Transgender Hormone Therapy

Transsexual Hormone Regimen

ADULTS

1. Treating endocrinologists confirm the diagnostic criteria of GID or transsexualism and the eligibility and readiness

criteria for the endocrine phase of gender transition.

2. Medical conditions that can be exacerbated by hormone depletion and cross sex hormone treatment can be evaluated and addressed prior to initiation of treatment .

3. Cross-sex hormone levels can be maintained in the normal physiologic range for the desired gender.

4. Endocrinologists review the onset and time course of physical changes induced by cross-sex hormone treatment.

ADVERSE OUTCOME PREVENTION AND LONG-TERM CARE

1. Regular clinical and laboratory monitoring every 3 months during the first year and then once or twice yearly.

2. Monitoring prolactin levels in male to-female transsexual persons treated with estrogens.

3. Transsexual persons treated with hormones should be evaluated for cardiovascular risk factors.

4. Bone mineral density (BMD) measurements should be obtained if risk factors for osteoporosis exist, specifically in those who stop hormone therapy after gonadectomy.

5. Male-to-female (MTF) transsexual persons, who have no known increased risk of breast cancer, follow breast screening guidelines recommended for biological women.

6. MTF transsexual persons treated with estrogens should follow screening guidelines for prostatic disease and prostate cancer recommended for biological men.

7. Female-to-male (FTM) transsexual persons evaluate the risks and benefits of including total hysterectomy and oophorectomy as part of sex reassignment surgery.

WPATH’s SOC states that “the act of fully adopting a new or evolving gender role or gender presentation in everyday life is known as the RLE.

The RLE is essential to the transition to the gender role that is congruent with the patient’s gender identity. The RLE tests the person’s resolve, the capacity to function in the preferred gender, and the adequacy of social, economic, and psychological supports. It assists both the patient and the MHP in their judgments about how to proceed. During the RLE, the person should fully experience life in the desired gender role before irreversible physical treatment is undertaken. Living 12 months full-time in the desired gender role is recommended .

Testing an applicant’s ability to function in the desired gender assists the applicant, the MHP and the endocrinologist in their judgments about how to proceed. During the RLE, the person’s feelings about the social transformation, including coping with the responses of others, is a major focus of the counseling. Applicants increasingly start the RLE long before they are referred for hormone treatment.

The two major goals of hormonal therapy are:

1) to reduce endogenous hormone levels and, thereby, the secondary sex characteristics of the individual’s biological (genetic) sex and assigned gender, and

2) to replace endogenous sex hormone levels with those of the reassigned sex by using the principles of hormone replacement treatment of hypogonadal patients.

The timing of these two goals and the age at which to begin treatment with cross-sex hormones is co-determined in collaboration with both the person pursuing sex change and the MHP who made the diagnosis, performed psychological evaluation, and recommended sex reassignment. The physical changes induced by this sex hormone transition are usually accompanied by an improvement in mental wellbeing.

Male-to-female transsexual persons

The hormone regimen for MTF transsexual individuals is more complex than the FTM regimen. Most published clinical studies report the use of an anti-androgen in conjunction with an estrogen . The anti-androgens shown to be effective reduce endogenous testosterone levels, ideally to levels found in adult biological women, to enable estrogen therapy to have its fullest effect. Two categories of these medications are progestins with anti-androgen activity and gonadotropin-releasing hormone agonists. Spironolactone has anti-androgen properties by directly inhibiting testosterone secretion and by inhibiting androgen binding to the androgen receptor . It may also have estrogenic activity.

Cyproterone acetate, a progestational compound with anti-androgenic properties is widely used in Europe. Flutamide blocks binding of androgens to the androgen receptor, but it does not lower serum testosterone levels; it has liver toxicity, and its efficacy has not been demonstrated. Dittrich, reporting a series of 60 MTF transsexual persons who used monthly the GnRH agonist goserelin acetate in combination with estrogen, found this regimen to be effective in reducing testosterone levels with low incidence of adverse reactions. Estrogen can be given orally as conjugated estrogens, or 17b-estradiol, as transdermal estrogen or parenteral estrogen esters. Measurement of serum estradiol levels can be used to monitor oral, transdermal, and intramuscular estradiol or its esters. Use of conjugated estrogens or synthetic estrogens cannot be monitored by blood.

Hormone regimens in the transsexual persons

Dosage

MTF TRANSSEXUAL PERSONSa

Estrogen

Oral: estradiol 2.0–6.0 mg/d

Transdermal: estradiol patch 0.1– 0.4 mg twice weekly

Parenteral: estradiol 5–20 mg im every 2 wk

valerate or cypionate 2–10 mg im every week

Antiandrogens

Spironolactone 100–200 mg/d

Cyproterone acetateb 50–100 mg/d

GnRH agonist 3.75 mg sc monthly

FTM TRANSSEXUAL PERSONS

Testosterone

Oral: testosterone 160–240 mg/d undecanoateb

Parenteral

Testosterone enanthate 100–200 mg im every or cypionate 2 wk or 50% weekly

Testosterone 1000 mg every 12 wk

undecanoateb,c

Transdermal

Testosterone gel 1% 2.5–10 g/d

Testosterone patch 2.5–7.5 mg/d

a Estrogens used with or without antiandrogens or GnRH agonist.

b Not available in the United States.

c 1000 mg initially, followed by an injection at 6 wk, then at 12-wk intervals

TABLE 11. Medical conditions that can be exacerbated by cross-sex hormone therapy

TRANSSEXUAL FEMALE (MTF) – ESTROGEN

Very high risk of serious adverse outcomes

• thromboembolic disease

Moderate to high risk of adverse outcomes

• macroprolactinoma

• severe liver dysfunction

(transaminases > 3x upper limit of normal)

• breast cancer

• coronary artery disease

• cerebrovascular disease

• severe migraine headaches

TRANSSEXUAL MALE (FTM) – TESTOSTERONE

Very high risk of serious adverse outcomes

• breast or uterine cancer

• erythrocytosis (hematocrit >50%)

Moderate to high risk of adverse outcomes

• severe liver dysfunction

(transaminases > 3x upper limit of normal)

Clear expectations for the extent and timing of sex-hormone-induced changes may prevent the potential harm and expense of unnecessary procedures.

TABLE 13. Masculinizing effects in FTM transsexual persons

EFFECT ONSETa (months) MAXIMUMa (years)

Skin oiliness/acne 1 – 6 1 – 2

Facial/body hair growth 6 – 12 4 – 5

Scalp hair loss 6 – 12 b

Increased muscle mass/strength 6 – 12 2 – 5

Fat redistribution 1 – 6 2 – 5

Cessation of menses 2 – 6 c

Clitoral enlargement 3 – 6 1 – 2

Vaginal atrophy 3 – 6 1 – 2

Deepening of voice 6 – 12 1 – 2

b Prevention and treatment as recommended for biological men.

c Menorrhagia requires diagnosis and treatment by a gynecologist.

TABLE 14. Feminizing effects in MTF transsexual persons

EFFECT ONSETa MAXIMUMa

Redistribution of body fat 3 – 6 months 2 – 3 years

Decrease in muscle mass and strength 3 – 6 months 1 – 2 years

Softening of skin/decreased oiliness 3 – 6 months Unknown

Decreased libido 1 – 3 months 3 – 6 months

Decreased spontaneous erections 1 – 3 months 3 – 6 months

Male sexual dysfunction Variable Variable

Breast growth 3 – 6 months 2 – 3 years

Decreased testicular volume 3 – 6 months 2 – 3 years

Decreased sperm production Unknown > 3 years

Complete removal of male sexual hair requires electrolysis or laser treatment or both.

Male-to-female transsexual persons

Physical changes that may occur in the first 3–6 months of estrogen and anti-androgen therapy include decreased libido, decreased facial and body

hair, decreased oiliness of skin, breast tissue growth, and redistribution of fat mass .

Breast development is generally maximal at 2 years after initiation of hormones . Over a long period of time, the prostate gland and testicles

will undergo atrophy.

Female-to-male transsexual persons

Physical changes that are expected to occur during the first 3 months of initiation of testosterone therapy

include cessation of menses, increased libido, increased facial and body hair, increased oiliness of skin, increased muscle, and redistribution of fat mass.

Changes that occur within the first year of testosterone therapy include deepening of the voice, clitoromegaly.

Transsexual persons have very high expectations regarding the physical changes of hormone treatment

and are aware that body changes can be enhanced by surgical procedures (e.g., breast, face, and body habitus).

Clear expectations for the extent and timing of sex-hormone-induced changes may prevent the potential harm and expense of unnecessary procedures.

Regular clinical and laboratory monitoring every 3 months during the first year and then once or twice yearly.

Monitoring of MTF transsexual persons on cross-hormone therapy

1. Evaluate patient every 2–3 months in the first year and then 1–2 times per year to monitor for appropriate signs of

feminization and for development of adverse reactions.

2. Measure serum testosterone and estradiol every 3 months.

a. Serum testosterone levels should be <55 ng/dl.

b. Serum estradiol should not exceed the peak physiologic range for young healthy females, with ideal levels, 200 pg/ml.

c. Doses of estrogen should be adjusted according to the serum levels of estradiol.

3. For individuals on spironolactone, serum electrolytes particularly potassium should be monitored every 2–3 months initially

in the first year.

4. Routine cancer screening recommended in non-transsexual individuals (breasts, colon, prostate).

5. Consider BMD testing at baseline if risk factors for osteoporotic fracture are present (e.g., previous fracture,

family history, glucocorticoid use, prolonged hypogonadism). In individuals at low risk, screening for osteoporosis should

be conducted at age 60 or in those who are not compliant with hormone therapy.

Monitoring of FTM transsexual persons on cross-hormone therapy

1. Evaluate patient every 2–3 months in the first year and then 1–2 times per year to monitor for appropriate signs of

virilization and for development of adverse reactions.

2. Measure serum testosterone every 2–3 months until levels are in the normal physiologic male range:*

a. For testosterone enanthate/cypionate injections, the testosterone level should be measured mid-way between injections.

If the level is >700 ng/dl or <350 ng/dl, adjust dose accordingly.

b. For parenteral testosterone undecanoate, testosterone should be measured just before the following injection.

c. For transdermal testosterone, the testosterone level can be measured at any time after 1 week.

d. For oral testosterone undecanoate, the testosterone level should be measured 3–5 hours after ingestion.

e. Note: During the first 3–9 months of testosterone treatment, total testosterone levels may be high although free testosterone

levels are normal due to high sex hormone binding globulin levels in some biological women.

3. Measure estradiol levels during the first 6 months of testosterone treatment or until there has been no uterine bleeding for

6 months. Estradiol levels should be <50 pg/ml.

4. Measure CBC and liver function tests at baseline and every 3 months for the first year and then 1–2 times a year. Monitor

weight, blood pressure, lipids, fasting blood sugar (if family history of diabetes) and hemoglobin A1c (if diabetic) at

regular visits.

5. Consider BMD testing at baseline if risk factors for osteoporotic fracture are present (e.g., previous fracture, family history,

glucocorticoid use, prolonged hypogonadism). In individuals at low risk, screening for osteoporosis should be conducted

at age 60 or in those who are not compliant with hormone therapy.

6. If cervical tissue is present, an annual pap smear is recommended by the American College of Obstetricians and

Gynecologists.

7. If mastectomy is not performed, then consider mammograms as recommended by the American Cancer Society.

4.2. We suggest monitoring prolactin levels in maleto- female transsexual persons treated with estrogens.4.3. We suggest that transsexual persons treated with

hormones be evaluated for cardiovascular risk factors.Male-to-female transsexual persons

A standard monitoring plan for individuals on

estrogens, gonadotropin suppression, or antiandrogens

avoiding supraphysiologic doses or blood levels of estrogen, which may lead to increased risk for thromboembolic disease, liver dysfunction, and

development of hypertension.

Estrogen therapy can increase the growth of pituitary lactotroph cells. There have been several reports of prolactinomas occurring after long-term estrogen therapy .

Up to 20% of transsexual women treated with estrogens may have elevations in prolactin levels associated with enlargement of the pituitary gland

The onset and time course of hyperprolactinemia during estrogen treatment are not known. Prolactin levels should be obtained at baseline and then at least

annually during the transition period and biannually.

Male-to-female transsexual persons

Studies in aging genetic males suggest that serum estradiol more positively correlates with BMD than does testosterone and is more important

for peak bone mass . Estrogen preserves BMD in MTF transsexuals who continue on estrogen and anti androgen therapies .

Fracture data in transsexual men and women are not available. Transsexual persons who have undergone gonadectomy may not continue consistent cross-sex

steroid treatment after hormonal and surgical sex reassignment, thereby becoming at risk for bone loss.

Recommendations

1. Male-to-female transsexual persons, who have no known increased risk of breast cancer, follow breast screening guidelines recommended for biological women.

2. Male-to-female transsexual persons treated with estrogens follow screening bone mineral density measurements be obtained if risk factors for

osteoporosis exist, specifically in those who stop sex hormone therapy after gonadectomy.

guidelines for prostatic disease and prostate cancer recommended for biological men.

Breast cancer is a concern in transsexual women. A few cases of breast cancer in MTF transsexual

persons have been reported in the literature

. In the Dutch cohort of 1800 transsexual women followed for a mean of 15 years (range 1 to 30 years), only one case of breast cancer was found.

The Women’s Health Initiative study reported that women taking conjugated equine estrogen without progesterone for 7 years did not have an increased

risk of breast cancer as compared with women taking placebo . Women with primary hypogonadism (XO) treated with estrogen replacement exhibited a

significantly decreased incidence of breast cancer as compared with national standardized incidence ratios . These studies suggest that estrogen

therapy does not increase the risk of breast cancer in the short term (<20–30 years). Long-term studies

are required to determine the actual risk and the role of screening mammograms. Regular exams and

gynecologic advice should determine monitoring for breast cancer.

Prostate cancer is very rare, especially with androgen deprivation therapy, before the age of 40 (129).

Childhood or pubertal castration results in regression of the prostate and adult castration reverses benign prostate hypertrophy (BPH) . Although estrogen therapy does

not induce hypertrophy or pre-malignant changes in the prostate of MTF transsexual persons, cases of BPH

have been reported in MTF transsexual persons treated with estrogens for 20–25 years .

Three cases of prostate carcinoma have been reported in MTF transsexual persons . However, these individuals initiated cross-hormone therapy

after age 50, and whether these cancers were present before the initiation of therapy is unknown.

MTF transsexual persons may feel uncomfortable scheduling regular prostate examinations.

Gynecologists are not trained to screen for prostate cancer or to monitor prostate growth.

Although surgery on several different body structures is considered during sex reassignment, the most important issue is the genital surgery and

removal of the gonads. The surgical techniques have improved markedly during the past 10 years.

Cosmetic genital surgery with preservation of neurological sensation is now the standard. The satisfaction rate with surgical reassignment of sex is now very high . In addition, the mental health of the individual seems to be improved by participating in a treatment program that defines a pathway of gender identity treatment that includes hormones

and surgery . The person must be both eligible and ready for such a procedure . Sex reassignment surgeries available to the MTF

transsexual persons consist of gonadectomy, penectomy, and creation of a vagina . The

kin of the penis is often inverted to form the wall of the vagina. The scrotum becomes the labia majora. Cosmetic surgery is used to fashion the clitoris and its

hood, preserving the neurovascular bundle at the tip of the penis as the neurosensory supply to the clitoris.

Most recently, plastic surgeons have developed techniques to fashion labia minora. Endocrinologists

hould encourage the transsexual person to use their tampon dilators to maintain the depth and width of the vagina throughout the postoperative period until the neovagina is being used frequently in intercourse.

Genital sexual responsivity and other aspects of sexual function should be preserved following genital sex reassignment surgery .

Ancillary surgeries for more feminine or masculine appearance are not within the scope of this guideline.

When possible, less surgery is desirable. For instance, voice therapy by a speech language pathologist is

preferred to current surgical methods designed to change the pitch of the voice (148).

Breast size in genetic females exhibits a very broad spectrum. For the transsexual person to make the

best-informed decision, breast augmentation surgery should be delayed until at least 2 years of estrogen

therapy have been completed given that the breasts continue to grow during that time with estrogen stimulation .

Another major effort is the removal of facial and masculine-appearing body hair using either electrolysis or laser treatments. Other feminizing surgery, such as that to feminize the face, is now becoming more popular

Sex reassignment surgeries available to the FTM transsexual persons have been less satisfactory. The cosmetic appearance of a neopenis is now very good, but the surgery is multistage and very expensive . Neopenile erection can be achieved only if some mechanical device is imbedded in the penis, e.g., a rod or some inflatable apparatus . Many choose a metadoioplasty that exteriorizes or brings forward the clitoris and allows for voiding while standing. The scrotum is created from the labia majora with a good cosmetic effect, and testicular prostheses can be implanted. These procedures, as well as oophorectomy, vaginectomy, and complete hysterectomy, are undertaken after a few years of androgen therapyand can be safely performed vaginally with laparoscopy.

The ancillary surgery for the female-to-male transition that is extremely important is the mastectomy. Breast size only partially regresses with androgen therapy. In adults, discussion about mastectomy usually takes place after androgen therapy is begun. Since some FTM transsexual adolescents present after significant breast development has occurred, mastectomy may be considered before age 18.

Recommendations

Transsexual persons should consider genital sex reassignment surgery only after both the physician responsible for endocrine transition therapy and the MHP find surgery advisable.

Genital sex reassignment surgery be recommended only after completion of at least 1 year of consistent and compliant hormone treatment.

Physician responsible for endocrine treatment medically clear transsexual individuals for sex reassignment surgery and collaborate with the surgeon regarding hormone use

during and after surgery.

When a transsexual individual decides to have sex reassignment surgery, both the endocrinologist and the MHP must certify that he or she satisfies the

eligibility and readiness criteria of the SOC.

There is some concern that estrogen therapy may cause an increased risk for venous thrombosis during or following surgery . For this reason, the surgeon

and the endocrinologist should collaborate in making a decision about the use of hormones during the month before surgery.

Dissatisfaction

* Treatment options, hormonal and surgical

Real life test — When hormone treatment starts, or maybe even earlier, the “real life test”, or “real life experience” should begin. It is an extended period of full-time living as a member of the desired sex. The “real life test” allows the subject and the attending professional to monitor the experience in the new sex status as he/she habituates his/her responses to other people. Without this test of how others react and how he/she reacts to others, the subject knows only his/her private convictions and fantasies of being a member of the opposite sex. Convictions and fantasies may be unrealistic and may lead to magical expectations of life in the new sex.

Embarking on the “real life test” may be done in a stepwise fashion; for instance, first in a trusted environment and later in public. The subject should have lived at least one full year full-time in the new sex before irreversible surgical reassignment is considered. The ‘real life test” may be prolonged if too many hurdles present themselves during the test period. During the “real life test” the subject should stay in contact with a mental health professional to allow assessment of the success of the test and to discuss how to overcome problems that almost inevitably arise during this perio

and diagnosis”.)

GENERAL PRINCIPLES OF TREATMENT

Standards of care — The international organization involved with professional help to transsexuals, the Harry Benjamin International Gender Dysphoria Association, has drafted Standards of Care [1]. The major purpose of the Standards of Care (SOC) is to articulate this organization’s professional consensus about the psychological, medical, and surgical management of gender identity disorders. These standards provide guidance to professionals practicing in this area, who often work in isolation from mainstream medicine. It may also be of help in legal medicine to identify professional standards. Persons with gender identity disorders, their families, and social institutions may use the SOC as a means to understand the current thinking of professionals.

Endocrine Society Guidelines — In 2009, the Endocrine Society published clinical practice guidelines on the diagnosis and treatment of transsexualism in adolescents and adults. We agree with their approach which emphasizes the following [2]:

* suppression of endogenous hormones of the individual’s biologic sex

* maintaining hormone levels within the normal range for the individual’s desired gender

* involvement of a mental health professional in all stages of the patient’s evaluation, diagnosis, endocrine therapy, and surgical reassignment

Procedures prior to sex reassignment therapy — Before initiating hormonal or surgical treatment that will change a person’s gender, the physician should counsel the patient about:

* tions from treatment. The only benefit sex reassignment can bring is relief of gender dysphoria; all human problems outside the area of gender dysphoria will remain. Unrealistic expectations that subjects may have of the success of hormonal and surgical treatment for their transition to the desired sex must be addressed. Contacts with other transsexuals who are already in the process of changing over to the new sex or who have completed this process may be helpful in shaping a subject’s expectations of what can be achieved and what problems, personally and socially, may arise in the transition to the new sex.

* Treatment options, hormonal and surgical

HORMONAL THERAPY — The hormonal therapy phase of sex reassignment has two aims:

* To reduce the hormonally-induced secondary sex characteristics of the original sex as much as possible, but complete elimination is rare. As an example, in male-to-female transsexuals, the previous effects of androgens on the skeleton, such as the greater height of men than women, the size and shape of hands, feet, jaws and pelvis, cannot be reversed. Conversely, the relatively lower height and the broader hip configuration of female-to-male transsexuals compared to men will not change with androgen treatment.

* To induce the secondary sex characteristics of the new sex [3]

Male-to-female — To male-to-female transsexuals, elimination of sexual hair growth, induction of breast formation, and a more female fat distribution are essential. To accomplish this, a near-complete reduction of the biological effects of androgens is required. Administration of estrogens alone will suppress gonadotropin output and therefore androgen production, but dual therapy with one compound that suppresses androgen secretion or action and a second compound that supplies estrogen is more effective.

Suppression of androgen secretion or action — Several agents are available to inhibit androgen secretion or action. In Europe, the most widely used drug is cyproterone acetate (usually 50 mg twice daily), a progestational compound with antiandrogenic properties. If it is not available, medroxyprogesterone acetate, 5 to 10 mg/day, which suppresses gonadotropin secretion and therefore testosterone secretion, is an alternative, although less effective. After orchiectomy use of progestational compound is no longer useful, it has no role in feminization of the body and may have harmful metabolic effects [4].

Nonsteroidal antiandrogens, such as flutamide and nilutamide, are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol; the latter is a desirable effect in this context. Spironolactone (100 mg twice daily), a diuretic with antiandrogenic properties, has similar effects. Long-acting GnRH agonists, used as monthly injections, also inhibit gonadotropin secretion [5]. Finasteride (5 mg/day), a 5-alpha-reductase inhibitor, might also be considered.

Estrogen — There is a wide range of estrogens from which to choose. Oral ethinyl estradiol (50 to 100 mcg/day) is a potent and inexpensive estrogen, but it may cause venous thrombosis, particularly in subjects over 40 years [6-8], and should no longer be used. Oral 17b-estradiol valerate 2 to 4 mg per day or transdermal 17b-estradiol, 100 mcg twice a week, is the treatment of choice [8].

Consequences — There are a variety of consequences of hormonal therapy in male-to-female transsexuals:

* Sexual hair — Adult male beard growth is very resistant to inhibition by combined hormonal intervention, and in Caucasian subjects additional measures to eliminate facial hair are necessary. Sexual hair growth on other parts of the body responds more favorably [9].

* Breast development — Breast formation starts almost immediately after initiation of estrogen administration and goes through periods of growth and standstill. Androgens have an inhibitory effect on breast formation and, therefore, estrogens will be most effective in a milieu devoid of androgen action. After two years of estrogen administration, no further development can be expected. It is quantitatively satisfactory in 40 to 50 percent of the subjects. The attained size is often disproportional to the male dimension of the chest and height of the subject, so the subject may desire surgical breast augmentation. Older age also impedes full breast formation.

* Skin — Androgen deprivation leads to a decreased activity of the sebaceous glands, which may result in a dry skin or brittle nails [9].

* Body composition — Following androgen deprivation there is an increase in subcutaneous fat and a decrease in lean body mass. Body weight usually increases.

* Testes — Lacking gonadotropic stimulation, the testes become atrophic and may enter the inguinal canal, which may cause discomfort.

* Prostate — Atrophy of the prostate may produce transient dribbling following micturition.

* Voice — Antiandrogens and estrogens have no effect on the properties of the voice, so male-to-female transsexuals may wish to consult a specialized phoniatric center for speech therapy. Maleness of the voice is not so much determined by the pitch of the voice as by chest resonance and volume. Speech therapy may lead to more feminine speech [10]. Laryngeal surgery may change the pitch of the voice but reduces its range.

Long-term therapy — After reassignment surgery, including orchiectomy, hormone therapy must be continued. Some subjects still experience growth of sexual hair in a male pattern, and antiandrogens appear to be effective in reducing it, although the dose may be reduced. Continuous estrogen therapy is required to avoid symptoms of hormone deprivation and, most importantly, to prevent osteoporosis [11]. We have found that estrogens alone are capable of maintaining bone mass in male-to-female transsexuals. There was an inverse relationship between serum LH concentrations and bone mineral density, so serum LH may serve as an indicator of the adequacy of sex steroid administration.

Female-to-male — The goal of treatment in female-to-male transsexuals is to stop menses and induce virilization, including a male pattern of sexual hair, male physical contours, and clitoral enlargement. The principal hormonal treatment is a testosterone preparation.

Androgen therapy — There are many available testosterone preparations and routes of administration, including injectables, gels, and buccal tablets. In this author’s experience in female-to-male transsexuals, the most commonly used preparations are testosterone esters (eg, testosterone enanthate), administered intramuscularly in doses that are similar to those given to hypogonadal men (200 to 250 mg every two weeks), or testosterone undecanoate 1000 mg every 12 weeks (available in Europe, but not the United States). Many patients find the 12-week regimen more convenient.

In a study of 35 female-to-male transsexuals receiving the testosterone undecanoate regimen for one year, clinical results included the following [12]:

* Increase in the serum testosterone to a mean of 27.5 nM (794 ng/dL) at 12 months of treatment. Since this determination was made three months after the last dose, and therefore was the nadir of the dosing period, the average testosterone concentration during the entire three month period between doses was likely more than 50 percent higher than the mean testosterone value in normal young men, which is about 500-600 ng/dL.

* Significant decreases in serum LH, prolactin, SHBG, and significant increases in hemoglobin, and hematocrit

* A significant decrease in HDL, and increase in triglycerides

* An increase in body mass index

* An increase in blood pressure, and two patients had to discontinue therapy because of hypertension

* A decrease in endometrial thickness

* A significant increase in libido and clitoral size

* Acne developed in five patients (14 percent)

Thus, while there were some gains made towards androgenization, there were adverse effects on lipids and blood pressure. Complications of hormone therapy are discussed in greater detail below. (See ‘Complications of hormone therapy’ below.)

Occasionally menstrual bleeding does not cease with this regimen, and addition of a progestational agent is necessary. If a transdermal testosterone preparation is used, addition of a progestational agent is nearly always necessary to stop menstrual bleeding which should then be discontinued after hysterectomy.

Outcome — There are a variety of consequences of hormonal therapy in female-to-male transsexuals

HORMONAL THERAPY — The hormonal therapy phase of sex reassignment has two aims:

* To induce the secondary sex characteristics of the new sex [3]

Consequences — There are a variety of consequences of hormonal therapy in male-to-female transsexuals:

* Skin — Androgen deprivation leads to a decreased activity of the sebaceous glands, which may result in a dry skin or brittle nails [9].

* Body composition — Following androgen deprivation there is an increase in subcutaneous fat and a decrease in lean body mass. Body weight usually increases.

* Testes — Lacking gonadotropic stimulation, the testes become atrophic and may enter the inguinal canal, which may cause discomfort.

* Prostate — Atrophy of the prostate may produce transient dribbling following micturition.

ed: February 8, 2010 (More)

INTRODUCTION — Transsexualism is the condition in which a person with apparently normal somatic sexual differentiation of one gender is convinced that he or she is actually a member of the opposite gender. It is associated with an irresistible urge to be that gender hormonally, anatomically and psychosocially. The biologic considerations, definition, and diagnosis of transsexualism will be discussed here while treatment will be discussed separately. (See “Treatment of transsexualism”.)

TRANSSEXUALISM AS A DISORDER OF SEXUAL DIFFERENTIATION — Traditionally, transsexualism has been conceptualized as a purely psychological phenomenon, but research on the brains of male-to-female transsexuals has found that the sexual differentiation of one brain area — the bed nucleus of the stria terminalis — follows a female pattern [1,2].

A second study reported an association of androgen receptor repeat length polymorphism with male-to-female transsexualism [3]. These findings support the concept of transsexualism as an intersex disorder, where the sexual differentiation of the brain is not consistent with chromosomal pattern and gonadal sex [4]. Thus, one could postulate that transsexualism is a disorder of sexual differentiation.

Sexual differentiation of the brain in lower mammals — Sexual differentiation in mammals takes place in distinctly different steps, each with a critical period and each contingent upon the previous one. (See “Normal sexual differentiation”.) From studies in rats, mice and other lower mammals, it appears that the brain undergoes a sexual differentiation process, similar to those of the internal and external genitalia. Sexual differentiation of the brain has two characteristics:

* It expresses itself in sex-dimorphic behavior, both sexual, such as copulatory positions, and nonsexual, such as aggression, defense of territory, and caring for the young

* It depends upon the presence or absence of androgens. In the presence of androgens prenatally or perinatally, male brain differentiation occurs, and in their absence, female brain differentiation occurs. This process has been termed the organization or “wiring” of the brain to prepare it for future sexual and nonsexual behavior in agreement with the gonadal status. This programming is laid down during the fetal period or shortly thereafter and becomes activated by the hormones of puberty. The experimental evidence for the androgen dependence is that androgen treatment of a female rat causes male copulatory behavior. In addition, male and female rat brains differ in their neuroanatomic structure [5]. A potential role of androgens has also been documented in humans [3].

Sexual differentiation of the brain in humans — There is also some evidence that sexual dimorphism exists in humans [5-7]:

* Sex differences in size and shape of certain nuclei in the hypothalamus have been described [5]. One of the sex-dimorphic nuclei becomes differentiated between the ages of two to four [5] while the sexual differentiation of the bed nucleus of the stria terminalis may extend into adulthood [8]. The time of differentiation of the other sex-dimorphic nuclei is not known.

* In male-to-female transsexuals, one of the brain nuclei that is sex-dimorphic in the human, the bed nucleus of the stria terminalis, shows all characteristics of a female differentiation in a sample of male-to-female transsexuals [1,2]. In the brain of a single female-to-male transsexual a male differentiation was found [2].

It is not known if the mechanism controlling sexual differentiation of the human brain is exclusively hormonally determined [7]. From clinical observations in patients with an intersex condition or cross-sex hormone exposure during pregnancy, the evidence for a hormonal mechanism alone is not convincing. Postnatal rearing is in all likelihood a significant factor in the development of gender identity; this is no longer irreconcilable with the existence of a biological substrate of gender identity, since one’s life history is a factor in shaping brain anatomy and function [6].

Influence of the sex of rearing — Some infants with one gonadal sex are born with the external genitalia of the other. Follow-up studies of these children show that sex of assignment is an important prognosticator of future gender identity and role. It further appeared that gender identity becomes largely fixed around the age of three years [9]. Clinical experience shows, however, that this is not universally the rule. Intersexed persons may transition to the other sex and this may occur well beyond the age of three years [10]. It happens mainly in subjects with a degree, be it deficient, of prenatal androgen exposure, such as subjects with 17b-hydroxysteroid dehydrogenase 3 or steroid 5a-reductase 2 deficiencies. Not rarely, later in life they develop a male gender identity after having been originally assigned to the female sex on the basis of the appearance of their female-looking genitalia [10].

In the final analysis, the etiologies of transsexualism and gender dysphoria are unknown. There is neither evidence that transsexualism can be satisfactorily explained by variations in chromosomal patterns or by gonadal, genital or hormonal abnormalities, nor is there convincing evidence of rearing in the self-experienced sex [11].

TRANSSEXUALISM, TRANSGENDERISM, AND HOMOSEXUALITY — Transsexualism must be

with social and physical outcomes during the hormone transition may be a contraindication to surgery Those who undergo gonadectomy will require hormone replacement therapy or surveillance or both to prevent adverse effects of chronic hormone deficiency.

Transgender Hormone Therapy

Transsexual Hormone Regimen

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