- Clinical science
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 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.
- 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
- Anovulatory cycle: The menstrual cycle may be irregular in adolescents during the first few months/years after menarche.
- See “ ” below.
- 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.
- General health (nutritional state, bodyweight) 
- Social environment (e.g., family stress)
- Normal age of onset: 8–13 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) 
- Normal age of onset: 9–14 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.
- 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
|Tanner Stages||Breast development (girls)|
|Genital development (boys)|
|Pubic hair development (boys and girls)|
Other morphological changes during puberty 
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 “ ”).
- Linear growth 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
Bodyweight and composition
- Boys: initial ↓ body fat (early puberty) → ↑ lean body mass (late puberty)
- Girls: gradual increase in body fat
- Affected by nutritional status
- Dermatological changes 
- Myopia: due to axial growth of the eye
- Other physical changes associated with menarche: anemia
Adolescence is the period of physical, cognitive, and psychosocial development from the onset of puberty to adulthood (age of majority).
Stage of adolescence 
|Middle|| || |
|Late|| || |
- The appearance of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys
- Incidence: 1:5,000 to 1:10,000 children
- Ten times more common in girls than boys.
- (gonadotropin-dependent precocious puberty, true 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 “” and “.”
- Girls: See “.”
- Benign pubertal variants
- Obesity-related precocious sexual development
Central precocious puberty 
- Idiopathic (most common cause)
- CNS lesions
- Systemic conditions: ,
- Early activation of the hypothalamo-hypophyseal axis → abnormally early initiation of pubertal changes → early development of secondary sexual characteristics
- 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).
- Serum LH and FSH: increased
- GnRH stimulation test (gold standard): evaluates the reactivity of the hypothalamic-pituitary-axis to GnRH stimulation
- Serum testosterone/estradiol: increased
- X-ray of the left hand and wrist: allows comparison between skeletal maturation and chronological age
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.
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 
- Precocious puberty without elevated GnRH levels (due to ↑ peripheral synthesis of or exogenous exposure to sex hormones)
↑ Androgen production
- Virilizing ovarian and adrenocortical tumors (e.g., , )
- ↑ Estrogen production
- ↑ β-hCG production
- Primary hypothyroidism
- Exogenous steroid use
- 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)
- Serum basal FSH and LH: decreased
- GnRH stimulation test
- 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
- 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 “”)
- 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 
- Benign precocious thelarche
- Precocious pubarche
- Benign precocious menarche/vaginal bleeding
Obesity-related precocious sexual development 
- Definition: Obesity is associated with early pubertal development, mainly due to obesity-related insulin resistance. This resistance leads to increased insulin and leptin levels.
- 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.
- A genetic syndrome caused by a G-protein and subsequent continuous stimulation of endocrine functions
- Accounts for 5% of cases of precocious puberty (more common in females) 
- Affects 1 in 100,000 to 1 in 1,000,000 individuals in the general population 
- Peak incidence: early childhood
- Mosaic mutation in the GNAS1 gene on chromosome 20 (autosomal recessive inheritance)
- If the mutation occurs before fertilization, it affects all cells → incompatible with life.
- in GNAS gene → impaired Gs-protein signaling → constitutively activated adenylate cyclase → excess production of cAMP
Clinical features 
- Unilateral with ragged edges
- (most common)
- Clinical features: See above.
- Laboratory tests
- Symptomatic: treat underlying endocrinopathies
- Estrogen synthesis inhibitors
- Selective estrogen receptor modulators (e.g., )
- Absent or incomplete development of secondary sex characteristics by the age of 14 years in boys or 13 years in girls
Physiological: constitutional growth delay, a temporary delay in growth and onset of puberty that is not caused by any pathological process (most common cause)
- Diagnosis: x-ray showing delayed bone age (less than the individual's chronological age)
- No treatment is needed; as catch-up growth eventually occurs and the individual reaches a normal adult height.
- Reassuring the child and parents is sufficient.
- Pathologic causes
- Primary gonadal insufficiency (e.g., , , )
- Secondary gonadal insufficiency (e.g., chemotherapy, pelvic irradiation, trauma/surgery, autoimmune disease, infections)
- Hypogonadotropic hypogonadism (e.g., , , , )
- Malnutrition (e.g., anorexia nervosa)
- Chronic diseases (e.g., inflammatory bowel disease, , )
- Hypergonadotropic hypogonadism
- Clinical features: depend on the underlying condition
- Physical examination
- Medical history (e.g., positive family history of delayed onset of puberty, tanner staging, BMI)
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 left hand and wrist
- First imaging study
- Shows delayed bone age (less than the individual's chronological age)
- Serum LH, FSH, and testosterone/estradiol
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 ( in girls, 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)
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.
- Treatment of the underlying disease
- Testosterone: used in boys to achieve secondary sex characteristics (e.g., virilization, growth spurt)
- Estradiol: used in girls with primary gonadal insufficiency (e.g., Turner syndrome)