Delayed Puberty

Delayed Puberty 

Delayed puberty is clinically defined as the absence or incomplete development of secondary sexual characteristics by an age at which 95% of the population begins to mature sexually.

0For girls, a delay in puberty is defined as an absence of breast bud development by age 13 or absence of menarche within 3 yr of thelarche; for boys, delay is defined as absence of testicular enlargement by age 14.

Synonym

  • Pubertal delay

Epidemiology & Demographics

Prevalence

The overall prevalence for children presenting with delayed puberty is unknown. The prevalence of congenital hypogonadotropic hypogonadism, however, is estimated at 1 out of 4000 to 10,000 males and is reported to be twofold to fivefold less frequent in females.

Genetics

Constitutional delay of growth and puberty (CDGP) is mostly inherited in an autosomal dominant fashion, with at least one parent with a history of delayed puberty. However, underlying genetic mechanisms are complex.

Congenital hypogonadotropic hypogonadism can be either sporadic or familial and has a stronger genetic predisposition. These instances are linked to either defects in gonadotropin-releasing hormone (GnRH) biosynthesis, secretion, poor maturation, or loss of GnRH function itself.

Hypergonadotropic hypogonadism from gonadal dysgenesis is often a result of underlying aneuploidy of sex chromosomes. Turner and Klinefelter syndromes are two well-known examples of this. 

The below table provides more details on the genetic etiologies involved in delayed puberty.

Causes of Delayed Puberty Other Than Constitutional Delay of Growth and Puberty

Adapted from Sperling MA: Sperling pediatric endocrinology, ed 4, Philadelphia, 2014, Elsevier, 697-733.

Hypergonadotropic HypogonadismPermanent Hypogonadotropic HypogonadismFunctional Hypogonadotropic Hypogonadism
Genetic syndromes
 Noonan syndrome and related disorders
Cryptorchidism
Gonadal dysgenesis
Vanishing testes syndrome
Trauma/testicular torsion
Chemotherapy/radiation therapy
Gonadal infection
 Mumps, Coxsackie
Autoimmune orchitis
Defects in steroidogenesis
 5-alpha reductase deficiency (SR5A2)
 17, 20 lyase deficiency (CYP17A1)
 Congenital lipoid adrenal hyperplasia (StAR)
 17-hydroxysteroid dehydrogenase deficiency (HSD17B3)
Androgen insensitivity
Sertoli cell only syndrome (Del Castillo syndrome)
CNS tumors/infiltrative diseases
 Astrocytoma
 Germinoma
 Glioma
 Craniopharyngioma
 Prolactinoma
 Langerhans cell histiocytosis
Rathke’s pouch cyst
Genetic defects
 Kallmann syndrome (KAL1, FGFR1, PROK2, PROKR2, FGF8, HS6ST1, and CHD7)
—Isolated hypogonadotropic hypogonadism (KAL1, GNRHRGNRH1GPR54FGFR1FGF8PROK2PROKR2TAC3TACR3, HS6ST1NELF, and CHD7)
 HPG axis development (DAX1, SF-1HESX-1LHX3, and PROP-1)
 Obesity and hypogonadotropic hypogonadism (LEP, LEPR, and PC1) syndromes
 Prader-Willi
 Bardet-Biedl
 CHARGE
Gaucher disease
Postcentral nervous system infection
Midline defects
 Septo-optic dysplasia
 Congenital hypopituitarism
Chemotherapy/radiation therapy
Trauma
Systemic illness/conditions
 Cystic fibrosis
 Asthma
 Inflammatory bowel disease
 Celiac disease
 Juvenile rheumatoid arthritis
 Anorexia nervosa/bulimia
 Sickle cell disease
 Hemosiderosis
 Thalassemia
 Chronic renal disease
 AIDS
Endocrinopathies
 Diabetes mellitus
 Hypothyroidism
 Hyperprolactinemia
 Growth hormone deficiency
 Cushing syndrome
Excessive exercise
Malnutrition

CNS, Central nervous system.

Physical Findings & Clinical Presentation

  • •Girls with pubertal delay have an absence of breast development by age 13.
  • •Boys with pubertal delay will have testes <2.5 cm or <4 ml by age 14. Other signs in boys may include cryptorchidism, hypospadias, and micropenis.
  • •Short stature and/or lack of pubertal growth spurt is often noted, especially in CDGP.
  • •Anosmia (in Kallman syndrome); webbed neck, widely spaced nipples, increased pigmented nevi (in Turner syndrome); and low IQ, gynecomastia in males, and abnormal facial/pubic hair distribution (in Klinefelter syndrome) are commonly present with some other causes of pubertal delay.
  • •Markers of chronic disease, nutritional status, neurologic abnormalities, and thyroid abnormalities should be assessed as well.

Etiology

Causes for pubertal delay can be separated into four categories (from most to least common):

  • 1.CDGP: A self-limited delay in puberty that is more common in boys than in girls (60% vs. 30%). Patients typically have growth deceleration during the first few yr of life followed by a normal growth rate (4 to 6 cm per yr) along lower height percentiles. Pubertal growth spurt is often delayed, and spontaneous pubertal onset occurs by age 18 in most cases.
  • 2.Functional hypogonadotropic hypogonadism (FHH): This is a transient form of delayed puberty caused by delayed maturation of hypothalamic-pituitary-gonadal (HPG) axis. FHH may be secondary to malnutrition from excessive weight loss (below the level of 80% of ideal body weight), chronic disease, excessive exercise, or stress leading to elevated cortisol and proinflammatory cytokines. Children with FHH have a lower than normal growth rate for chronologic age and low levels of gonadotropins and sex steroids. Once the disease state and/or nutrition level is corrected, puberty is often reinstated.
  • 3.Hypergonadotropic hypogonadism: This is caused by primary gonadal failure; organic dysfunctions that result in gonadal failure despite adequate hypothalamic-pituitary function. Serum gonadotropins are elevated by the time of puberty with low sex steroids, leading to absence or developmental arrest of secondary sex characteristics.
  • 4.Permanent hypogonadotropic hypogonadism (PHH): This category may be congenital (secondary to genetic defects) or acquired, leading to suppression of the HPG axis. Serum gonadotropins are usually low with low levels of sex steroids, leading to the absence or developmental arrest of secondary sex characteristics.

Workup

  • •Given the extensive differential diagnosis for pubertal delay, a systematic and focused approach is necessary. A careful history, including family and social history, can identify eating and exercise habits, chronic illnesses, weight loss or poor weight gain, changes in bowel habits, and parental history of pubertal delay. 
  • •Auxologic measurement should include height and weight, a growth chart to assess growth velocity, and calculation of the sex-adjusted mid-parental height

Laboratory Tests

  • •Testing serum luteinizing hormone, follicle-stimulating hormone, testosterone (in males), and estradiol (in females) can help establish delayed puberty as well as distinguish between disorders of hypogonadotropic and hypergonadotropic hypogonadism. Laboratory tests alone may not be able to distinguish between CDGP and PHH, although a low inhibin B level in males may point to a diagnosis of PHH over CDGP.
  • •Complete blood count, complete metabolic panel, erythrocyte sedimentation rate, thyroid-stimulating hormone, free thyroxine, prolactin, testosterone (males), estradiol (females), cortisol, and insulin-like growth factor 1 should be drawn when indicated.
  • •Chromosomal analysis is indicated if there is suspicion of gonadal dysgenesis.

Imaging Studies

Bone age skeletal radiograph of the left hand and wrist determines skeletal age, which can be delayed in children with CDGP and PHH. MRI of the head should be considered if there is high clinical suspicion for intracranial tumors or structural abnormalities. Pelvic ultrasound can be helpful in detecting intraabdominal testes and for evaluating pelvic anatomy and maturity.

 Treatment

  • •CDGP can be managed with reassurance and longitudinal assessments. However, short-term therapy with either low-dose testosterone (in boys) or estrogen (in girls) can help to hasten puberty and improve psychological well-being. In boys, intramuscular depot testosterone in doses of 50 to 100 mg every 4 wk for 3 to 6 mo is considered safe and therefore most commonly used. For girls, there are four options for the induction of puberty: Oral ethinylestradiol, oral conjugated estrogens, and oral or transdermal forms of 17β-estradiol.
  • •Malnutrition and chronic disease can best be treated by correcting the underlying cause. A short (3-6 months) treatment course, as previously described, may be indicated for children with psychosocial difficulties.
  • •Permanent causes of pubertal delay are treated as with CDGP, but dosages are gradually increased to adult doses over 3 to 4 yr. In girls, cyclic progesterone is added approximately 2 yr from the start of estrogen therapy, or sooner, at the time of menarche.
  • •The below table summarizes hormonal substitution therapy in hypogonadism.

Hormonal Substitution Therapy in Hypogonadism

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier, 2019.

Boys
•Goal: To approximate normal adolescent development when diagnosis is established•Initial therapy: At 13 yr of age, testosterone enanthate (or other long-acting testosterone ester) 50 mg IM every month for ∼9 mo (6-12 mo)•Over the next 3-4 yr: Gradually increase dose to adult replacement dose of 200 mg q2-3wk•Testosterone gel is coming into widespread use, as discussed in the text•Begin replacement therapy in boys with suspected hypogonadotropic hypogonadism by bone age ≤14 yr•To induce fertility at appropriate time in hypogonadotropic hypogonadism: Pulsatile GnRH or FSH and hCG therapy
Girls
With a firmly established diagnosis of hypogonadism (e.g., girls with 45,X gonadal dysgenesis), begin hormonal substitution therapy at age 12-13 yr•Goal: To approximate normal adolescent development•Initial therapy: Ethinylestradiol 5 mg PO or conjugated estrogen 0.3 mg (or less) PO daily for 4-6 mo or preferably estradiol transdermally•After 6 mo of therapy (or sooner if breakthrough bleeding occurs), begin cyclic therapy:1.Estrogen: First 21 days of month2.Progestogen (e.g., medroxyprogesterone acetate 5 mg PO) days 12-21 monthly3.Gradually increase dose of estrogen over next 2-3 yr to conjugated estrogen 0.6-1.25 mg or ethinylestradiol 10-20 mg daily for first 21 days of month, or estradiol patch•In hypogonadotropic hypogonadism, to induce ovulation at appropriate time: Pulsatile GnRH or FSH and hCG therapy

FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; PO, orally; q, every.

Referral

Pediatric endocrinology

Patient & Family Education

Seek Additional Information

  • Harrington J., Palmert M.R.: Clinical review: distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin Endocrinol Metab 2012; 97: pp. 3056-3067.
  • Howard S.R., Dunkel L.: Delayed puberty-phenotypic diversity, molecular genetic mechanisms, and recent discoveries [published correction appears in Endocr Rev. 2020 Feb 1;41(1)]. Endocr Rev 2019; 40 (5): pp. 1285-1317.
  • Lazar L., Phillip M.: Pubertal disorders and bone maturation. Endocrinol Metab Clin North Am 2012; 41 (4): pp. 805-825.
  • Palmert M.R., Dunkel L.: Delayed puberty. N Engl J Med 2012; 166: pp. 443-453.
  • Wei C., Crowne E.C.: Recent advances in the understanding and management of delayed puberty. Arch Dis Child 2016; 101 (5): pp. 481-488.
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