription.

Follow-up might take place in a specialist gender clinic, or with a primary care physician or other generalist with sufficient training in hormonal supplementation. Long term follow-up would include checking the hormone levels in trans men and trans women and haematocrit in trans men at every visit (yearly or two yearly). Other measurements must be guided by risk factors of the individual, such as blood lipids in case of cardiovascular risk. If there are sex specific laboratory reference values, use the reference values of the person’s new gender. 30 An exception is bone density measurement. From puberty on there are sex specific increases in bone mineral density, and reference values of the sex at birth should be used for assessment of T and Z values.

Trans women can develop prostate cancer, and breast cancer can develop in minimal residual breast cells in trans men. It would be important to consider and discuss withdrawal of hormonal treatment in these situations. We advise following the local guidelines for population screening of the cis population according to the relevant anatomy present (either prostate, cervix, or breasts).

Transgender elderly

Sex hormones rise in puberty. There is a sharp drop at menopause in women and a more gradual decrease in men. Data are lacking on whether to follow these patterns in transgender people. Many transgender people prefer to continue hormone use. The side effects of prolonged supplementation at dosages that induce young adult levels are not well studied. In our view, it seems prudent to taper the dose at increasing age, but there are no clinical data to support or dissuade from this approach. It is important, therefore, to discuss this uncertainty with the person and frame it in a general discussion about their overall health. 31

Education into practice

How confident do you feel about discussing hormone treatment with trans people in your practice?

Are you aware of any resources that might support you with their longer term care?

What might you do differently as a result of reading this article?

How patients were involved in the creation of this article

Our author group includes a trans person. The review group included a trans person. AB was asked to join us as author to enhance the patient perspective. AB is trans man with 20 years of experience taking hormonal therapy. Our first version was extensively reviewed by five reviewers (including a trans person). Their comments helped us to improve the manuscript, especially in the use of sensitive phrasing.

How this article was made

A first draft was written by MdH and LG with focus on long term hormonal treatment. We performed a search in www.pubmed.gov with search term “transgender OR transsexual” and “hormones OR oestrogen OR testosterone,” which revealed 485 papers. We largely focused on papers that were published in English in the last five years. AB was asked to join us as author to enhance the patient perspective. Our first version was extensively reviewed by five reviewers (including a trans person) and the BMJ editor. Their comments were very helpful in improving and clarifying the manuscript. They helped us to broaden the scope to practices used in other countries as well.

Case Vignettes

A 66 year old trans woman comes to her general practitioner. She started oral oestradiol (4 mg daily) 10 years ago together with an anti-androgen (cyproterone acetate 50 mg daily). She decided not to have a vaginoplasty because of the risk of complications of her obesity (she has a body mass index of 40). Two weeks ago, she was diagnosed with a deep vein thrombosis of the left leg and she commenced warfarin. She now wonders if she should stop her hormone treatment.

To consider

It is widely believed that there is a relationship between oestrogens and venous thrombosis. However, most evidence is based on cis women that use ethinyl oestradiol in combination with a prostagen. Little is known about the thrombogenicity of cyproterone acetate, although the combination of ethinyl oestradiol and cyproterone acetate in cis women is associated with increased thrombosis risk. 32 In this trans woman we would advise that she switches the cyproterone acetate for a GnRH analogue. If she wants to continue the oestrogens we would advise that she switches to a transdermal method of application.

A 36 year old trans man comes for his biannual visit to his endocrinologist. He started testosterone injections (250 mg every two weeks) eight years ago. He is feeling well, works as a bus driver, and smokes 20 cigarettes a day. His blood tests show testosterone of 15 nmol/L just before the next injections. Haematocrit is 0.55.

The definition of polycythaemia in terms of haematocrit levels differs among guidelines, but 0.55 is high. Our first advice would be to quit smoking. Furthermore, a short-acting (2-3 week) course of testosterone injections gives high peak levels and is associated with higher haematocrit levels. Therefore, we would advise he switch to either a testosterone gel or a long acting testosterone injection.

This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Albert Ferro, professor of cardiovascular clinical pharmacology, King’s College London. To suggest a topic, please email us at [email protected].

We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none.

Provenance and peer review: Commissioned; externally peer reviewed.

Patient consent not applicable.

• Reisner SL ,
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• Health concerns for transgender people

Understand common health concerns for transgender and gender-diverse people, and get tips for maintaining good health.

Everyone faces certain health risks. But there are specific health concerns that transgender and gender-diverse people need to be aware of.

Some of these health concerns may be due to an experience called gender minority stress, which often involves:

• Negative attitudes and disapproval toward transgender and gender-diverse people. This is sometimes called social stigma.
• Discrimination, abuse, harassment, neglect, rejection or unfair treatment of transgender and gender-diverse people.
• Turning the negative attitudes or behaviors of others into negative attitudes and thoughts about oneself. This is called internalized stigma.

Gender minority stress is linked to transgender and gender-diverse people seeking preventive health care and health screenings less often than do other people. This might be due to a lack of insurance coverage, being refused care, difficulty finding a health care provider with expertise in transgender care or fear of discrimination in a health care setting.

Because of gender minority stress, transgender people may be at higher risk of:

• Emotional and psychological abuse.
• Physical and sexual violence.
• Sexually transmitted infections.
• Substance misuse.
• Mental health problems, such as depression, anxiety and thoughts of suicide.

What you can do

Make health care a priority.

Don't avoid getting health care out of concern that you may have a negative interaction with a health care provider. Look for a provider who has expertise in transgender health, who understands your concerns and who puts you at ease.

For guidance finding a provider with transgender expertise, check the websites for WPATH: World Professional Association for Transgender Health and GLMA: Health Professionals Advancing LGBTQ Equality.

Once you find a health care provider with whom you feel comfortable and safe, be open about your health history. Talk with your provider about:

• Your gender identity.
• Medicines or supplements you take or have taken.
• Surgeries or procedures you've had.
• Health problems or concerns you may have.
• Any family history of medical conditions you may have.
• Your sexual history.
• Stress or discrimination you may have experienced and how you cope.
• Mental health concerns you may have, including anxiety, depression or any past suicidal thoughts or attempts.

The more your provider knows about you, the better equipped your provider will be to help guide your health care.

Get preventive care

It's important that you get the vaccinations you need, as well as tests to screen for possible health problems. Talk with your health care provider about what's right for you.

Recommended screenings may include tests for the following conditions:

• Breast cancer.
• Cervical cancer.
• Colon cancer.
• Heart disease.
• High blood pressure.
• High cholesterol.
• Osteoporosis.
• Prostate cancer.

Your provider also may recommend screenings for:

• Mental health conditions.
• Sexually transmitted infections, including HIV.
• Intimate partner violence.

If you've had gender-affirming care — such as hormone therapy or surgery, or other gender-related health care — tell your health care provider about it. Based on that information, your provider may recommend additional screenings or preventive care.

Your health is important. If you're due for a screening, don't put it off. And share with your health care provider any health concerns you might have. Open communication between you and your provider can help promote good long-term health.

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• AskMayoExpert. Healthcare for transgender and gender diverse people. Mayo Clinic; 2022.
• Keuroghlian AS, et al., eds. Basic principles of trauma-informed and gender-affirming care. In: Transgender and Gender Diverse Health Care: The Fenway Guide. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed Dec. 19, 2022.
• Coleman E, et al. Primary care. In: Standards of Care for the Health of Transsexual, Transgender and Gender Nonconforming People. 8th version. World Professional Association for Transgender Health; 2022. https://www.wpath.org/publications/soc. Accessed Dec. 19, 2022.
• Feldman J, et al. Primary care of transgender individuals. https://www.uptodate.com/contents/search. Accessed Dec. 15, 2022.
• American College of Obstetricians and Gynecologists. Committee Opinion No. 823: Health care for transgender and gender diverse individuals. Obstetrics & Gynecology. 2021; doi:10.1097/AOG.0000000000004294.
• Erickson-Schroth L, ed. General, sexual and reproductive health. In: Trans Bodies, Trans Selves: A Resource by and for Transgender Communities. 2nd ed. Kindle edition. Oxford University Press; 2022. Accessed Dec. 21, 2022.

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Medications for Gender Affirming Hormone Therapy

Other names: GAHT

Gender-affirming hormone therapy (GAHT) is used to change secondary sex characteristics to align with gender identity, this can be feminizing or masculinizing hormone therapy.  Hormone therapies are prescription medications that are taken by mouth, patch, gel, or injection.

Drugs used for Gender Affirming Hormone Therapy

The medications listed below are related to or used in the treatment of this condition.

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• v.1(1); 2016

A Systematic Review of the Effects of Hormone Therapy on Psychological Functioning and Quality of Life in Transgender Individuals

Jaclyn m. white hughto.

1 The Fenway Institute, Fenway Health, Boston, Massachusetts.

2 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.

Sari L. Reisner

3 Division of General Pediatrics, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts.

4 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Objectives: To review evidence from prospective cohort studies of the relationship between hormone therapy and changes in psychological functioning and quality of life in transgender individuals accessing hormone therapy over time.

Data Sources: MEDLINE, PsycINFO, and PubMed were searched for relevant studies from inception to November 2014. Reference lists of included studies were hand searched.

Results: Three uncontrolled prospective cohort studies, enrolling 247 transgender adults (180 male-to-female [MTF], 67 female-to-male [FTM]) initiating hormone therapy for the treatment of gender identity disorder (prior diagnostic term for gender dysphoria), were identified. The studies measured exposure to hormone therapy and subsequent changes in mental health (e.g., depression, anxiety) and quality of life outcomes at follow-up. Two studies showed a significant improvement in psychological functioning at 3–6 months and 12 months compared with baseline after initiating hormone therapy. The third study showed improvements in quality of life outcomes 12 months after initiating hormone therapy for FTM and MTF participants; however, only MTF participants showed a statistically significant increase in general quality of life after initiating hormone therapy.

Conclusions: Hormone therapy interventions to improve the mental health and quality of life in transgender people with gender dysphoria have not been evaluated in controlled trials. Low quality evidence suggests that hormone therapy may lead to improvements in psychological functioning. Prospective controlled trials are needed to investigate the effects of hormone therapy on the mental health of transgender people.

Introduction

Transgender people have a gender identity or expression that differs from their sex assigned at birth. Research documents high prevalence of depression, anxiety, and suicidal ideation among transgender individuals relative to the general population. 1–3 Many transgender people experience psychological distress related to the discrepancy between their birth sex and felt a sense of being male, female, or otherwise gender nonconforming. 4 Some individuals experience gender-related psychological distress at such an extreme level that their distress meets criteria for a formal psychiatric diagnosis— Gender Dysphoria . 4 The critical element of gender dysphoria is the presence of clinically significant distress associated with the strong and persistent difference between one's expressed/experienced gender and one's sex assigned at birth. 5 The World Professional Association of Transgender Health's Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People (Version 7) lists social transition (living full or part-time in one's gender identity), psychotherapy, surgery, and hormone therapy as treatment options for individuals with gender dysphoria. 6 While each person's treatment plan is individualized, and may include one or multiple interventions, hormone therapy is generally the first medical intervention accessed by individuals with gender dysphoria who seek to masculinize or feminize their body to be consistent with their gender identity. 6

Feminizing or masculinizing hormone therapy is the administration of exogenous endocrine agents to induce changes in physical appearance. 6 Since hormone therapy is inexpensive relative to surgery and highly effective in the development of secondary sex characteristics (e.g., facial and body hair in female-to-male [FTM] individuals or breast tissue in male-to-females [MTFs]), hormone therapy is often the first, and sometimes only, medical gender affirmation intervention accessed by transgender individuals looking to develop masculine or feminine characteristics consistent with their gender identity. In some cases, hormone therapy may be required before surgical interventions can be conducted. 6

Changing one's physical characteristics through hormone therapy is considered medically necessary for many transgender individuals and may relieve the psychological distress associated with gender dysphoria, reduce psychiatric comorbidities, and improve patients' quality of life. 6 The efficacy of hormone therapy in relieving psychiatric distress related to gender dysphoria has largely been inferred through clinical practice and low quality evidence. 7 In 2008, the first systematic review exploring the relationship between hormone therapy and the mental health of transgender individuals was conducted. 7 Published in 2010, the review found that hormone therapy in individuals with gender identity disorder (the DSM-IV diagnostic name for gender dysphoria) likely improves gender dysphoria, psychological function, comorbidities (e.g., depression, anxiety, and suicidality), sexual functioning, and overall quality of life. 7 However, the quality of the empirical evidence was very low. All of the reviewed studies pertaining to psychological functioning were nonrandomized and largely cross-sectional designs. Moreover, the majority of the studies evaluated hormone therapy in concert with sex reassignment surgery and so an evaluation of the specific relationship between hormone therapy and the psychological functioning of transgender individuals independent of surgical interventions was not possible. Since 2008, several higher quality studies exploring the relationship between hormone therapy and psychological functioning in transgender individuals have been published, thus an updated systematic evaluation of the research literature is warranted.

The primary objectives of this review were to locate and describe studies examining the relationship between hormone therapy and the psychological functioning of transgender individuals; determine the risk of experiencing psychiatric distress in transgender individuals receiving hormone therapy compared with those not receiving hormone therapy or the general population; examine whether transgender individuals with poor mental health experience an improvement in their mental health status after the initiation of a hormone regimen; and assess whether any differences in the strength and direction of the association between hormone therapy and psychological functioning exist by gender identity (i.e., for MTF vs. FTM subjects). Additionally, the review aimed to assess the strength of evidence showing a relationship between hormone therapy and healthy psychological functioning in transgender individuals and identify future research and clinical practice needs.

PRISMA 8 reporting guidelines were used in the development of this protocol-driven report. The protocol was not published, but is available upon request.

Eligibility criteria

Studies were eligible for this review if they enrolled transgender or transsexual (or another term used to describe individuals with a gender identity different from their assigned sex at birth) individuals who were seeking hormone therapy to masculinize or feminize the body. All participants had been diagnosed with having gender identity disorder (prior diagnostic name for gender dysphoria).

Because the goal was to assess changes in psychological functioning and quality of life after initiating hormone therapy, only studies with a longitudinal design were included in the review. No randomized controlled trials were identified. All included studies were nonrandomized (observational) and uncontrolled, prospective cohort studies. One-time cross-sectional studies, single case reports, case series, review articles, commentaries, letters, and studies that did not contain original data were excluded. Studies were included regardless of sample size. Only English language publications were included in the search. Studies following participants for less than 3 months were excluded.

Interventions were limited to the administration of feminizing or masculinizing hormone therapy. Due to the wide variation of doses and types of hormones, all forms of hormone administration (e.g., self or provider injection, oral pill, intramuscular, transdermal patch or gel, or subcutaneous implant), dosing levels, dose frequency, and types (e.g., estrogen, androgen-reducing medications, progestins, testosterone, bioidentical, and compounded hormones) were included. Psychiatric disorders (DSM diagnosis or clinically significant symptomology), general psychological functioning, and general quality of life outcomes were assessed.

Study identification

The first author consulted an expert reference librarian to design and conduct the electronic search strategy with input from the second author and collaborators with expertise in conducting systematic reviews. To identify eligible studies, electronic databases (Ovid MEDLINE, Ovid PsycInfo, and PubMed) were searched from inception to November 2014. Controlled vocabulary supplemented with keywords was used to define the concept areas (transgender/transsexual, hormone therapy, psychiatric disorder, psychological functioning, and quality of life). A hand search of the bibliographies of retrieved articles was also conducted. A detailed list of subject headings and text words is available upon request.

The first author examined abstracts and titles from the initial search to identify studies that appeared to meet the inclusion criteria. Abstracts were screened twice for inclusion. The full article was then obtained for all studies appearing to meet inclusion criteria or in instances where there was insufficient information from the title, keywords, and abstract to make a clear decision. The studies meeting the inclusion criteria were checked for validity assessment (see the Quality assessment section) and data extraction.

Data collection

Data were extracted for the studies that met inclusion criteria, and then entered into RevMan5. Data were extracted using specially developed data extraction forms to ensure standardization, which included the following headings:

Participant characteristics

Age, birth sex, gender identity, income, education, and psychiatric comorbidities (all at baseline).

Study characteristics

Recruitment method, inclusion/exclusion criteria, setting, allocation procedure, sample size analyzed, study design features, and follow-up period.

Intervention

Description of intervention, mode and frequency of delivery, number, and explanation for any dropouts.

Description of measures used, continuous/dichotomous nature, and validated or unvalidated method of administration.

Statistical results

Adjusted and unadjusted effect estimates (if available) and measures of variability, frequency counts for dichotomous variables, and number of patients.

Confounding

Specific confounders included the following factors, which could impact the mental health of participants independently of hormone therapy: receiving psychotherapy in addition to hormone therapy; accessing other medical gender affirmation technologies (i.e., silicon injections, surgeries, electrolysis) in addition to hormone therapy; possessing any underlying treated or untreated comorbid psychiatric conditions; relationship factors and social support (positive or negative relationships with family, friends, sexual partners); discrimination experiences (in employment, housing, etc.); barriers and facilitators to healthcare access (insurance coverage for hormones or surgeries; feasibility in accessing trained and competent providers, etc.); prior or concurrent use of street-based hormones; and patient characteristics (age, income, level of education).

Quality assessment (risk of bias)

In consultation with an expert in systematic reviews, the first author assessed the risk of bias for each study and reported the bias in the Risk of Bias table according to the Cochrane Handbook for Systematic Reviews of Interventions. 9 Specifically, sequence generation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential sources of bias were assessed. Items were assessed by first providing a description of what occurred in the study and then providing a judgment on the adequacy of the study as it relates to each item. When assessing bias, studies were scored as low risk of bias, high risk of bias, and unclear for studies with unclear or unknown risk of bias. Since this tool was developed specifically for RCTs, items from the Downs and Black instrument 10 and the Newcastle-Ottawa Scale 11 were included in the assessment. The authors intended to explore selective outcome reporting through sensitivity analyses in cases where missing data were likely to introduce serious bias; however, none of these factors were reported in the included studies.

Measures of treatment effect

For prospective cohort studies, statistically significant ( p <0.05) within-group pre–post changes (%) were analyzed. The summary measure was the weighted mean difference (standardized mean difference [SMD]) in change in mental health from baseline to follow-up among transgender individuals initiating hormone therapy. For outcomes based on a single study, mean change scores were reported.

The Cochrane Collaboration statistical guidelines were followed for data synthesis. 9 Data were collated into evidence tables and grouped according to each outcome. The reported primary and secondary outcome variables were grouped as follows: Primary: psychological functioning, depression, anxiety, somatization, interpersonal sensitivity, hostility, phobic anxiety; and Secondary: quality of life.

Data analysis

Data were analyzed using RevMan software and reported according to Cochrane Collaboration criteria. 9 A summary statistic for each study was created where possible. A generic inverse variance method was used to create a weighted average for each study according to the amount of information in each study and a fixed-effects model was employed. For continuous data, pooled outcomes were expressed as SMDs with associated 95% confidence intervals (CIs) when outcomes used different scales or different versions of the same scale. When outcomes used the same scale, the weighted mean difference was used and 95% CIs reported.

To avoid a unit of analysis error, several different outcomes based on different periods of follow-up were defined and not combined in a meta-analysis. When missing data were found, the data were assumed to be missing at random. Only available data were analyzed and missing data were ignored.

Inconsistency in treatment effects across studies was quantified using the I 2 statistic, which represents the proportion of variability across trials that is not attributable to random error or chance. 9 Assessment of heterogeneity was made based on the following levels: none <25%, low=25–49%, moderate=50–74%, and high=75%+. 8 Since study outcomes and measurement were too heterogeneous, a narrative synthesis was performed.

Figure 1 depicts the study selection process. Three studies that met inclusion criteria were identified. 12–14 Of the three studies, data were available for a total of 154 participants (two studies) for the primary psychological functioning outcomes; 12 , 14 one study reported on secondary quality of life outcomes ( n =83). 13 Lack of data and variation in follow-up period of assessment time points precluded meta-analysis for the reviewed studies.

Flow diagram of study inclusion for systematic review of masculinizing and feminizing hormone therapy and psychological functioning and quality of life in transgender patients.

In all three studies, a cohort of transgender patients initiating hormone therapy was followed longitudinally after initiating hormone therapy at baseline. The timing of follow-up for these studies ranged from 3 to 6 months and 12 months after baseline. One study used a 3–6-month follow-up 14 and two used a 12-month follow-up. 12 , 13 One study 14 followed participants beyond 12 months after completion of gender affirmation surgery; however, this time point was not included in the analyses as per the protocol. All studies lacked a control group.

The three studies enrolled 247 participants (180 MTF, 67 FTM). Only two studies reported the age of participants, 12 , 13 and the mean age for MTF individuals across studies was similar to FTM individuals (mean age 31 and 30, respectively). All three of the included studies originated in Europe (two in Italy; one in Belgium) and were published in English.

Participants were all recruited from specialty gender identity clinics serving patients diagnosed with having gender identity disorder (prior DSM diagnosis for gender dysphoria). Patients were recruited into the study during a routine visit and all were seeking surgical gender affirmation surgery (i.e., sex reassignment surgery).

All three studies administered hormone therapy following diagnosis of gender identity disorder. All participants lived full-time in their gender role (socially transitioned) and were receiving concurrent psychotherapy. Specific details of the hormone regimen were reported by two studies, which used similar regimens. Both studies administered either transdermal or oral estrogen and antiandrogens to MTF patients, although dosing varied. 12 , 13 For FTM patients, both studies used intramuscular injections of testosterone, although dosing quantity and frequency differed and one study provided daily low-dose transdermal gel testosterone at the beginning of the treatment period (10–15 days). 13

The outcomes were ascertained by a self-reported questionnaire in all three studies. Two studies administered assessments in the clinic and one mailed the questionnaire to the participants at follow-up, resulting in missing data. Two studies used the Symptom Checklist-90 (SCL-90) to assess psychological functioning. 12 , 14 However, one study 12 used the Italian revised version (SCL-90-R) 15 and the other study 14 used the traditional Dutch-adapted version. 16 Two studies assessed anxiety; 12 , 14 however, only one 12 used a validated scale (Zung Self-Reported Anxiety Scale). 17 One study 12 also measured depression using a second validated depression measure (Zung Depression Scale). 18 Only one study assessed quality of life as a secondary outcome 13 and used the World Health Organization Quality of Life-100 (WHOQOL-100) questionnaire. 19

Table 1 describes the summary of findings for reported outcomes in included studies.

Hormone Therapy at Follow-Up Compared to No Hormone Therapy at Baseline for Improving Psychological Functioning and Quality of Life in Transgender Patients

Patient or population, transgender individuals with Gender Dysphoria; settings, European gender identity clinic; intervention, hormone therapy; comparison, no hormone therapy at baseline. Due to heterogeneity in the length of follow-up for all outcomes, the overall effect estimates are not presented. Formal GRADE 20 evaluation was not conducted; however, quality was ranked using GRADE terminology: high quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low quality, we are very uncertain about the estimate.

CI, confidence interval; FTM, female-to-male; GSI, Global Severity Index; MTF, male-to-female; SCL-90, Symptom Checklist-90; SMD, standardized mean difference; WHOQOL-100, World Health Organization Quality of Life-100.

Psychological functioning

Two studies ( n =154) assessed psychological functioning and both used continuous outcomes as measured by the SCL-90. 12 , 14 Two studies used different versions of the SCL-90 (revised version, Italian version; 12 Dutch-adapted SCL-90 14 ), with one study assessing outcomes at 3–6 months posthormone initiation 14 and the other assessing outcomes at 12 months posthormone initiation. 12 One study 12 used additional measures for anxiety and depression (Zung scale), the outcomes of which are reported below. All psychological functioning outcomes were measured continuously with mean change scores reported for the SCL-90 and for the Zung depression and anxiety scales (see summary of findings: Table 1 ).

Global score of psychological functioning

The SCL-90-R Italian version provides a global score of psychological functioning (Global Severity Index), while the SCL-90 Dutch version provides an overall psychoneurotic distress score, which are similar, but scored differently. Both studies measuring overall psychiatric distress saw a significant change in global distress scores at follow-up: SMD=−0.52 [95% CI: −0.79, −0.25] (12 months of follow-up) 12 and −0.88 [95% CI: −1.29, −0.48] (3–6 months of follow-up). 14

Participants in both studies had depression scores in the normal range at baseline as indicated by the SCL-90-R Italian version depression subscale, Zung Depression Scale, 12 and SCL-90 Dutch depression subscale. 14 Nonetheless, the SCL-90-R Italian version 12 and SCL-90 Dutch version each showed statistically significant reductions in depression posthormone therapy across the two studies with an SMD of −0.51 [95% CI: −0.78, −0.24] (12-month follow-up) 12 and −0.89 [95% CI: −1.30, −0.48] (3–6 months of follow-up). 14 One study also assessed depression scores using the Zung Depression Scale and saw a similar statistically significant reduction at 12-month follow-up (mean difference=−8.06 (95% CI: −10.91, −5.21). 12 Meta-analysis of these two studies was precluded due to statistical heterogeneity (I 2 =0%) and disparate follow-up periods.

Two studies measured changes in anxiety scores from baseline to 3–6-month 14 and 12-month 12 posthormone therapy initiation using the SCL-90 anxiety subscale (SCL-90-R Italian version; 12 SCL-90 Dutch version 14 ). One study also used an additional validated continuous measure of anxiety (Zung Anxiety Scale). 12

The SCL-90 anxiety subscales showed higher than normal anxiety for participants in both studies at baseline (mean=1.05, SD=0.94; normal <1.0; 12 mean=17.0, SD=6.4; general population mean=12.8, SD=4.4). 14 At follow-up, both studies saw a statistically significant reduction in anxiety with scores in the normal range at 3–6-month follow-up (mean=12.4, SD=5.1) 14 and 12-month follow-up (mean=0.54, SD=0.56), 12 as well as significant standardized mean change scores (−0.66 [95% CI: −0.93, −0.38]; 12 −0.78 [95% CI: −1.18, −0.38] 14 ).

One study also showed a reduction in anxiety using a different continuous measure (Zung Anxiety) from above the normal range at baseline (mean=44.91, SD=9.59; normal=24–44) to within the normal range at 12-month follow-up (mean=37.90, SD=8.97) 12 and this change was highly significant (mean difference=−7.01 [95% CI: −9.50, −4.52]).

Somatization

Two studies assess somatization as a subscale measure in the SCL-90 (SCL-90-R Italian version; 12 SCL-90 Dutch version 14 ). One study had somatization scores within the normal range at baseline (mean=0.54, SD=0.59; normal <1.0). 12 The other study had significantly higher baseline somatization scores compared with the general population at baseline (mean=18.6, SD=6.7; general population mean=16.7, SD=5.3); 14 however, scores remained significantly higher than the general population even at 3–6-month follow-up (mean=15.2, SD=2.7). Nonetheless, both studies saw a significant reduction in somatization scores posthormone therapy initiation as measured by mean change scores at 3–6-month follow-up (−0.64 [95% CI: −1.04, −0.24]) 14 and 12-month follow-up (−0.38 [95% CI: −0.65, −0.10]). 12

Interpersonal sensitivity

Two studies assessed interpersonal sensitivity using the SCL-90 (SCL-90-R Italian version; 12 SCL-90 Dutch version 14 ). Participants in one study had significantly higher scores than the general population at baseline (mean=31.8, SD=11.7; general population mean=24.1, SD=7.6). 14 The other study had normal interpersonal sensitivity scores at baseline (mean=0.97, SD=0.82; normal <1.0). 12 Participants in both studies evinced a significant reduction in standardized mean change scores posthormone initiation at 3–6-month follow-up (SMD=−0.70 [95% CI: −1.10, −0.30]) 14 and 12-month follow-up (SMD=−0.47 [95% CI: −0.75, −0.20]). 12 One study showed a reduction in interpersonal sensitivity scores that no longer differed significantly from those of the general population at 3–6-month follow-up (mean=16.6, SD=7.0; general population mean=24.6, SD=7.9). 14 While both studies 12 , 14 lacked statistical heterogeneity (I 2 =0%), the interpersonal sensitivity outcomes were measured at different time points (12 months; 12 3–6 months 14 ), making meta-analysis inappropriate.

Using the SCL-90, two studies assessed hostility (SCL-90-R Italian version; 12 SCL-90 Dutch version). 14 Participants in both studies had hostility scores in the normal range, consistent with that of the general population (mean=0.57, SD=0.69; normal <1.0; 12 mean=8.2, SD=3.0; general population mean=7.2, SD=2.1). 14 Nonetheless, both studies showed a reduction in hostility scores posthormone therapy initiation, although the reduction was not statistically significant at 3–6 month follow-up (SMD=−0.31 [95% CI: −0.70, −0.08]) 14 and the other was statistically significant at 12-month follow-up (SMD=−0.34 [95% CI: −0.61, −0.07]). 12 One study demonstrated a reduction in scores to a similar level as the general population at 3–6 month follow-up (mean=7.4, SD=2.0; general population mean=7.2, SD=2.1). 14

Phobic anxiety

Two studies assessed phobic anxiety using the SCL-90 (SCL-90-R Italian version; 12 SCL-90 Dutch version). 14 Participants in one study had phobic anxiety scores in the normal range before initiating hormone therapy (mean=0.53, SD=0.61; normal <1.0). 12 The other study had phobic anxiety called agoraphobia in the SCL-90 Dutch version 14 scores that were significantly higher than the general population at baseline (mean=9.5, SD=4.2; general population mean=7.9, SD=2.3). 14

Both studies saw a statistically significant change in phobic anxiety scores from baseline to follow-up (SMD=−0.37 [95% CI: −0.64, −0.10]; 12 SMD=−0.42 [95% CI: −0.81, −0.03]), 14 with one study showing a reduction in phobic anxiety in scores to a level that was similar to those of the general population (mean=8.1, SD=1.8; general population mean=7.9, SD=2.3). 14

Quality of life

Only one study ( n =83) assessed quality of life using the validated WHOQOL-100 questionnaire. Mean baseline scores and 12-month postintervention follow-up scores are reported overall and by subgroup (MTF/FTM). The study reported data for subgroups (MTF/FTM) and the mean follow-up scores were calculated for the full sample. The mean standard deviations for both subgroups were not reported and the p -value from the paired t -tests was only reported for the MTF subgroup, thus it was not possible to calculate a standard deviation for the full sample and compare pre/post means. Thus, findings must be considered in light of lack of reported data. See summary of findings ( Table 1 ).

One study reported on general quality of life. 13 At baseline, general quality of life, as measured through the WHOQOL-100, was in the normal/good range (i.e., ≥50) at 62.74. At follow-up, the quality of life score increased to 71.08 (max=100); however, the significance of this increase cannot be determined. Among MTF participants, paired t-tests showed a significant increase in overall quality of life from 62.5 to 72.2 ( p <0.05) at 12-month follow-up. For FTM participants, increases were observed (63.25 [baseline]; 68.75 [follow-up]); however, the increase in overall quality of life was not significant. 13 Given that only one study reported on quality of life outcomes, meta-analysis was not possible.

Methodological quality

See summary of findings ( Table 1 ) and risk of bias ( Fig. 2 ). The overall quality of evidence is low. While the studies used a prospective design, which is better quality than one-time cross-sectional studies, all studies lacked a control group. No studies used a randomized design. Moreover, all outcomes were based on self-report, which is subject to bias. However, all the measures used were based on psychometrically valid and reliable scales.

Risk of bias: Assessment of each risk of bias item presented as percentages across all included studies.

One confounding factor is that all studies provided psychotherapy to patients as part of standard of care for their clinic and all patients socially transitioned while accessing hormone therapy. While concurrent psychotherapy is often accessed by transgender patients on hormone therapy, and transgender patients have generally socially transitioned before initiating hormones, the effects of psychotherapy and social transition on mental health outcomes could have masked the true effects of hormone therapy on the mental health of patients. The studies were careful, however, to exclude participants with serious untreated psychiatric comorbidities (e.g., schizophrenia, substance abuse, and personality disorder).

Many studies failed to assess important confounders such as access to other medical gender affirmation technologies (e.g., surgeries) and none of the studies adjusted for confounders in their results such as the use of psychotropic medications.

Although the studies differ with regard to outcome measures and most studies have methodological shortcomings, the three prospective cohort studies reviewed here offer provisional conclusions about the effects of hormone therapy on the psychological functioning of transgender individuals accessing it. Two studies 12 , 14 reported on psychological functioning and found a statistically significant reduction in depression, somatization, interpersonal sensitivity, anxiety, hostility, and phobic anxiety/agoraphobia after initiating hormone therapy, with one study observing significant results 3–6 months posthormone initiation and the other 12 months posthormone initiation. There is insufficient evidence about whether changes in quality of life occur for FTM individuals who initiate hormone therapy. However, low quality evidence suggests that quality of life may be improved for MTF individuals accessing hormone therapy.

Findings support and extend the findings of another review, 7 which provided very low quality evidence that hormone therapy may improve the mental health of transgender people. However, the prior systematic review, which included 28 studies, assessed the effects of hormone therapy together with sex reassignment surgery on mental health, psychological functioning, sexual functioning, and quality of life and thus was unable to parse out the effects of hormone therapy separately from surgical interventions.

Given that many transgender people may never access sex reassignment surgery, it was important to study the effects of hormones alone with regard to mental health and quality of life outcomes. Moreover, the majority of studies included in the prior review were cross-sectional and none of the studies assessing mental health or psychological functioning used prospective study designs with a follow-up period of 3 months or more. Furthermore, the only studies that included a control group in the prior review assessed sex reassignment surgery and hormone therapy together, without comparing hormone therapy with an untreated control. Nonetheless, the prior review did find that the studies assessing sex reassignment surgery together with hormone therapy were strongly associated with improved psychological functioning, 7 thus findings from the current review extend these results.

Like the previous systematic review, 7 results of this review demonstrate low quality evidence (previous review demonstrated very low quality evidence), suggesting that hormonal therapies given to individuals diagnosed with having gender identity disorder (i.e., gender dysphoria) improve psychological functioning. However, unlike the previous review, this review is unable to offer conclusive evidence regarding the effects of hormone therapy on quality of life for transgender individuals overall.

Contrary to the prior review, 7 which found that MTF transgender people may have worse outcomes than FTM individuals, the study reviewed here found that MTF individuals had statistically significant improvements in quality of life 12 months after initiating hormone therapy, while FTM individuals did not experience increases that reached statistical significance, which was likely due to the small sample size. 13 Additional research is needed to confirm quality of life results overall and by gender subgroups.

Limitations regarding potential sources of bias in the review process should be noted. Three databases were used to identify studies for inclusion in this review and the search was limited to studies published in English. These search limitations may have resulted in the loss of relevant studies and influenced the results of the review. However, the electronic search was supplemented by checking references and citations of other articles, which yielded additional studies. Moreover, while the field of transgender health is truly global, English represents the predominant scientific publication language, thus significant findings, using less biased observational results, would have been likely to be published in English.

Nonstatistically significant findings may not have been published in English (i.e., publication bias). Nonetheless, it is feasible that all relevant studies have been identified. Additionally, study identification was completed by a single reviewer (the first author) in consultation with an expert reference librarian and researchers with expertise in systematic reviews. While the reviewer thoroughly conducted the search and review process, it is possible that studies that met inclusion criteria were not included in the review or were subject to a single reviewer's biases.

The restriction to prospective cohort studies also meant that the reviewer was unable to consider data from other types of evaluations of hormone therapy interventions such as one-time cross-sectional studies or qualitative evaluations. Although prospective cohorts are a stronger design than cross-sectional studies due to temporal ordering of exposure and outcomes, the cohort studies in this review were subject to a number of biases and other limitations (see the risk of bias section above and Fig. 2 ).

Uncontrolled prospective cohort studies suggest that hormonal therapies given to individuals diagnosed with having gender identity disorder (i.e., gender dysphoria) likely improve psychological functioning 3–12 months after initiating hormone therapy. Findings from the review support current clinical care guidelines such as the WPATH Standards of Care, 6 which recommend the use of hormone therapy as a treatment option to reduce gender dysphoria. Future research should assess the effects of hormone therapy on the mental health of transgender individuals using more robust study designs, including those which utilize clinician-delivered mental health outcome measures, longitudinal designs with control groups, and those examining U.S.-based transgender people over time.

Abbreviations Used

Acknowledgments.

We would like to thank Jan Glover from the Yale University Medical School Library for helping to develop the search for relevant articles and Dr. Michael Bracken for providing guidance on the practice of evidence-based medicine and the proper completion of a systematic review.

Author Disclosure Statement

No competing financial interests exist.

Cite this article as: White Hughto JM, Reisner SL (2016) A systematic review of the effects of hormone therapy on psychological functioning and quality of life in transgender individuals, Transgender Health 1:1, 21–31, DOI: 10.1089/trgh.2015.0008.