Medical Support for the Families of Intergender and Transgender Children and Youth

Explain things as clearly and simply as possible about the medical condition to the family. Medical checkups regarding the condition are not needed unless there is medical problem. Discuss the possibilities of social and legal gender assignment and medical treatment with hormones and surgery in the framework of family therapy with a gender specialist team approach. Include referrals to community gender support groups for the child and family, so that they know they are not alone, and for them to network for resources and learn from the experiences of others. It is a good thing for them to meet adults with the condition who can reassure them. You are the advocate and resource to help the family with schools, the government, insurers and the community for the well-being of the child.

GnRH Agonists

In both sexes, the hypothalamus releases GnRH (Gonadotropin Releasing Hormone) to stimulate the pituitary to produce LH (luteinizing hormone) and FSH (follicle stimulating hormone,) which in turn signal the gonads to produce sex steroids. In transgender adolescents of either sex, GnRH agonists may be considered to delay puberty which will make subsequent therapy in adulthood more effective. GnRH agonists initially over-stimulate the pituitary then rapidly desensitize it to the effects of GnRH. Over a period of weeks, gonadal steroid production is greatly reduced. The most significant problems with this therapy are the very high cost, and a risk of local reactions to injected forms (occasionally severe.) An additional benefit for transgender boys treated for years with GnRH agonists may be the potential for a modest (about 1cm/year of treatment) increase in final adult height. However, in studies of children treated with GnRH agonists to induce growth, a delay in puberty may be associated with impaired bone development which may predispose to later osteoporosis.

The cost for treating a pubertal transgender child from age fourteen to eighteen would be approximately $14,000. However, some physicians are beginning to advocate treatment of very select adolescents with cross gender hormonal therapy at an earlier age. This early cross gender hormonal therapy would, in the case of transgender adolescents, be significantly less expensive than GnRH agonists. In addition, it would allow transgender adolescents to experience a more normal puberty appropriate to their gender identity.

FTM Hormone Therapy

Androgens

Both androgens and estrogens are required (in differing amounts) in both males and females for optimal health. At low doses, testosterone is increasingly used to improve sexual function, muscle and bone mass, and energy levels in post-menopausal women. This is especially the case in those who may have a relative deficiency of androgens such as after bilateral oophorectomy or adrenal failure. Testosterone replacement therapy may be used for primary or secondary hypogonadal disorders, for example: eunuchoidism, endocrine impotence, osteoporosis due to androgen deficiency, rise of plasma concentrations of testosterone, dihydrotestosterone and androstenedione, as well as a decrease of SHBG (sex hormone binding globulin). In males with primary hypergonadotropic hypogonadism, treatment results in a normalization of gonadotropin levels.

The majority of androgen in blood is bound to protein, chiefly Sex Hormone Binding Globulin (SHBG) with the remainder bound primarily to albumin. Only 1-2% is unbound, ‘free’ androgen. Androgen bound to SHBG is neither bioavailable nor vulnerable to metabolism. In individuals with lower levels of SHBG more free androgen is bioavailable however, metabolism and destruction occur more rapidly. Normally, women have about twice the circulating levels of SHBG that men do. SHBG is increased by: estrogen (especially oral estrogens) and thyroid hormone. SHBG is decreased by: obesity, testosterone, high levels of growth hormone, high levels of insulin, and high levels of glucocorticoids. Additionally the binding of testosterone to SHBG varies between individuals. So two patients with similar SHBG and total serum androgen levels might have very different relative androgen effects at the tissue level. DHT is 5-10 times more potent than testosterone. In women, DHT is more highly protein bound, with only 0.5% existing as free DHT. Testosterone is more bioavailable however, with approximately 1.4% unbound. The varied actions of androgens in different tissues are not the result of distinct androgen receptors but because of different levels of activity of Aromatase and 5-?-Reductase and therefore different relative levels of testosterone, DHT, and estrogens.

Physiologically active testosterone is sometimes roughly estimated by the free androgen index (FAI). FAI is the ratio of total testosterone to SHBG. FAI = 100 x Total Testosterone(nmol/L) / SHBG(nmol/L). However, in transgender men the FAI may not be as accurate or have values comparable to cisgender men. Moreover, the FAI even if accurately measured may not correlate well with end-organ effects due to the local steroid hormone metabolism that occurs in many tissues as well as the variable binding of testosterone to SHBG.

Normal FAI values are age and gender specific: Male: • 20-29 years: 30-128 • 30-39 years: 24-122 • 40-49 years: 14-126 • Older than 49 years: 18-82 Females aged 20-49 years: 0.4-8.4. Females older than 49 years: 0.4-6.6

Readiness for Hormonal Therapy

Transgender patients have been expected to complete either a three month 'Real Life Experience' (RLE) or period of psychotherapy before hormones are provided. However, for patients who must pay for their own care, the cost of three months or more of psychotherapy may be prohibitive. In addition, for many transgender people, a RLE experience before treatment may place some patients at significant risk of violence and even death if they are discovered to be transgender. It may in fact, represent a violation of the medical ethics principle of non-malfeasance to require some patients to fulfill a three month RLE as a condition of receiving hormonal therapy. Moreover, as providers who advocate the harm reduction model are aware, often the provision of hormones represents the least harmful and potentially most helpful way to address patients' concerns.

Patients should be evaluated with respect to readiness for therapy, presence of other coexisting mental health problems, and understanding of treatment. We would certainly not advise evaluation by a novice primary care provider for a nineteen year old patient with coexisting untreated significant mental health problems, an unstable home life, and whose decision to transition was made in the past month. However, an experienced provider presented with an otherwise stable and mature patient who has a durable male gender identity could likely make the determination with confidence that such a patient is an appropriate candidate for hormonal therapy.

Androgen Therapy – Contraindications

Absolute Medical Contraindication in Transgender Men • Pregnancy or breast feeding. • Uncontrolled coronary artery disease. • Active endometrial cancer.

Androgen Therapy Overview

The half-life of testosterone in blood is approximately 70 minutes, so it is necessary to deliver a continuous supply of the hormone for masculinization. Dosage must be individualized and may be lower in post-oophorectomy patients. Decisions regarding the best method for testosterone therapy should be individualized with regard to patient preference, likelihood of compliance, cost, and safety. Testosterone formulations in the US are DEA controlled (schedule 3) primarily due to the risk of diversion and abuse by athletes. All formulations are pregnancy category X. Prices are estimated based on retail pharmaceutical sales. Some compounding pharmacists are able to make testosterone (including depot, transdermal, and pellet formulations) for a substantially lower cost. The International Academy of Compounding Pharmacists (IACP) (http://www.iacprx.org/index.html) has a referral service for providers or patients searching for local compounding pharmacists.

Types of Therapy

Injected

The two commonly used injected testosterone esters in the US are testosterone cypionate (Depo-Testosterone®) and testosterone enanthate (Delatestryl®) and cost approximately $100-125 for a 10 cc (2000mg) vial. Depending on dosing a vial may last from 3-10 months. Unpleasant fluctuations in mood, energy, and sexual function may be ameliorated by dosing 100 mg weekly rather than 200 mg every two weeks. Injected testosterone is started at a range of doses (25 – 125 mg/week) and titrated upwards based on clinical effects and trough levels. After several cycles, trough level around the mid-normal eugonadal range for men of 500 ng/dl is sought. (Normal range for a biological male is 290 to 900 ng/dl.) However, clinical effects not specific lab values are the target of therapy. If a transgender man achieves cessation of menses and satisfactory masculinization at relatively low serum levels, titration upwards to reach 500 ng/dl or higher is unwarranted. With any self-administered parenteral therapy, proper technique is essential. It is imperative for the provider to either teach this skill herself, or arrange for patient instruction to avoid preventable complications such as infection, nerve injury, pain, and inadvertent intravenous injection. The dorsogluteal, ventrogluteal, or anterolateral thigh are the preferred locations as each readily accommodates 1-4ml injections. Patients should be taught the air bubble method to decrease seepage.

Testosterone cypionate Depo-Testosterone Injection, solution Pharmacia Limited DEPO-TESTOSTERONE is a slightly yellow viscous solution available in vials containing 100mg/ml testosterone cypionate injection, USP.

Testosterone enanthate Primoteston Depot Injection, solution Schering (NZ) Limited 1 ml PRIMOTESTON DEPOT 250 mg contains 250 mg testosterone enanthate (the equivalent of about 180 mg testosterone) in clear, oily solution.

Testosterone decanoate Sustanon Orgaject Injection, solution Pharmaco (NZ) Ltd Each ml of the solution contains: testosterone proprionate 30mg testosterone phenylpropionate 60mg testosterone isocaproate 60mg testosterone decanoate 100mg in 1ml arachis oil

Testosterone isocaproate Sustanon Orgaject Injection, solution Pharmaco (NZ) Ltd Each ml of the solution contains: testosterone proprionate 30mg testosterone phenylpropionate 60mg testosterone isocaproate 60mg testosterone decanoate 100mg in 1ml arachis oil

Testosterone phenylpropionate Sustanon Orgaject Injection, solution Pharmaco (NZ) Ltd Each ml of the solution contains: testosterone proprionate 30mg testosterone phenylpropionate 60mg testosterone isocaproate 60mg testosterone decanoate 100mg in 1ml arachis oil

Testosterone propionate Sustanon Orgaject Injection, solution Pharmaco (NZ) Ltd Each ml of the solution contains: testosterone proprionate 30mg testosterone phenylpropionate 60mg testosterone isocaproate 60mg testosterone decanoate 100mg in 1ml arachis oil

Transdermal

Both testosterone patches and gel are available. Both approximate normal physiological levels of testosterone better than the higher peaks and troughs associated with injection of testosterone esters. Both can cause local skin irritation, however the effect is much more pronounced with patches (about 2/3 of patients) due to substances that increase transdermal absorption, than with gel (about 1/20.) Both also have a risk of inadvertent exposure to others who come in contact with the patient's skin. This transfer is completely eliminated by covering the application area with a tee-shirt.

Delivered doses of both patches and gel are generally in the range of 5-10 mg/day. Testosterone gel is absorbed quickly when it is applied and produces a temporary drug depot in the skin which diffuses into the circulation, peaking at 4 hours and decreasing slowly over the rest of the day. A steady state is reached within days. Cost is about $160-210/month in the US. Typical dose is 2.5-10g of 1% gel applied daily but must be individualized for each patient. Each gram of the 1% gel contains 10mg of testosterone, of which only 9-14% is absorbed. So if 5 g of gel is applied daily, 9-14% of the 50mg (4.5-7mg) should be systemically available. Two commercial formulations are available in the US AndroGel® and Testim®. Patches (2.5 and 5mg size) slowly diffuse testosterone through skin and are replaced daily. Cost is about $120-200/month in the US. Dosages range from 2.5-7.5mg daily. Because of skin irritation, rotation of sites is important. A small open label study demonstrated that skin irritation can be alleviated by applying a tiny amount of 0.1% triamcinolone cream onto the site prior to application.

Subcutaneous Implants

Testosterone pellets were one of the first effective forms of testosterone replacement in men in the 1930s. Multiple pellets are inserted under the skin with a trocar every three to six months. This must be done in a physicians office, but is a relatively minor procedure done under local anesthetic. The only brand name pellet available in the US is Testopel® (75mg) which cost $15-20 each. The trocar kit sold by the manufacturer (Bartor) costs approximately $150. Other pellet formulations are available in the US through some compounding pharmacies and pellets as large as 200 mg are often used. Three to six 200mg pellets (600-1200mg) should provide physiologic testosterone levels for approximately four to six months, with each 100mg of pellet inserted delivering approximately 0.65mg of testosterone daily. Total cost to patients may be greater than injected testosterone when the cost of the physician visit, supplies, and procedure are included but may be less than or comparable with transdermal. The primary advantages of pellets are that they give a much more constant blood level of testosterone than injections yet require attention at most four times yearly. Each insertion is associated with a transient peak of testosterone lasting 1-2 days. However this does not exceed the peak associated with each injection of bimonthly testosterone esters. This procedure is performed by some gynecologists (the pellets are inserted in the same manner as estradiol pellets.) Providers unfamiliar with the procedure may wish to refer patients to a gynecologist who is familiar with it.

Testosterone Testosterone Implant, subcutaneous Organon Laboratories Ltd A white to pale yellow, opaque or translucent cylinder in a sealed glass tube, secured by a white, wool plug, and containing 100mg of testosterone B.P. Diameter 4.5mm. TESTOSTERONE IMPLANTS, when inserted subcutaneously, provide a slow release of the natural androgenic hormone, testosterone. They can be used in conditions requiring a uniform and sustained androgenic activity. After a gradual rise of serum testosterone levels in the first few weeks physiological levels are maintained for 4-5 months. A dosage of 600mg (6 x 100mg) usually maintains plasma testosterone levels within the normal physiological range for 4-5 months.

Oral

The safest of the oral formulations is Andriol® (testosterone undecanoate.) Unfortunately, testosterone undecanoate is not currently available in the US, but is licensed in Canada and Europe. Serum levels of testosterone are ten times higher when testosterone undecanoate is taken with fatty food. In addition to lower testosterone blood levels, relatively higher DHT levels are often found with testosterone undecanoate. Typical dose for testosterone undecanoate is 160-240 mg daily divided bid-qid.

Testosterone undecanoate Panteston Capsule, liquid filled NV Organon HDPE bottles containing 60 capsules.40mg capsules: glossy, oval, soft gelatin capsule, reddish-brown in colour, coded DV/3 and ORG in white, and containing 40mg testosterone undecanoate. Dimensions about 11mm in length and about 8mm in diameter.

Testosterone undecanoate Panteston Testocaps Capsule, liquid filled NV Organon A box of PANTESTON TESTOCAPS contains either 3, 6 or 12 sachets, each containing a blister with 10 capsules. PANTESTON TESTOCAPS must be taken with a meal, with some fluid and swallowed whole without chewing. It is preferable that half of the daily dose be taken in the morning and the other half in the evening. If an uneven number of capsules is to be taken, the larger dose should be taken in the morning. 40mg capsules: soft, oval (No. 6), glossy capsule, transparent, orange in colour, with a yellow, oily fill, coded DV/3 in white. Each capsule contains 40mg testosterone undecanoate dissolved in a mixture of castor oil and propylene glycol laurate.

Sublingual/Buccal

In 2003 the FDA approved a buccal form of testosterone (Striant®.) Sublingual testosterone can also be made by some compounding pharmacies. Price for Striant® is slightly higher than transdermal testosterone ($180-210/month.) Striant® lozenges can cause gum irritation, taste changes, or headache. However the majority of side effects diminish after two weeks. The lozenge is 'mucoadhesive' and will soften but not dissolve completely. It must be removed from the mucosa when the next lozenge is applied. Levels of testosterone peak within hours and remain in the eugonadal range achieving a steady state within 24 hours with consistent twice daily dosing. Serum testosterone levels are reported above the lower limit of normal for males approximately 80-100% of the time with Striant®. Total testosterone delivered is comparable with or greater than transdermal testosterone. However dosage titration is not possible with Striant® (available in a single 30 mg dose) for transmen who may require more or less testosterone.

Approximate Cost Comparison

This is based on non-compounded prices. Compounded formulations may well be substantially less. The cost for Testopel® is based on the manufacturers information and does not include physician procedure fees.

Formulation Dose Approximate Monthly Cost (USD) Striant® 60mg/day 180-210 Androgel® 5mg/day 160-210 Androderm® 5mg/day 120-200 Testopel® 5 pellets plus trocar kit q3months 80-90 Injected Enanthate 100mg/wk 35-50 Injected Cypionate 100mg/wk 25-35 Testim® 5mg/day 160-210

Non-Testosterone Hormonal Therapy

Depo-Provera®

Generally after the first cycle, menses are greatly reduced or eliminated. This may be useful for transgender men prior to initiation of testosterone therapy to reduce or eliminate vaginal bleeding which may be a source of distress for some transmen. Depo-Provera® is relatively inexpensive, readily available, and also prevents unintended pregnancy in sexually active bisexual and homosexual transmen. In November 2004 however, the FDA issued a black box warning for Depo-Provera which states that prolonged use can result in decreased bone density. The FDA warning states that a woman should use Depo-Provera® long term (greater than 2 years) only if no other birth control methods are adequate. Physicians and patients must weigh the risks and benefits of this treatment, however short term use may be reasonable as a temporizing measure until full hormonal transition is begun.

Andro ‘Pro-hormones’

These drugs are available in the US without a prescription as 'dietary supplements.' Androstenedione, 4-androstenediol, 5-androstenediol, 19-androstenediol, and 19-norandrostenediol cause elevated estrogen levels with predominantly estrogenic effects. Provision of appropriate and medically monitored therapy may decrease patients’ use of these alternatives which are of questionable safety and efficacy.

Risks of Non-Provision of Hormonal Therapy to Transgender Patients

Transsexual patients who present for treatment are almost universally highly motivated and often anxious to pursue medical and surgical sexual reassignment. Occasionally he may have already begun non-medically supervised hormonal therapy with its increased risks. Providers must consider the adverse consequences of denying access to medically supervised hormonal therapy.

Patients unable to access medically supervised therapy may use 'dietary supplements,' buy hormones on the street, and may share prescriptions for hormones as well as needles for injection. The risks of blood borne infections can be substantial in some transgender populations. Moreover, in addition to the purely medical risks of unsupervised hormonal therapy, non-treatment of transgender patients can result in significantly worse psychological outcomes. Suicide rates are significantly lower in treated transgender patients than in non-treated. Untreated transsexual patients have suicide rates as high as 20% while treated transmen have suicide rates of less than 1%. Transgender patients, by virtue of their gender identity are also at significant risk for harassment and hate-related violence. Trans men report a decrease in dangers of interpersonal harassment and violence when they transition as the effects of testosterone make them more readily able to 'pass' in society.

Another concern sometimes expressed by providers as a reason for hesitating to provide hormonal therapy is the possibility that patients will be unhappy with the results of sexual reassignment and will regret having undertaken such treatment. However in actual practice, the vast majority of patients are satisfied with therapy and true regrets are quite rare.

In summary, providers should realize that while there may be some risks for patients who undertake hormonal reassignment, there are probably far greater risks associated with non-provision of such care. While the dictum primum non nocere is important, it is crucial to consider the entire quote from Hippocrates' Epidemics: “As to diseases, make a habit of two things - to help, or at least do no harm.”

Therefor the personal feelings of reticence individual providers may have toward prescribing cross gender hormonal therapy as 'altering' a normal healthy body should be examined. For a trans man, a female body is neither normal nor healthy and failure to address this may have disastrous consequences for the patient. No provider would hesitate to offer a largely safe and effective treatment that decreases the relative risk of a life threatening outcome by 2000%! Yet providers do hesitate to offer androgen therapy to transsexual male patients despite a decrease in sucidality from approximately 20% to less than 1%. (Absolute risk reduction ~ 20%, relative risk reduction ~ 2000%.)

Informed Consent

The following is an example of an informed consent form that might be utilized to start this discussion with patients.

Patient Informed Consent Information

Testosterone treatment will cause some permanent and many reversible changes in your body.

Permanent Changes

These will not go away if you stop taking testosterone

Will Happen: • Increased facial and body hair. Not just on your face, chest and stomach. You may also get hairs on your back, buttocks, and even in your ears. • Deepened voice. • Clitoromegaly (enlargement of the clitoris to an average of 4-5 cm after 1-3 years).

May Happen: • If you have not finished puberty, you might have a growth spurt and closure of growth plates. • Male pattern baldness (may be partially treatable with certain medicines.) • Changes in your ovaries that may make it difficult or impossible for you to produce eggs or get pregnant even if you stop taking testosterone. • Possible but uncertain increases in risks of ovarian or uterine cancer. • Changes in your uterus (like fibroids) or ovaries (like cysts) that may make hysterectomy (removal of uterus) and oophorectomy (removal of ovaries) more difficult if you eventually choose to have these surgeries. • Possible but uncertain increase risk of developing osteoporosis (thinning and weakening of bones) that may become worse after oophorectomy or if you stop taking testosterone.

Reversible Changes

These occur with testosterone treatment but generally will go away if you stop taking testosterone • Increased libido (sex drive). • Increased muscle mass (especially upper body strength) • Redistribution of fat to a more typical male pattern (to the stomach instead of the hips and thighs) • Interference with other medications that you may take. • Increased sweat and changes in body odor. • Increased appetite, weight gain, and fluid retention. • Prominence of veins and coarser skin. • Acne of the face, back, and chest, especially in the first few years of treatment • Emotional changes • Worsening of blood cholesterol levels which might increase your risks of heart attacks and strokes. • Increase in red blood cell count • Stopping menstruation (periods) This may take several months or may be immediate. • Vaginal dryness • Worsening of or increased chance of getting certain diseases. If you think you have or are developing these diseases, it is important to tell your doctor. They can be treated and having them doesn't necessarily mean you have to stop taking testosterone. • Type 2 diabetes • Liver disease • High blood pressure • High cholesterol • Heart disease • Migraine headaches • Sleep apnea • Epilepsy (seizures)

Consent

I have read and understand the above risks and benefits of testosterone therapy.

I understand that taking testosterone does not make me immune to, and in fact may possibly increase my risk to develop certain gynecological problems including cancer. I understand that even if I have a hysterectomy (removal of the uterus) and oophorectomy (removal of the ovaries) I must still continue yearly gynecological exams and screenings.

I have discussed with my provider options for retaining my fertility. I understand that being transgender does not necessarily preclude future reproduction and/or parenting. However I understand that pursuing hormonal therapy may make it more difficult or even impossible for me to have a genetic offspring in the future.

I understand that fertility (ability to become pregnant) will not immediately cease when I start testosterone. I understand that it is imperative that I must use a barrier method until my periods stop for at least two months. I understand this is because testosterone can cause major birth defects if I become pregnant while taking it.

I understand that testosterone is a DEA controlled substance and that it is illegal to share these medicines to other people. I also understand that sharing needles with anyone can place me at risk for blood borne diseases.

Signed _______________________________________

Printed Name _______________________________________

Date _______________________________________

Witness _______________________________________

Printed Name _______________________________________

Date _______________________________________

Health Maintenance for Transgender Men

It is important for providers to be aware that their patients frequently pay for part or all of their transgender related care out of pocket either because they lack insurance or their insurance plan refuses to pay for transgender related care. Providers should be sensitive to this when deciding what tests patients should undergo. Providers may be called upon to advocate for patients with regard to insurance reimbursement if patients request this. Medi-Cal (the California Medicaid program) now pays for transgender related care. In addition, recently a large US insurance provider (Aetna) concluded that the scientific evidence supported the medical necessity and safety of transgender related care and has changed their corporate policy of excluding transgender related care from all insurance policies.

Initial visit: Generally a clinical evaluation only - complete history (includes assessment of prior hormone use especially non-medically supervised treatment) and physical (particular attention should be paid to diagnosis of polycystic ovarian syndrome (PCOS), as this disorder is much more prevalent in transgender men.). Labs only if indicated based on history and physical (including assessment of pregnancy risk.) Gynecologic referral if no evaluation in the past year. Mental health referral if indicated. Informed Consent. Start on dose of 100-150 mg every two weeks.

1-2 months: Telephone or if necessary, in person follow-up. If no significant adverse effects, consider increasing dose to 150-200 mg every two weeks. If significant side effects occur consider increasing frequency and lowering dose while maintaining same total administered amount of testosterone. We suggest 50-75 mg per week instead of 100-150 mg every two weeks and plan to reevaluate the patient after 4 weeks on his new dose.

2-3 months: Clinical reevaluation – directed history and physical. ALT, fasting glucose, lipid profile, CBC. Consider titrating dose (generally with an ultimate goal of 100mg per week in most transmen.)

3 months after stable and effective dose achieved (generally 5-6 months after initiating therapy): Clinical reevaluation – directed history and physical. Trough testosterone level, sometimes LH level, ALT, fasting glucose, CBC, and if indicated by other risk factors – serum lipids.

Yearly thereafter: Clinical reevaluation – screening history and physical with special attention to systems affected by testosterone. ALT, fasting glucose, CBC, if indicated by other risk factors – serum lipids.

Yearly thereafter: Gynecologic evaluation or referral.

Every 1-3 years thereafter: Bone Density DEXA (Dual Energy X-ray Absorptiometry) scan within two years after oophorectomy and if indicated by prior results or by assessing risk factors.

Testosterone Effects

Cardiovascular

Transgender men have a much higher incidence of Polycystic Ovarian Syndrome and the resultant pre-existing androgenization. PCOS in turn has a much higher incidence of hypertension, glucose intolerance, and dyslipidemia. The most important modifiable risk factor for many transmen is tobacco abuse. Other modifiable risk factors include: diet, exercise, and control of hypertension, hypercholesterolemia, and diabetes.

Integument

Hair

Thinning of scalp hair is related to duration of testosterone therapy and is present in approximately fifty percent of transmen after thirteen years on hormonal therapy. Propecia® (finasteride) is a Type-II 5-?-Reductase inhibitor that works by blocking the conversion of testosterone to DHT. Males with congenital deficiency of Type-II 5-?-Reductase have little or no beard growth and do not develop MPB. Inhibiting the enzyme in transmen would therefor be expected to both decrease hair loss in the scalp and slow or stop facial hair growth (although growth that has occurred should not regress.) It is important to discuss this effect with patients as they may begin to develop MPB prior to achieving the quantity of facial hair they desire. Alternatively, topical minoxidil might be used while awaiting sufficient beard growth. Finasteride is sold as 5mg tablets as Proscar® for prostatic hypertrophy for $2.40/pill in the US (or $0.60/day if quartered to take approximately 1.25 mg daily.) As Propecia® it is $1.60/1 mg tablet ($1.60/day to take 1mg daily.) Rogaine® (Minoxidil – available without prescription) is sold as 2% and 5% solutions. 1 cc is applied twice daily to the scalp (predominantly in the areas where hair loss is greatest.) It may take several months to show effects and may cause a slight paradoxical worsening of hair loss initially (which does eventually recover.)

Skin

Acne is the most frequently reported negative side effect of hormone therapy, followed by weight gain, and should be anticipated and treated.

Gynecological Effects

Menses

Menses cease due to anovulation caused by the suppression of the hypothalamic-pituitary axis by testosterone. If doubt exists whether continued bleeding is due to insufficient testosterone dose versus pathological bleeding, testosterone levels, endometrial biopsy, and LH levels may clarify the cause. Occasionally, especially in patients with lower serum testosterone levels, the addition of a progestin such as medroxyprogesterone acetate 5 to 10 mg may be required to induce complete cessation of menses.

Clitoral Development

Clitoromegaly occurs and reaches its apex within 1-3 years of therapy. Sizes range from 3-7 cm with 4-5 cm being about average. In a minority this may be sufficient to engage in penetrative intercourse with a partner. Topical clitoral testosterone cream as an adjunct to growth before anecdotally it seems to be effective for some patients. Increased clitoral sensitivity and responsiveness to stimulation is expected. Occasionally transgender men, especially in the initial phases of testosterone therapy, have reported discomfort.

Ovarian Effects

After long-term androgen therapy, ovaries may develop PCOS (Polycystic Ovarian Syndrome) morphology. PCOS is associated with an increased risk of endometrial cancer. In addition to any effects of exogenous testosterone, a significant proportion of transgender men may have hirsutism and menstrual irregularities prior to initiation of testosterone therapy and as many as half of these men may have pre-existing PCOS. This contrasts with an incidence of approximately 6% in the general adult female population. However, interestingly, self-identified lesbians also have higher rates of PCOS that are intermediate between heterosexual women and pre-treatment transgender men. Another advantage of oophorectomy is that testosterone dose can then frequently be decreased, often by as much as 50%. It is generally not necessary to add-back estrogen after oophorectomy because like cisgender men, transgender men should produce some estrogen by aromatizing testosterone. In those transmen with congenital predisposition to ovarian cancer, this may be used as a justification to encourage insurers to cover the costs of surgery.

Endometrial Effects

Endometrial cancer is known to have a three times greater risk in patients with PCOS. A high prevalence of endometrial hyperplasia has been noted in a small study of transgender men undergoing hysterectomy. Trans men with any bleeding after the cessation of menses with adequate uninterrupted androgen therapy must have an endometrial biopsy (and generally an ultrasound) done to rule-out endometrial cancer. Like post-menopausal women, any bleeding in transmen on continuous testosterone therapy who have previously ceased menstruation should be considered cancerous until proved otherwise. While malignancy is not the only cause of such bleeding, it must be ruled-out. A transgender man with endometrium that is not thinned on ultrasound may require progesterone to cause sloughing of the endometrium. Vaginal bleeding from progesterone may be unpleasant for a trans man, but the timing of such progesterone induced bleeding can however be discussed with the patient so that it can be planned for a time when it is least disruptive for him.

Cervical Screening

It goes without saying that any patient with a uterus/cervix should ideally have yearly pelvic exams with Pap smears. However, rigid adherence to guidelines in the face of patients who suffer significant physical or emotional discomfort with exams may have the reverse of the desired effect. It should be remembered that the goal is to preserve patient health and well-being. A pap smear and pelvic exam done regularly every 3 years is far superior to no preventative examinations at all. Providers unable to provide gynecologic well-checks should assist patients by referring to sensitive providers in the their area. These referrals should be discussed in advance with the gynecologic provider to ensure that she and her staff are comfortable providing care for transgender men and will be sensitive to their individual needs.

Vaginal Effects

Especially after oophorectomy, transgender men may experience vaginal atrophy and dryness, which can be alleviated with topical vaginal estrogen.

Breast Effects

A portion of administered testosterone will be aromatized to estrogen. This is a reason not to take higher than appropriate doses of testosterone, as excess testosterone may also lead to higher amounts of circulating estrogens.

Sexual Function

Almost all transgender men report a significantly increased libido with testosterone therapy. Some female partners of heterosexual trans men may become anxious if they are unprepared for the significant increase in their partner's libido. Office counseling including anticipatory guidance may be helpful for both patients and their partners.

Reproduction

Future reproductive capability and plans should be discussed with all transgender patients before the initiation of medical but especially surgical therapy. Options for preserving fertility include: o Embryo banking – oocyte harvest as above with immediate fertilization and banking of the embryo. Best survival of all techniques, but the sperm donor (whether known or anonymous) must be chosen before oophorectomy. o Ovarian tissue banking – probably the most flexible option for many transmen especially those unsure of future reproductive desires, but still experimental and performed in only certain centers.

Voice

Voice changes are generally present by 6-8 weeks. Occasional trans men may, like adolescent males, experience transient throat pain or vocal weakness during transition.

Musculoskeletal

In adolescent and premenopausal women, higher androgen levels are associated with higher BMD. Estrogens and androgens are necessary in both males and females for optimal bone health. Estrogen is the predominant sex hormone that slows bone loss (even in men.) A study in trans men demonstrated that after two years on hormone therapy that was sufficient to elevate testosterone levels to upper normal male ranges and suppress estradiol levels to near menopausal ranges, a clinically and statistically significant increase in BMD was found. In osteoporotic women treated with hormonal therapy, combined estrogen and androgen therapy has been shown to be more effective than estrogen therapy alone. Transgender men, even prior to hormonal therapy, tend toward a more typical male body shape which may represent pre-existing differences in hormonal milieu. Estrogen supplementation should not be necessary because some testosterone will be aromatized into estrogen sufficient to maintain bone. If the only indication for estrogen supplementation is bone loss, other treatments such as bisphosphonates may have a superior risk-benefit profile. If estrogen replacement is prescribed, transdermal therapy is preferred because oral estrogens cause a significant elevation in SHBG and therefor lower free androgen levels. Daily calcium supplementation is important after oophorectomy. Vitamin D supplementation may also be beneficial. A DEXA scan at the time of oophorectomy and periodically thereafter diagnose osteoporosis in the pre-symptomatic stage when it is more easily treated. Providers should be sensitive to cost however as many transmen pay out of pocket for transgender related care (DEXA in the US $150-400.)

Muscle Effects

Resistance training should be encouraged in trans men because it may have significant protective effects against loss of BMD in addition to both the overall health benefits and the gender confirming effect of producing a more masculine body habitus.

Hematologic

Erythrocyte Effects

A transgender man’s hematocrit should only be judged high when compared to normal values for men. While levels vary with altitude, normal male hematocrit is generally 40.7 - 50.3% (Female normal levels are 36.1 - 44.3%.) However, not all transmen will achieve normal male range hematocrit, so evaluation of anemia should only be triggered by either a hematocrit lower than normal for women. Low does aspirin therapy or non-parenteral testosterone formulation or traditional therapy for polycythemia via scheduled phlebotomy (donating blood) may be helpful when hematocrit is high.

Coagulation System Effects

Testosterone increases the anticoagulant effects of warfarin. It suppresses clotting factors II, V, VII, and X. Patients who require concomitant anticoagulation may need lower doses of warfarin. Additionally, with warfarin therapy, intramuscular injections should be avoided.

Neurological/Psychiatric

Obstructive Sleep Apnea

OSA may be worsened or unmasked by androgen therapy. Risk is greater in patients who are obese, smoke, or have chronic obstructive pulmonary disease. In addition, OSA is more common in Polycystic Ovarian Syndrome patients. So transmen with pre-existing androgenization and PCOS may be at higher baseline risk. Patients should be informed of the symptoms of OSA: noisy sleeping (snoring,) excessive daytime sleepiness, morning headache, personality changes, and problems with judgment, memory, and attention. Patients with OSA may develop a reactive erythrocytosis which can be mistaken for polycythemia from testosterone. Any patient with abnormally elevated hematocrit should be screened for possible sleep apnea. Modalities to treat OSA allow continued and appropriate hormonal therapy. Sleep deprivation worsens many seizure disorders, so concurrent OSA may be responsible for worsening seizure control.

Headaches

Some trans men with migraines may have an improvement of their symptoms on testosterone.

Peripheral Nervous System Effects

Generalized paresthesias are reported as adverse reactions from testosterone.

Mood and Psychiatric Issues

Some transgender men report mood swings, increased anger, and increased aggressiveness after starting androgen therapy. In a study, during and after reassignment, trans men showed more contentment, greater extroversion, and less somatization than pretreatment. Decrease in depression and suicidality are found in treated transgender patients. The partners of transgender patients can often provide useful information about mood changes and adjustment to gender role. Patients should be encouraged to feel comfortable bringing their partners or close intimates with them to appointments. When adverse mood changes occur these can often be managed by in office counseling and reassurance. Alterations in mood are also sometimes reported by some trans men using injected testosterone during the few days before their next injection or the first few days after an injection. Changing dosing, interval, and/or route may be effective in alleviating many of these symptoms.

Metabolic

Weight

Testosterone generally increases appetite and body weight. Moderate amounts of exercise will produce larger gains in muscle mass and may ameliorate some of the adverse metabolic consequences of testosterone.

Treatment of Impaired Glucose Tolerance and Diabetes

Among patients with PCOS, 40% have impaired glucose tolerance and 10% have frank NIDDM by the fourth decade. Metformin is the agent most widely used and studied to treat insulin resistance and NIDDM in PCOS patients. Metformin is associated with a decrease in serum androgens and an increase in SHBG in PCOS patients. Although studied less extensively in PCOS patients, the thiazolidinediones have been shown to improve metabolic abnormalities and hyperandrogenemia. Any deleterious effect that testosterone may have on metabolic profile would likely be overshadowed by improvements through diet and exercise. With NIDDM, PCOS, and obesity, weight control through exercise and diet remain a cornerstone of therapy.

Drug Interactions

• Cyt P-450 Inducers – May cause decreased levels of testosterone (and other sex steroid) levels: Phenobarbital, Dilantin, Rifampin, and Alcohol are examples. • Cyt P-450 Inhibitors – May cause increased levels of testosterone: Serzone, Prozac, Paxil, Sporanox, Diflucan, and other ‘azole’ antifungals, Tagamet (which can cause gynecomastia in men because of this effect.) Biaxin and other macrolide antibiotics, and protease inhibitors.

Testosterone can also alter the effects of certain drugs: o Increases the anticoagulant effect of Coumadin. o Decreases the effectiveness of propranolol. o Increases the hypoglycemic effect of oral diabetes medicines and can decrease the insulin requirement and predispose to dangerous episodes of hypoglycemia.