Delayed puberty medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Medical Therapy

General approach to pharmacological medical therapy for delayed puberty

• Generally, the main pharmacological medical therapy for delayed puberty is sex hormone replacement therapy.
• The aim of treatment is to initiate the puberty progress and to merge the secondary sexual characteristics in patients.
• Regarding that the delayed puberty involve only adolescents, all of the therapy options are for them.

Delayed puberty

• 1 Stage 1 - Constitutional delay of growth and puberty
  • 1.1 Boys
    • Preferred regimen (1): Testosterone, not indicated before 14 years of age
      • Initial dose: 50-100 mg IM every 4 weeks for 3-6 months
      • Repeated treatment: To add 25-50 mg in dose (maximum, 100 mg per dose)
    • Preferred regimen (2): Letrozole 2.5 mg PO per day
    • Preferred regimen (3): Anastozole 1mg PO per day
  • 1.2 Girls
    • Preferred regimen (1): Ethinyl estradiol (EE)
      • Initial dose: 2 μg PO per day for 6-12 months
      • Repeated treatment: Increase to 5 μg PO per day after 6-12 months
    • Preferred regimen (2): 17β-estradiol (pill)
      • Initial dose: 5 μg/kg PO per day for 6-12 months
      • Repeated treatment: Increase to 10 μg/kg PO per day after 6-12 months
    • Preferred regimen (3): 17β-estradiol (transdermal patch)
      • Initial dose: 3.1-6.2 μg (1/8-1/4 of 25 μg patch) per day for 6 months
      • Repeated treatment: Increase 3.1-6.2 μg (1/8-1/4 of 25 μg patch) per day every 6 months
    • Preferred regimen (4): Conjugated equine estrogens (CEE)
      • Initial dose: 0.1625 mg PO per day for 6-12 months
      • Repeated treatment: Titrating to 0.325 mg PO per day after 6-12 months
    • Alternative regimen (1): Progestogens/Progestins in various formulations, only if treatment last more than 12 months

• 2 Stage 2 - Hypogonadism
  • 2.1 Pediatric
    • 2.1.1 Boys
      • Preferred regimen (1): Testosterone, can be started after 12 years of age
        • Initial dose of 50 mg IM per month
        • Increase with 50 mg in dose IM every 6-12 months
        • After reaching 100-150 mg IM monthly, decrease interval to every 2 weeks
      • Preferred regimen (2): Pulsatile GnRH
        • Initial dose: 5-25 ng/kg/pulse SC every 90-120 min
        • Continued treatment: Increase to 25-600 ng/kg/pulse SC every 90-120 min
      • Alternative regimen (1): Testosterone undecanoate 1000 mg IM every 10-14 weeks
      • Alternative regimen (2): Testosterone gel, apply at bed time
        • Started when approximately 50% adult dose has been achieved with intramuscular testosterone
      • Alternative regimen (3): hCG plus recombinant FSH
        • hCG: 500 to 3000 IU SC or IM twice weekly, increased to every 2 days
        • rhFSH: 75 to 225 IU SC 2-3 times weekly
    • 2.1.2 Girls
      • Preferred regimen (1): Ethinyl estradiol (EE)
        • Initial dose: 2 μg PO per day for 6-12 months
        • Repeated treatment: Increase every 6-12 months to 5 μg, 10 μg, and 20 μg PO per day
      • Preferred regimen (2): 17β-estradiol (pill)
        • Initial dose: 5 μg/kg PO per day for 6-12 months
        • Repeated treatment: Increase to 10 μg/kg PO per day after 6-12 months, then to 15 μg/kg, and to 20μg/kg per day
      • Preferred regimen (3): 17β-estradiol (transdermal patch)
        • Initial dose: 3.1-6.2 μg (1/8-1/4 of 25 μg patch) per day for 6 months
        • Repeated treatment: Increase 3.1-6.2 μg (1/8-1/4 of 25 μg patch) per day every 6 months
      • Preferred regimen (4): Conjugated equine estrogens (CEE)
        • Initial dose: 0.1625 mg PO per day for 6-12 months
        • Repeated treatment: Increase every 6-12 months to 0.325, 0.45, and 0.625 mg PO per day
      • Alternative regimen (1): Progestogens/Progestins in various formulations, only if treatment last more than 12 months
  • 2.1 Adults
    • 2.1.1 Male
      • Preferred regimen (1): Testosterone 200 mg IM every 2 weeks
      • Preferred regimen (2): Testosterone undecanoate 1000 mg IM every 10-14 weeks
      • Preferred regimen (3): Testosterone gel 50-80 mg transdermal per day
      • Alternative regimen (1): Pulsatile GnRH
        • Initial dose: 5-25 ng/kg/pulse SC every 90-120 min
        • Continued treatment: Increase to 25-600 ng/kg/pulse SC every 90-120 min
      • Alternative regimen (2): hCG plus recombinant FSH
        • hCG: 500 to 3000 IU SC or IM twice weekly, increased to every 2 days
        • rhFSH: 75 to 225 IU SC 2-3 times weekly
    • 2.1.2 Female
      • Preferred regimen (1): Ethinyl estradiol (EE) 20 μg PO per day
      • Preferred regimen (2): 17β-estradiol (pill) 1-2 mg PO per day
      • Preferred regimen (3): 17β-estradiol (transdermal patch) 50-100 μg transdermal per day
      • Preferred regimen (4): Conjugated equine estrogens (CEE) 0.625 mg PO per day
      • Alternative regimen (1): Progestogens/Progestins 5-10 mg of medroxyprogesterone acetate (MPA) PO per day during the last 7 days of menstrual cycle
      • Alternative regimen (2): Micronized progesterone 100-200 μg PO per day

	Group	Medicine	Route	Constitutional Delay of Growth and Puberty (CDGP)	Hypogonadism	Side effects	Notes
Girls	Estrogen	Ethinyl estradiol (EE)	PO	Initial dose 2 μg daily. Increase after 6-12 months to 5 μg daily	Initial dose 2 μg daily. Increase every 6 to 12 months to 5 μg, 10 μg, and 20 μg daily (adult dose).	Hepatotoxicity Increasing plasma binding proteins Higher risks of thromboembolism and arterial hypertension than natural estrogens.	Component of oral contraceptive pills. Lower dose EE oral pills are available in Europe.
		17β-estradiol	PO	Initial dose 5 μg/kg daily Increase after 6-12 months to 10 μg/kg daily	Initial dose 5 μg/kg daily Increase every 6-12 months to 10 μg/kg daily, then to 15 μg/kg, and to 20μg/kg daily. Adult dose 1-2 mg daily.	Transdermal is better than oral administration.	Natural estrogen is preferable to synthetic estrogens.
			Transdermal patch or gel	Initial dose 3.1-6.2 μg/24h (1/8-1/4 of 25 μg/24h patch) Increase by 3.1-6.2 μg/24h every 6 months	Initial dose 3.1-6.2 μg/24h (1/8-1/4 of 25 μg/24h patch) Increase by 3.1-6.2 μg/24h every 6 months. Adult dose 50-100 μg/24h	-	Patches applied overnight Topical gel applied during the day No dosage equivalent data between patches and gel available in younger patients
		Conjugated equine estrogens (CEE)	PO	Initial dose 0.1625 mg daily for 6-12 months, and then titrating to 0.325 mg daily Dosing depends on formulation	Initial dose 0.1625 mg for 6-12 months, increase every 6-12 months to 0.325, 0.45, and 0.625 mg daily Common adult dose 0.625 mg	Use cautiously because of reported increased cardiovascular risks in postmenopausal women	CEE are not estradiol precursors.
	Progestogens	Progestogens/Progestins	PO	Only if treatment continues longer than 12 months	5-10 mg of medroxyprogesterone acetate (MPA) daily during the last 7 days of menstrual cycle. Alternative: micronized progesterone, dose 100-200 μg daily.	-	Progesterone added to induce endometrial cycling after 12-18 months of estrogen therapy: Later if estrogen dose increased slowly Sooner if break-through bleeding
	Pulsatile GnRH	Subcutaneous pump	SC	Not recommended routinely	Used for fertility	-	Very expert route of treatment Most physiological form therapy
Boys	Testosterone	Testosterone enanthate (most potent) Testosterone cypionate Testosterone propionate	IM	Not recommend for less than 14 years old. Initial dose 50-100 mg every 4 weeks for 3 to 6 months Repeated treatment with 25-50 mg increment in dose (not exceeding 100 mg)	Can administered after 12 years old. Initial dose 50 mg every 4 weeks. Increase with 50 mg increments every 6 to 12 months. After reaching 100-150 mg monthly, decrease interval to every 2 weeks. Adult dose 200 mg every 2 weeks.	Local side effects (pain, erythema, inflammatory reaction, and sterile abscess). Priapism can occur in patients with sickle cell disease.	General side effects: Erythrocytosis Weight gain Prostate hyperplasia High doses can cause premature epiphyseal closure Not for use in boys with bone age < 10 years
		Testosterone undecanoate	IM	No data available	Adult dose is 1000 mg every 10-14 weeks
		Testosterone gel	Transdermal	No data available	Initiated when approximately 50% adult dose achieved with IM testosterone Adult dose 50-80 mg daily	Local irritation Avoid close skin contact after applying
	Aromatase inhibitors	Letrozole	PO	2.5 mg daily	No data available	Decreased level of high-density lipoprotein (HDL) cholesterol Erythrocytosis Vertebral deformities	Not yet approved for this indication. After onset of puberty, may increase gonadotropin secretion and circulating testosterone levels.
		Anastozole	PO	1.0 mg daily	No data available	-
	Pulsatile GnRH	Subcutaneous pump	SC	Not recommended routinely	Initial dose 5-25 ng/kg/pulse every 90-120 min Maintenance dose increase to 25-600 ng/kg/pulse	-	Very expert route of treatment Most physiological form therapy
	Combination therapy	hCG plus recombinant FSH	subcutaneous or intramuscular hCG subcutaneous rhFSH	Not recommended routinely	hCG 500 to 3000IU twice weekly Increased to every 2 days Dose adjusted based on serum testosterone levels rhFSH 75 to 225 IU 2-3 times weekly.	hCG Testicular local inflammation Maybe germ cell apoptosis	In hypogonadotropic hypogonadism with prepubertal onset, in order to testicular development and also spermatogenesis, FSH is needed. No data on effects on future fertility.