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Delayed Puberty

By

Andrew Calabria

, MD, The Children's Hospital of Philadelphia

Last full review/revision Aug 2022| Content last modified Sep 2022
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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.

Delayed puberty may result from constitutional delay, which often occurs in adolescents with a family history of delayed growth. Prepubertal growth velocity is normal, but skeletal maturation and adolescent growth spurt are delayed; sexual maturation is delayed but normal.

Other causes include genetic disorders (Turner syndrome Turner Syndrome In Turner syndrome, girls are born with one of their two X chromosomes partly or completely missing. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis. Treatment... read more Turner Syndrome in girls, Klinefelter syndrome Klinefelter Syndrome (47,XXY) Klinefelter syndrome is the presence of two or more X chromosomes plus one Y, resulting in a phenotypic male. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis... read more Klinefelter Syndrome (47,XXY) in boys), central nervous system (CNS) disorders (eg, hypothalamic or pituitary tumors that reduce gonadotropin secretion), CNS radiation, certain chronic disorders (eg, poorly controlled diabetes mellitus Diabetes Mellitus in Children and Adolescents Diabetes mellitus involves absence of insulin secretion (type 1) or peripheral insulin resistance (type 2), causing hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more , inflammatory bowel disorders Overview of Inflammatory Bowel Disease Inflammatory bowel disease (IBD), which includes Crohn disease and ulcerative colitis, is a relapsing and remitting condition characterized by chronic inflammation at various sites in the gastrointestinal... read more , renal disorders, cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Cystic Fibrosis ), Kallman syndrome Secondary hypogonadism , undernutrition Overview of Undernutrition Undernutrition is a form of malnutrition. (Malnutrition also includes overnutrition.) Undernutrition can result from inadequate ingestion of nutrients, malabsorption, impaired metabolism, loss... read more / eating disorders Introduction to Eating Disorders Eating disorders involve a persistent disturbance of eating or of behavior related to eating that Alters consumption or absorption of food Significantly impairs physical health and/or psychosocial... read more , and excess physical activity, especially in girls (1 General reference 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... read more ).

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. Although adolescents are typically uncomfortable about being different from their peers, boys are more likely than girls to feel psychologic stress and embarrassment resulting from short stature and delayed puberty.

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).

Diagnosis 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 one 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 Precocious Puberty ).

In boys, delayed puberty is diagnosed if one 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 Evaluation of primary amenorrhea [a] Evaluation of primary amenorrhea [a] ). FSH is most helpful for establishing evidence of gonadal failure, whereas LH is helpful for determining the onset of puberty Diagnosis Precocious puberty is onset of sexual maturation before the average age. Diagnosis is by comparison with population standards, x-rays of the left hand and wrist to assess skeletal maturation... read more . 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

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

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 Secondary hypogonadism 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.

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 one or two 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 anomalies. 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 Secondary hypogonadism Male hypogonadism is decreased production of testosterone, sperm, or both or, rarely, decreased response to testosterone, resulting in delayed puberty, infertility, or both. Diagnosis is by... read more ). If other pituitary hormone deficiencies are noted, specific genetic abnormalities may be present (eg, PROP1).

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 50 to 100 mg IM once/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 after several weeks or months testosterone levels are measured; 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 two 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 Treatment Male hypogonadism is decreased production of testosterone, sperm, or both or, rarely, decreased response to testosterone, resulting in delayed puberty, infertility, or both. Diagnosis is by... read more ).

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 worn days 1 to 10 of the calendar month) 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.

Drugs Mentioned In This Article

Drug Name Select Trade
DELATESTRYL
ESTRADERM, ESTROGEL, VIVELLE
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