10/2/2020 1 Uncommon Mangement in Adult

10/2/2020

UNCOMMON MANGEMENT IN ADULT TRANSGENDER MEDICINE

By Steven R. Wolfe, DO, MPH, FAAFP, AAHIVS LGBTQIA Medicine Physician

Assistant Dean, AHN Clinical Professor, LECOM Department of Family Medicine Clinical Professor, Drexel Department of Family, Community and Preventive Medicine October 9, 2020

OBJECTIVES

1. List topics that should be discussed during the verbally informed consent process.

2. Describe at least one way to potentially enhance breast development when initiating HRT and testosterone blockers.

3. Describe ways to manage fluctuating estradiol or testosterone levels.

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DISCLOSURES

No financial disclosures.

This lectures is meant to discuss some of the challenges I have encountered outside of routine adult management of transgender and non-binary individuals. However, it is not meant to be all encompassing.

PRE-PRESENTATION QUESTIONS

1. During the informed consent process, it is important that patients understand all the following except: A. There is individual genetic and physiologic variation in blood levels and response to treatment B. Treatment course is years not months. C. Some treatment regimens are predictive of obtaining specific characteristics. D. Predictive factors of speed and degree of feminization include genetics, age at initiation of therapy and body habitus E. Most medical management recommendations are based of expert opinion from cis patient research

2. Which statement is true: A. Weak evidence suggests that initiation of low-dose estrogen with slow titration upward may result in enhanced breast development. B. Higher estrogen levels are associated with larger breasts. C. Spironolactone has estrogen receptor activity which may prematurely cause breast fusion and reduce breast development. D. A and C are true E. A, B and C are true

3. Which are the following are true about testosterone treatment in transgender men: A. Maximum dosing means maximum effect. B. Intramuscular is more efficacious over subcutaneous, though patients are less satisfied. C. Testosterone gel should be placed on the stomach or legs. D. If patient is having cyclical symptoms, consider changing to transdermal or reducing injection interval at the same dose. E. For a patient with no other medical issues, the only routine labs needed are total testosterone, hemoglobin and hematocrit.

GOALS AND EXEPECTATIONS

• What are the individual’s goals?

• What are the individual’s expectations? – Often based on peer outcomes

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GOALS AND EXEPECTATIONS

• Need for patient understanding – Individual genetic and physiologic variation in blood levels and response to treatment – Course of treatment takes years not months – No one regimen is predictive of obtaining a specific characteristic – Predictive factors of speed and degree of feminization or masculinization include genetics, age at initiation of therapy and body habitus – Most recommendations are based of expert opinion from cis patient research.

INFORMED CONSENT

• Individualized discussion • Risks, benefits, alternative • Unknowns • Risk of no treatment • Consent forms no longer needed – OCP and PrEP does not require consents – NO additional legal protection – Elimination helps demystify and destigmatize HRT

FEMINIZING MANAGMENT

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TESTOSTERONE BLOCKAGE

• Spironolactone – Initial dose: 50 mg BID – Maximum dose: 200 mg BID – Direct anti-androgen receptor blocker – Suppressive effect on testosterone synthesis – Caution: CKD and with use of ACEI/ARB – Usually self-limited polyuria, polydipsia and orthostasis

TESTOSTERONE BLOCKAGE

• 5-alpha reductase inhibitors – Less than full blockade – Less potent than spironolactone – Finasteride 1-5 mg daily • Blocks type 2 and 3 conversion of testosterone to potent dihydrotestosterone – Dutasteride 0.5 mg daily • Blocks type 1 conversion • May have more dramatic feminizing effects – Neither medications block production or action of testosterone

5-ALPHA REUCTASE INHIBITORS

• Why use these medications? – Unable to tolerate spironolactone • “I’m feel lightheaded when I stand up.” – Good as a single agent for partial feminization • “I would rather not have breasts.” – Patient continues to have virilized features with tradition treatment – Hair loss after complete androgen blockade or orchiectomy

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TESTOSTERONE BLOCKAGE ALONE

• Reduced masculinization and minimal breast development • Explore reduced testosterone levels alone • Estrogen therapy is contraindicated

• Caveats – Long term full androgen blockade without HRT in biologic men may result in bone loss

TESTOSTERONE BLOCKAGE ALONE

• Bicalutamide – Direct anti-androgen used for treatment of prostate cancer – Has small but not fully quantified risk of liver function abnormalities including fulminant hepatitis – Risks are less justified for feminization

WHAT IF COMPLETE ANDROGEN BLOCKADE IS CHALLENGING?

• Compliance? • Using testosterone also? • Rule out a testosterone producing tumor – Scrotal exam/US, hCG, LDH, AFP • Consider gonadotropin releasing hormone analogues (GnRH) or orchiectomy

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GNRH

• Drawbacks are cost and insurance coverage • Delivery – Need repeated injections (Lupron, $1800-10,000) – Surgical implantation (Vantas, $4400) • Orchiectomy may be ideal option ($5000; though many insurances will cover.) – Inexpensive, outpatient procedure

MEDROXYPROGESTERONE (PROVERA)

• Initial: 2.5 mg q HS • Maximum: 5-10 mg q HS • Effect: Possible improve breast development, improved mood or libido • No evidence of harm • Most common side effects (> 10%): Weight gain, abdominal pain and headache

RECTAL PROGESTERONE

• Oral oil-filled micronized progesterone capsules (Prometrium) – There are not rectal progesterone suppositories available in US • Touted by William Powers, DO, a LGBTQIA family physician in Michigan • Usual dose 200 mg rectally nightly – Usually achieves level of 20 ng/dL • Rectal bypasses liver metabolism – Achieves leves 2-4x higher than oral or sublingual • Suggested to titrate progesterone level of 12-24 ng/mL

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RECTAL PROGESTERONE

• Has mild anti-gonadatropin effect • Progesterone will lower FSH and LH • If LH low, then testosterone production will drop • Used as a testosterone blocker • Claims it works just as well as Lupron • His regimen: Start with estradiol valerate for 6-12 months then add progesterone

FEMINIZING TREATMENT TIPS

• Many patients want to go to maximum feminizing therapy quickly • Weak evidence suggests that initiation of low-dose estrogen with slow titration upward may result in enhance breast development • Higher estrogen levels are not associated with larger breasts • Spironolactone – Has estrogen receptor agonist activity which may prematurely cause breast bud fusion and reduced breast development – Begin with low-dose estrogen only titrating up over several months then add spironolactone

LAB MONITORING

• Spironolactone – monitor kidney function and electrolytes • Lipids – no need for monitoring unless patient has other underlying reason to monitor like obesity, cardiovascular disease, diabetes, etc • A1C or glucose – no need unless patient has risk factors • Estradiol – start q 3 months for first year, then spread out • Total testosterone – start q 3 months for first year, then spread out until < 55 • Prolactin – PRN if symptomatic – Even if prolactin elevated and patient has microprolactinoma, the likelihood of treating is small unless patient symptomatic

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FLUCTUANT ESTRADIOL LEVELS

• Consider more frequent dosing of IM/SC estradiol • Change to oral or transdermal route

NON-HORMONE LABS

• Hgb/Hct – Use broad range of lower limits of female and upper limits of male • Creatinine and alkaline phosphatase – Use upper limit of normal for men – Retained muscle and bone mass

TOBACCO

• Not an absolute contraindication • Counsel at each visit • Use informed decision and harm reduction approach • Transdermal estrogen preferred • Consider ASA 81 mg daily – No evidence to discuss risk vs benefit between venous thromboembolism (blood clot) and gastrointestinal bleeding

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POST GONADECTOMY

• No reduction of estrogen dosing required after gonadectomy • Adequacy of dosing in those on low estrogen replacement may be assessed by following FSH and LH

PROLACTINOMA

• Management of prolactinoma are expectant management only in absence of symptoms • Symptoms would include visual changes, galactorrhea and/or new-onset headaches • Routine screening of serum prolactin should be checked only in symptomatic patients • Could result in increased cost or harm to patient if further work-up pursued

WHAT IF PATIENT HAS GALACTORRHEA ALONE?

• Some transwomen experience a minimal amount of galactorrhea early in course • Almost always physiologic (nipple stimulation) and would not warrant further evaluation

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ESTROGEN COULD WORSEN CHRONIC MEDICAL ISSUES

• Autoimmune disorders – Testosterone associated with immune suppression – Autoimmune disorders are more common in cis women • Migraine headaches – Use oral or transdermal estradiol • Mental health – Consider avoiding injectable estrogen due to potentially cyclical levels could bring about or worsen existing mood symptoms

MASCULINIZING MANAGMENT

TESTOSTERONE

• All testosterone preparations are bioidentical and equivalent to testosterone secreted from the testicle • Maximum dosing does not mean maximum effect • Does should be based on patient response and monitored hormone levels • IM and SC have similar efficacy and patient satisfaction • Gels should be applied to upper arm or shoulders

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TESTOPEL

• Dissolvable testosterone pellets that implanted subcutaneously implanted in upper outer quadrant of hip • Last 3-6 months • Commits patient to dose with ability to change • Requires 2-4 additional visits to urologist on top of visits to your transgender specialist • Limited insurance coverage

AVEED (TESTOSTERONE UNDECANOATE)

• Testosterone injection lasting up to 10 weeks • Restricted distribution in US – Must see urologist – Participate in drug safety program • Risk Evaluation and Mitigation Strategy (REMS) – Associated with rare cases of oil microembolism and anaphylaxis • Must fail traditional testosterone injections

LAB MONITORING

• Lipids – based on USPSTF guidelines – Obesity, age and other chronic medical issues drive monitoring • A1C or glucose – based on USPSTF guidelines • Total testosterone – every three months for first year then spread out • Hgb/Hct – baseline then every three months for first year then spread out • Liver function tests (LFTs) – no longer recommended given < 0.5% chance of LFT abnormalities when dosed correctly

• Optional in complex cases to calculate bioavailable testosterone – Sex Hormone Binding Globulin (SHBG) – every three months then spread out – Albumin – every three months for first year then spread out

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LAB MONITORING

• Clinical response can be measured objectively by the presence of amenorrhea at 6 months • Once total testosterone is greater than the midpoint (600-700 ng/dL), it is unclear if an increase dose will have any positive effects on perceived slow progress or mood symptoms • Calculation of bioavailable can guide complicated patients or in cases where results or side effects exist while having normal range testosterone – Calculated from total testosterone, albumin and SHBG level – Bioavailable testosterone > 72 ng/dL

MEASURING TESTOSTERONE LEVEL

• Measure mid-cycle • If patient having cyclical symptoms (migraine headaches, pelvic cramping, mood swings), consider changing to transdermal or reducing injection interval with reduction of testosterone dose

SPECIFIC CONSIDERATIONS

• Post-gonadectomy – no reduction in testosterone needed • Erthrocytosis/polycythemia – Careful that you are using male reference ranges – Changing to more frequent injection schedule or transdermal may limit the risk • Age – No upper age limit for HRT – Consider cessation at 50 YO when normally non- transgender women undergo menopause

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PERSISTENT MENSES

• Those using testosterone, cessation of menses is expected typically within 6 months – Ovulation is suppressed and endometrium atrophies • Factors that affect time to cessation – Dose of testosterone – Route of administration – Frequency of administration – Presence and functioning of ovaries – Body habitus – Other medical conditions of the uterus or ovaries

PERSISTENT MENSES

• History of abnormal cycles prior to testosterone • May have underlying pathology resulting in prolonged and complicated path to cessation of menses • May need gynecologic evaluation

CARDIOVASCULAR DISEASE

• Evidence from several studies suggests that CV risk is unchanged among transgender men using testosterone compared to non-transgender women • Some studies in transgender women have found increased morbidity and mortality from heart attack and stroke compared to non-transgender men – Did not adjust for tobacco, obesity and diabetes • Factors contributing to an elevation of CV disease in transgender women – Higher rates • Tobacco use • Obesity • Diabetes • Lipid disorders – Lower rates • Physical activity

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CARDIOVASCULAR DISEASE

• Older studies used higher doses of ethinyl estradiol, a known thrombogenic synthetic estrogen used in OCP • Direct study of the effects of hormones on lipids and blood pressure in transgender people has been limited

CALCULATING RISK

• Currently no guidance on using risk calculator based on sex at birth or affirmed gender • Consider using sex at birth for those transitioning later in life given long-term exposure to natal hormones • For those transitioning early in life, using affirmed gender-based calculations may be more appropriate

REDUCING RISK

• For transgender women with CV risk factors or established CV disease, using transdermal route of estrogen may be preferred – Lower rates of venous thromboembolism – Lack of associated changes in lipids and markers of coagulation

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REDUCING RISK

• Modifiable risk factors – Smoking cessation – Weight loss – Tighter control of diabetes – Increased physical activity • Consider psychosocial benefit of HRT that could have protective effect – Reduction of stress – Improved body image • Healthier life choices • Reduced tobacco use • Increase physical activity

PRE-PRESENTATION QUESTIONS

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PRE-PRESENTATION QUESTIONS

QUESTIONS AND COMMENTS