Delayed puberty medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Overview

The mainstay of pharmacological medical therapy for delayed puberty is sex hormone replacement therapy. The aim of treatment is to initiate the process of puberty and to merge the secondary sexual characteristics in patients. Since delayed puberty occurs only in adolescents, therapy is targeted towards this age group. The various formulations of estrogen, progesterone, and testosterone are used in both genders for medical therapy of delayed puberty. Other types of treatments are low-dose oxandrolone, dihydrotestosterone (DHT), and kisspeptin agonist.

Medical Therapy

General approach to pharmacological medical therapy for delayed puberty[1]

 
 
 
 
 
 
 
 
Delayed Puberty
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Clinical history
• Physical examinations
• Pubertal phenotype
• Left wrist radiograph for bone age
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unremarkable
 
 
 
 
Abnormal
 
 
 
 
Chronic disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Delayed puberty
• Lack of growth spurt
Bone age delayed upon chronological age
 
 
 
 
• Possibility of chromosomal disorder
Bone age may delayed
 
 
 
 
• Chronic disease
• Decreased growth rate or short stature
Bone age delayed upon chronological age
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis:
Constitutional delay of growth and puberty (CDGP)
Gonadotropin deficiency
• Primary gonadal failure
• Extreme athletic exercise
 
 
 
 
Diagnosis:
Girls:
Turner syndrome
Boys:
Klinefelter syndrome
 
 
 
 
Diagnosis:
Hypopituitarism
• Chronic systemic diseases
Anorexia nervosa
• Malnutrition
Kallman syndrome
Iatrogenic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Actions:
• Evaluation hypothalamus-pituitary-gonadal axis
• Consider an MRI to exclude the CNS lesions
 
 
 
 
Actions:
Chromosome analysis (Karyotyping)
 
 
 
 
Actions:
• Upon the underlying disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment:
1. Psychologic support
2. Observation
3. Sex hormone replacement therapy
 
 
 
 
Treatment:
1. Psychologic support
2. Sex hormone replacement
3. Excision of ovaries in Turner syndrome because of risk of malignancy
 
 
 
 
 
 
 


Delayed puberty[2]

  • 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): Anastrozole 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: 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
        • 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 20 μg/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

All medical therapy options for delayed puberty at a glance[2][3][4]

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
  • Year 1: 2 μg daily
  • Year 2: 4 μg daily
  • Year 2½: 6 μg daily
  • Year 3: 8 μg daily
  • Year 3½: 10 μg daily
  • Adult dose: 20–30 μg daily
  • Hepatotoxicity
  • Increasing plasma binding proteins
  • Higher risks of thromboembolism and arterial hypertension than natural estrogens.
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 patch or gel

(Evorel 25 patches= 25 μg/24 h)

  • 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
  • Year 1: Evorel 25 ¼ patch twice a week
  • Year 2: Evorel 25 ½ patch twice a week
  • Year 2½: Evorel 25 alternate ½ and whole patch twice a week
  • Year 3: Evorel 25 whole patch twice a week
  • Adult dose: Evorel 50 whole patch twice a week
-
  • 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
Progestogens Progestogens/Progestins PO
  • Only if treatment continues longer than 12 months
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 SC
  • Not recommended routinely
-
Boys Testosterone 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.
PO
  • No data available
  • Initial dose 40 mg once daily
  • Titrated up every 6 months to a maximum dose of 80 mg three times a day after 2–3 years
  • Adult dose is 1000 mg every 10-14 weeks
Transdermal
  • No data available
  • Initial dose 10–20 mg (1–2 metered applications) daily
  • Increase by 10 mg per 6 months to 60–80 mg in 3–4 years
  • Adult dose 50-80 mg daily
  • Local irritation
  • Avoid close skin contact after applying
Aromatase inhibitors PO
  • 2.5 mg daily
  • No data available
PO
  • 1.0 mg daily
  • No data available
-
Pulsatile GnRH SC
  • Not recommended routinely
  • Initial dose 5-25 ng/kg/pulse every 90-120 min
  • Maintenance dose increase to 25-600 ng/kg/pulse
-
Combination therapy
  • Not recommended routinely
  • hCG
    • 500 to 3000IU twice weekly
    • Increased to every 2 days
    • Dose adjusted based on serum testosterone levels
  • FSH
    • 75 to 225 IU 2-3 times weekly.
Synthetic anabolic steroid PO
  • Initial dose 0.1 mg/kg/day
  • Maintenance 2.5 mg/day for 3–12 months
  • No data available
  • Adjuvant therapy to speed up the height growth
  • The effect would be continued after treatment
Androgen sex steroid IM
  • 50 mg every 2 weeks, for 4 months
  • No data available

Other types of treatments

Low-dose oxandrolone

Dihydrotestosterone (DHT)

Testosterone (other therapeutic regimens)

  • Recently, researchers suggested that twice monthly low doses of testosterone with gradual and periodic increase would be better for CDGP management, especially in early to middle stages of puberty.
  • The protocol consists of:[3]
  1. Testosterone enanthate IM 15 mg Q 2 weeks for 2 months
  2. Testosterone enanthate IM 20 mg Q 2 weeks for 2 months
  3. Testosterone enanthate IM 25 mg Q 2 weeks for 2 months
  4. Testosterone enanthate IM 30 mg Q 2 weeks for 2 months
  5. Testosterone enanthate IM 35 mg Q 2 weeks for 2 months
  6. Testosterone enanthate IM 40 mg Q 2 weeks for 2 months
  7. Testosterone enanthate IM 45 mg Q 2 weeks for 2 months
  8. Testosterone enanthate IM 50 mg Q 2 weeks for 2 months
  9. Testosterone enanthate IM 60 mg Q 2 weeks for 2 months.

Kisspeptin-10 agonist

Reference

  1. Blondell RD, Foster MB, Dave KC (1999). "Disorders of puberty". Am Fam Physician. 60 (1): 209–18, 223–4. PMID 10414639.
  2. 2.0 2.1 Palmert, Mark R.; Dunkel, Leo (2012). "Delayed Puberty". New England Journal of Medicine. 366 (5): 443–453. doi:10.1056/NEJMcp1109290. ISSN 0028-4793.
  3. 3.0 3.1 3.2 3.3 Soliman AT, De Sanctis V (2012). "An approach to constitutional delay of growth and puberty". Indian J Endocrinol Metab. 16 (5): 698–705. doi:10.4103/2230-8210.100650. PMC 3475892. PMID 23087852.
  4. Wei C, Crowne EC (2016). "Recent advances in the understanding and management of delayed puberty". Arch. Dis. Child. 101 (5): 481–8. doi:10.1136/archdischild-2014-307963. PMID 26353794.
  5. Hero M, Toiviainen-Salo S, Wickman S, Mäkitie O, Dunkel L (2010). "Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty". J. Bone Miner. Res. 25 (7): 1536–43. doi:10.1002/jbmr.56. PMID 20200972.
  6. Wickman S, Dunkel L (2001). "Inhibition of P450 aromatase enhances gonadotropin secretion in early and midpubertal boys: evidence for a pituitary site of action of endogenous E". J. Clin. Endocrinol. Metab. 86 (10): 4887–94. doi:10.1210/jcem.86.10.7927. PMID 11600558.
  7. Crowne EC, Wallace WH, Moore C, Mitchell R, Robertson WH, Holly JM, Shalet SM (1997). "Effect of low dose oxandrolone and testosterone treatment on the pituitary-testicular and GH axes in boys with constitutional delay of growth and puberty". Clin. Endocrinol. (Oxf). 46 (2): 209–16. PMID 9135704.
  8. Joss EE, Schmidt HA, Zuppinger KA (1989). "Oxandrolone in constitutionally delayed growth, a longitudinal study up to final height". J. Clin. Endocrinol. Metab. 69 (6): 1109–15. doi:10.1210/jcem-69-6-1109. PMID 2584350.
  9. Saad RJ, Keenan BS, Danadian K, Lewy VD, Arslanian SA (2001). "Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty?". J. Clin. Endocrinol. Metab. 86 (10): 4881–6. doi:10.1210/jcem.86.10.7913. PMID 11600557.
  10. George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA (2013). "Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism". Clin. Endocrinol. (Oxf). 79 (1): 100–4. doi:10.1111/cen.12103. PMID 23153270.



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