Table 5.

Gender-affirming pharmacological interventions—examples of agents used, mechanism of action, effects, and suggested monitoring

Indication	Examples of agents and dosinga	Mode and frequency of administrationa	Mechanism(s) of action	Effects considered reversibleb	Potentially irreversible effectsb	Monitoringc
Puberty suppression	GnRHa		Central suppression of HPG axis	Suppression of HPG axis	Bone health: reduced BMD accrual may not fully revert; long term effect unclear.	3-6 monthly:
	Leuprolide 7.5/22.5/30/45 mg Triptorelin 11.25/22.5 mg Goserelin 3.6/10.8 mg Histrelin 5 mg	IM 4/12/16/24 weekly IM 3/6 monthly SC 4/12 weekly SC annually				Growth: height, weight BP, puberty
						6-12 monthly:
						LH, E2/T, 25OHD
						Annual DXA
Modulation of androgen effect	Cyproterone acetate (CPA) 50-100 mgd Spironolactone (S) 50-100 mg Bicalutamide (B) 50 mg	PO; daily (or less frequentlyd) PO; daily or bd PO: daily	AR antagonist: B, CPA, S PR agonist: CPA, S HPG suppression: CPA Inhibition of steroidogenic pathway (T production): S	Reduction of body and facial hair Decreased oiliness of skin Reduced libido	Unclear If it arises, breast development (B, S) may not fully revert	Electrolytes (S) LFT (B)
Suppression of menstruation	Progestogens		Altered endometrial angiogenesis; inhibition of endometrial proliferation Central GnRH inhibition (higher dose M) IU levonorgestrel—local inhibitory effects on endometrium	Suppression of menses	Unclear: reduced BMD accrual (with depot M implant) may not fully revert	Depot M: bone healthe BP
	Medroxyprogesterone (M): 150-mg implant/104 mg injection/10-20 mg tablet	IM/SC 12-14 weekly or PO od-bd
	Lynestrenol 5 mg	PO od
	Norethisterone 5-20 mg	PO od-tdsf
	Levonorgestrel	IUD ~5 yearly
	Combined OCPg	PO—daily
	Testosterone (see next section)
Feminization	17ß estradiol/estradiol valerate		Stimulation of estrogen receptor Central suppression of HPG axisi	Softening of skin	Breast tissue	3-6 monthlyh:
	Oral: 5 μcg/kg/day-2 mg/day; up to 6 mg/day reported	PO daily		Body fat redistribution	Epiphyseal fusion/growth	Growth: height, weight BP, reported feminization
	Transdermal: 6.25 mcg-100 mcg	Patch: apply once-twice per week		Decreased libido; decreased erections	Fertility effects (spermatogenesis)	6-12 monthly: Prolactin, E2 25OHD 1-2 yearly: BMD with DXA
	Estradiol valerate/cypionate 5-30 mg	IM every 14 days		Reduction of body and facial hair
Masculinization	Testosterone cypionate or Testosterone enanthate 12.5-50 mg increasing to 200-250 mg (higher dose less frequently)
		SC: 1-4 weekly or	Stimulation of androgen receptor	Acne skin changes	Voice lowering	3-6 monthly:
		IM 2-4 weekly	Central suppression of HPG axisi	Increased libido; increased muscle mass	Alopecia	FBE (hematocrit); lipids; T Growth: height, weight
	Testosterone undecanoatej	IM 1000 mg 12 weekly (once adult dosing established)		Menstrual suppression	Facial hair; genital changes/clitoral growth	BP, reported virilization
	Testosterone gel 1% (12.5-50 mg) Testosterone pelletsj (2-4 mg pellets)	Topical daily		Body fat redistribution	Vaginal mucosal thinning	6-12 monthly:T, FBE, lipids, 25OHD
						1-2 yearly: BMD with DXA

Abbreviations: 25OHD, 25-hydroxyvitamin D; AR, androgen receptor; B, bicalutamide; bd, twice daily; BMD, bone mineral density; BP, blood pressure; CPA, cyproterone acetate; DXA, dual energy X-ray absorptiometry; E2/T, estrogen/testosterone; FBE, full blood examination; GnRHa, Gonadotropin releasing hormone agonist; HPG, hypothalamic-pituitary-gonadal; IM, intramuscular; IUD, intrauterine device; LFT, liver function tests; LH, luteinising hormone; od, once daily; od-bd, once-twice daily; PBM, peak bone mass; PO, by mouth; PR, progestogen receptor; S, spironolactone; SC, subcutaneous; T, testosterone; tds, three times daily; TGD, trans and gender-diverse

^a Relates to reports in the literature in TGD populations; note—use in this context may be off-label and not all agents have reported data in adolescent TGD populations.

^b Either gender-affirming or potentially unwanted effects.

^c Ongoing monitoring of potential unwanted/ adverse effects (eg, drug reaction, mood effects, fatigue/altered energy, fluid retention, headaches).

^d Optimal dosing of antiandrogenic agents is unknown; studies of smaller and less frequent doses of agents such as CPA are under way.

^e Consider DXA if additional bone health risk factors (eg, low 25-OHD, history of low impact fracture).

^f Titrate to response—may need 5-10 mg bd-tds to achieve amenorrhoea; use lowest effective dose.

^g Numerous combined oral contraceptive pills are available, commonly containing a synthetic estrogen and progestogen. First- or second-generation oral contraceptive pills contain more androgenic progestins, which may be more acceptable in TGD youth; however, they also have a higher thromboembolic risk profile.

^h Reiteration of need for preventive measures to reduce thromboembolic risks. Need for prolactin monitoring can be individualized (eg, if also on CPA).

ⁱ Through negative feedback—greater effect when used in supraphysiological doses.

^j Limited data in adolescent TGD cohorts.