#71923: Clinical Care of the Transgender Patient

Anti-Androgens

Anti-androgens reduce endogenous testosterone levels, allowing the full effect of estrogen therapy. The anti-androgen of choice in the United States is usually spironolactone (Aldactone), a potassium-sparing diuretic that directly inhibits testosterone secretion and inhibits androgen binding to the androgen receptor. It is usually given orally at a dose of 50 mg twice daily [82]. Side effects of spironolactone include gastrointestinal upset, hyperkalemia, increased urinary output, and hypotension. It is contraindicated in patients with renal insufficiency or with serum potassium levels greater than 5.5 mEq/L. Spironolactone should not be given with digoxin, angiotensin-converting enzyme inhibitors, other potassium-sparing diuretics, and angiotensin receptor blockers [82]. Patients taking spironolactone should have baseline levels of electrolytes, blood urea nitrogen (BUN), and creatinine, and repeat levels in two months or at every dose change, and then every six months when the dose is established [82].

Another commonly used anti-androgen is finasteride (Propecia or Proscar). This is a 5-alpha reductase inhibitor that blocks the conversion of testosterone to its potent form of dihydrotestosterone (DHT). The Propecia brand is approved to treat male pattern baldness, and the Proscar brand is approved for the treatment of benign prostatic hypertrophy; the use of finasteride to facilitate gender/sex transition is off label. Typical dosage for male pattern baldness is 1–5 mg per day [82,83]. Larger dosages are required to facilitate transition and range from 5–10 mg per day [82]. Finasteride for transition is generally only used as second-line therapy for patients intolerant to spironolactone. It does not have any significant food or drug interactions.

As mentioned, another category of anti-androgens is the GnRH agonists. These drugs occupy GnRH receptors in the pituitary, leading to a decrease in LH and follicle-stimulating hormone (FSH) secretion. This leads to a decrease in estradiol and testosterone levels in both sexes. Drugs in this class include nafarelin (Synarel), goserelin (Zoladex), and leuprorelin (Lupron). GnRH agonists are particularly useful in the treatment of adolescents, because their effects are fully reversible should there be a change in the desire to transition. Goserelin has been shown to be effective in reducing testosterone levels with a low incidence of adverse reactions [82]. When GnRH agonists are first given, testosterone levels go up briefly before falling to very low levels; this effect is called flare [82]. It can be avoided by giving other anti-androgen drugs for a few weeks when starting treatment.

Leuprolide is given at a dose of 3.75 mg monthly as intramuscular (IM) injections. Nafarelin is given via nasal spray, and goserelin is given via a monthly implant that delivers 3.6 mg over 28 days [82]. All these methods are relatively expensive and not as commonly used as spironolactone.

There are also progestins with anti-androgen activity. In Europe, a commonly used progestin is cyproterone, but this agent is not approved for use in the United States. When included in hormone therapy for MTF individuals, cyproterone is prescribed for the initial two weeks of GnRH therapy to reduce the effects of the androgen flare [82]. Side effects of cyproterone include fatigue, depression, and rarely, liver dysfunction.

Estrogen

In the MTF individual, estrogen will soften the skin, stimulate breast development, and cause a more feminine redistribution of fat while reducing testosterone levels via negative feedback on the hypothalamus. Estrogen also down-regulates gonadotropins to lower serum testosterone levels. This reduces the frequency of erections and ultimately causes prostate and testicular atrophy and infertility. It is unclear whether estrogen has a permanent effect on spermatogenesis, though it is likely to be related to the duration of therapy. However, there are no data on restoration of spermatogenesis after prolonged estrogen treatment [17].

Breast growth is moderate in MTF individuals taking estrogen. In a large multicenter study of 229 transwomen, breast development predominantly occurred in the first six months of estrogen therapy [86]. Only seven patients (3%) gained a bra size larger than an A cup. While transwomen treated with transdermal estradiol experienced more rapid breast growth, overall breast growth did not differ by route of administration after one year. Serum estradiol level did not predict breast development, possibly because exposure to high testosterone during male puberty induces structural changes in the breasts' adipose and fibrous connective tissue that inhibit development [86]. Breast development is generally maximal after two years of therapy [17].

Prior to initializing treatment with estrogen, baseline tests that should be performed include: liver panel, renal panel, lipid profile, prolactin level, and glucose level. These should be rechecked one to two months after starting, three months after changing dose, and every six months after establishing a stable dose [82]. Testosterone levels may be checked for patients not showing expected feminization after six to 12 months on maximum anti-androgens. While some practitioners recommend monitoring serum estradiol levels to maintain the mean daily level for premenopausal women, other providers feel that serum estrogen levels are not useful [82]. Additionally, use of conjugated estrogens makes it difficult to evaluate serum estradiol levels.

It is generally recommended that estrogen initially be given at lower dosages and increased gradually [82]. Excessive initial estrogen doses may cause early breast duct fusion, leading to small, hard, conical breasts [87]. This can be avoided by starting at a daily dose of 2 mg and progressively increasing the dose every three months until the serum estradiol level is 400–600 pmol/mL—typically 2 mg three times per day [87].

Estrogen can be given orally, transdermally, or parenterally, and each type of delivery has advantages and disadvantages. Estrogen given sublingually, transdermally, and parenterally avoids first-pass metabolism (with less effect on liver enzymes) and is associated with fewer vascular complications in patients older than 40 years of age [17]. Oral forms of estrogen have the additional advantage of being easy to titrate or stop. One study of long-term cross-sex hormone usage revealed that the use of ethinyl estradiol in MTF individuals was associated with an increased risk of death from thrombotic events [88]. This is one reason that the Endocrine Society, the Waddell protocols, and the WPATH Standards of Care no longer recommend ethinyl estradiol as a safe medication for feminizing hormone therapy [17,71,82].

One commonly prescribed oral estradiol product is Estrace. Generally, dosing of oral estradiol starts at 0.5–1 mg per day and gradually increases to a typical dose of 4 mg daily [82]. Conjugated estrogens are sometimes used, starting at 1.25–2.5 mg per day and increasing over time to 5 mg per day [82]. Some providers and patients have ethical issues with how this product is obtained (from the urine of pregnant mares) and the theoretical increased risk of thrombotic events [82].

Many providers prefer the injectable form of estrogen, either estradiol valerate (Delestrogen) or estradiol cypionate (Depo-Estradiol). Both of these products are typically started at 20–40 mg IM every two weeks, with an average maintenance dose of 40 mg every two weeks [82].

Estrogen can also be delivered transdermally via patch. Patches are started at 0.1 mg per day and increased as necessary to achieve the desired result. The average dose is 0.2 mg per day.

Common side effects of estrogens include breast tenderness, nausea and vomiting, depression, dry skin, brittle nails, headaches, and in some cases, increased appetite and weight gain [17,82,87]. More rarely, patients may experience migraines, gallbladder disease, abnormal liver function tests, mood disorder/depression, melasma, acne, lipid abnormalities, hypertriglyceridemia, increased risk of myocardial infarction, hepatitis, stroke, and increased risk of breast and other cancers [82,89]. In addition, estrogens may interact with other medications and foods (Table 2).

MTF individuals taking estrogen are at a greater risk of forming thrombotic emboli as a result of increased production of coagulation factors and pituitary prolactin production. This complication has been linked specifically to synthetic estrogens, such as ethinyl estradiol [91]. Deep vein thrombosis and pulmonary embolism are particular concerns for individuals who are older than 40 years of age, cigarette smokers, sedentary, or obese [82]. Two systematic reviews and meta-analyses of hormone use and cardiovascular risk found that estrogens increase serum triglycerides in MTF individuals, but data were too weak to draw conclusions about long-term cardiovascular morbidity and mortality [92,93]. Due to the increased risk of thrombosis and peripheral vascular disease, tobacco use is strongly discouraged [37,82]. Among oral estrogen users, there is potential for transient liver enzyme abnormalities, increased triglycerides, diabetes, and hypertension [82].

Hyperprolactinemia may occur, and there have been reported cases of prolactinomas in MTF individuals [17]. If present, hyperprolactinemia may respond to GnRH agonist therapy. Liver damage is also possible, particularly with oral therapy; it may be avoided by using parenteral or transdermal delivery. Other potential adverse effects include cholelithiasis, Budd-Chiari syndrome (a condition caused by occlusion of the hepatic veins that drain the liver and characterized by abdominal pain, ascites, and hepatomegaly), hepatic adenoma, and pancreatitis [87]. Estrogens and anti-androgens reduce circulating levels of phenylalanine, tyrosine, and tryptophan, which may lead to depressive and anxiety disorders [94].

Conversely, estrogen therapy reduces prostatic malignancy rates, as the prostate is not removed during GCS [87]. However, a prostate exam and cancer screening should be done as in the general male population.

The risk of breast cancer from estrogen therapy during MTF transition has not been clearly established. It is believed that progesterone used along with estrogen may raise this risk, but very few cases have ever been reported [87,95]. Nevertheless, if MTF patients are taking high levels of estrogen, they may be at increased risk for breast cancer, and providers should consider monitoring with a mammogram or breast ultrasound according to age and other risk factors (e.g., family history, duration of therapy) [81,96].

Response to estrogen is highly variable. Younger age and less body hair before initiation of therapy are predictive of a more satisfactory outcome [82]. Although estrogen administration will reduce body hair growth after six to 36 months, electrolysis or laser hair removal is commonly necessary to remove facial hair [17]. Clinicians providing care to MTF individuals who are undergoing electrolysis may consider prescribing topical lidocaine or lidocaine/prilocaine cream to reduce the discomfort associated with electrolysis. Approximately 2–2.5 g of the cream is applied to the area to be treated for one hour under an occlusive dressing.

Estrogens should be used with caution in patients with hyperlipidemia, diabetes, a history of smoking, hepatitis, alcoholic liver disease, renal insufficiency, migraines, seizure disorder, retinopathy, obesity, coronary heart disease, valvular heart disease, congestive heart failure or other cardiac dysfunction, any condition causing tendency to thrombosis, or a strong family history of breast cancer or other estrogen-dependent tumor [82]. Absolute contraindications to estrogen therapy include previous thrombotic events related to an underlying hypercoagulable condition, a history of estrogen-sensitive neoplasm, and end-stage liver disease [71].

Suggested annual laboratory tests for MTF individuals taking estrogens include lipid profile, liver function tests, glucose, and prolactin. BUN, creatinine, and electrolytes should be measured more frequently (i.e., every six months) [82].

Estrogen should be discontinued two weeks before GCS or any major surgery or immobilizing event and may be resumed one week after the surgery/event [82]. Estrogen doses should be reduced to the minimum necessary after GCS or maximum feminization is evident, usually after two years of treatment [82]. There are reports of decreased libido among MTF individuals who have taken estrogen for long periods, possibly due to long-term androgen depletion. Androgens play an important role in female libido and sexual enjoyment, and in MTF individuals, circulating androgen levels are lower than those in cisgender women [97]. To address this side effect, some providers add a small amount of testosterone to the hormonal regimen of MTF individuals.

Progesterones

There is some evidence that progesterone improves breast development and may decrease facial hair [184]. However, progesterone may cause an increased risk of thrombotic illness when combined with estrogen [98]. One study that examined patients receiving progesterone over a seven-year period showed no incidents of venous thromboembolism, cardiac disease, prolactinoma, galactorrhea, cholelithiasis, breast cancer, hypotension, hyperkalemia, or type 2 diabetes. However, some patients reported mood swings, depression, and increased androgenic effects. Progesterone may cause salt/water retention, leading to elevated blood pressure or varicose veins [99].

If indicated, medroxyprogesterone may be used as an adjunct for patients on maximum estrogen doses with unsatisfactory effects or in patients intolerant of other drugs. Typical dosing starts at 2.5 mg per day, increasing to a maximum dose of 20 mg per day. It can be given in 10-day cycles per month to reduce the total amount given [82].

The precautions and contraindications for progesterones are the same as those described for estrogens. Adverse effects may include lipid abnormalities, weight gain, edema, mood disorders (primarily depression or irritability), and facial and body hair growth and coarsening.

According to The Endocrine Society, for MTF individuals receiving hormone therapy, hormone levels should be monitored approximately every three months during the first year (or with each dose adjustment), focusing on achieving testosterone and estradiol levels in the normal female range. Medications should be adjusted to correct the specific sex-steroid hormone level that is out of range. For example, if testosterone levels remain too high, the testosterone-lowering medication dose should be increased. If estradiol levels are not in the female range, the dosage of estradiol should be adjusted accordingly. For transgender women receiving spironolactone, which is a potassium-sparing diuretic, potassium levels should be checked along with hormone levels to ensure that the patient is not hyperkalemic. After appropriate testosterone and estradiol levels are achieved, laboratory monitoring can be repeated once or twice each year. It is important for the provider to ask whether the patient is comfortable with the regimen or is experiencing adverse events, including mood changes [183].

When boys reach puberty, the increase of androgens causes the larynx to grow and the vocal cords to lengthen and thicken, resulting in a deeper pitch. Additionally, the growth of facial bones, sinus cavities, the nose, and the throat creates more vocal resonance in men. Being perceived as a woman in vocal interactions is of importance to MTF individuals. Because the physiologic changes affecting the voice are not reversed with the use of female hormones, many MTF individuals will seek out voice therapy (with a speech therapist or speech-language pathologist) to change the quality of the voice to a more feminine range.

Voice therapy involves the conscious manipulation of the vocal mechanism to produce a more feminine-sounding voice [100]. The goal of therapy is not merely raising the pitch of the voice, but also "feminizing" the resonance, intonation (rhythm of speech), rate of speech, volume, intensity, choice of language, articulation, and social rules of communication [101]. The process includes an assessment of the individual's current voice, resonance, articulation, spoken language, and non-verbal communication. The patient is also assessed for vocal health and current practices that may be damaging to the voice.

Feminine voices have a higher pitch and breathier vocal quality, and they resonate at higher frequencies and have different speech rates, inflections, and intonations. The fundamental frequency (pitch) of the adult male voice is about 100 Hz, with a range of 77–482 Hz; the adult female voice has an average frequency of 195 Hz, with a range of 137–634 Hz. There is considerable overlap between the two ranges, but in order to be perceived as female, the fundamental frequency should be around 172 Hz (165–180 Hz). According to a study by King et al., a mean speaking pitch above 180 Hz and maintaining a speaking pitch range of approximately 140–300 Hz appear to be the most powerful acoustic features or markers in the perception of a female voice in MTF individuals [102]. Raising the fundamental frequency near this range is one of the goals of voice therapy.

MTF speakers can effectively raise their resonance by learning to speak with the tongue positioned relatively more forward in the oral cavity. Because women tend to use a smaller range of semitones than men when speaking declarative and interrogative sentences, MTF individuals can change intonation by reducing the range of semitones they use and utilizing more upward intonations and downward shifts in conversational speech.

In addition to voice characteristics, MTF individuals also may alter their nonverbal communication to a more feminine manner by maintaining eye contact, using hand gestures, using more varied facial expressions, altering posture, and nodding more. Women tend to move their heads during conversation and often mirror the movements of their conversational partner. They are also generally more expressive with their hands and use arm movements that are closer in proximity to their own body. Feminine gestures tend to be more fluid than those perceived as masculine and tend to move toward and away from the body. Additionally, women may have conversations with more disclaimers and qualifiers and be more emotionally expressive [103]. Another important area of therapy is alerting patients to the difference in lexicon between the genders. The words commonly used by men and women are different, and therapy can include the differences in masculine and feminine language and word usage [104].

Voice therapy may involve individual and/or group sessions. The frequency and duration of treatment will vary according to a patient's needs. During voice therapy, the MTF patient can easily become fatigued, and one goal is to build vocal stamina in order to prevent harming the vocal folds [101]. Exercise is a prerequisite to voice modification, as building strength and flexibility will increase the likelihood of success and reduce the risk of vocal stress and strain [104,105].

The goal of hormone therapy for FTM individuals is masculinization of the body through the use of testosterone (Table 3). Testosterone therapy in FTM individuals results in cessation of menses within three to five months due to suppression of the hypothalamic-pituitary axis. However, ovulation may continue, and pregnancies have been reported in FTM persons even after prolonged testosterone treatment [17,106]. As such, it is important to discuss contraception with FTM individuals who have sex with men. Other effects of testosterone therapy include increased libido, increased facial and body hair, increased skin oiliness, increased muscle, mild breast atrophy, and redistribution of fat mass, usually within three months of the initiation of testosterone therapy.

Within one year, the voice usually deepens, clitoromegaly occurs, and male pattern hair loss may be apparent [17]. After 13 years of testosterone use, androgenic alopecia occurs in 50% of FTM individuals [99]. On average, the clitoris enlarges to 3–5 cm, and in some cases, testosterone may be applied topically to the clitoris to stimulate growth [106]. These changes in voice range, hair follicles, and clitoral size are permanent. Other effects, such as increased muscle mass, acne, increased libido and energy level, and amenorrhea are reversible if testosterone is discontinued [82]. FTM individuals report a better quality of life after receiving male hormones regardless of the duration of treatment [50].

Contraindications to testosterone include estrogen receptor-sensitive breast cancer; uterine, endometrial, and/or ovarian cancer; pregnancy; and hypersensitivity to sesame or cottonseed oil, if injectable testosterone is used. Testosterone should be used with caution in individuals with uncontrolled coronary heart disease or any unstable heart disease, hyperlipidemia, diabetes, liver disease, cigarette smoking, extreme obesity, hypertension, kidney failure, prolactinoma, or active thyroid disease [106].

There is an increased incidence of polycystic ovarian syndrome (PCOS) in FTM individuals regardless of testosterone use. Because PCOS is associated with insulin resistance, obesity, hypertension, cardiac disease, and endometrial cancer, it is important that candidates for testosterone therapy be evaluated for PCOS prior to the initiation of treatment; testosterone may exacerbate many of these conditions [71].

Baseline levels should be established before initiating testosterone therapy for the lipid profile, comprehensive metabolic profile (CMP), CBC, free and total testosterone, estrogen, and prolactin. Free testosterone, CBC, and CMP should be repeated four to six weeks later, as well as blood pressure and weight. At four to six months and then every six to 12 months, a fasting lipid panel, CMP, CBC, and free testosterone should be assessed. Specimens should be drawn mid-way between testosterone injections, and clinicians should strive to maintain testosterone levels within the normal male range [71,106].

Because a common side effect of testosterone therapy is polycythemia, hematocrit levels should be carefully monitored. Polycythemia is exacerbated by excessive testosterone dosages and is more likely in smokers [87]. If necessary, treatment involves reducing the dosage or switching to transdermal delivery.

FTM individuals receiving testosterone may have elevated renin, triglyceride, and cholesterol levels, putting them at a higher risk for heart disease. If they smoke cigarettes, their risk of coronary heart disease is increased even more [81]. In two systematic reviews and meta-analyses, testosterone therapy was associated with increased serum triglycerides and low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol, and a small increase in systolic blood pressure in FTM individuals [92,93]. However, there is a lack of evidence that these changes result in increased morbidity or mortality [106].

Testosterone also increases plasma tryptophan levels, reducing vulnerability to depressive and anxiety disorders [94]. All FTM individuals of reproductive age who wish to preserve reproductive options should be counseled about gamete (unfertilized ova) or fertilized embryo banking by a fertility specialist prior to initiation of testosterone therapy [84,85]. Although menses and ovulation will resume after testosterone is withdrawn and pregnancies have occurred in FTM individuals even while on testosterone therapy, there are no studies that examine the long-term impact of testosterone on fertility or the health of offspring.

There is little standardization in hormone regimens for FTM individuals, and the choice of product may be limited by a patient's economic situation or geographic location. The Endocrine Society guidelines provide specific guidance regarding the types of hormones and suggested dosages that have proven effective [17]. In the United States, oral testosterone is not available, so it will not be discussed in this course.

In the United States, most regimens involve parenteral or transdermal testosterone in the form of testosterone cypionate or enanthate. These agents avoid the first-pass effect and can achieve testosterone levels in the normal male range of 320–1,000 ng/dL. Intramuscular testosterone is released slowly from the muscle, so injections are spaced every two to four weeks.

It is important to advise patients using transdermal testosterone to avoid contact with others immediately after administration in order to prevent accidental virilization. In the United States, transdermal testosterone is available as the Androderm patch, AndroGel topical gel, or Axiron topical solution [17,107].

Testosterone is associated with some food/drug and drug/drug interactions, which are similar to those found with estrogens (Table 4). It increases the anticoagulant effect of warfarin, increases the clearance of propranolol, and increases the hypoglycemic effects of sulfonylureas [107].

The effect of testosterone on endometrial hyperplasia is unclear. While some studies indicate an increased risk of endometrial cancer, others have found that testosterone causes endometrial atrophy or decreased endometrial thickness [108,109]. If FTM individuals are receiving large doses of testosterone, it may be converted into estrogen through aromatization. Without progesterone, this estrogen is unopposed, and if the patient has a uterus, unopposed estrogen increases the risk of endometrial hyperplasia and uterine cancer. Therefore, twice-yearly ultrasonic monitoring of endometrial thickness after three years of testosterone therapy is recommended if hysterectomy has not been performed [87]. Paradoxically, patients on smaller doses of testosterone may have better effects because less estradiol circulates [37].

While FTM individuals perceive that receiving gynecologic care is important, many struggle with dealing with healthcare providers [110]. Use of improper pronouns and the male/female boxes on standard forms are considered barriers to care. Breast exams cause considerable anxiety in FTM individuals, and special care should be taken during a pelvic exam to reduce patients' anxiety.

Ongoing care for FTM individuals includes cervical Pap tests according to guidelines while the patient still has a cervix. With testosterone therapy, the cervix will atrophy, showing an increase of parabasal cells or other atrophic changes on Pap reports. Because of this, patients may require 25 mcg of estrogen intravaginally one to two weeks prior to a pelvic exam to achieve proper cell collection from the squamocolumnar junction. It is important to note on the lab slip that the patient is on testosterone and is amenorrheic [108].

Spontaneous vaginal bleeding may be caused by missed testosterone doses, excessive testosterone, weight increase, or thyroid disorders. Atrophic vaginitis may occur, resulting in bacterial vaginitis or candidiasis. If bacterial vaginitis is suspected, the vagina should be cultured for atypical bacteria [108]. Pelvic cramping has been noted in some people on testosterone for longer than three to six months, in some cases associated with orgasm. The pain typically lasts 10 to 15 minutes and can be alleviated by pre-medicating with nonsteroidal anti-inflammatory drugs [108].

Care of the FTM patient should include a sensitive history of sexual practices and partners. It is important not to assume sexual orientation based on gender identity. Instead, consider asking "What sexual practices do you engage in?" or "What body parts do your sexual partner(s) have, and which of your body parts do you use?" [108]. Screening for HIV and other sexually transmitted infections should be based on history, symptoms, or risk factors. Patients should be counseled regarding the safe use of sex toys and safer sex practices, including the use of condoms, gloves, and dental dams, as appropriate. If the patient is having sex that could lead to pregnancy, contraception should also be discussed. If the patient desires to conceive, counseling would include the use of folic acid, prenatal vitamins, and stopping testosterone.

Some FTM individuals have had successful pregnancies during transition. A survey of 41 FTM individuals who gave birth after transitioning with or without the use of testosterone showed that FTM individuals may desire to have children and be willing and able to conceive, carry a pregnancy, and give birth [111]. Ovarian function may not be completely suppressed by testosterone, and it is possible that ovulation continues regardless of the presence of amenorrhea. One-third of pregnancies in FTM individuals are unplanned, as many transmen believe that testosterone acts as a contraceptive [111].

FTM individuals may be averse to taking estrogen in any form, so may prefer to avoid a combined oral contraceptive. Moreover, there is a theoretical risk of venous thromboembolism when combining estrogen and testosterone. Progestin-only contraceptives (e.g., levonorgestrel intrauterine device [LNG IUD], depot medroxyprogesterone acetate [DMPA or Depo Provera], etonogestrel implants, progestin-only pills) are reasonable contraceptive options. The DMPA injection and the LNG IUD may be desirable because they contribute to amenorrhea, a desirable situation in transmen [185].

Pregnancy outcomes were not significantly different from the general population, except for an increased incidence of postpartum depression. Most FTM individuals who had used testosterone gave birth via cesarean section. Although most transgender men in the study received prenatal care from physicians and delivered in hospitals, participants used non-physician providers and nonhospital birth locations more frequently than the general public. The researchers speculate that the choice of healthcare provider and delivery location may have been responses to actual or anticipated negative experiences [111].

Because serum testosterone levels are lower in individuals using transdermal testosterone, progestin, most commonly medroxyprogesterone, is often needed to assist with menstrual cessation [18]. Drug interactions include potentiation of warfarin and hypoglycemic agents [82].

Because hormone therapy will result in voice changes for FTM individuals, voice therapy is often overlooked or considered unnecessary. However, research has indicated that voice change in FTM individuals is not always fully achieved through hormone therapy [112]. In a study of 38 FTM transsexual persons, pitch-lowering difficulties occurred in about 10% of cases and appeared, at least in part, to be associated with diminished androgen sensitivity [113]. Aside from changes in pitch and voice quality, voice therapy may also help inform nonverbal communication and gestures to reinforce a masculine presentation.

An estimated 60% to 70% of all MTF individuals seek breast augmentation in addition to hormone therapy [86]. Breast augmentation is generally performed as an outpatient procedure under general anesthesia. During the procedure, saline or silicone gel implants are placed, most commonly below the pectoral muscle through a periareolar, inframammary, axillary, or trans-umbilical incision.

The periareolar incision has the advantage of hiding the incision scar along the skin-areola border. However, this is only practical if the areolae are large enough to insert the implants. The inframammary incision provides an easier approach to creating a pocket to place and inflate the implant, but the incision may be more noticeable. The axillary approach moves the incision away from the breast area, but it makes visualization of the surgical area and control of bleeding more difficult. The trans-umbilical approach involves making an incision at the umbilicus and tunneling to the implant site, where a deflated saline implant is placed and then inflated. Various sizes and shapes of implants are available, and patients generally discuss their wishes and expectations with their surgeon so consensus can be reached on what is possible [116].

After the procedure, the dressings will remain in place for about three days, but the strips over the incision are generally left in place until they fall off, usually in seven to 10 days. Showering is permitted, but the wound closure strips should not be soaked and should be patted dry afterwards. A sports bra should be worn for compression and support.

Erythema at the incision site is normal, provided it does not extend beyond 1–2 cm from the incision. Edema is also normal and is only concerning if it is an unusually large, one-sided mass. Suture knots may be visible or felt at the end of the incision and may eventually work their way to the surface of the skin. Shooting pains, burning sensations, and general discomfort during the healing process are common. Mild analgesics are usually prescribed to control these.

Patients often resume normal routines within one to two weeks, with strenuous activity avoided for three to four weeks. Patients are instructed to perform implant displacement massage beginning three to five days post-procedure [116].

The most common complications of breast augmentation surgery include the general surgical complications of bleeding, infection, or hematoma. Complications specific to augmentation mammoplasty are capsular contraction, asymmetry, malpositioned implants, and altered nipple sensation. Infection is rare [87,117].

Facial feminization surgery is a set of surgical procedures that alter typically male facial features to provide a more feminine appearance. This is achieved by procedures such as brow lift, rhinoplasty, cheek implants, lip augmentation, scalp advancement, frontal cranioplasty, and reduction mandibuloplasty [118]. Through the 1980s and 1990s, facial feminization surgery as part of MTF transition was pioneered in the United States by maxillofacial surgeon Douglas K. Ousterhout. Since then, other surgeons in the United States and abroad have continued to develop and improve approaches to facial feminization.

There are notable differences between the male skull and the female skull (Table 5). The male skull usually has a square or rectangular shape; forehead brow bossing with a steep, flat slope; a larger and thicker mandible; a wider, rectangular chin; and more muscle and less fat. The zygomatic prominence is usually larger and flatter [117].

Facial feminization surgery includes forehead modifications, cheek/zygomatic bone modifications, rhinoplasty, mandibular angle changes, and genioplasty. Modifications to the brow include burring of the brow or removal of the anterior table along with osteotomies and miniplates and repositioning of the periosteum. Very often, this is combined with a brow lift and scalp advancement, as women generally have less distance between the brows and the hairline.

Cheek implants or fillers are used to provide a fuller cheek with more projection. The chin can be rounded with a burr or implants to improve the contour. The mandible may be repositioned downward and posteriorly, and a mandibular angle reduction may be performed [117].

A chondrolaryngoplasty (tracheal shave) may be requested to remove or reduce the laryngeal prominence (Adam's apple). This procedure is not designed to feminize the voice—only to alter the appearance. A small incision is made on the upper crease of the neck or in a wrinkle in the skin. Using a laryngoscope, the vocal cords are visualized and this location is marked externally. The surgeon then exposes the thyroid cartilage and removes all of the prominent cartilage and its borders above the vocal cord marking. The incision is then closed and cleaned and a bandage is placed over the incision. During the first 24 to 48 hours after the surgery, it is common to experience some bruising and swelling as well as a sore throat. Discomfort is typically minor; however, pain medication is often given in order to keep the patient as comfortable as possible [119]. Complications may include a scar, changes in vocal quality, pain, and difficulty swallowing [117].

There is a paucity of data on patient satisfaction following facial feminization surgery. However, one study of 247 MTF individuals revealed that those who had facial feminization surgery scored higher on measures of satisfaction and quality-of-life outcomes in regard to physical, mental, and social functioning compared with those who did not have facial feminization surgery [118].

Occasionally, MTF individuals who are seeking an inexpensive alternative to cosmetic surgery may resort to injectable silicone and body molding substances that are not approved for human use. These injections are often industrial grade silicone and/or substances such as paraffin, oil, and other industrial materials (e.g., caulk, tire sealant). They are illegal, often performed by unlicensed practitioners, and may be injected at so-called "pumping parties." Common areas for injection include the cheeks, breasts, and buttocks.

Immediate dangers of these injections include transmission of HIV, hepatitis B and C, methicillin-resistant Staphylococcus aureus, embolism, and foreign substance reaction. Possible long-term effects include migration of the substance to other body areas, disfigurement, nodules, granulomata, and pain. Treatment is palliative, as there is no safe way to remove encapsulated silicone from body tissue [82].

Bilateral orchiectomy is commonly performed as part of GCS. However, it may also be done as a separate procedure to reduce total testosterone levels by about 90%, particularly in individuals who are intolerant of anti-androgen therapy. This also reduces the amount of estrogen needed to achieve feminization. In performing this procedure for MTF individuals, the scrotal skin is preserved as much as possible if there is a desire for vaginoplasty/labiaplasty in the future. Disadvantages of orchiectomy are the irreversibility of the procedure and the shrinkage/potential scarring of scrotal tissue, which would be used in subsequent GCS to create the neovagina. For this reason, some surgeons recommend performing the orchiectomy at the same time as the vaginoplasty. Combining procedures also minimizes the risks if general anesthesia is used [116].

Orchiectomy is usually performed on an outpatient basis, but in some circumstances, it may require an overnight hospital stay. Intravenous sedation is generally used for the procedure. A midline incision is made in the scrotum, through which the testes are removed and the spermatic cords are cut as short as possible [120].

The patient should occasionally massage the incision (as needed) for one to two weeks after surgery to prevent scarring and adhesions. The scrotal skin can be kept supple by stretching and moisturizing the area on occasion. Postoperative pain is usually minimal. The patient is prescribed antibiotics to prevent infection, and a thin coating of an antibiotic ointment is applied to the incision site twice daily for two weeks. After two weeks, the area may be treated with aloe vera as needed. All activity is limited for the first 24 hours, and no heavy lifting should be done for two weeks [120].

Orchiectomy has the lowest complication rate of all GCSs [121]. One potential complication of the procedure is scrotal hematoma, which usually resolves spontaneously but may require aspiration, drainage, or even surgical removal to achieve the best result. If the scar does not heal properly, a skin graft may be necessary for subsequent vaginoplasty.

Some MTF transgender individuals will choose to undergo voice feminization surgery, particularly if voice therapy has not achieved satisfactory results. There are varying degrees of satisfaction, safety, and long-term improvement in patients who have had such surgery. The WPATH recommends that individuals undergoing voice feminization surgery consult a voice and communication specialist in order to maximize the surgical outcome, help protect vocal health, and learn non-pitch-related aspects of communication [71]. Voice surgery procedures are followed by sessions with a licensed and/or credentialed voice and communication specialist [71].

Historically, the most commonly performed surgery to raise the fundamental frequency of the voice was cricothyroid approximation. The procedure is commonly performed under local anesthesia with monitored anesthesia care. A small incision is made in the natural skin fold of the neck, and the thyroid cartilage is pushed against the cricoid cartilage that lies below it. The two cartilages are held together with sutures or metal clips. This increases the tension on the vocal cords by stretching them posteriorly, causing them to vibrate at a higher pitch. Postoperatively, patients are placed on vocal rest for 10 days to allow for the stretching of laryngeal soft tissues and reduce the risk of edema. Potential complications include difficulty swallowing, sore throat, and frequent throat clearing. Long-term follow-up has shown inconsistent results. Following surgery, the voice frequently has a falsetto quality. Some patients will experience a re-stretching of their vocal cords, even though the surgical sutures remain tight, which results in a drop in frequency back to the male range. If stretching occurs, it is usually evident within one to two months of the procedure [122].

Feminization laryngoplasty (FemLar) is a newer surgical technique that reshapes the larynx to make it smaller and the vocal cords shorter. In this procedure, a strip of the thyroid cartilage is removed, making the larynx smaller. The vocal cords are then stretched, and the front one-third to one-half of the cords are removed. A thyrohyoid elevation may also be performed at the same time to feminize a portion of the resonance chamber (pharynx). A thyrohyoid elevation consists of passing sutures around the hyoid bone to hold the larynx in an elevated position in the neck and shorten the pharynx. This surgery carries some significant risks, including potential loss of vocal range and volume. The vocal cords may also heal with an asymmetric tension, resulting in a rough voice. Granulomas may form on the inside of the larynx; these are either coughed out or removed. Other risks include infection, bleeding, and an occluded airway due to postoperative edema [122].

The Wendler laser reduction glottoplasty involves CO2-laser de-epithelialization of the anterior commissure of the vocal cords and the anterior one-third of the two vocal folds. The two vocal folds are sutured, and fibrin sealant is applied to strengthen the stitches. Neither the larynx nor the muscles around it are altered; only the folds and cords are changed. Laser reduction glottoplasty is less invasive than either a cricothyroid approximation or FemLar. However, the changes are usually less impressive than with the other techniques, and the procedure is more effective in younger individuals [123].

GCS, also known as gender-affirmation surgery or sex reassignment surgery, is an option for persons with marked and sustained gender incongruence and capacity for understanding and consent [71]. The primary goals of GCS for MTF individuals include the creation of a sensate and aesthetically realistic vulva, including the clitoris, labia minora and majora, and vagina; creation of a urethral opening that allows a downward urinary stream; creation of a stable and sensate neovagina with adequate dimensions for penetrative sexual intercourse; and preservation of orgasmic capability.

In most cases, GCS consists of several procedures, including bilateral orchiectomy, partial penectomy (penile dissection), vaginoplasty, labiaplasty, and clitoroplasty, that are performed in a single session. However, some surgeons prefer a two-stage approach, performing the labiaplasty and clitoroplasty after the initial vaginoplasty has fully healed. Construction of the neovagina is typically done using the inverted penile skin. However, in some cases, a segment of the rectosigmoid colon or skin grafts from the abdomen, buttocks, hips, or scrotum are used when sufficient vaginal depth cannot be achieved using penile tissue alone [124,125]. Scrotal skin is generally used to create the labia.

Techniques for GCS are evolving. Some surgeons are now using a loop of sigmoid colon as well as inverted penile skin to create a neovagina that is self-lubricating and deeper than the traditional penile inversion method. It is also useful for patients with small penile size or who have had hormone suppression in puberty. This approach is also associated with less need for postoperative vaginal dilation [127]. An alternative approach is to use a segment of ilium to line the neovagina. Both methods can be performed laparoscopically in many cases [192]. More recently, a peritoneal pull-through technique has been employed in patients undergoing primary and revision vaginoplasty using a combined abdominal and perineal approach. Typically, a tubular flap of peritoneum is created laparoscopically from the anterior and posterior pelvic peritoneum and brought through an incision at the apex of the neovagina. It is then anastomosed to the perineal skin [193].

As the use of puberty-suppressing hormonal treatment in preadolescent patients has become more routine, penile and scrotal hypoplasia is common, making vaginoplasty with this tissue infeasible [126]. Some surgeons have begun to offer sigmoid vaginoplasty to all MTF individuals with a phallus length of less than 11.4 cm [127].

As a prerequisite to GCS surgery, patients often undergo genital electrolysis to remove hair from the scrotum and base of the penis in order to prevent intravaginal hair growth in the neovagina [116]. If the individual smokes, smoking cessation is recommended for at least one month prior to surgery and six months following surgery. Some surgeons also require that the patient's body mass index be less than 28 [128]. Two to four weeks before the surgery, estrogens are discontinued to prevent potential thromboembolic events. Any other medications that may inhibit blood clotting are also discontinued. The day/evening before surgery, a bowel preparation is necessary to evacuate the bowels. Some institutions also recommend a skin scrub using chlorhexidine prior to surgery, and prophylactic antibiotics may be administered either the night prior to surgery or just before incision. The patient is kept NPO (nothing by mouth) after midnight prior to surgery, which is common to most surgical procedures [116].

Preoperative medical clearance for surgery typically includes a history and physical, CBC, an electrocardiogram (EKG) if the individual is older than 50 years of age, and a chest x-ray if the individual is a smoker or is older than 50 years of age. Cardiology clearance is needed if the patient has current or previous coronary heart disease, a pacemaker, automatic internal defibrillator, or arrhythmias [117].

A longitudinal incision is made in the perineum dorsal from the scrotal base to about 3 cm from the anus. Blunt dissection creates a space for the neovagina between the rectum and the bladder. The neovagina is positioned posterior to the prostate, which is left intact during this procedure [124]. The scrotum and testes are incised and an orchiectomy performed, with the skin preserved to form the labia majora. The spermatic cords are cut and ligated at the level of the external inguinal ring. Penile skin is dissected away from the corpora, and the urethra is divided from the cavernosa and cut at the usual female length. The urethra is then sutured through an opening at the female position. The penile skin is inverted to form the neovagina [31].

The labia are constructed using existing male genital skin segments. The labia minora are fashioned from the penile skin, or prepuce, while the labia majora are created using scrotal skin [124]. There are multiple techniques noted in the literature for creation of the neoclitoris. Most use a segment of the glans penis that remains attached to its dorsal nerve and blood vessels, known as the sensate pedicled clitoroplasty technique [124,125,129].

A prosthesis is inserted into the neovagina during surgery to maintain side-to-side junction of the penile skin flap and any other skin grafts used to create the vaginal walls while also maintaining maximum vaginal dimensions. This prosthesis is removed approximately five days after surgery, but regular dilation of the neovagina must be continued for the remainder of the individual's life in order to maintain vaginal depth and width [124]. Dilation techniques and schedules vary, but typically begin at three times daily and are gradually spaced to longer intervals [87]. Some recommend the use of progressively larger dilators to gradually widen and maintain the neovagina [117].

Hospital stays for GCS vary from two to eight days. Because many patients travel long distances to have GCS, there may be an additional stay at a local recovery or guest house for an additional two to six days after discharge from the hospital. Generally, patients are able to ambulate and resume a regular diet on the second postoperative day. Patient-controlled analgesics, antibiotics, compression hose, stool softeners, and anticoagulants may be prescribed [124]. A Foley catheter is inserted prior to surgery and left in place until approximately five to six days following vaginoplasty. Ice packs may be placed over the surgical site for the first 24 hours to reduce edema. Intraoperative venous thromboembolism prophylaxis in the form of subcutaneous heparin and sequential compression devices is essential [114].

The level of discomfort improves daily, and by the time individuals are discharged home, they are often no longer taking pain medication. It is recommended that the patient do no heavy lifting or straining for the first two weeks following surgery, followed by a gradual return to normal activity. Individuals may return to work in four to six weeks [120]. Surgeons generally recommend that sexual intercourse not be attempted for 8 to 12 weeks postoperatively [120,130].

While intraoperative complications are rare, revision surgeries are common, mainly for labiaplasty, clitoroplasty, or correction of urine stream. Surgical competence increases with practice. At the present time, there are few fellowship programs in the United States that teach GCS, such as vaginoplasty, but the number is growing. Research indicates that for optimal outcomes, the surgeon should have performed approximately 50 vaginoplasties [187].

Potential complications of GCS include bladder damage, nerve injury, rectovaginal fistula, urethro-vaginal fistula, urethral stenosis, vaginal stenosis, granulation tissue, and vaginal prolapse [117]. In a retrospective review of 117 patients who underwent penile inversion vaginoplasty, the most common complications were granulation tissue (26%), intravaginal scarring (20%), and prolonged pain (20%) [131]. The majority of patients (90%) were satisfied with the outcomes despite complications.

The main risk of GCS is rectal wall tear resulting in rectovaginal fistula, which is estimated to occur in 1 of 400 vaginoplasties [117]. This complication may develop in the immediate postoperative period or following discharge from the hospital. Symptoms include intestinal distress and intrusion of intestinal fluids, gases, and feces into the vagina. For a small fistula, the only clue may be a brown discharge. If rectovaginal fistula is suspected, a tampon may be inserted into the vagina and an enema of clear water with food coloring administered to determine if the tampon is stained [130]. Some fistulas spontaneously resolve as the neovagina heals. A liquid or low-residue diet will help during the healing process, and dilation and sexual intercourse should be discontinued. If the fistula does not heal spontaneously, surgical repair with skin grafts may be indicated.

Urethral stricture or stenosis is another common complication that usually presents as inability to or difficulty voiding, dysuria, diminished stream, and/or increased time and effort to urinate. If urethral stricture or stenosis occurs following the removal of the Foley catheter, the catheter should be reinserted for an additional two to three days until urethral swelling subsides and the patient is able to void without problem. Rarely, surgical revision may be required [124]. Urethral swelling or irregularities resulting in urine spray generally resolve several weeks following surgery.

The patient should also be monitored for partial or complete flap necrosis, which presents early in the postoperative course as non-blanching erythema or mottling of the skin that becomes progressively darker. If this is suspected, the surgeon should be notified immediately [124].

Vaginal bleeding and/or discharge may be a sign of hypergranulation. This complication can be treated with the application of silver nitrate or Monsel's solution. Some experts recommend treatment with intravaginal estradiol until the issue has been resolved [130].

Vaginal stenosis is often related to a lack of adherence to the vaginal dilation regimen [132]. Conservative treatment is gradual dilation with lidocaine 2% jelly or lidocaine (2.5%)/prilocaine (2.5%) cream to lubricate the dilators. Estradiol vaginal tablets or cream may also be used to soften the tissue [130].

Since the WPATH Standards of Care have been in place, there has been a steady increase in patient satisfaction with the outcome of GCS. The vast majority of follow-up studies have shown an undeniable beneficial effect of GCS on postoperative outcomes such as subjective well-being, cosmesis, and sexual function [71]. A meta-analysis of 32 studies found that positive results were achieved, both aesthetically and functionally, in most cases [125]. One study reported 90% of patients were satisfied with both aesthetic outcomes and orgasmic capability, although only 58% acknowledged sexual intercourse at that time. Orgasmic capability following vaginoplasty ranges from 63% to 92% [124].

Researchers from one facility reported maintenance of sexual sensation in 98.6% and achievement of orgasm (at least occasionally) in 94% of 71 MTF individuals after an average of 4.2 years following vaginoplasty [124]. A separate study reported decreased orgasmic ability but 75% more sex, resulting in high overall sexual satisfaction [124]. Due to the massive reconstruction necessary in vaginoplasty, postoperative orgasms may be more difficult to achieve. In some cases, transdermal testosterone or a phosphodiesterase-5 enzyme inhibitor (e.g., sildenafil, tadalafil, vardenafil) may improve a patient's ability to achieve orgasm [130].

Procedures that maintain attachment of the dorsal portion of the glans penis to the dorsal neurovascular bundle result in lasting neoclitorides and higher levels of sexual satisfaction [125]. Higher risk of sexual dissatisfaction is associated with techniques in which reattachment of the glans onto the dorsal neurovascular bundle was attempted.

An estimated 87% of MTF individuals experience improved psychosocial function following GCS [133]. A study of 247 MTF individuals showed that those who had GCS surgery had higher mental health quality of life ratings than those who did not have surgery. The mental health quality of life in postoperative individuals was not significantly different to that of the general female population [118]. In one study with a small sample of 19 patients who had received GCS (18 MTF, 1 FTM) two to five years previously, the subjects reported improved sexual experience and improved ability to initiate and maintain relationships [134].

An estimated 1% to 2% of individuals who have had GCS regret it; MTF patients with late (adult)-onset gender dysphoria are at the greatest risk for regret [18]. This may be a reflection of difficulties in making the transition to a different gender because of personal appearance or limited social skills. It is imperative for patients with late-onset gender dysphoria who have lived in their natal sex for a long time to understand the importance and impact of actually living as the other sex before undergoing GCS [18].

The costs of GCS range from $7,000 to $30,000 [20]. The estimated cost of GCS surgery (completed in one stage with penile inversion, clitoroplasty, and labiaplasty) plus hospital stay in a Philadelphia, Pennsylvania, transgender center is $19,500. In addition, breast implants are approximately $8,100 and facial and body augmentation surgeries range from $3,500 to $10,600. Due to the high cost of surgery and the paucity of surgeons, many transgender individuals in the United States seek care in Thailand or Canada. In Thailand, the total for all of these procedures can range between $9,000 and $20,000 [20].

The presence of breasts in FTM individuals causes significant gender identity discomfort, and these patients, particularly those who have significant breast development, wear a breast binder daily in order to better pass as male. In many cases, binding is one of the first physical acts in the FTM transition process [135]. Bilateral mastectomy is the most common surgical procedure performed in FTM individuals [121]. Indeed, it may be the only surgical treatment undertaken by some FTM individuals because it greatly increases their ability to pass as a man and greatly improves their psychological and social functioning [136].

There are two basic mastectomy techniques used in FTM surgery, based on the patient's anatomical classification: the periareolar, or "keyhole," approach with or without liposuction, or the double incision method using free nipple grafts. The periareolar technique is used when there is small or moderate breast size with little skin redundancy. For marked breast size with skin redundancy, the inframammary fold double incision technique is used [117].

Mastectomy is an outpatient surgery unless medical conditions require hospitalization, in which case an overnight stay for observation is indicated. The procedure takes two to three hours to perform, depending on the amount of skin and symmetry of the breasts [136].

The patient is discharged home with analgesics and antibiotics as well as a tensor bandage around the chest, which is kept in place for about one month. The compression garment helps to achieve a symmetric outcome. The patient may shower after three days with wound-closing adhesive strips kept in place, patted dry, and left intact until they fall off on their own in seven to 10 days. In some cases, home care nursing may be necessary to empty and monitor surgical site drains, which are removed at a follow-up visit three to seven days after the procedure. To prevent or minimize scarring, topical application of onion extract gel (Mederma), silicone gel (Scar Fade), or silicone sheeting or tape may be useful.

Moderate postoperative edema is normal, as is erythema that does not exceed 1 to 2 cm beyond the incision. It is not uncommon to see or feel the suture knots at the end of the incision, which may be trimmed if they work their way to the skin surface [124]. The patient is generally able to resume normal routines within one to two weeks, but should avoid strenuous activity for three to four weeks [136]. Potential complications following mastectomy include seroma, hematoma, infection, areolar spreading (with the keyhole technique), or nipple hypo/hyperpigmentation (usually temporary) [117].

FTM individuals who received top surgery report a higher quality of life than FTM individuals who have not received surgery [50]. The prices of subcutaneous mastectomies/mammoplasty range from $5,000 to $7,900 in the United States [20].

"Bottom surgery" includes procedures such as hysterectomy, salpingo-oophorectomy, vaginectomy, metoidioplasty/phalloplasty, scrotoplasty, and urethral lengthening. The timing of these procedures varies by surgeon; some perform the hysterectomy and salpingo-oophorectomy in one procedure along with genital reconstruction, while others complete the hysterectomy, salpingo-oophorectomy, vaginectomy, and urethral lengthening in the first session, followed by a separate metoidioplasty or phalloplasty four to six months later [136].

Hysterectomy

Hysterectomy with oophorectomy is generally performed as a total laparoscopic hysterectomy procedure. Vaginal hysterectomy or a laparoscopically assisted vaginal hysterectomy is difficult in transsexual women who have been taking testosterone, as this treatment results in a small, non-compliant, and atrophic vagina [137].

Vaginectomy

Vaginectomy is often performed in combination with metoidioplasty or phalloplasty. It involves removal of the vaginal mucosa, with approximation of the levator ani muscles to obliterate the dead space. The procedure is relatively safe, with few complications (e.g., reopening of the surgical site) [108,117].

Metoidioplasty

In some cases, the clitoris becomes sufficiently hypertrophied after testosterone exposure to serve as a microphallus. Otherwise, a phalloplasty or metoidioplasty may be performed (Table 6). The choice of technique may be restricted by anatomical or surgical considerations or the patient's financial considerations. If a patient wishes to have a phallus of good appearance, the ability to urinate while standing, sexual sensation, and/or coital ability, there are several separate stages of surgery and frequent technical difficulties that may require additional operations. Even metoidioplasty, which in theory is a one-stage procedure for construction of a microphallus, often requires more than one surgical procedure, and the goal of standing micturition with this technique cannot always be ensured [71].

Metoidioplasty involves elongation and reconstruction of the hormonally enlarged clitoris as a small neophallus with erectile function, analogous to penile tissue. During this procedure, the clitoris is released from its surrounding tissue and a flap of skin from the labia minora is wrapped around the clitoris to create a small phallus. The resulting neophallus is sensate. With ring metoidioplasty, a variation of the simple metoidioplasty, the urethra is lengthened using a flap of tissue from the anterior vaginal wall and labia minora to create the urethral extension. This carries urine to the distal end, similar to a natural penis. This procedure is less complex than a phalloplasty, has fewer complications, and has the benefit of providing greater erogenous sensation. However, the resulting neophallus is often not large enough to use for sexual penetration. Using this technique results in an average phallus length of 5.7 cm, with a range of 4–10 cm [136]. Testicular implants may be placed in the labia majora as part of the procedure.

If urethral lengthening is not performed, patients are kept in the hospital overnight. If urethral lengthening is performed, it may require a suprapubic catheter for two to four weeks until the urethra heals. For simple metoidioplasty with testicular implants, recovery time is about three weeks. Ring metoidioplasty and hysterectomy have a six-week recovery period.

Possible complications of metoidioplasty include hematoma, urethral stricture or fistula, urinary incontinence, spraying or dribbling urine (usually due to inflammation), bleeding, flap necrosis, and rarely, infection [108,117]. Other problems that may arise include migration of testicular implants, reopening of a vaginectomy, or hypergranulation along suture lines [108].

Phalloplasty

The goal of phalloplasty is the creation of a neophallus that is aesthetic and has tactile and erogenous sensation, the ability to urinate from a standing position, and the ability to penetrate (with implantation of a penile prosthesis). Ideally, the procedure should result in minimal donor site morbidity and be completed in one to two operative procedures [117]. In phalloplasty, free or pedicled flaps of tissue removed from the radial forearm, myocutaneous latissimus dorsi, osteocutaneous fibula, and/or anterior lateral thigh or groin/abdomen are used to construct a neophallus. A scrotum may be constructed from the labia majora along with implantation of testicular prostheses.

In a pedicled flap, tissue is left attached to the donor site and simply transposed to a new location, keeping the pedicle intact as a conduit to preserve blood supply to the tissue. The advantages of a pedicled flap phalloplasty include decreased operative time, lower failure rates, and more easily concealed donor sites. In the pedicled pubic phalloplasty, the penis is created from a flap of anterior abdominal wall skin (11 cm wide and 12 cm long) that is anchored at the clitoris [138]. The neourethra is fashioned from skin from the labia majora. Both the neourethra and the flap are rolled over an 18 French catheter and anastomosed to the native urethral meatus. The penis created in this manner is sometimes rigid enough for penetrative sexual intercourse without a prosthesis. However, the disadvantages are a less aesthetic appearance and less sensation, making insertion of a penile prosthesis riskier [117].

In a free-flap procedure, the surgeon uses a flap of tissue (usually from the forearm) rolled into a tube to create the urethra, which is then rolled within a larger flap that includes fat and skin to make a "tube within a tube," resulting in an adult-sized phallus that transmits urine. The ulnar side of the forearm is generally used because of the reduced hair growth [136]. Alternatively, a radial artery-based forearm free flap graft may be used to create a urethra [139]. The advantages of a free radial forearm flap include the relative hairlessness of the donor site, the pliability of the flap, increased erogenous sensation, and the ability to do the urethral reconstruction in a single session. The disadvantages are that the donor site cannot be closed primarily and may be difficult to conceal and a rigid prosthesis is usually required for penetration. With the introduction of perforator flaps, the anterolateral thigh flap has begun to replace the radial forearm free flap as first choice. Benefits of the anterolateral thigh flap are a hidden donor area and lack of microsurgical expertise requirement. Possible complications include flap failure, urethral fistula, urethral stricture, and stiffener-related problems [140]. When combined with radial forearm free flap urethral reconstruction, anterolateral thigh flap phalloplasty has been shown to be a feasible alternative for FTM patients who desire a less conspicuous scar [141].

In an attempt to preserve nerve function, and therefore erotic sensation, the pre-existing clitoris is often de-epithelialized and covered by the base of the newly created phallus. The most common complications of this procedure are urologic fistula or stricture. In a survey of 287 patients, virtually all had tactile sensation after one year and 80% reported erogenous sensation. Establishing anatomic and functional stability of the neophallus can take about one year, at which time an erectile prosthesis may be inserted [117].

Various procedures have been developed to provide rigidity for penetration, including insertion of autologous cartilage or bone, rigid implants, or an inflatable prosthesis, but these procedures, and their outcomes, remain problematic [18]. A hydraulic erectile prosthesis is the best option for achieving the possibility of sexual intercourse, though there is a high complication rate due to infection. The life expectancy of this type of implant is about 50% after four years [142].

General surgical risks of phalloplasty include infection, deep vein thrombosis, pulmonary embolism, and death. In a review of 7,905 transgender patients, phalloplasty had the largest rate of complications, mainly from infection and delayed wound healing [121]. Prevention of these complications may be possible with appropriate postoperative interventions, such as sequential compression devices; management of intravenous hydration; turn, cough, and deep breathing; close monitoring of patient status and medication regimen; and ambulation as ordered [136]. The donor site also requires careful assessment. An occlusive dressing is maintained over the donor site for five days, followed by a sheet of gauze that assimilates into the eschar and may be trimmed as it peels up from the edges over the next two weeks. Sensation and function are often impaired in the hand distal to the flap donor site, but this generally resolves within a few weeks. However, approximately 5% of patients require long-term physical therapy to fully recover, so sensation and movement of the donor site should be monitored [136].

A major complication of phalloplasty is partial or complete flap necrosis, which can lead to loss of the neophallus. This often presents early in the postoperative course as a blanching erythema or skin mottling that becomes continually darker. Postoperatively, the phallus is monitored hourly for temperature, color, turgor, pulse, and capillary refill for two days to assure that vascularity is maintained. If signs of necrosis occur, the surgeon should be notified immediately.

Urethral fistulas occur in up to 45% of phalloplasty procedures [124]. This is characterized by urine flow from sites other than the urethral opening. It should be assessed, but urethral fistulas often resolve spontaneously after two to three weeks. They should be kept clean and monitored during this period. Fistulas that do not heal require surgical revision. Urethral stricture presents as a progressive inability to urinate and may be accompanied by fistulas. Both stricture and fistulas commonly occur at the site where the neourethra is anastomosed to the existing urethral meatus. Correction requires dilation under anesthesia, and if this is unsuccessful, surgical revision will be necessary.

After hospital discharge, the patient is usually seen in the office in five to seven days, at which time the catheter is removed and antibiotics may be discontinued if healing is adequate [136]. It is also important to inspect the phallus and scrotum (if scrotoplasty was done simultaneously), as well as the skin and vein graft sites.

Scrotoplasty

Scrotoplasty is the surgical creation of a scrotum. This procedure is considered very important to many FTM individuals; a survey of 200 FTM individuals undergoing GCS found that 96% desired scrotoplasty, compared with 52% who desired phalloplasty [124]. This procedure is accomplished by hollowing out the labia majora to create the scrotal space and inserting testicular implants. Risks specific to scrotoplasty, while rare, include implant ejection, rupture, and migration or dislocation, which may require surgical removal and replacement later on [108,124]. Some surgeons will perform scrotoplasty simultaneously with metoidioplasty or phalloplasty, while others prefer to do the scrotoplasty in a separate procedure, using tissue expanders for three to six months to create space for the testicular prostheses. The incision site should be monitored for increased drainage, visible extrusion of testicular prostheses or erectile prosthesis, and inflammation or changes in the size and shape of the scrotum.

Annual breast exam, including mammogram, is indicated in MTF women who are older than 50 years of age who have been taking estrogen for five or more years [57]. While this is recommended as a screening protocol, the actual risk is likely no different than in natal males. In a series of 2,200 MTF individuals studied between 1975 and 2005, there were no cases of breast cancer reported [99].

When breast cancer does occur among MTF individuals, the onset of symptoms (usually a palpable mass) occurs earlier than in natal females, at an average age of 51 years [146]. The most common type of cancer in this population is adenocarcinoma, accounting for 59% of all reported cases. There is no evidence to suggest that estrogen administration results in an increase in breast cancer. Given an earlier age at presentation, consideration should be given to starting breast cancer screening before 45 years of age. In addition, breast implant-associated anaplastic large-cell lymphoma is a concern for MTF individuals who have had breast implants. Clinicians should have a high degree of suspicion when these patients present with late periprosthetic fluid collection [146].

Prostate examinations should be performed as part of an annual physical examination [57]. The prostate gland is not removed in GCS; however, because the patient has likely been on estrogen, the prostate is generally atrophied. The risk of prostate cancer is small, as estrogen inhibits the effect of testosterone. There has been a case report of benign prostatic hyperplasia in an MTF individual 25 years after GCS and continuous estrogen therapy. The patient required transurethral resection of the prostate gland due to obstruction of urinary flow [147]. The authors hypothesize that mutations of androgen receptors on the prostate can cause the receptors to work "normally" even in the absence of androgens. As such, performing a transvaginal digital prostate exam on an MTF individual may be of value [148].

Opinion varies regarding the need for Pap testing in postoperative MTF individuals. On one hand, there is no possibility of cervical dysplasia. However, the penile skin that lines the vagina can show the same cytologic findings as biological females. Cytologic samples from postoperative MTF individuals have shown a greater incidence of inflammation than in natal women, and only about 4% of MTF individuals have identical cytology to natal women [149]. Because the glans penis is used to create a clitoris, a Pap test of this area may be used to screen for squamous cell carcinoma. While cancer of the glans penis is rare, the glans is more prone to cancerous changes than the skin of the penile shaft, and intraepithelial neoplasia of the glans is more likely to progress to invasive carcinoma than is intraepithelial neoplasia of other penile skin [57]. It is theorized, though not proven, that the incidence of HPV in postoperative MTF individuals is similar to that of men [148].

While 43% of cisgender women in the United States have had a Pap test in the past year, only 27% of FTM individuals have done so [146]. FTM individuals are uniquely vulnerable to cervical cancer because of undetected HPV infection, lower rates of routine health screenings, discrimination and refusal of services in healthcare settings, and increased rates of smoking [146]. It may be difficult to get a good sample, as the cervix will be atrophic; intravaginal estrogen cream can be used a few days prior to the Pap test to improve results. FTM individuals who have been on testosterone will also experience a shift in the vaginal microbiome from majority Lactobacillus to a more diverse flora, such as Atopobium, Prevotella, Peptostreptococcus, Sneathia, and Finegoldia, bacteria that are associated with bacterial vaginosis [188]. While this can be improved with the administration of intravaginal estrogen, some FTM individuals object to receiving any medication containing estrogen.

Bone health should be monitored in MTF individuals according to guidelines for female patients. However, the risk of osteoporosis is low, particularly if the individual has been maintained on estrogen supplementation.

Postoperative MTF patients may present with symptoms of vaginitis, with or without malodorous discharge. In a study of postoperative MTF individuals, there was a higher incidence in inflammation in the neovaginas than in the vaginas of cisgender women, probably due to the fact that penile skin is normally ectopically located [150]. Screening for bacterial vaginosis in MTF patients is complicated by the fact that the microflora of the neovagina includes mixed species of gram-negative and gram-positive bacteria normally found either on the skin, in the intestinal microflora, or in a bacterial vaginosis microflora. Also, the mean vaginal pH of the neovagina is 5.8, as opposed to the more acidic microflora of the biologic vagina, which is 3.8 to 4.5 [150].

Postoperative MTF individuals who are sexually active with men may experience a build-up of sebum, lubricant, semen, and sometimes granulation tissue in the neovagina, resulting in a malodorous vaginal discharge. If present, treatment consists of metronidazole and fluconazole and douching with plain water [130].

Aging postoperative MTF patients may have increased risk for genitourinary complications caused by the compounded effects of aging and postsurgical complications [30]. Complaints of frequency, hesitancy, urgency, and dysuria should be followed up as with other patients, keeping in mind that the complaints could be prostate-related.

It is recommended that MTF transgender patients receiving estrogen therapy have an annual prolactin level assessment and visual field examination to screen for prolactinoma [57]. Prolactinoma is the result of a benign adenoma of the pituitary gland and results in hyperprolactinemia, hypopituitarism, headaches, and bilateral loss of vision.

Among FTM individuals who have not had a mastectomy, the risk of breast cancer is likely similar to cisgender females. Those who have had mastectomy seem to have a lower risk of breast cancer, possibly due to GCS, but this is based on limited research [151]. Excess exogenous testosterone can be converted to estrogen, which has been linked to breast cancer [152]. As such, regular examination of remaining breast tissue is indicated. Although a mastectomy may have been performed, the axillary lymph nodes should be examined for enlargement. If a mastectomy has not been performed, annual mammograms are recommended.

The pelvic exam may be a traumatic and anxiety inducing procedure for transgender men and other trans-masculine persons. Transgender men are less likely to be up to date on cervical cancer screenings and have a higher rate of inadequate cytologic sampling. Should the individual express distress or concern about the examination, it may be deferred until a later date once a trusting relationship has been developed.

(https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf Last Accessed: July 26, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

For patients using androgen therapy who have not had a complete hysterectomy, there may be an increased risk of endometrial and ovarian cancer [57]. Therefore, a regular Pap test is indicated. It is important to be sensitive when performing a pelvic exam on a transsexual man. As noted, FTM individuals often experience emotional and psychological distress with pap testing due to gender dissonance. This may be given as a reason for avoiding gynecologic examinations altogether [146]. It may be difficult to get a good sample, as the cervix will be atrophic; intravaginal estrogen cream can be used a few days prior to the Pap test to improve results.

Other interventions to consider are the use of a pediatric or long, narrow speculum; use of non-interfering lubricant on the speculum; application of topical lidocaine to the vaginal introitus; and informing FTM individuals of the likelihood of Pap test results being unsatisfactory [153,154]. In some cases, providers may consider the use of sedative-hypnotics (e.g., benzodiazepines) prior to testing [154].

Aging FTM patients may have an increased risk of cardiovascular disease and diabetes due to the effects of long-term testosterone and should be screened accordingly [30]. A small amount of research indicates that FTM individuals on long-term testosterone therapy do not have an increased risk of low bone mass [155]. Part of testosterone is converted to estradiol at levels that will support bone mineral density [99]. Dual-energy x-ray absorptiometry screening is suggested for FTM individuals older than 65 years of age, or after 50 years of age if not on testosterone [156].