Delayed Puberty

Signs of possible chronic disease include an abrupt change in growth, undernutrition, discordant development (eg, pubic hair without breast development), or stalled pubertal development (ie, puberty starts then fails to progress).

Neurologic symptoms (eg, headaches, vision problems), polydipsia, and/or galactorrhea could suggest a CNS disorder. Hyposmia or anosmia could indicate Kallman syndrome.

Gastrointestinal symptoms could suggest an inflammatory bowel disorder. An abnormal body image (eg, false belief in being overweight) suggests the need to evaluate for an eating disorder.

Primary amenorrhea could suggest Turner syndrome.

Although many children seem to be starting puberty earlier than in past years, there are no indications that the criteria for delayed puberty should change.

In girls, delayed puberty is diagnosed if 1 of the following occurs:

• No breast development by age 12 to 13 years

• > 3 years elapsed between the beginning of breast growth and menarche

• Menstruation does not occur by age 15 (in the presence of normal secondary sexual characteristics)

For girls, differences in timing of puberty are associated with race and ethnicity. Puberty begins earlier in Black and Hispanic girls compared to White girls (see Precocious Puberty).

In boys, delayed puberty is diagnosed if 1 of the following occurs:

• No testicular enlargement by age 13 or 14

• > 4 years elapsed between initial and complete growth of the genitals

Onset of pubic hair is not included in the definition of delayed puberty because it is a sign of adrenarche as opposed to true puberty.

Children who have no evidence of pubertal progression (referred to as stalled or interrupted puberty) for a sustained period of time (typically > 1 year) can be evaluated sooner, even if before the established age threshold for delayed puberty.

LH and FSH are measured, and testosterone in boys or estradiol in girls is measured. LH and FSH are gonadotropins secreted by the pituitary, which stimulate production of sex hormones. LH and FSH levels are the most useful initial tests (see also algorithm Evaluation of Primary Amenorrhea). FSH is most helpful for establishing evidence of gonadal failure, whereas LH is helpful for determining the onset of puberty. Testing should be done in the morning and requires pediatric-specific assays (often labeled as ultrasensitive or immunochemiluminometric [ICMA]).

Elevated serum LH and FSH levels indicate

• Gonadal failure caused by defects of the gonads themselves (primary hypogonadism [hypergonadotropic hypogonadism])

In children who have elevated serum LH and FSH levels, karyotype analysis should be done to investigate for Klinefelter syndrome in boys and Turner syndrome in girls. If karyotype is normal, girls with severe pubertal delay should be further investigated for other causes of primary ovarian insufficiency.

Low or normal FSH and LH levels along with low testosterone and estradiol levels in children with short stature and delayed pubertal development may indicate

• Constitutional delay

• Secondary hypogonadism (hypogonadotropic hypogonadism)

• Functional hypogonadotropic hypogonadism (caused by hypothyroidism, inflammatory conditions, undernutrition, or excessive exercise)

FSH measurement is particularly important for the diagnosis of primary hypogonadism because FSH has a longer half life, is more sensitive, and shows less variability than LH. FSH levels > 20 mIU/mL (> 20 units/L) suggest probable gonadal dysfunction.

Assays for testosterone and estradiol levels do not always distinguish early pubertal from prepubertal levels.

Constitutional delay of puberty is more commonly diagnosed in boys, partly because adolescent boys are more distressed if they do not mature at the same rate as their peers and are thus more likely to present for evaluation. It can be difficult to distinguish constitutional delay of puberty from permanent causes of hypogonadotropic hypogonadism. Inhibin B and anti-müllerian hormone (AMH) may be helpful markers of gonadal function (see Diagnosis of Male Hypogonadism in Children) (1, 2).

Chronic disorders that cause inadequate nutrition can delay puberty by impairing gonadotropin-releasing hormone release.

When growth is abnormal, bone age x-ray should be the first test. Bone age is determined from an x-ray of the left hand (by convention) and can provide an estimate of remaining growth potential and help predict adult height.

Evaluating the pituitary gland with MRI may be indicated to rule out tumors and structural anomalies in suspected hypogonadotropic hypogonadism.

For girls with primary amenorrhea, a pelvic ultrasound can be performed to identify the presence of a uterus. If the uterus is absent, a karyotype and testosterone analysis are done to evaluate for chromosomal abnormalities. A 46,XY karyotype may indicate 5-alpha-reductase deficiency or complete androgen insensitivity syndrome, and a 46,XX karyotype may indicate müllerian agenesis. If the uterus and breast development are present, an outflow tract obstruction is more likely.

About one third of cases of hypogonadotropic hypogonadism are genetic, and Kallman syndrome is the most common cause (see Secondary hypogonadism). If other pituitary hormone deficiencies are noted, specific genetic abnormalities may be present (eg, PROP1).

1. 1. Varimo T, Miettinen PJ, Känsäkoski J, et al: Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod 32(1):147-153, 2017. doi: 10.1093/humrep/dew294

2. 2. Rohayem J, Nieschlag E, Kliesch S, Zitzmann M: Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology 3(5):882-887, 2015. doi: 10.1111/andr.12088