Gender-Affirming Hormone Therapy

Clinical Snapshot

Gender-affirming hormone therapy (GAHT) uses exogenous sex steroids to align a person's secondary sex characteristics with their affirmed gender, relieving the distress of gender dysphoria/gender incongruence and improving quality of life and mental health outcomes.^[1] Two broad regimen categories are used, matched to the person's affirmed gender: feminizing hormone therapy — an estrogen (almost always estradiol) combined with an agent that suppresses or blocks testicular androgen production or action — and masculinizing hormone therapy — testosterone alone, which both suppresses ovarian estrogen/androgen production and drives virilization directly.^[2] This chapter covers both regimens in adults: formulation and route selection, dosing and titration, target hormone levels, baseline and ongoing laboratory monitoring, and the specific adverse-effect issues that define safe long-term prescribing.

Access to gender-affirming care in Canada has shifted decisively toward an informed consent model. Rather than requiring an extended course of psychotherapy, a formal letter from a mental health provider, or a minimum period of social transition before prescribing, current Canadian protocols — reflected in Rainbow Health Ontario/Sherbourne Health's Guidelines for Gender-Affirming Primary Care and consistent with the Canadian Professional Association for Transgender Health's (CPATH) position — hold that any clinician competent to assess capacity to consent can initiate hormone therapy once the patient understands the expected effects, risks, and irreversible components of treatment.^[2] See Assessment & Diagnosis for the specific elements this model still requires before prescribing.

Referral volumes to specialized gender-affirming care services have risen substantially across Canada over the past decade, and hormone therapy — not surgery — is what most pharmacists will actually encounter in practice, through prescription dispensing, drug interaction screening (spironolactone in particular), and monitoring-related patient counseling.

Recognize the Condition

Feminizing hormone therapy — physiologic effects and timeline

Effects begin within the first few months but continue to evolve for one to several years; set expectations with the patient accordingly rather than judging a regimen as inadequate too early (see Treatment Failure/Next Step).^[2]

Effect	Reversibility	Onset	Maximum effect
Body fat redistribution to a more typically feminine pattern	Reversible	3-6 months	2-3 years
Decreased muscle mass and strength	Reversible	3-6 months	1-2 years
Softer, less oily skin	Reversible	3-6 months	Ongoing with continued therapy
Slowed facial and body hair growth	Partially reversible	6-12 months	More than 3 years
Breast growth	Irreversible	3-6 months	1-2 years
Decreased testicular volume, libido, and spontaneous erections; variably decreased sperm production	Variable — sperm changes may represent irreversible infertility	3-6 months	2-3 years

Feminizing hormones do not change vocal pitch — voice-related dysphoria requires dedicated voice therapy or, for some patients, laryngeal surgery (see Non-Pharmacologic Treatment). Existing terminal facial/body hair is only slowed, not eliminated, by hormones alone; hair removal (electrolysis or laser) is needed for established hair.^[2]

Masculinizing hormone therapy — physiologic effects and timeline

Effect	Reversibility	Onset	Maximum effect
Voice deepening	Irreversible	6-12 months	1-2 years
Facial and body hair growth	Irreversible	3-6 months	4-5 years
Clitoral enlargement	Irreversible	3-6 months	1-2 years
Increased muscle mass and strength	Reversible	6-12 months	2-5 years
Menstrual cessation	Reversible	1-6 months	N/A
Vaginal/genital tissue atrophy	Reversible	1-6 months	1-2 years

Menstrual cessation on testosterone is not reliable contraception — ovulation is suppressed but not eliminated, so a patient with retained ovaries and uterus who could become pregnant and does not want to needs a separate reliable contraceptive method (see Special Populations).^[2]

Risk Factors

VTE risk factors relevant to estrogen route selection: age over 40, current smoking, obesity, personal or family history of venous thromboembolism, immobility, migraine with aura, known thrombophilia, and cerebrovascular disease — each favours a transdermal or injectable estradiol route over oral.^[2]
Hyperkalemia risk factors relevant to spironolactone candidacy: renal impairment, and concomitant use of an ACE inhibitor, ARB, potassium-sparing diuretic, NSAID, or trimethoprim-sulfamethoxazole.^[2]
Hepatic risk factors relevant to cyproterone acetate candidacy: pre-existing liver disease — favour spironolactone or a GnRH agonist instead, or monitor ALT more closely if cyproterone acetate is still used.^[2]
Erythrocytosis risk factors relevant to testosterone route/dose selection and monitoring intensity: current smoking, obesity, initiating therapy between roughly 40 and 50 years of age, pre-existing pulmonary disease, and choice of a long-acting injectable ester over transdermal gel, which carries the lowest observed risk of the available routes.^[3]
Cardiovascular risk factors relevant to individualized risk-benefit discussion in either regimen, particularly in older patients: hypertension, dyslipidemia, diabetes, and established cardiovascular or cerebrovascular disease.^[2]
Active liver disease, active hormone-sensitive malignancy, and an unstable or untreated psychiatric condition affecting capacity to consent are factors requiring additional assessment before initiating either regimen, though under the informed consent model they are rarely treated as absolute, indefinite bars to treatment.^[2]

Red Flags & Refer

The following presentations change the plan from routine ongoing prescribing to urgent assessment or an immediate medication hold:

VTE symptoms on feminizing (estrogen-containing) therapy — unilateral leg swelling, warmth, or pain, or sudden shortness of breath, chest pain, or hemoptysis — hold estrogen and arrange urgent assessment.^[2]
Symptomatic erythrocytosis on masculinizing (testosterone) therapy — headache, facial plethora/flushing, visual disturbance, or any symptom of a thrombotic event (limb swelling or pain, chest pain, stroke symptoms) in the setting of an elevated hematocrit — arrange urgent assessment; see Monitoring & Follow-Up and Treatment Failure/Next Step for the specific hematocrit-based action thresholds.^[3]
Significant new or worsening mood symptoms, or any suicidal ideation, at any point during treatment — integrate mental health support promptly; do not assume hormone therapy is either the cause or an adequate fix without a proper assessment.^[1]
Symptoms of significant hyperkalemia (muscle weakness, palpitations, arrhythmia) in a patient on spironolactone, especially with a concurrent ACE inhibitor/ARB or renal impairment — hold spironolactone and check potassium urgently.
Signs of hepatotoxicity in a patient on cyproterone acetate — jaundice, right upper quadrant pain, or dark urine — hold the drug and check liver function urgently.^[2]

Assessment & Diagnosis

The informed-consent model of access

Current Canadian primary-care protocols for gender-affirming care are built around an informed consent model rather than extensive psychological gatekeeping.^[2]^[1] Rainbow Health Ontario/Sherbourne Health's guidelines frame this as five planning-period tasks that must genuinely be completed before prescribing — not a fixed number of visits logged or a mandatory period of time elapsed: (1) a respectful, trauma-informed patient history; (2) baseline physical and laboratory data; (3) patient education on the realistic timeline, reversibility, and costs of treatment; (4) risk management (mental health, lifestyle, and medical precautions); and (5) a differential assessment to rule out an alternative explanation for the presentation.^[2] No mandatory minimum duration of psychotherapy, formal mental-health-provider letter, or "real-life experience" period is required once these tasks are genuinely complete and the patient demonstrates capacity to consent.^[2]

Adult eligibility criteria

Broadly consistent with WPATH Standards of Care, Version 8: gender incongruence that is marked and sustained over time; demonstrated capacity to consent to the specific hormone treatment being considered, including its risks, benefits, and irreversible components; any mental health or physical condition that could affect treatment outcome has been assessed, with risks and benefits discussed and, where feasible, optimized rather than treated as an automatic bar; and the person understands the effect of treatment on reproduction and has had the opportunity for fertility preservation counseling before starting (see Non-Pharmacologic Treatment).^[1]^[4]

Baseline assessment before starting hormone therapy

A focused physical exam — blood pressure, weight/BMI, and screening for hypertension, obesity, or active liver disease — plus baseline labs common to both regimens: CBC, ALT, creatinine and electrolytes, HbA1c or fasting glucose, and a lipid profile, along with total testosterone; hepatitis B/C screening is considered where relevant.^[2] For feminizing therapy specifically, add baseline estradiol and prolactin. For masculinizing therapy specifically, add a pregnancy test where relevant, since testosterone is contraindicated in pregnancy (see Special Populations).^[2]

Differential and comorbidities to assess before or alongside prescribing

Distinguish sustained gender incongruence from a transient period of identity exploration, body dysmorphic disorder, or an unstable/untreated psychotic disorder driving beliefs about the body — this is a case-by-case capacity assessment, not an automatic exclusion from treatment.^[2]
Differences of sex development (intersex conditions) are assessed through history and baseline hormone levels rather than through a routine genital examination.^[2]
Uncontrolled hypertension, obesity, or active liver disease are ideally managed prior to or concurrently with starting hormone therapy, rather than treated as an indefinite bar to treatment.^[2]

Treatment Targets

Achieve and maintain target physiologic hormone levels for the affirmed gender: for feminizing therapy, serum estradiol roughly 200-500 pmol/L with testosterone suppressed below 1.7 nmol/L (below 50 ng/dL); for masculinizing therapy, serum testosterone within the typical adult male reference range, generally targeting the midpoint of that range — once the midpoint is reached, pushing the dose higher adds little further physical effect but does add risk.^[2]^[4]
Produce the secondary sex characteristic changes the patient is seeking, with realistic expectations set for which changes are reversible, irreversible, partial, or simply unaffected by hormones altogether (for example, vocal pitch in feminizing therapy).^[2]
Avoid supraphysiologic hormone levels, which add adverse-effect risk without added benefit once the target range is reached.^[4]
Prevent, detect early, and manage the regimen-specific adverse effects that define safe long-term therapy: venous thromboembolism risk with estrogen, hyperkalemia with spironolactone, hepatotoxicity with cyproterone acetate, and erythrocytosis with testosterone.
Support the patient's fertility goals through counseling completed before treatment starts, since some reproductive effects of hormone therapy may not be reversible.^[2]
Integrate mental health and psychosocial support throughout treatment as needed, without making it a prerequisite to prescribing under the informed consent model.^[1]

Choose Initial Treatment

Direct treatment rule

Match the regimen to the patient's affirmed gender and individual risk profile

Feminizing therapy requires two components — an estrogen and an androgen-suppressing/blocking agent — while masculinizing therapy is testosterone alone, since testosterone itself suppresses ovarian hormone production. Route selection within each regimen is driven chiefly by venous thromboembolism risk (feminizing) and erythrocytosis risk (masculinizing).

Feminizing hormone therapy — estrogen route selection

Oral estradiol, reasonable starting route for a patient without elevated VTE risk factors. Transdermal or injectable estradiol preferred for a patient with VTE risk factors (age over 40, smoking, obesity, personal/family VTE history, migraine with aura, cerebrovascular disease) — both routes avoid first-pass hepatic metabolism and carry a lower VTE signal than oral estrogen at an equivalent dose.^[2]

Feminizing hormone therapy — anti-androgen selection

Spironolactone, most commonly used in North America — effective, inexpensive, and familiar to most prescribers, but requires baseline and ongoing potassium/creatinine monitoring given its hyperkalemia risk.^[2] Cyproterone acetate, low dose is a Canadian-available alternative, effective at lower doses than historically used, but requires baseline and periodic ALT monitoring and is less preferred with pre-existing liver disease.^[2] GnRH agonist (leuprolide or goserelin) is reserved for a patient with a contraindication to, or an inadequate response to or intolerance of, spironolactone or cyproterone acetate — it produces more complete gonadal androgen suppression with less potassium/liver-function monitoring burden, but its use is genuinely limited by cost, since it is not always covered for this indication on public drug formularies.^[2]

Masculinizing hormone therapy — testosterone route selection

Injectable testosterone (IM or SC), preferred first-line for most patients given its superior efficacy and lower cost relative to transdermal options.^[2] Transdermal testosterone (patch or gel) is a reasonable alternative for a patient who wants to avoid injections, and carries a lower erythrocytosis signal than long-acting injectable esters — particularly testosterone undecanoate — making it a reasonable preferred choice in a patient with elevated baseline erythrocytosis risk (smoker, obesity, initiating therapy between roughly 40 and 50 years of age, or pre-existing pulmonary disease).^[3]

The informed consent framework, applied to prescribing itself

Do not require a mandatory minimum duration of therapy, a mental health provider letter, or a fixed "real-life experience" period before initiating either regimen once capacity to consent and understanding of risks, benefits, and irreversible components are confirmed — see Assessment & Diagnosis for the specific planning-period tasks this model still requires.^[2]

Non-Pharmacologic Treatment

Fertility preservation counseling, completed before starting hormone therapy: sperm banking (or testicular sperm extraction as an alternative) before starting feminizing therapy; oocyte or embryo cryopreservation before starting masculinizing therapy — testosterone's effect on future fertility is variably reversible, so this counseling needs to happen before, not after, hormones are started.^[2]^[1]
Contraception counseling for masculinizing therapy: testosterone-induced amenorrhea does not reliably prevent pregnancy, and testosterone is not itself a contraceptive — a patient with retained ovaries and uterus who is sexually active and does not want to become pregnant needs a separate reliable contraceptive method (see Special Populations).^[2]
Voice and communication therapy for feminizing patients — feminizing hormones do not change vocal pitch, so voice therapy or, for some patients, laryngeal surgery is the only way to address voice-related dysphoria.^[2]
Hair removal (electrolysis or laser) for feminizing patients — hormones slow new terminal hair growth but do not eliminate hair that is already established.^[2]
Chest binding and genital packing are non-hormonal options that address masculinizing-related dysphoria alongside, not instead of, hormone therapy.
Smoking cessation reduces VTE risk on estrogen and reduces erythrocytosis risk on testosterone — counsel on cessation at every visit regardless of regimen.^[2]^[3]
Ongoing psychosocial and mental health support, offered throughout treatment and integrated promptly if significant mood symptoms emerge, without being made a prerequisite to starting or continuing hormone therapy.^[1]

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Estradiol, oral Preferred	Feminizing therapy, estrogen component — reasonable starting route without elevated VTE risk factors	Start 1-2 mg PO once daily; usual maintenance 4 mg/day (or 2 mg BID); maximum 6 mg/day (or 3 mg BID)	Breast tenderness, nausea, headache, mood changes; VTE risk (higher than transdermal/injectable at equivalent doses)	Reassess dose and labs at 1 month, then 3 months; effects continue evolving over 1-3+ years — avoid escalating dose purely for a slow visible response
Estradiol, transdermal Preferred	Feminizing therapy, preferred route with elevated VTE risk factors, or by patient preference	Patch: start 50 mcg/day (applied twice weekly), titrate to a maximum of 200 mcg/day	Application-site irritation; lower VTE signal than oral at equivalent doses	Avoids first-pass hepatic metabolism. Rotate application sites.
Estradiol, injectable (compounded) Alternative	Feminizing therapy, alternative parenteral route with a VTE profile similar to transdermal	Estradiol valerate/cypionate: start 3-4 mg IM weekly, or 6-8 mg IM every 2 weeks; maximum 10 mg/week	Injection-site reactions; lower VTE signal than oral at equivalent doses	A compounded product — no Pharmasist Drug Database monograph exists for this specific injectable formulation.
Spironolactone Preferred	Feminizing therapy, anti-androgen — most commonly used option in North America	Start 50 mg PO once daily; titrate to 100 mg PO BID; rarely exceed 150 mg PO BID	Hyperkalemia, hypotension, polyuria, gynecomastia (additive to feminizing goal)	Check potassium/creatinine at baseline, 4-6 weeks after starting or any dose change, then periodically. Avoid with an ACE inhibitor/ARB or renal impairment without close monitoring.
Cyproterone acetate Alternative	Feminizing therapy, anti-androgen alternative — effective at low doses	12.5-25 mg PO once daily	Hepatotoxicity, fatigue, mood changes	Requires baseline and periodic ALT monitoring. Less preferred with pre-existing liver disease — favour spironolactone or a GnRH agonist instead.
Leuprolide Special situation	Feminizing therapy — GnRH agonist reserved for a contraindication to, or inadequate response/tolerance of, spironolactone/cyproterone acetate	Depot formulation per product-specific monograph, typically monthly or every-3-month injection	Initial testosterone flare (transient), hot flashes, decreased bone mineral density with prolonged use, injection-site reactions	More complete androgen suppression with less potassium/liver-function monitoring burden; cost/public-formulary access is the main limiting factor for this indication.
Goserelin Special situation	Feminizing therapy — GnRH agonist alternative to leuprolide	Depot implant per product-specific monograph, typically every 4 or 12 weeks	Same class effects as leuprolide	Same role and access limitations as leuprolide — an alternative brand/formulation within the same drug class.
Testosterone cypionate Preferred	Masculinizing therapy — injectable, preferred first-line route for most patients	Start 20-50 mg IM/SC weekly, or 40-100 mg every 2 weeks; maximum 100 mg weekly or 200 mg every 2 weeks	Erythrocytosis, acne, androgenic alopecia, mood changes, injection-site reactions	Check trough level (immediately before the next dose) to titrate. Monitor hematocrit closely — see Monitoring & Follow-Up for action thresholds.
Testosterone enanthate Preferred	Masculinizing therapy — injectable, equivalent alternative ester to cypionate	Start 20-50 mg IM/SC weekly, or 40-100 mg every 2 weeks; maximum 100 mg weekly or 200 mg every 2 weeks	Erythrocytosis, acne, androgenic alopecia, mood changes, injection-site reactions	Same dosing/monitoring approach as cypionate — the two esters are interchangeable by convention/availability.
Testosterone, transdermal Alternative	Masculinizing therapy — patch/gel, avoids injections and carries a lower erythrocytosis signal than long-acting injectable esters	Patch: start 2.5-5 mg/day, maximum 5-10 mg/day. Gel 1%: start 2.5-5 g/day	Application-site irritation; skin-to-skin transfer risk to others; lower erythrocytosis risk than injectable esters	No Pharmasist Drug Database monograph exists for a transdermal testosterone product. Check a mid-interval level (after steady state, roughly 1 week) rather than a trough.

Special Populations

Adolescents

Puberty blockers (GnRH agonists such as leuprolide or histrelin) are a distinct, earlier-stage intervention used to pause endogenous puberty at Tanner stage G2/B2 in a gender-dysphoric or gender-incongruent adolescent, per the current Endocrine Society guideline — this is a separate clinical pathway from the adult hormone therapy covered in the rest of this chapter and is managed by a multidisciplinary pediatric/adolescent gender-affirming care team.^[4] Gender-affirming hormones are generally added later, once persistence of gender incongruence and capacity for this next, less readily reversible step have been reassessed. CPATH is a co-signatory, alongside WPATH, EPATH, USPATH, AsiaPATH, AusPATH, and PATHA, to a December 2020 joint statement affirming puberty blockers as an appropriate, harm-reducing intervention for eligible transgender adolescents.^[5]

Older adults and patients with cardiovascular risk factors

Age alone is not a barrier to starting or continuing GAHT, but cardiovascular risk factors (hypertension, dyslipidemia, diabetes, established cardiovascular or cerebrovascular disease) warrant an individualized risk-benefit discussion. On the feminizing side, this favours transdermal or injectable estradiol over oral to reduce VTE risk; on the masculinizing side, it favours closer hematocrit monitoring, given the age-related rise in erythrocytosis risk observed with testosterone initiation between roughly 40 and 50 years of age.^[2]^[3]

Pregnancy and contraception

Testosterone is contraindicated in pregnancy and should be discontinued if pregnancy occurs or is being actively pursued. Because testosterone-induced amenorrhea does not reliably suppress ovulation, a patient with retained ovaries and a uterus who is sexually active with potential for pregnancy and does not want to become pregnant needs a separate reliable contraceptive method alongside testosterone.^[2] A patient pursuing pregnancy should generally complete fertility preservation and stop testosterone before conception; ovulatory function typically returns within a few months of stopping.

Hepatic and renal impairment

Active liver disease is a specific caution for cyproterone acetate given its hepatotoxicity signal — favour spironolactone or a GnRH agonist instead, or monitor ALT closely if cyproterone acetate is still used.^[2] Renal impairment increases hyperkalemia risk with spironolactone — monitor potassium more closely, or favour cyproterone acetate or a GnRH agonist instead with more significant impairment.^[2]

Monitoring & Follow-Up

Feminizing hormone therapy

Baseline: CBC, ALT, creatinine/electrolytes, HbA1c or fasting glucose, lipid profile, total testosterone, estradiol, and prolactin. At 1 month: repeat creatinine/electrolytes if on spironolactone. At 3 months: repeat CBC and ALT if on cyproterone acetate, plus total testosterone, estradiol, and prolactin (if on cyproterone acetate). At 6-12 months and then annually: repeat the same panel, adding a lipid profile.^[2] Confirm serum estradiol trending toward the 200-500 pmol/L target range with testosterone suppressed below 1.7 nmol/L (below 50 ng/dL).^[2]

Masculinizing hormone therapy

Baseline: CBC (including hematocrit/hemoglobin), ALT, HbA1c or fasting glucose, lipid profile, and total testosterone; hepatitis B/C screening and a pregnancy test at baseline where relevant. Repeat this panel at 3, 6, and 12 months, then annually; add luteinizing hormone once post-gonadectomy.^[2]

Hematocrit — the specific, genuinely important safety monitor for testosterone therapy. Roughly 1 in 9 patients on long-term testosterone develop a hematocrit above 0.50 L/L (50%), with the risk rising further with continued exposure years, smoking (roughly double the risk), obesity, pre-existing pulmonary disease, and use of a long-acting injectable ester rather than transdermal gel.^[3] At a hematocrit between 0.50 and 0.54 L/L (50-54%), investigate contributing factors and consider a dose reduction or a lower-risk route (transdermal); at a hematocrit above 0.54 L/L (54%), hold testosterone, investigate and correct reversible contributors, consider therapeutic phlebotomy, and resume only at a lower dose once the hematocrit has normalized.^[3]

Bone mineral density is not routinely monitored in a patient maintained at physiologic hormone levels on either regimen, but should be assessed when osteoporosis risk factors exist, and specifically in a patient who has undergone gonadectomy and then stops or significantly interrupts hormone therapy, since bone loss can accelerate without either endogenous or replacement sex steroid.^[4]

Treatment Failure / Next Step

Inadequate testosterone suppression on spironolactone despite dose optimization (up to 150 mg PO BID): confirm adherence first, then consider adding cyproterone acetate or switching to a GnRH agonist rather than escalating the spironolactone dose further.
Inadequate feminization despite hormone levels at target: confirm that adequate treatment duration has elapsed — most secondary sex characteristic changes continue evolving over 1-3+ years — before concluding the regimen itself is inadequate and adjusting dose or route.
Persistent hyperkalemia on spironolactone: reduce the dose, address reversible contributors (a concurrent ACE inhibitor/ARB, worsening renal function), or switch to cyproterone acetate or a GnRH agonist.
Elevated ALT on cyproterone acetate: hold the drug and reassess; switch to spironolactone or a GnRH agonist if hepatotoxicity is confirmed.
Inadequate virilization on testosterone despite apparently adequate dosing: confirm injection technique and adherence, and the timing of the level drawn (trough for injectable, mid-interval for transdermal), before escalating the dose; consider a route switch if technique/absorption is the issue.
Rising hematocrit on testosterone: follow the stepwise hematocrit-based action plan in Monitoring & Follow-Up (closer monitoring and consider dose/route change at 0.50-0.54 L/L, hold and consider phlebotomy above 0.54 L/L) rather than assuming continued dose escalation is safe.
Persistent significant mood symptoms despite optimized hormone levels: integrate or intensify mental health support rather than assuming further hormone dose escalation will resolve them.

Common Errors to Avoid

Requiring an extended psychotherapy course, a mental health provider letter, or a fixed "real-life experience" period before prescribing, rather than following the informed consent model's actual planning-period requirements.
Withholding hormone therapy indefinitely for a modifiable risk factor (e.g., uncontrolled hypertension, active smoking) rather than treating the risk factor and offering therapy once it is optimized.
Assuming testosterone therapy is a reliable contraceptive — menstrual cessation does not equal reliable ovulation suppression.
Starting spironolactone without a plan to check, and continue monitoring, potassium and renal function, especially alongside an ACE inhibitor, ARB, or another potassium-sparing agent.
Skipping fertility preservation counseling, or raising it only after hormone therapy has already started rather than before.
Failing to obtain baseline and periodic hematocrit on testosterone therapy, or not acting on a result once it rises.
Promising vocal pitch change from feminizing hormones — voice does not change without dedicated voice therapy or surgery.
Treating puberty blockers and adult gender-affirming hormone therapy as the same intervention with the same risk-benefit profile — they are separate clinical pathways for separate populations.
Judging a fixed number of clinic visits, rather than completion of the informed-consent planning-period tasks, as what determines readiness to start.
Continuing to escalate a hormone dose without first confirming an adequate trial duration has elapsed, since most secondary sex characteristic changes evolve over one to several years.

Clinical Decision Algorithm

Feminizing hormone therapy

Patient requests feminizing hormone therapy; capacity to consent and understanding of risks/benefits/irreversibility confirmed (informed consent model)

Complete baseline assessment (BP/weight, CBC, ALT, creatinine/electrolytes, HbA1c/fasting glucose, lipids, testosterone, estradiol, prolactin) and fertility preservation counseling before starting^[2]

Assess VTE risk factors: age over 40, smoking, obesity, personal/family VTE history, migraine with aura, cerebrovascular disease

Elevated VTE risk

Start transdermal or injectable estradiol

No elevated VTE risk

Oral estradiol is a reasonable starting route

Add an anti-androgen: spironolactone (potassium/creatinine monitoring) as the usual first choice, or cyproterone acetate (ALT monitoring) as an alternative^[2]

Inadequate suppression or intolerance

Consider a GnRH agonist (leuprolide or goserelin) — more complete suppression, less K+/LFT monitoring burden, limited by cost/access

Adequate suppression and tolerated

Continue; titrate estradiol toward a target of roughly 200-500 pmol/L with testosterone suppressed below 1.7 nmol/L

Monitor per schedule; reassess secondary sex characteristic changes over 1-3+ years

Masculinizing hormone therapy

Patient requests masculinizing hormone therapy; capacity to consent and understanding of risks/benefits/irreversibility confirmed

Complete baseline assessment (CBC including hematocrit, ALT, HbA1c/fasting glucose, lipids, testosterone; pregnancy test if relevant) and fertility preservation counseling before starting^[2]

Select route: injectable testosterone (IM/SC) preferred first-line for efficacy/cost, or transdermal (patch/gel) as an alternative — particularly with elevated baseline erythrocytosis risk^[3]

Titrate every 4-6 weeks toward the midpoint of the adult male testosterone reference range, checking trough levels (injectable) or mid-interval levels (transdermal)

Hematocrit rises above 0.50 L/L (50%)

Increase monitoring frequency and reassess route/dose — see the erythrocytosis algorithm

Hematocrit remains at or below 0.50 L/L

Continue the standard monitoring schedule

Monitor per schedule; reassess virilization over 1-5 years depending on the specific effect

Erythrocytosis monitoring on testosterone therapy

Hematocrit checked at baseline, then 3, 6, and 12 months, then annually on testosterone therapy^[3]

Hematocrit at or below 0.50 L/L (50%)

Continue standard monitoring — this is the expected range

Hematocrit 0.50-0.54 L/L (50-54%)

Investigate contributing factors (smoking, sleep apnea, dehydration, route); consider a dose reduction or switching to a lower-risk route (transdermal)

Hematocrit above 0.54 L/L (54%)

Hold testosterone; investigate and correct reversible contributors; consider therapeutic phlebotomy; resume at a lower dose only once hematocrit has normalized

Once stable, resume standard monitoring intervals

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Feminizing hormone therapy — Estrogen

Route selection is driven chiefly by venous thromboembolism (VTE) risk — transdermal and injectable routes avoid first-pass hepatic metabolism and carry a lower VTE signal than oral at an equivalent dose.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Estradiol, oral	Starting dose: 1-2 mg PO once daily Usual maintenance: 4 mg/day, or 2 mg PO BID Maximum: 6 mg/day, or 3 mg PO BID	Breast tenderness, nausea, headache, mood changes, VTE (higher risk than transdermal/injectable)	CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's Wort) lower levels; CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) raise levels	Reasonable starting route without elevated VTE risk factors. Target serum estradiol roughly 200-500 pmol/L.
Estradiol, transdermal	Patch, starting: 50 mcg/day, applied twice weekly Patch, maximum: 200 mcg/day	Application-site irritation, VTE (lower risk than oral)	Fewer clinically relevant hepatic interactions than oral estrogen given bypass of first-pass metabolism	Preferred with elevated VTE risk factors (age over 40, smoking, obesity, personal/family VTE history, migraine with aura, cerebrovascular disease). Rotate application sites.
Estradiol, injectable (compounded)	Starting: 3-4 mg IM once weekly, or 6-8 mg IM every 2 weeks Maximum: 10 mg/week	Injection-site reactions, VTE (lower risk than oral)	Fewer clinically relevant hepatic interactions than oral estrogen given bypass of first-pass metabolism	Estradiol valerate or cypionate, compounded — no Pharmasist Drug Database monograph exists for this specific injectable formulation.

Feminizing hormone therapy — Anti-androgens

Combined with an estrogen — an anti-androgen alone does not produce feminization.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Spironolactone	Starting: 50 mg PO once daily Titration: Increase to 100 mg PO BID; rarely exceed 150 mg PO BID	Hyperkalemia, hypotension, polyuria, gynecomastia (additive to the feminizing goal)	Additive hyperkalemia risk with ACE inhibitors, ARBs, potassium-sparing diuretics, NSAIDs, or trimethoprim-sulfamethoxazole	Most commonly used anti-androgen in North America. Check potassium/creatinine at baseline, 4-6 weeks after starting or a dose change, then periodically.
Cyproterone acetate	Dosing: 12.5-25 mg PO once daily	Hepatotoxicity, fatigue, mood changes	None significant	Effective at low doses. Requires baseline and periodic ALT monitoring; less preferred with pre-existing liver disease.

Feminizing hormone therapy — GnRH agonists

Reserved for a contraindication to, or an inadequate response to or intolerance of, spironolactone or cyproterone acetate. More complete androgen suppression with less potassium/liver-function monitoring burden, but access is genuinely limited by cost, since these agents are not always covered for this indication on public drug formularies.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Leuprolide	Dosing: Per product-specific depot monograph	Initial transient testosterone flare, hot flashes, decreased bone mineral density with prolonged use, injection-site reactions	None significant	Depot injection, typically monthly or every 3 months per the specific product monograph.
Goserelin	Dosing: Per product-specific depot monograph	Same class effects as leuprolide	None significant	Depot implant, typically every 4 or 12 weeks per the specific product monograph — an alternative brand/formulation within the same drug class.

Masculinizing hormone therapy — Testosterone

Testosterone alone both suppresses ovarian hormone production and drives virilization — no second agent is added. Target serum testosterone within the adult male reference range, generally aiming for the midpoint; once reached, higher doses add little further physical effect but do add risk, particularly erythrocytosis.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Testosterone cypionate	Starting: 20-50 mg IM/SC once weekly, or 40-100 mg every 2 weeks Maximum: 100 mg weekly, or 200 mg every 2 weeks	Erythrocytosis, acne, androgenic alopecia, mood changes, injection-site reactions	None significant	Injectable, preferred first-line route for most patients. Check a trough level (immediately before the next dose) to titrate. Monitor hematocrit closely — see Monitoring & Follow-Up for action thresholds.
Testosterone enanthate	Starting: 20-50 mg IM/SC once weekly, or 40-100 mg every 2 weeks Maximum: 100 mg weekly, or 200 mg every 2 weeks	Erythrocytosis, acne, androgenic alopecia, mood changes, injection-site reactions	None significant	Equivalent alternative ester to cypionate — interchangeable by convention/availability, same dosing and monitoring approach.
Testosterone, transdermal	Patch, starting: 2.5-5 mg/day Patch, maximum: 5-10 mg/day Gel 1%, starting: 2.5-5 g/day	Application-site irritation, skin-to-skin transfer risk to others, erythrocytosis (lower risk than injectable esters)	None significant	No Pharmasist Drug Database monograph exists for a transdermal testosterone product. Check a mid-interval level (after steady state, roughly 1 week) rather than a trough. Lower erythrocytosis signal than long-acting injectable esters, particularly undecanoate.

References

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 — International Journal of Transgender Health, World Professional Association for Transgender Health (Coleman E, Radix AE, Bouman WP, et al.). Int J Transgend Health 2022;23(S1):S1-S259
Guidelines for Gender-Affirming Primary Care with Trans and Non-Binary Patients, 4th Edition — Sherbourne Health / Rainbow Health Ontario (Bourns A). 4th Edition, with medication updates through 2026
Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long-Term Follow-Up Study on Prevalence, Determinants, and Exposure Years — Journal of Clinical Endocrinology & Metabolism (Madsen MC, van Dijk D, Wiepjes CM, Conemans EB, Thijs A, den Heijer M). J Clin Endocrinol Metab 2021;106(6):1710-1717
Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline — Journal of Clinical Endocrinology & Metabolism (Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG). J Clin Endocrinol Metab 2017;102(11):3869-3903
Statement Regarding Medical Affirming Treatment including Puberty Blockers for Adolescents — WPATH, EPATH, USPATH, AsiaPATH, CPATH, AusPATH, PATHA (joint statement). Released December 16, 2020

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.