Delayed Puberty

Delayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay. Classified as central or gonadal, delayed puberty has multiple etiologies, expressed as a lack of development of secondary sexual characteristics. Diagnosis is made by clinical criteria and confirmed through laboratory testing. Management involves sex-steroid replacement therapy when indicated.

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Overview

Definitions

  • Delayed puberty (DP) is also called sexual infantilism.
  • DP in boys: no testicular enlargement by age 14
  • DP in girls: no thelarche (onset of secondary breast development) by age 13

Epidemiology

  • Affects 2.5%–5% of healthy boys and girls
  • Constitutional growth delay accounts for 50% of cases.
  • Primary hypogonadism accounts for 13% of cases.
  • Types of DP:
    • Constitutional growth delay
      • 50% of cases
      • Often family history of delay
      • Can be associated with high athletic performance
    • Central (hypogonadotropic hypogonadism): problem with the pituitary gland (↓ secretion of gonadotropins; luteinizing hormone (LH) and follicle-stimulating hormone (FSH))
    • Gonadal (hypergonadotropic hypogonadism): problem with testes/ovaries (↓ sensitivity to gonadotropins)

Etiology

Delayed puberty is most commonly a constitutional growth delay or normal variant in child development.

When hypogonadism is the cause of delayed puberty, it can be central or gonadal in origin.

Causes of hypogonadism:

  • Central (gonadotropin problem):
    • Isolated deficiency and anosmia (Kallmann syndrome)
    • Functional (anorexia nervosa, athletic amenorrhea)
    • Pituitary hormone deficiency 
    • Brain tumors: pituitary adenoma, glioma, prolactinoma, craniopharyngioma, astrocytoma
    • Chronic illness: celiac disease, chronic inflammatory bowel disease, hypothyroidism, severe asthma, cystic fibrosis
    • Chemotherapy or radiation
  • Gonadal (primary gonadal failure): 
    • Klinefelter syndrome (karyotype 47,XXY)
    • Turner syndrome (karyotype 45,XO)
    • Acquired primary hypogonadism (trauma, irradiation of the testes)
    • Autoimmune-related gonadal
    • Congenital adrenal hyperplasia: unable to synthesize sex steroids (rare)
    • Disorders of sex development (complete androgen insensitivity, gonadal dysgenesis, testicular regression or “vanishing testes” syndrome)
    • Chemotherapy or radiation

Clinical Presentation

History

  • A family history of delayed puberty
  • Undernutrition 
  • High exercise intensity
  • Chronic disease
  • Affected sense of smell (anosmia, hyposmia)
  • Cryptorchidism (when 1 or both of the testes fails to descend into the scrotum)
  • Midline or ventral developmental defects (neural tube defects, oral-facial clefts, anal/rectal defects, diaphragmatic defects, and abdominal wall defects)
  • Malignancy treated with chemotherapy and radiation

Physical examination

  • Pediatric growth charts: height percentile, weight percentile, and growth velocity
  • Tanner staging for secondary sexual characteristic classifications (see charts below) 
  • Monitor testicular growth and penile length:
    • Testes’ length > 2.5 cm and penile length > 3 cm indicate the onset of puberty.
    • Testicular size should be measured by a Prader orchidometer (wooden beads to assist the provider in sizing the testes). 
    • A micropenis is indicative of hypogonadotropic hypogonadism.
  • Breast buds development in girls signifies the onset of puberty.
  • Eunuchoid proportionality (in Klinefelter syndrome) 
    • Arm span 5 cm > height
    • Upper-to-lower segment ratio of < 0.9 
  • Neurological abnormalities
  • Signs of adrenarche (pubic hair, body odor) 
  • Partial progression through puberty may indicate stalled puberty.
  • Signs of genetic syndromes (e.g., Turner syndrome, Klinefelter syndrome)

Tanner staging in girls:

Tanner scale, also called sexual maturity rating (SMR) showing the different stages of breast and pubic hair development in girls

Image by Lecturio.

Tanner staging in boys:

Tanner scale, also called the SMR, showing the different stages of penis, scrotum, and pubic hair development in boys

Image by Lecturio.

Diagnosis

Clinical findings and diagnostic aids (e.g., growth charts) help establish the diagnosis. Constitutional growth delay can only be diagnosed by ruling out other pathologies.

Workup:

  • Serum LH and FSH
    • ↓ in hypogonadotropic hypogonadism
    • ↑ in hypergonadotropic hypogonadism
  • Serum estradiol in girls, serum testosterone in boys → access gonadal function
  • Serum prolactin and hCG levels → if a tumor is suspected
  • Serum laboratories: CBC, ESR, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, TSH, and free T4 → to rule out chronic disease
  • Hand X-ray → for bone age delay > 2 years
  • Magnetic resonance imaging (MRI) for:
    • Hypogonadotropic hypogonadism
    • Central nervous system (CNS) lesions
  • Ultrasonography of the testes → for abnormal exam
  • Genetic testing/karyotyping → if a genetic cause is suspected

Example of a hand X-ray with an automatic bone age calculator

Image: “X-ray of a hand with automatic bone age calculation” by Mikael Häggström. License: Public Domain

Management and Complications

Management

The overall goal in the management of DP is pubertal induction and the initiation of secondary sexual development.

  • Constitutional growth delay:
    • Psychological support: Address potential embarrassment about short stature and lack of secondary sexual development.
    • Calcium supplementation may be beneficial (risk of low bone density).
  • Hypogonadism in boys:
    • Testosterone injections for 4–8 months
    • Aromatase inhibitors may ↑ adult height in addition to initiating puberty.
    • Encourage weight loss in obese patients.
  • Hypogonadism in girls:
    • Estrogen replacement therapy
    • In permanent hypogonadism, once menarche or Tanner stage IV breast development has been achieved, progesterone is added.
    • Life-long sex-steroid supplementation:
      • Start with low doses and ↑ over time.
      • Keep doses stable once adulthood is reached to maintain secondary sexual characteristics.

Complications

  • Osteoporosis: Treatment with exogenous testosterone during adolescence has been shown to improve bone density.
  • Pathologically increased adult height (taller height due to growth hormone replacement)

Clinical Relevance

The following conditions are potential causes of central hypogonadism:

  • Anorexia nervosa: an eating disorder marked by self-imposed starvation due to a strong fear of weight gain. Most common in adolescent girls. The reduced intake of calories and nutrients often leads to a decrease in sex hormones, causing amenorrhea. Patients have low body weight (BMI (body mass index) ≤ 18.5 kg/m2) and diverse physiological and psychological complications. Treatment mainly consists of psychotherapy and support for weight gain.
  • Athletic amenorrhea: secondary amenorrhea caused by the lack of menses due to the aberrant pulsatile secretion of gonadotropin-releasing hormone in the context of high athletic performance. Diagnosis is made clinically by the presence of amenorrhea in the setting of extreme athleticism. Management is supportive and may include supplemental hormones. 
  • Celiac disease: also called gluten-sensitive enteropathy, is an autoimmune sensitivity to gliadin, a component of gluten. Patients present with diarrhea, malabsorption, and failure to thrive. Hypogonadism and delayed puberty are potential complications. Patients are screened with serological antibody testing, and diagnosis is confirmed by small intestine biopsy. Treatment consists of a lifelong gluten-free diet. 
  • Hypothyroidism: a state of decreased thyroid hormone secretion that can cause delayed sexual development or incomplete isosexual precocity. Hypothyroidism is defined as a deficiency in the T3 and T4 hormones. Clinical features of hypothyroidism are primarily due to the accumulation of matrix substances and a decreased metabolic rate. Hypothyroidism is treated by administration of synthetic T4.

The following conditions are potential causes of primary hypogonadism:

  • Turner syndrome: a genetic syndrome characterized by a 45,X0 karyotype. Patients present as short girls with a webbed neck. Decreased sex hormone levels lead to primary amenorrhea. Further anomalies can be observed in the cardiac, renal, reproductive, skeletal, and lymphatic systems. Diagnosis is confirmed by genetic testing. Treatment is supportive and the use of estrogen and progesterone is needed. 
  • Klinefelter syndrome: a genetic syndrome characterized by a 47, XXY karyotype, which causes testicular dysfunction and male infertility. Symptoms are not usually observed during childhood. During adulthood, individuals suffering from this pathology are usually tall and present with gynecomastia and hypogonadism. Treatment is supportive, with sex-steroid replacement. 

The following condition is a potential complication of delayed puberty:

  • Osteoporosis: a condition characterized by decreased bone density. Age of onset of puberty is inversely related to bone density and mass. Diagnosis is established by a low bone mineral density test on a dual energy X-ray absorptiometry (DEXA) scan. Management is based on maintaining adequate levels of calcium and vitamin D and the use of bisphosphonates. Complications include increased risk of fractures.

References

  1. Crowley, W and Pitteloud, N. Approach to the patient with delayed puberty. (2020). UpToDate. Retrieved November 10, 2020, from: https://www.uptodate.com/contents/approach-to-the-patient-with-delayed-puberty?search=delayed%20puberty&source=search_result&selectedTitle=1~98&usage_type=default&display_rank=1
  2. Haddad, N. G., & Eugster, E. A. (2016). Delayed puberty. In Endocrinology: Adult and pediatric (pp. 2142–2154.e4). Retrieved November 10, 2020, from https://www.clinicalkey.es/#!/content/3-s2.0-B9780323189071001220
  3. Styne, D. (2017). Puberty. In D. G. Gardner, & D. Shoback (Eds.), Greenspan’s basic & clinical endocrinology, 10e. New York, NY: McGraw-Hill Education. Retrieved December 16, 2020, from accessmedicine.mhmedical.com/content.aspx?aid=1144818197
  4. Gilsanz, V. et al. (2011). Age at onset of puberty predicts bone mass in young adulthood. The Journal of pediatrics, 158(1), 100–105.e1052. doi:10.1016/j.jpeds.2010.06.054

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