Delayed puberty is absence of sexual maturation at the expected time. Diagnosis is by measurement of gonadal hormones (testosterone and/or estradiol), luteinizing hormone, and follicle-stimulating hormone; imaging studies; and genetic testing. Treatment, when necessary, usually involves specific hormone replacement.
(See also puberty in males and puberty in females.)
Delayed puberty may result from constitutional delay, which often occurs in adolescents with a family history of delayed growth.
Constitutional delay of puberty is absence of pubertal development before age 14 years; it is more common among boys. By definition, children with constitutional delay show evidence of sexual maturation by age 18 years, but pubertal delay and short stature, while not abnormal, may generate anxiety in adolescents and their families. Many children have a family history of delayed sexual development in a parent or sibling. Typically, stature is usually short during childhood, adolescence, or both but ultimately reaches the normal range. Growth velocity is nearly normal, and growth pattern parallels the lower percentile curves of the growth chart. The pubertal growth spurt is delayed, and at the expected time of puberty, height percentile begins to drop, which may contribute to psychosocial difficulties for some children. Skeletal age is delayed and is most consistent with the child's height age (age at which a child's height is at the 50th percentile) rather than chronologic age. Sexual maturation is delayed but normal.
Other causes of delayed puberty include (1)
Genetic disorders (Turner syndrome in girls, Klinefelter syndrome in boys)
Central nervous system (CNS) disorders (eg, hypothalamic or pituitary tumors that reduce gonadotropin secretion)
Other causes of hypogonadism
Testicular disorders such as injury (eg, testicular torsion) or infection (eg, mumps) in boys
CNS radiation
Certain chronic disorders (eg, poorly controlled diabetes mellitus, inflammatory bowel disorders, renal disorders, cystic fibrosis, anemia)
Autoimmune disorders (eg, Hashimoto thyroiditis, Addison disease, and some disorders that directly affect the ovaries)
Excess physical activity, especially in girls
General reference
1. Howard SR, Dunkel L: The genetic basis of delayed puberty. Neuroendocrinology 106(3):283–291, 2018. doi: 10.1159/000481569
Symptoms and Signs of Delayed Puberty
In girls, breast development, pubic hair growth, and/or menarche do not occur.
In boys, genital and/or pubic hair development are absent.
Short stature, decreased growth velocity, or both may indicate delayed puberty in either sex.
Adolescents with delayed puberty may be teased or bullied, and often need help in coping with and managing social concerns. Boys are more likely than girls to feel psychological stress and embarrassment because of short stature and delayed puberty, but both boys and girls may perceive an effect on school and social performance.
Manifestations of possible causes of 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.
Diagnosis of Delayed Puberty
Family history of delayed puberty
Clinical criteria
Measurement of testosterone or estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
Imaging studies
Genetic testing
The initial evaluation of delayed puberty should consist of a complete history and physical examination to evaluate pubertal development, nutritional status, and growth. Depending on findings, laboratory tests for other causes of slow growth should be considered:
Hypothyroidism (eg, thyroid-stimulating hormone, thyroxine)
Renal disorders (eg, electrolytes, creatinine levels)
Inflammatory and immune conditions (eg, tissue transglutaminase antibodies, C-reactive protein)
Hematologic disorders (eg, complete blood count with differential)
Criteria for delayed puberty
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.
Hormonal testing
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.
Permanent forms of hypogonadotropic hypogonadism are more likely if there is a lack of response to 1 or 2 short courses of testosterone therapy. If a pituitary disorder is suspected, levels of other pituitary hormones should be measured because hypogonadotropic hypogonadism can be isolated or associated with other hormone deficiencies.
Imaging studies
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.
Genetic testing
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).
Diagnosis references
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. 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
Treatment of Delayed Puberty
Hormone therapy
If boys show no sign of pubertal development or of skeletal maturation beyond 11 to 12 years by age 13 or 14, they may be given a 4- to 6-month course of low-dose testosterone enanthate or testosterone cypionate once per month. These low doses induce puberty with some degree of virilization and do not jeopardize adult height potential. After the course is complete, treatment is stopped and testosterone levels are measured several weeks or months later to differentiate temporary from permanent deficiency; an increase to pubertal levels suggests the deficiency was temporary rather than permanent.
If testosterone levels are not higher than the initial value and/or pubertal development does not continue after completion of treatment, a second course of low-dose treatment can be given. If endogenous puberty has not begun after 2 courses of treatment, the likelihood of permanent deficiency is higher, and patients need to be reevaluated for other causes of hypogonadism. For permanent forms of hypogonadism, the testosterone dose is increased over an 18- to 24-month period towards adult replacement doses (see treatment of male hypogonadism in children).
In girls, depending on the cause, hormone therapy may be used to induce puberty or, in some cases (eg, Turner syndrome), may be needed for long-term replacement. Estrogen replacement is given in the form of pills or patches, and the dose is increased over an 18- to 24-month period. Doses are lower than those used in adults, and transdermal patches are generally preferred over pills. Girls can be transitioned to transdermal estrogen patches with cyclic progestin (often given orally on days 1 to 10 of the calendar month either as medroxyprogesterone or micronized progesterone) or to combined estrogen-progestin oral contraceptive preparations for long-term treatment.
Key Points
Delayed puberty may represent constitutional delay or be caused by a variety of genetic or acquired disorders.
Measure levels of testosterone or estradiol, luteinizing hormone, and follicle-stimulating hormone.
Do a bone age x-ray as part of initial evaluation.
Pituitary imaging, pelvic ultrasonography in girls, and genetic testing may be done to diagnose cause.
Hormone therapy may be indicated to induce puberty or as long-term replacement.
