Precocious Puberty

High-amplitude pulses of GnRH from the hypothalamus at the onset of puberty cause pulsatile increases in the pituitary gonadotropins LH and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex steroids by testicular Leydig cells or ovarian granulosa cells. Pubertal levels of androgens or estrogens cause the physical changes of puberty, including penile enlargement and sexual hair in boys and breast development in girls. These levels also mediate the pubertal growth spurt. Increased FSH levels cause enlargement of the gonads in both sexes and eventually promote follicular maturation in girls and spermatogenesis in boys. Research has implicated a family of peptides called kisspeptins, produced in the central nervous system (CNS), in the regulation of GnRH secretion.

The hypothesized mechanisms that suppress the onset of puberty in early childhood include (1) the HPG axis, which is highly sensitive to feedback inhibition by small amounts of sex steroids, and (2) central neural pathways that suppress the release of GnRH pulses.

Most patients, particularly girls suspected of having CPP, are otherwise healthy children whose pubertal maturation begins at the early end of the normal distribution curve. CNS imaging studies of these girls aged 6-8 years usually reveal no structural abnormalities. While older studies reported a significant proportion of abnormal findings such as tumors, subsequent reports have found an incidence of clinically significant brain imaging findings of less than 1%, even in girls below age 6 years.[2]  Abnormal computed tomography (CT) or MRI scans are more frequent among boys with CPP than among girls with the condition.

CNS abnormalities associated with precocious puberty include the following:

• Tumors (eg,  astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin [HCG])
• Hypothalamic hamartomas
• Acquired CNS injury caused by inflammation, surgery, trauma, radiation therapy, or abscess
• Congenital anomalies (eg, hydrocephalus, arachnoid cysts, suprasellar cysts)

Frequency

The frequency of findings suggestive of precocious puberty in girls and boys depends on whether one is looking at genital hair or breast development, as well as the age at which the condition is considered precocious. The prevalence also depends on whether one is doing population-based screening or assessing the number of patients who are referred to specialists for evaluation. One of the very few studies looking at the prevalence and incidence of precocious puberty based on a national patient register was a Danish report covering the period 1993-2001. The investigators estimated the prevalence at about 0.2% of girls (0.8% for girls ages 5-9 years) and less than 0.05% of boys.[3] This is far lower than indicated in the studies noted below, which are based on the examination of larger groups of children.

United States

In 1969, Marshall and Tanner published the results of their study of 192 White British girls, stating that the average age of thelarche was 11 years and defining precocious puberty in girls as commencing before age 8 years.[4] No studies that looked at the age of appearance of breast and pubic hair in normal children were performed in the United States during that time. However, many in the United States had the impression that girls had been maturing earlier than in the past.

No data were available to confirm this impression until 1997, when Herman-Giddens et al reported on the incidence of breast and pubic hair development by age and race in 17,000 US girls aged 3-12 years.[5]  They used the established definition that breast or pubic development in girls was precocious before age 8 years and estimated that approximately 8% of White and 25% of Black girls in the United States exhibited evidence of sexual precocity.

In 1999, as a result of the Herman-Giddens study, Kaplowitz and Oberfield published new guidelines recommending that puberty be considered precocious only when breast development or pubic hair appear before age 7 years in White girls and age 6 years in Black girls.[6]  However, most clinicians continue to use the 8-year definition.

In 2010, a study by Biro et al reported that in a cohort of 1239 girls aged 7-7.99 years from three urban centers, the proportion who had reached Tanner 2 breast development was 10.4% of White girls, 23.4% of Black girls, and 14.9% of Hispanic girls.[7]  While this was a cross-sectional study, the results confirmed that in the United States, the appearance of breast development prior to age 8 years is quite common. Follow-up of this cohort has indicated that none of these apparently early maturing girls were actually diagnosed with and treated for CPP (Biro F, personal communication, 2020). This suggests that the majority of girls who have breast development before age 8 years do not have the rapidly progressive form of CPP, which requires treatment.

Reliable estimates of the frequency of precocious puberty in boys have not been published. However, several centers have reported that they evaluate between one fifth and one tenth as many boys as girls for sexual precocity. Whether early puberty in boys is becoming more common over time, as is the case in girls, is unclear. However, a study from Denmark found that the mean age of testicular enlargement in boys declined from age 11.92 years to 11.66 years between 1991-1993 and 2006-2008, suggesting that more boys may be starting puberty before age 9 years.[8]

International

A 2003 review of trends in timing of puberty around the world showed no clear progression toward earlier puberty in northern Europe. However, earlier mean age of menarche has been reported in some southern European countries and other warmer parts of the world.[9]  A Danish study showed that over a 15-year period (1991-1993 vs 2000-2008), the mean age at which breast tissue appeared in girls decreased from age 10.88 years to 9.86 years, with a much smaller decline in the mean age at menarche (age 13.42 y vs age 13.13 y).[10]  A study of over 20,000 girls from urban China performed from 2003-2005 showed that the mean age of breast development was 9.2 years, with the mean age at menarche falling to 12.27 years; about 20% of girls aged 8 years already had evidence of breast development.[11]  Thus, in certain parts of the world, a decline in the age of puberty in girls has been noted, with parallel changes seen in US females. Similarly, a literature review by Eckert-Lind et al indicated that worldwide, from 1977 to 2013, the mean age of thelarche fell by a mean of nearly 3 months per decade. The investigators therefore state that at least in some parts of the world, precocious puberty needs to be redefined.[12]

An interesting and still unexplained finding is the high incidence of precocious puberty in girls adopted into Western Europe from various underdeveloped countries. This has been studied extensively in Denmark, where the mean age at thelarche and at menarche in internationally adopted girls was significantly lower than that observed in a reference group of Danish-born girls.[13]  Exposure to chemicals in the environment has been proposed as the cause, but the fact that LH, FSH, and estradiol levels rise earlier in adopted girls suggests that their earlier puberty is centrally mediated and not chemically induced. A commentary published in 2013 suggested that frequent underreporting of age of adoptees from certain countries such as China may be the real explanation for this phenomenon.[14]

Mortality/Morbidity

Isolated sexual precocity of unknown etiology carries no increased risk of mortality; however, distinguishing between children with idiopathic CPP and the rare patient with a CNS, an adrenal, or an ovarian tumor is important because the latter group may be at risk for tumor-related complications. Moreover, some studies have found an association between early puberty in girls and a higher risk of breast cancer.[15]

Children with precocious puberty may be stressed because of physical and hormonal changes that they are too young to understand and may be teased by peers because of their physical difference. Girls who reach menarche before age 9-10 years may become withdrawn and may have difficulty adjusting to wearing and changing pads. Both sexes, but more so boys than girls, may have increases in libido leading to increased masturbation or inappropriate sexual behaviors at a young age. In girls with a history of early puberty, initiation of sexual activity may occur at a slightly earlier age than usual.

Some studies have found that children with precocious puberty more frequently exhibit behavioral problems and are less socially competent than age-matched peers. Some, but not all, studies find evidence of emotional problems persisting into adulthood. The distress associated with early menses can be decreased if parents are encouraged to prepare their daughters for this event when they reach stage III-IV of breast development.

Early puberty accelerates growth, with the result being that children with this condition may initially be considerably taller than their peers. Because bone maturation is also accelerated, however, growth may be completed at an unusually early age, resulting in short stature. Short stature is more likely if puberty starts very early (ie, before age 6 y) than if it begins moderately early (ie, ages 6-8 y). Several studies show that most untreated girls with idiopathic CPP reach an adult height within the reference range. Determination of bone age can be used to predict adult height and to select patients with high risk for short stature if left untreated.

Race/ethnicity

The study by Herman-Giddens et al, as well as data from a National Health and Nutrition Examination Survey (NHANES) III report and a study by Biro et al, conclusively showed that Black females in the United States have onset of breast development and pubic hair about 1 year earlier than White girls. Thus, using the same age definition of precocious puberty for White and Black females yields a higher incidence in Black girls.[5, 16, 17]  No current evidence shows that Black males mature earlier than White ones; thus, the incidence of precocious puberty among boys is similar in both races. The NHANES III study found that Mexican-American girls start breast development at a similar age as White girls and that pubic hair appears slightly later,[16] while the study by Biro et al indicates that Hispanic girls fall between Black and White females in the age of onset of breast development.

Sex

In a series of more than 200 patients evaluated at a single medical center, CPP occurred five times more often in girls than boys;[18] idiopathic CPP occurred eight times more often. A possible explanation for this difference is that many girls whose puberty is considered precocious are actually healthy girls at the early end of the normal distribution.

Without treatment

Most girls who are aged 6-8 years at the onset of puberty achieve an adult height within the normal range or appropriate for their genetic potential.[19, 20] This is because most such girls are significantly taller than average at the time of diagnosis, and thus early cessation of growth typically brings their height into, but not below, the normal range.

Consider therapy following initial evaluation for girls who have predicted heights of less than 4 ft 11 in or who are well below their target height (ie, average of parents' heights, less 2.5 in), when the patient also has very advanced bone age, a height below the 25th percentile, or both.

Controversy surrounds the significance of several studies (mostly with small numbers of patients and no control group) that appear to indicate that girls with CPP are at increased risk for significant behavior problems, such as poor self-esteem and higher anxiety, irritability, or withdrawal. Other studies, however, have no shown such problems. A review of this topic by Walvoord and Mazur concluded that CPP may become a risk factor for psychosocial problems, mainly in the setting of other risk factors, but they cautioned against medical therapy as a means of avoiding presumed negative psychological consequences of precocious puberty.[21]

In a study of 36 girls with signs of early puberty, including 15 patients with CPP, eight with premature adrenarche, and 13 with early normal puberty, GnRH agonist treatment was administered to all girls with CPP. Normal findings were seen, on average, for baseline psychological assessments of cognitive competence, peer acceptance, physical competence, and maternal acceptance. At 1-year follow-up, results were “largely reassuring regarding concerns of adverse psychological consequences of early puberty in girls.”[22]

With treatment

Most studies show significant improvement in adult height compared with height predicted at the start of therapy, but the extent of this improvement depends to some extent on the age of onset of CPP.[23] For example, a study from Israel showed that height gained in girls after discontinuation of GnRH analogue therapy at age 11-12 years (and bone age of 12-12.5 y) is greater for girls with onset of CPP before age 6 years than at age 6-8 years or after age 8 years. Mean adult height was better than genetic target height in the younger group and was less than target height in the group whose puberty started after age 8 years.[24]  This indicates that the benefit of treatment in terms of increased adult height is the greatest in patients who are diagnosed with CPP and started on GnRH analogues at younger ages. The lack of effect in the older girls was confirmed by a meta-analysis showing that treatment of mildly early puberty in girls (onset between ages 8 and 9 y) did not improve adult height.[25]

A review of the effects of GnRH analogue on adult height highlighted several problems with assessing outcomes. These include (1) a paucity of well-designed, randomized, controlled studies, and (2) problems in accurately estimating predicted height based on bone age readings, which may be differently interpreted by different readers. A table in this review summarizing 29 studies from 1994-2015 with differing patient populations found that the mean value for adult height after treatment minus predicted adult height based on bone age varied widely from 2-10 cm.[26]

Patient resources that may be helpful include the following publications:

• Guidelines for sexuality education for children and adolescents have been established by the American Academy of Pediatrics ^[27]
• Kaplowitz P. Early Puberty in Girls: The Essential Guide to Coping With This Common Problem. Ballantine Books New York, 2004
• Greenspan L and Deardorff J.  The New Puberty: How to Navigate Early Development in Today’s Girls. Rodale, New York, 2014

Precocious puberty in girls

The first and most obvious sign of early puberty is usually breast enlargement, which may initially be unilateral.

Pubic and axillary hair may appear before, at about the same time as, or well after the appearance of breast tissue. Axillary odor usually starts about the same time as the appearance of pubic hair.

Menarche is a late event and does not usually occur until 2-3 years after the onset of breast enlargement.

The pubertal growth spurt occurs early in female puberty and usually is evident by the time of initial evaluation.

Precocious puberty in boys

The earliest evidence of puberty is testicular enlargement, a subtle finding that often goes unnoticed by patients and parents.

Growth of the penis and scrotum typically occurs at least a year after testicular enlargement.

Accelerated linear growth (the pubertal growth spurt) occurs later in the course of male puberty than in female puberty but often takes place by the time other physical changes are noted.

Precocious puberty in girls

The most reliable sign of increased estrogen production is breast enlargement. Initially, breast budding may be unilateral or asymmetrical. Gradually, the breast diameter increases, the areola darkens and thickens, and the nipple becomes more prominent. Distinguishing glandular breast tissue from fat, which can mimic true breast tissue, is essential. Examining the patient while she is in the supine position usually minimizes the chance of misinterpreting fat as true breast enlargement.

Genital examination may or may not reveal pubic hair, but enlargement of the clitoris indicates significant androgen excess that must be promptly evaluated. The vaginal mucosa, which is a deep-red color in prepubertal girls, takes on a moist pastel-pink appearance as estrogen exposure increases.

Mild acne may be normal in early puberty, but rapid onset of severe acne, like clitoral enlargement, should increase suspicion of an androgen-excess disorder.

Precocious puberty in boys

The earliest sign of CPP is enlargement of the testes, which depends on increased production of follicle-stimulating hormone (FSH); testicular length is more than 2.5 cm, or testicular volume (with Prader orchidometer beads) is 4 mL or more. If progressive signs of androgen excess occur in a boy without increased testicular size, consider possible causes of precocious pseudopuberty, including congenital adrenal hyperplasia, familial male precocious puberty, and Leydig-cell tumors (a testicular nodule is usually palpable). Human chorionic gonadotropin (HCG)–secreting tumors somewhat increase testicular size by stimulating testicular Leydig-cell LH receptors.

Other signs of puberty (eg, penis growth, reddening and thinning of the scrotum, increased pubic hair) are a consequence of increased testosterone production and occur within 1-2 years after testicular enlargement.

Pubic hair growth that occurs without penis and testicular enlargement and other signs of increased androgen production indicate a condition such as premature adrenarche or a mild, nonclassic form of congenital adrenal hyperplasia rather than true puberty.

Later signs of puberty include the pubertal growth spurt, acne, voice change, and facial hair.

The timing of puberty has a genetic component. A history of early puberty in a parent or sibling is relevant and decreases the likelihood that early puberty has an organic cause. A study from Israel estimated that precocious puberty was familial in one fourth of cases and that the predominant mode of inheritance was autosomal dominant.[28]

An increased body mass index (BMI) has been strongly associated with earlier onset of thelarche and menarche,[29]  with, in some studies, the association being stronger in White females than in Black ones. However, the relationship between body fat and puberty is complex and has many exceptions, and although body weight and fat mass are clearly among the factors that may influence puberty onset in girls, obesity is not definitely associated with early puberty in boys, with only some studies showing a relationship.

A longitudinal study of 354 girls by Lee et al found that increased BMI at age 3 years and the rate of increase in BMI from age 3-6 years were both positively associated with an earlier onset of puberty.[30]  In addition, a meta-analysis of two datasets from adolescent girls in 34 countries in Europe and North America revealed an inverse association between age at menarche and individual BMI.[31]

Genetic factors that have been associated with idiopathic central precocious puberty in females include gain of expression in the kisspeptin gene (KISS1) and gain- or loss-of-function mutations in the kisspeptin receptor gene (KISS1R), the makorin ring finger protein 3 gene (MKRN3), and the delta-like homologue 1 gene (DLK1). Genes that are suspected to play a role in the progression of idiopathic precocious puberty, but whose function in this condition requires clarification, include gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), lin-28 homolog B (LIN28B), neuropeptide Y (NPYR), tachykinin 3 (TAC3), and tachykinin receptor 3 (TACR3).[32, 33]

If the history, physical examination, and laboratory data suggest that a child exhibits early and sustained pubertal maturation, the clinician must differentiate CPP from precocious pseudopuberty. In CPP, which is gonadotropin-dependent, early maturation of the entire hypothalamic-pituitary-gonadal (HPG) axis occurs, with the full spectrum of physical and hormonal changes of puberty. Precocious pseudopuberty is much less common and refers to conditions in which increased production of sex steroids is gonadotropin-independent (see Precocious Pseudopuberty). Correct diagnosis of the etiology of sexual precocity is critical because the evaluation and treatment of patients with precocious pseudopuberty are quite different from those of patients with CPP.

Sex steroid levels

Measurement of serum testosterone is useful in boys with suspected precocious puberty. Early morning testosterone levels in boys in early puberty are higher than afternoon levels because luteinizing hormone (LH) and testosterone levels rise with sleep onset in early puberty.

The stages of puberty as indicated by serum testosterone levels are as follows:

• Testosterone level less than 30 ng/dL - Generally prepubertal (Depending on the laboratory, testosterone levels of 20-30 ng/dL may represent early puberty)
• Testosterone level of 30-100 ng/dL - Early pubertal
• Testosterone level of 100-300 ng/dL - Mid-to-late pubertal
• Testosterone level of more than 300 ng/dL - Adult

For girls, estradiol measurements are less reliable indicators of the stage of puberty. Many commercial assays are not sufficiently specific or sensitive enough to demonstrate an increase during early puberty. Levels that exceed 20 pg/mL usually indicate puberty, but some girls who are clearly pubertal may have levels of less than 20 pg/mL. In addition, estradiol levels may fluctuate from week to week. Girls who have ovarian tumors or cysts often have estradiol levels that exceed 100 pg/mL.

Levels of adrenal androgens (dehydroepiandrosterone [DHEA] and dehydroepiandrosterone sulfate [DHEA-S]) are usually elevated in boys and girls with premature adrenarche. DHEA-S, the storage form of DHEA, is the preferred steroid to measure because its levels are much higher and vary much less during the day. In most children with premature pubarche, DHEA-S levels are 20-100 mcg/dL, whereas in rare patients with virilizing adrenal tumors, levels may exceed 500 mcg/dL.

Consider obtaining a 17-hydroxyprogesterone (17-OH progesterone) serum study if mild or nonclassic congenital adrenal hyperplasia is suspected, which is more likely in children of Hispanic or Ashkenazi Jewish origin. One study from Paris found that if a basal level is below 200 ng/dL, the diagnosis of nonclassic congenital adrenal hyperplasia can be excluded; however, if the random 17-OH progesterone level is elevated, a corticotropin (ie, Cortrosyn)–stimulation test provides the greatest diagnostic accuracy, with a post-corticotropin 17-OH progesterone level of greater than 1000 ng/dL being diagnostic.[40]

Gonadotropins

Because of the development of more sensitive third-generation assays for LH, which can detect levels as low as 0.1 IU/L or below, random LH is now considered a good screening test for CPP, with levels of 0.3 IU/L or above considered diagnostic. However, many children with CPP have prepubertal basal LH levels but will respond to a challenge with GnRH with an increase to 5 IU/L or above, which is considered pubertal.

The immunochemiluminometric assay (ICMA) method for LH assessment seems more specific than the immunofluorometric assay (IFMA) method. An LH level of less than 0.1 IU/L is generally prepubertal, and one study suggested an upper reference range limit for IMCA-measured LH of 0.2 IU/L in both boys and girls, with no overlap between prepubertal and pubertal levels in boys and a 10% overlap in girls.[41]  Another study found that a basal LH level measured by two different ICMA assays was sufficient to document CPP in 90% of girls, with levels of more than 0.83 IU/L in all but one patient; 29 of 34 prepubertal girls had undetectable values (< 0.15 IU/L to < 0.2 IU/L).[42]

A study by Carel et al stated that the peak LH level measured by ICMA that defines CPP is 4.1 IU/L in boys and 3.3 IU/L in girls.[23]

Random follicle-stimulating hormone (FSH) levels do not discriminate between prepubertal and pubertal children. Suppressed levels of LH and FSH accompanied by highly elevated testosterone or estradiol levels suggest precocious pseudopuberty rather than CPP.

A definitive diagnosis of CPP may be confirmed by measuring LH and FSH levels 30-60 minutes after stimulation with GnRH at 100 mcg or with a GnRH analogue. Because native GnRH is no longer available, most centers are using the analogue leuprolide (aqueous form) at a dose of 20 mcg/kg, up to a maximum of 500 mcg. An increase in FSH levels much greater than the increase in LH levels suggests that the child is prepubertal.

Another study suggested that when the baseline LH level is prepubertal, an increase in LH level to 5 IU/L or more after leuprolide correlates well with progression of pubertal signs during a 6-month period of observation.[43]  No increase in LH and FSH levels after the infusion of GnRH suggests precocious pseudopuberty.

Thyroid

Thyroid tests are not a routine requirement in the evaluation of precocious puberty. Mild to moderate hypothyroidism does not lead to early puberty, and severe hypothyroidism only rarely does, in a phenomenon known as Van Wyk-Grumbach syndrome. Major clues suggesting severe hypothyroidism include growth arrest instead of growth acceleration, goiter, and symptoms of thyroid hormone deficiency (fatigue, cold intolerance).

Other

A study by Chen et al indicated that in girls, serum anti-Müllerian hormone and inhibin B offer markers for differentiating progressive CPP from slowly progressive CPP, with anti-Müllerian hormone levels being lower and inhibin-B levels being higher in girls with the progressive form of the condition.[44]

Radiography

As used to determine bone age, radiography of the hand and wrist is a quick and helpful means of estimating the likelihood of precocious puberty and its speed of progression. If bone age is within 1 year of chronologic age, puberty either has not started or the duration of the pubertal process has been relatively brief. If bone age is advanced by 2 years or more, puberty likely has been present for a year or more or is progressing more rapidly.

Head MRI

Many authors have recommended that a brain MRI be performed to look for a tumor or a hamartoma in any child after hormonal studies indicate a diagnosis of CPP.[45] However, subsequent studies have suggested that the finding of tumors or hamartomas in girls between the ages of 6 an 8 years is very low, while incidental findings are more common.[2]  Thus, many now advise limiting such studies to girls younger than age 6 years at the onset of puberty, unless there are signs and symptoms suggestive of a CNS tumor or mass.[46]  In such cases, consultation is suggested with a pediatric endocrinologist who can order the study, if indicated, and ask the radiologist to obtain a high-resolution study that focuses on the hypothalamic-pituitary area.

For boys younger than 9 years, the incidence of CNS findings is much higher than in girls, and MRI should be part of the evaluation.

Pelvic ultrasonography

Ultrasonography is unnecessary for girls with a definite diagnosis of CPP. If performed, however, ultrasonography usually reveals bilaterally enlarged ovaries, often with multiple small follicular cysts, and an enlarged uterus with an endometrial stripe.

Pelvic ultrasonography is essential when precocious pseudopuberty is suspected in girls (based on examination or hormone levels), because an ovarian tumor or cyst may be detected.

If CPP is caused by a tumor in the hypothalamic-pituitary area, the histology of the tumor can be important to the patient's prognosis. Gliomas tend to grow more rapidly than astrocytomas, whereas hamartomas are benign.

Treatment of precocious puberty associated with a hamartoma suppresses gonadotropin production by the pituitary without affecting the hamartoma itself.

For information on different non-CNS tumors associated with precocious puberty, see Precocious Pseudopuberty.

Early onset of puberty can lead to several problems. The early growth spurt initially can result in tall stature, but rapid bone maturation can cause linear growth to cease too early and may result in short adult stature. Moreover, the early appearance of breasts or menses in girls and increased libido in boys can cause emotional distress for some children. However, not all patients with CPP who are age 7 years or older at the time of onset require treatment.

When CPP is caused by a CNS tumor other than a hamartoma, a resection should be attempted to the extent possible without impinging on vital structures such as the optic nerves. Radiation therapy is often indicated if surgical resection is incomplete. Unfortunately, removal of the tumor rarely causes regression of precocious puberty.

Patients treated with GnRH agonists

For patients with precocious puberty treated with GnRH agonists:

• Follow up every 4-6 months to ensure that progression of puberty has been arrested
• Favorable signs include normalization of accelerated growth, reduction (or at least no increase) in breast size, and suppression of gonadotropin levels after a challenge of GnRH
• The ideal testing frequency has not been established, although one approach is to obtain a GnRH test about 4 months after starting the drug to confirm suppression and then conduct such testing no more often than yearly, as long as clinical indicators suggest that the drug is working as intended; some clinicians advocate dispensing with formal GnRH testing as long as growth has slowed and breasts have decreased in size; in boys, a decrease in the size of the testes and a fall in the serum testosterone level to less than 20 ng/dL are good indications of efficacy
• Monitor bone age yearly to confirm that the rapid advancement seen in the untreated state has slowed, typically to a half year of bone age per year or less

A literature review by Wang et al found that the addition of growth hormone to GnRH agonist therapy resulted in significant height increase, as well as increases in predicted adult height and height standard deviation for bone age, in children with CPP. Efficacy was greater in patients whose initial treatment began prior to age 10 years or whose therapy lasted more than 12 months.[47]  However, the high cost of combined growth hormone–GnRH agonist therapy relative to its modest benefit has generally limited its use to children with a very poor adult height prediction.

Patients not treated with GnRH agonists

In many cases, the physician may elect to observe the child with CPP, either because the age of onset is borderline (ie, 7-8 y) and the child and family are coping well, or because the progression of puberty is not rapid and the bone age is only mildly advanced, so that predicted adult height falls well within the broad normal range. In these cases, thoughtful counseling of parents about the manageable risks of withholding treatment and follow-up at 6-month intervals are appropriate.[48] Testing and treatment may be initiated if the tempo of puberty begins to accelerate and predicted adult height deteriorates.

Class Summary

Continuous administration of GnRH agonists suppresses pituitary production of gonadotropins because they provide constant stimulus, whereas the pituitary responds only to pulsatile GnRH stimulation. In use since the late 1970s, GnRH agonists are safe and effective, resulting in decreased levels of LH, FSH, and sex steroids within 4 weeks after initiation of treatment. An excellent review and consensus statement on the use of GnRH analogues in children by Carel et al was been published in 2009,[23]  and an update to the consensus statement was published in 2019.[49] In the past, the 1-month formulation of leuprolide, called Lupron Depot, was the mainstay of therapy. In 2011, 3-month formulations of Lupron Depot, 11.25 mg and 30 mg, were approved for children with precocious puberty. A study comparing the 1-month 7.5-mg leuprolide with the 11.25-mg 3-month leuprolide found that both preparations resulted in prompt and effective suppression of puberty, but LH and FSH levels were slightly higher with the 3-month dosing, which has the advantage of being more convenient for the family.[50]

Triptorelin (Triptodur, Trelstar, Trelstar Depot)

Indicated for central precocious puberty (CPP) in pediatric patients aged 2 years or older; works by the same mechanism as leuprolide. In 2017, the US Food and Drug Administration (FDA) approved a formulation of Triptodur 22.5 mg for CPP that needs to be administered only every 6 months.

Histrelin (Supprelin LA, Vantas)

Histrelin is a potent inhibitor of gonadotropin secretion when administered long-term. The implant provides continuous SC release of histrelin at a nominal rate of 50-65 mcg/d over 12 months and is safe and effective for CPP. One study found that the implant remains effective in suppressing puberty for at least 2 years. The main disadvantage is the need to have visits with a surgeon to place and remove the implant, usually with light sedation, which increases the already high cost of about $40,000 per implant.

Leuprolide (Lupron Depot 3 Month, Eligard, Fensolvi)

Available in a monthly depot formulation in 7.5-, 11.25-, and 15-mg doses and for the every 3-month formulation, in 11.25- and 30-mg doses. Annual cost is approximately $20,000-40,000. Individualize duration of therapy according to age and maturity of child and predicted adult height; in most cases, continuing treatment after age 10 years is unnecessary.

Class Summary

Before the availability of GnRH agonists, these agents were the mainstay of therapy. Progestins work by providing feedback suppression of pituitary gonadotropin secretion. They lack significant androgenic or estrogenic activity.

Medroxyprogesterone (Depo-Provera)

Inhibits secretion of pituitary gonadotropin. Inhibits effect of LH. Effective at slowing breast growth and preventing or stopping menses when administered q3mo, although breakthrough bleeding may occur. Less used now due to relative ineffectiveness in reversing rapid advancement of skeletal maturation seen in CPP. Relatively inexpensive; consider when leuprolide cost is a factor and when adult height prediction is close to reference range or is not a major concern.