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

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.

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
      - 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 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
  - 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

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.	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.
		17β-estradiol	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	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.	Mild nausea Diarrhea Bloating Dizziness Hot flashes Headache	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	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
		Testosterone gel	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	Letrozole	PO	2.5 mg daily	No data available	Decreased level of high-density lipoprotein (HDL) cholesterol Erythrocytosis Vertebral deformities^[5]	Not yet approved for this indication. After onset of puberty, may increase gonadotropin secretion and circulating testosterone levels.^[6]
	Aromatase inhibitors	Anastrazole	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 FSH	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.	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.
	Synthetic anabolic steroid	Oxandrolone	PO	Initial dose 0.1 mg/kg/day Maintenance 2.5 mg/day for 3–12 months	No data available	Gynecomastia Impotence Priapism Bladder irritability	Adjuvant therapy to speed up the height growth The effect would be continued after treatment
	Androgen sex steroid	Dihydrotestosterone (DHT)	IM	50 mg every 2 weeks, for 4 months	No data available	Dry skin Changes in bowel habits Dry mouth Muscle pain Increased thirst Hypertension Loss of appetite Weight loss	It can result in: Appearance of secondary sex characteristics Decreased body fat percentage with no change in IGF-I, GH, and estradiol concentrations

Other types of treatments

Low-dose oxandrolone

It is used in constitutional delay of growth and puberty (CDGP). The main purpose of the oxandrolone is to speed up the height.^[3]
The increase in the height continues even after treatment is stopped.^[7]
The use of this medication earlier in the disease process is an advantage. However, other treatment options are available if puberty is delayed later.^[8]

Dihydrotestosterone (DHT)

This drug can help patients with CDGP to develop secondary sex characteristics (Tanner II), increase lean body mass, and decreased body fat percentage; with no change in IGF-I, mean nocturnal GH, and estradiol concentrations.^[9]
Theoretically, lack of estradiol can affect the final adult height, that a child with CDGP could reach in the future; like the influence of adding aromatase inhibitor.^[3]

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]

Testosterone enanthate IM 15 mg Q 2 weeks for 2 months
Testosterone enanthate IM 20 mg Q 2 weeks for 2 months
Testosterone enanthate IM 25 mg Q 2 weeks for 2 months
Testosterone enanthate IM 30 mg Q 2 weeks for 2 months
Testosterone enanthate IM 35 mg Q 2 weeks for 2 months
Testosterone enanthate IM 40 mg Q 2 weeks for 2 months
Testosterone enanthate IM 45 mg Q 2 weeks for 2 months
Testosterone enanthate IM 50 mg Q 2 weeks for 2 months
Testosterone enanthate IM 60 mg Q 2 weeks for 2 months.

Kisspeptin-10 agonist

It stimulates the hypothalamus-pituitary-gonadal (HPG) axis and plays role in treatment of idiopathic hypogonadotropic hypogonadism.
In male patients the kisspeptin agonist infusion can increase the testosterone level.^[10]

Reference

↑ Blondell RD, Foster MB, Dave KC (1999). "Disorders of puberty". Am Fam Physician. 60 (1): 209–18, 223–4. PMID 10414639.
↑ ^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.
↑ ^3.0 ^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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

Template:WS Template:WH

[pmid10414639-1] Blondell RD, Foster MB, Dave KC (1999). "Disorders of puberty". Am Fam Physician. 60 (1): 209–18, 223–4. PMID 10414639.

[PalmertDunkel2012-2] 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.

[pmid23087852-3] 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.

[pmid26353794-4] 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.

[pmid20200972-5] 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.

[pmid11600558-6] 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.

[pmid9135704-7] 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.

[pmid2584350-8] 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.

[pmid11600557-9] 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.

[pmid23153270-10] 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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