What are the guidelines for using cyproterone acetate (Cyproterone Acetate) in adolescents?

Guidelines for Use of Cyproterone Acetate in Adolescents

Cyproterone acetate is not recommended as a first-line treatment for adolescents in most clinical scenarios due to significant hepatotoxicity concerns and the availability of safer alternatives, though it has historical use in precocious puberty and limited contemporary application in late-pubertal transgender care. 1

Primary Clinical Applications in Adolescents

Precocious Puberty (Historical Use)

• Cyproterone acetate has been largely replaced by GnRH analogues for central precocious puberty, which are now considered the standard of care 2
• When used historically, oral cyproterone acetate was administered at 70-150 mg/m² per day (typically 50 mg twice daily or 70-100 mg/day total) to suppress pituitary gonadotropic secretion 2, 3
• Treatment was most effective when initiated early, particularly in patients with bone age under 11 years, showing beneficial effects on linear growth and bone maturation 3
• Final heights achieved with cyproterone acetate (157.8 ± 5.1 cm) were comparable to those achieved with GnRH analogues (159.6 ± 6.3 cm) 2

Contemporary Limited Use

• Short-term cyproterone acetate may be used to counteract the initial stimulatory "flare" effect when initiating GnRH analogues for central precocious puberty 2
• It can serve as an adjunct medication when very active adrenarche causes advanced bone age despite GnRH analogue treatment 2

Transgender Healthcare (Late-Pubertal Adolescents)

• In late-pubertal transgender female adolescents (Tanner stage G4 or later), cyproterone acetate has been used as an antiandrogen component of gender-affirming hormone therapy 1, 4
• Cyproterone acetate monotherapy produced only modest feminizing effects (decreased facial/body hair, breast development to Tanner B2-B3 in one-third of patients) over approximately 12 months 4
• When combined with incremental estradiol doses, more rapid feminization occurred (breast development to B3-B4 in 76% of patients) 4
• This approach should only be considered when GnRH analogues are not available or not reimbursed, as GnRH analogues remain the preferred treatment 4

Critical Safety Concerns and Contraindications

Hepatotoxicity - The Primary Concern

• Liver toxicity is the most significant complication of long-term cyproterone acetate use and is the primary reason it has fallen out of favor 1, 2
• Among 1552 children treated with cyproterone acetate for precocious puberty, five hepatoma cases developed, with four requiring surgery 5
• Hepatoma risk appears related to cumulative dose: 2 of 5 cases occurred with >500g cumulative dose, and 3 of 5 cases with >1000g cumulative dose 5
• One case of liver cirrhosis developed in a boy with severe hypothalamic disease 3 years after stopping cyproterone acetate following 5 years of treatment 2
• Liver function tests must be monitored regularly throughout treatment, though they were normal in most patients 2

Absolute Contraindications

• Cyproterone acetate is absolutely contraindicated in patients with hereditary angioedema, as it may worsen the condition 6, 1
• Pre-existing liver disease is a contraindication due to hepatotoxicity risk 1
• Caution is advised in patients with history of thromboembolic disorders, particularly when combined with estrogens 1

Adverse Effects Profile

Common Side Effects

• Occasional fatigue due to partial adrenal insufficiency was reported in some patients 2
• Gynecomastia occurred in a few boys treated for precocious puberty 2
• In transgender adolescents, reported side effects included breast tenderness, emotionality, fatigue, and hot flushes 4

Metabolic and Hematologic Effects

• Hemoglobin and hematocrit decreased during treatment 4
• Liver enzymes showed transient and modest increases during cyproterone acetate monotherapy 4
• Triglycerides and cholesterol levels slightly decreased during monotherapy but returned to baseline when combined with estradiol 4
• Glucose metabolism remained unaffected 4
• No clinically significant weight changes were observed 4

Hormonal Effects

• Gonadotropins decreased when cyproterone acetate was combined with estradiol 4
• Total and free testosterone levels decreased throughout treatment 4
• Prolactin levels increased during cyproterone acetate monotherapy but normalized when combined with estradiol 4
• Despite treatment, gonadotropin release from the pituitary remained evident after LRH injection, even after several months of therapy 7

Practical Dosing Considerations

For Precocious Puberty (Historical Reference Only)

• Oral administration proved superior to intramuscular depot injections 3
• Oral dosing: 70-150 mg/m² per day (typically 50 mg twice daily) 2, 3
• Intramuscular depot: 107-230 mg/m² once every 2-4 weeks (less effective) 3
• Treatment duration in historical studies ranged from 6 months to over 3 years 3, 5

For Transgender Adolescents (When GnRH Analogues Unavailable)

• Initiate with cyproterone acetate monotherapy for at least 6 months (mean 12 months in studies) 4
• Subsequently combine with incremental doses of estradiol (mean 16 months in studies) 4
• Specific dosing protocols should follow transgender healthcare guidelines and be managed by specialists experienced in this population 1

Clinical Pitfalls to Avoid

• Do not use cyproterone acetate as first-line therapy for central precocious puberty when GnRH analogues are available, as they are safer and more effective 2
• Never prescribe cyproterone acetate without establishing a rigorous liver function monitoring protocol given the documented hepatotoxicity risk 1, 2, 5
• Avoid cumulative doses exceeding 500g when possible, as hepatoma risk increases substantially above this threshold 5
• Do not overlook the need for adrenal function monitoring, as partial adrenal insufficiency can occur 2
• Screen carefully for hereditary angioedema before initiating treatment, as cyproterone acetate is absolutely contraindicated in this population 6, 1

Monitoring Requirements

• Baseline and regular liver function tests throughout treatment 1, 2
• Monitor for signs of adrenal insufficiency (fatigue, weakness) 2
• Assess growth velocity and bone age in patients with precocious puberty 3
• Monitor testosterone levels to assess treatment efficacy 7, 4
• Regular clinical assessment for feminization progress in transgender patients 4

Alternative Treatments to Consider First

• GnRH analogues are the current standard of care for central precocious puberty and should be used preferentially over cyproterone acetate 2
• For transgender adolescents, GnRH analogues remain the preferred antiandrogen approach when available and reimbursed 4
• Combined oral contraceptives containing progestins other than cyproterone acetate (such as levonorgestrel or norgestimate) are safer alternatives for hormonal management in adolescent females when appropriate 6, 8