Puberty is a period of growth and development between childhood and adulthood that results in attainment of secondary sex characteristics, adult height, and reproductive capacity. The normal progression of pubertal stages was defined by Tanner through cross-sectional and longitudinal studies of healthy children [1–3]. Puberty in girls starts with breast development to Tanner stage 2. Most girls have breast development at age 8–13 years, with peak height velocity at Tanner 3 breasts, and menarche occurring 2–3 years after breast development begins. The appearance of pubic hair, axillary hair, and body odor are called adrenarche and occur in parallel to the breast changes but may start before or after breast development begins. Adrenarche is controlled by hormones produced in the adrenal gland, in contrast to breast development (puberty) that is controlled by hormones produced by the ovaries. At the time of puberty, the hypothalamus secretes gonadotropin-releasing hormone (GnRH) at increasing frequency and amplitude. GnRH stimulates the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which act on the ovary to make estrogens. Estrogens promote the development of secondary sex characteristics such as breast development and widening of the hips. Estrogens also promote linear growth and, ultimately, cause the epiphyses (growth plates) of the long bones to fuse and prevent further increase in height.

Delayed puberty is defined as puberty occurring two standard deviations beyond the mean age. Girls should be evaluated for delayed puberty in the following situations: (1) no breast development by age 13, (2) no menarche within 3 years of thelarche, (3) no menarche by age 14 with signs of hirsutism, (4) no menarche by age 14 with history or exam suggestive of excessive exercise or eating disorder, and (5) no menarche by age 15 [4]. Patients with delayed puberty will not have achieved the pubertal growth spurt, so they may appear to have dropped percentiles on the growth curve. An x-ray of their left hand (bone age x-ray) will show the maturity of the patient’s epiphyses that can be compared to a standard (such as the atlas of Greulich and Pyle) and used to predict height based on current height and bone age.

The differential diagnosis of delayed puberty includes many causes of endocrine and non-endocrine nature. The causes may be separated into three categories: (1) functional delayed onset of hypothalamic-pituitary-gonadal (HPG) activity (low LH/FSH, reversible or resolves with time), (2) hypogonadotropic hypogonadism (low LH/FSH), and (3) hypergonadotropic hypogonadism (high LH/FSH – primary gonad problem ) (Table 3.1) [5]. There are some additional conditions that do not clearly fit into these categories and may have normal or abnormal LH and FSH levels. A careful history and examination may help to focus the differential diagnosis and subsequent workup (Table 3.2). An LH level under 0.2–0.6 mIU/ml or FSH level under 0.2–1.0 mIU/ml, depending on the assay, may be considered low [6]. An LH or FSH level above the normal range for a menstruating female is considered high, though it should be repeated as normal girls may have sporadic high levels.

Functional delayed onset of HPG activity is most commonly due to constitutional delay of growth and puberty , which is a diagnosis of exclusion [6]. Constitutional delay occurs more often in males than in females and is seen in families with a history of delayed puberty (and associated pubertal growth spurt). Asking the parents’ age at puberty can help establish this as a possibility; most mothers remember their age at menarche, and fathers may recall when they first started shaving or if they continued growing after high school. LH and FSH will be low, but they will rise appropriately when the child’s puberty starts at a later age. The child may have a lower height percentile that will improve after the delayed pubertal growth spurt.

Functional delayed onset of HPG activity may be due to poor nutrition or energy balance, inflammatory disease, or states of chronic disease. Women with anorexia, malnutrition, and the female athlete triad (primary amenorrhea, disordered eating or low energy, low bone mineral density) may present with low body mass index and decreased fat tissue composition. This is associated with low levels of the hormone leptin, which has a key role in GnRH release and stimulation of puberty. Clues in the patient’s history that may suggest these conditions include food restriction, binging/purging behavior, or excessive exercise. Some patients with uncontrolled or undiagnosed illnesses such as inflammatory bowel disease (IBD), celiac disease, or systemic lupus erythematosus may have pubertal delay related to both malnutrition and inflammation. Pro-inflammatory cytokines, including IL-1 and TNFα, may impair both GnRH and gonadal steroid production [7]. Growth failure may be an early sign of IBD or celiac disease, related to both poor nutrition and inflammation affecting the growth plate and growth hormone pathway. Other warning signs of gastrointestinal disease may include abdominal pain, constipation, diarrhea, or bloody stools. In this setting, helpful tests m ay include a celiac panel testing for antibodies, specifically tissue transglutaminase IgA and IgG and total IgA level, as well as ESR to look for inflammation. Hypothyroidism or hyperthyroidism may affect pubertal development if the condition is uncontrolled or undiagnosed. Hypothyroidism may present as weight gain, fatigue, depression, concentration difficulty, constipation, or cold intolerance. Hyperthyroidism may present as weight loss, fatigue, anxiety, tremor, diarrhea, or heat intolerance. Evaluation includes a thyroid-stimulating hormone (TSH) level, with or without a paired free thyroxine (free T4) level. Other medical conditio ns such as cystic fibrosis, chronic kidney disease, or sickle cell disease may need to be brought into better control in order for puberty to progress. Some genetic causes of obesity such as Prader-Willi syndrome and Bardet-Biedl syndrome are associated with functional hypogonadism as well.