Puberty

Puberty refers to the phase of development between childhood and adulthood in which complete functional maturation of the reproductive glands and external genitalia occurs. The other processes that characterize this transitional phase are the development of secondary sex characteristics, growth spurts, and psychosocial changes. The stages of development during puberty are classified according to the Tanner stages. Although there is considerable variation between individuals, puberty begins on average at the age of 11 in girls and 13 in boys. When puberty begins abnormally early it is referred to as precocious puberty and is classified into two main types: peripheral precocious puberty, which is independent of gonadotropin-releasing hormone secretion; and central precocious puberty, which involves the hypothalamo-hypophyseal axis. At the other end of the disease spectrum, puberty may be delayed or absent. This delay can be constitutional (most common), secondary to underlying conditions, or due to hypogonadism.

Definition

• A phase of development between childhood and complete, functional maturation of the reproductive glands and external genitalia (adulthood)

Phases of pubertal changes

The age of pubertal onset may vary, but the order of changes that occur in each person is consistent.

• Adrenarche: activation of adrenal androgen production (axillary and pubic hair, body odor, and acne)
• Gonadarche: activation of reproductive glands by the pituitary hormones FSH and LH
• Thelarche: onset of breast development
• Pubarche: onset of pubic hair growth
• Menarche: onset of menstrual bleeding
  • Anovulatory cycle: The menstrual cycle may be irregular in adolescents during the first few months/years after menarche.
    • Immaturity of the hypothalamic-pituitary-gonadal axis; → irregular secretion of gonadotropins → short luteal phase, and lack of progesterone → endometrium remains in the proliferative phase → irregular menses and heavy menstrual bleeding
    • Does not require treatment because menses become regular as hypothalamic-pituitary-gonadal axis matures
• See “Physical changes during puberty” below.

Physiology

• Unknown initial trigger → ↑ activators and/or ↓ inhibitors of GnRH secretion → pulsatile GnRH secretion→ ↑ FSH and ↑ LH secreted by the anterior pituitary gland → stimulation of the Leydig cells and Sertoli cells in the testicles, and the theca and granulosa cells in the ovary.
• The hypothalamic-pituitary-gonadal axis is tightly regulated by a negative feedback mechanism.
• Testosterone inhibits further GnRH secretion from the hypothalamus.
• FSH-stimulated Sertoli cells also secrete inhibin, which further inhibits FSH secretion from the pituitary.

Influential factors

• General health (nutritional state, bodyweight) ^[1]
• Genetics
• Social environment (e.g., family stress)

Girls

• Normal age of onset: 8–13 years (average 11 years)
• Normal order of changes: adrenarche → gonadarche → thelarche (age of onset 8–11 years) → growth spurt (age of onset 11.5–16.5 years) → pubarche (mean age of onset 12 years) → menarche (age of onset 10–16 years, mean age: 13 years) ^[2]

Boys

• Normal age of onset: 9–14 years (average 13 years)
• Normal order of changes: adrenarche → gonadarche; (age of onset 9–14 years) → pubarche (mean age of onset 13.5 years)→ growth spurt (mean age of onset 13.5 years)→ androgenic hair growth

The first visible sign of puberty in males is testicular enlargement, while in females it is breast development.

Tanner stages

• A sexual maturity rating (SMR) scale used to assess the development of secondary sexual characteristics (e.g., breast, genital, pubic hair development) in both males and females

Other morphological changes during puberty ^[3][4][5]

• Breast development (boys)
  • Occurs approximately within 18 months of pubertal onset in males
  • Usually during Tanner stage 3
  • Lasts for ∼ 6–18 months
  • Gynecomastia is diagnosed in a pubertal male when the palpable subareolar gland and ductal tissue is ≥ 2 cm (see “Pubertal gynecomastia”).
• Growth spurt
  • Linear growth during adolescence is approx. 5 cm/year from 4 years of age to puberty
  • Varies between the sexes, generally occurs between ages 13–15 years (in girls, it can begin two years earlier).
  • Includes ↑ growth in trunk and limbs
  • Assessed using growth velocity charts
  • It generally lasts ∼ 2 years, girls complete it at age 15 and boys at age 17.
• Bone growth
  • Accelerated during puberty
  • Determined by: testosterone, estrogen, IGF-1, calcitriol, and GH
  • Testosterone initiates and accelerates bone mineralization.
  • Order of growth: ↑ length → ↑ width → ↑ mineral content → ↑ density
• Bodyweight and composition during adolescence
  • Boys: initial ↓ body fat (early puberty) → ↑ lean body mass (late puberty)
  • Girls: gradual increase in body fat
  • Affected by nutritional status
• Dermatological changes ^[6]
  • Acne vulgaris, hyperhidrosis, and hair problems (e.g., seborrheic dermatitis)
  • Activation of the adrenal cortex → pubertal hormonal fluctuation → ↑ sebum secretion and excessive sweating → skin and hair changes
• Myopia: due to axial growth of the eye
• Other physical changes associated with menarche: anemia

Adolescence is a time of not only pubertal physical change but also cognitive, psychological, and social development that may or may not be associated with reaching sexual maturity.

• Anticipatory guidance should be offered to adolescents and their parents regarding:
  • The increased risk of morbidity and mortality due to an increase in risk-taking behavior.
    • Sexually transmitted infections, unplanned pregnancy
    • Eating disorders, depression, suicide
    • Motor vehicle accidents, homicide
  • A healthy lifestyle and preventive measures, including the topics of:
    • Balanced nutrition and physical exercise
    • Traffic safety (e.g., seatbelt usage, bike helmet usage)
    • Safer sex practices (see “Counseling on safer sex practices”)
    • Substance use
    • See “Primary prevention” for more details.

Definition ^[9]

• The appearance of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys

Epidemiology ^[3][10]

• Incidence: 1:5,000 to 1:10,000 children
• Ten times more common in girls than boys.

Classification

• Central precocious puberty (gonadotropin-dependent precocious puberty, true precocious puberty)
• Peripheral precocious puberty (gonadotropin-independent precocious puberty, peripheral pseudopuberty, peripheral precocity)
• Isosexual precocious puberty: premature development of secondary sexual characteristics appropriate for gender (can be complete or incomplete)
• Heterosexual precocious puberty: masculinization of girls or feminization of boys
  • Boys: See “McCune-Albright syndrome” and “Leydig cell tumors.”
  • Girls: See “Congenital adrenal hyperplasia.”
• Benign pubertal variants
  • Benign precocious thelarche
  • Idiopathic premature pubarche
  • Idiopathic premature adrenarche
  • Benign precocious menarche
• Obesity-related precocious sexual development

Central precocious puberty ^[3][9][11]

Definition

• Precocious puberty with elevated GnRH levels

Etiology

• Idiopathic (most common cause)
• CNS lesions
  • Intracranial tumors (e.g., hamartoma, glioma, craniopharyngioma)
  • Trauma
  • Infections (e.g., encephalitis, meningitis)
  • Hydrocephalus
• Obesity-related precocious sexual development
• Systemic conditions: tuberous sclerosis, neurofibromatosis
• Radiation

Pathophysiology

• Early activation of the hypothalamo-hypophyseal axis → abnormally early initiation of pubertal changes → early development of secondary sexual characteristics

Clinical features

• Premature sexual development typically follows the normal pattern of puberty, except that it is early.
• Symmetric development of secondary sexual characteristics or, occasionally, as isolated premature thelarche, adrenarche, or menarche.
• Increased growth velocity: Children tend to be taller than their peers during adolescence, but are of shorter stature by the time they reach adulthood (due to early closure of the epiphyseal plate).

Diagnosis

• Laboratory tests
  • Serum LH and FSH: increased
  • GnRH stimulation test (gold standard): evaluates the reactivity of the hypothalamic-pituitary-axis to GnRH stimulation
    • Indications: suspicion of precocious puberty or delayed puberty
    • Method: base LH and FSH values → administer GnRH → blood is drawn after a certain time for reevaluation of LH and FSH levels
    • Gonadotropin (LH and FSH) levels increase after intravenous administration of GnRH.
  • Serum testosterone/estradiol: increased
• Imaging
  • X-ray of the nondominant hand and wrist: allows comparison between skeletal maturation and chronological age
    • Assess and confirm accelerated bone growth.
    • Bone age is within 1 year of a child's age: Puberty likely has not started.
    • Bone age is > 2 years of the child's age: Puberty has been present for a year or longer.
  • MRI/CT of the brain with contrast: when ↑ LH is confirmed
    • Perform in girls ≤ 6 years of age, all boys, and children with neurologic symptoms.
    • Rule out intracranial causative pathology.

Treatment

• GnRH agonist (e.g., leuprolide, buserelin, goserelin): to prevent premature fusion of growth plates
  • Close monitoring of therapy
  • Follow-up is recommended every 4–6 months to assess progression.
• Manage underlying cause.

Peripheral precocious puberty ^{[3][9][11][12]}

Definition

• Precocious puberty without elevated GnRH levels (due to ↑ peripheral synthesis of or exogenous exposure to sex hormones)

Etiology

• ↑ Androgen production
  • Congenital adrenal hyperplasia
  • Virilizing ovarian and adrenocortical tumors (e.g., Sertoli-Leydig cell tumor, Leydig-cell tumor)
• ↑ Estrogen production
  • McCune-Albright syndrome
  • HCG-secreting germ cell tumors (e.g., dysgerminomas)
• ↑ β-hCG production
  • Dysgerminoma
  • Malignant embryonal cell carcinoma
  • Choriocarcinoma
• Primary hypothyroidism
• Exogenous steroid use
• Obesity-related precocious sexual development

Clinical features

• May not follow the normal developmental pattern (signs of estrogen or androgen excess)
• May exhibit possible features of an underlying condition (e.g., cafe-au-lait spots in McCune-Albright syndrome, testicular mass in Leydig-cell tumor)

Diagnosis

• Laboratory tests
  • Serum basal FSH and LH: decreased
  • GnRH stimulation test
    • No increase in LH levels after GnRH administration.
    • Precocious pseudopuberty is associated with low basal LH levels (prepubertal values).
  • Serum testosterone/estradiol levels: increased (depending on the tumor)
  • TSH, T₃ hormone: suspicion of hypothyroidism
  • Serum DHEA-S and 17-hydroxyprogesterone: in cases of hyperandrogenism
  • Corticotropin stimulation test: suspicion of congenital adrenal hyperplasia or an adrenal tumor
• Imaging
  • X-ray of the nondominant hand and wrist: accelerated bone growth
  • Ultrasound of the ovaries, testicles, and abdomen (cases of increased ovarian and/or uterine volume than expected for age, diagnostic uncertainty)

Treatment

• Precocious puberty caused by excessive hormonal production from a tumor in the body: surgical removal
• Precocious puberty caused by CAH: cortisol replacement (see “Treatment” in “Congenital adrenal hyperplasia”)
• Ovarian cysts: no intervention is necessary (spontaneous resolution is common)

Central precocious puberty has a central cause (e.g., hypothalamic lesions) and high GnRH levels, while peripheral precocious puberty has a peripheral cause (e.g., germ cell tumors), without elevated GnRH levels.

Benign pubertal variants ^[11]

Obesity-related precocious sexual development ^[16][17][18]

• Definition: Obesity is associated with early pubertal development, mainly due to obesity-related insulin resistance. This resistance leads to increased insulin and leptin levels.
• Pathophysiology
  • Central mechanism: Obesity causes increased secretion of leptin, which leads to increased GnRH pulsatility → ↑ production of gonadotropins and sex hormones → early development of secondary sexual characteristics and early gonadarche.
  • Peripheral mechanism: Obesity causes insulin resistance and compensatory hyperinsulinemia → premature adrenarche, thelarche, and pubarche.
    • Adrenals and ovaries: ↑ androgens
    • Liver: ↓ SHBG
    • Adipocytes: ↑ aromatase → ↑ bioavailability of sex steroids

Definition ^[19]

• A genetic syndrome caused by a G-protein activating mutation and subsequent continuous stimulation of endocrine functions

Epidemiology

• Accounts for 5% of cases of precocious puberty (more common in females) ^[20]
• Affects 1 in 100,000 to 1 in 1,000,000 individuals in the general population ^[20]
• Peak incidence: early childhood

Etiology

• Mosaic mutation in the GNAS1 gene on chromosome 20 (autosomal recessive inheritance)
  • Some cells have a normal version of the GNAS1 gene, while other cells have the mutated version.
  • Embryos only survive if mosaicism occurs.
• If the mutation occurs before fertilization, it affects all cells → incompatible with life.

Pathophysiology ^[21]

• Activating mutation in GNAS gene → impaired G_s-protein signaling → constitutively activated adenylate cyclase → excess production of cAMP

Clinical features ^[19]

• Unilateral café-au-lait spots with unilateral, ragged edges
• Polyostotic fibrous dysplasia
• Endocrinopathies
  • Peripheral precocious puberty (most common)
  • Cushing syndrome
  • Acromegaly
  • Hyperthyroidism

Diagnostics ^[19][22]

• Clinical features: See above.
• Laboratory tests
  • Increased hormone levels (e.g., estradiol, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C)
  • Increased alkaline phosphatase (see “Diagnostics” in “Fibrous dysplasia”)
  • Molecular testing: GNAS1 analysis
• Imaging
  • X-rays of long bones: well-defined, lobulated lesions with a thin cortex and a radiolucent, ground-glass appearance
  • CT/MRI: identify fibrodysplastic lesions
  • Bone scan: determine the extent of bone disease

Treatment

• Symptomatic: treat underlying endocrinopathies
• Estrogen synthesis inhibitors
  • Ketoconazole
  • Testolactone: an aromatase inhibitor that prevents the conversion of androstenedione to estrone and testosterone to estrogen
• Selective estrogen receptor modulators (e.g., tamoxifen)

Differential diagnosis

• Neurofibromatosis type 1
• Fibrous dysplasia

Prognosis

• The condition is lethal when the mutation affects all cells (i.e., occurs before fertilization), but survivable in patients affected by mosaicism.

The 3 P's of McCune-Albright syndrome are Polyostotic fibrous dysplasia, Pigmentation (café-au-lait spots), and Precocious puberty.

Definition ^[23][24]

• Absent or incomplete development of secondary sex characteristics by the age of 14 years in boys or 13 years in girls

Etiology ^[25]

• Physiological causes: constitutional growth delay
• Pathologic causes
  • Hypergonadotropic hypogonadism
    • Primary gonadal insufficiency (e.g., Klinefelter syndrome, Turner syndrome, androgen insensitivity syndrome)
    • Secondary gonadal insufficiency (e.g., chemotherapy, pelvic irradiation, infections, trauma/surgery, autoimmune disease)
  • Hypogonadotropic hypogonadism; (e.g., CNS lesions, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, Prader-Willi syndrome, Gaucher disease)
  • Malnutrition (e.g., anorexia nervosa)
  • Chronic diseases (e.g., inflammatory bowel disease, hypothyroidism, cystic fibrosis)

Clinical features

• Clinical features: depend on the underlying condition
• Physical examination
  • Tanner staging (testes ≤ 3 ml, absent breast buds, pubic/axillary hair or menarche)
  • Assessment of height (short stature)
  • Assessment of weight
  • Neurological exam (anosmia)

Diagnosis ^[25]

• Medical history (e.g., positive family history of delayed onset of puberty, tanner staging, BMI)
• Routine tests
  • Serum LH, FSH, and testosterone/estradiol
    • Low or normal with low testosterone/estradiol: constitutional growth delay, isolated GnRH deficiency, functional hypogonadotropic hypogonadism (e.g., medical illness, malnutrition), or hypothalamic-pituitary disorders (e.g., malformations, hemochromatosis, injury, tumors)
    • Elevated: primary hypogonadism
  • X-ray of the nondominant hand and wrist
    • First imaging study
    • Shows delayed bone age (less than the individual's chronological age)
• Additional tests: based on suspected etiology
  • Serum prolactin level (elevated in prolactinoma)
  • IGF-1 levels (exclude growth hormone deficiency)
  • TSH and T₄ hormone: evaluate amenorrhea and hypothyroidism
  • Karyotype (Turner syndrome in girls, Klinefelter syndrome in boys)
  • Complete blood and biochemical tests (e.g., CBC, ESR, LFT, BUN, creatinine): suspected systemic disorder in children
  • Antiendomysial antibody: screen for celiac disease in patients with signs of malabsorption
  • Abdominal ultrasound (streak ovaries in Turner syndrome, testicular mass)
  • Head MRI: suspected prolactinoma (e.g., headaches, bitemporal hemianopia)

Treatment ^[25]

• Constitutional growth delay: expectant management
  • No treatment is needed as catch-up growth eventually occurs and the individual reaches a normal adult height.
  • Serial growth measurements at frequent intervals (∼ every 6 months)
  • Reassuring the child and parents is sufficient.
• Other pathologies
  • Treatment of the underlying disease
  • Hormonal therapy
    • Testosterone: used in boys to achieve secondary sex characteristics (e.g., virilization, growth spurt)
      • Boys with constitutional growth delay usually respond well after one or two courses of testosterone therapy.
      • If little or no response is seen, isolated GnRH deficiency should be suspected in boys over the age of 18 years.
    • Estradiol: used in girls with primary gonadal insufficiency (e.g., Turner syndrome)
      • Initially: low-dose estradiol that is gradually increased
      • After 2 years: Add cyclic progestin therapy to induce menstruation.