Treatment of precocious puberty

INTRODUCTION — Precocious puberty is traditionally defined as the onset of secondary sexual development before the age of eight years in females and nine years in males. Because of trends towards earlier pubertal development, some healthy females will have breast or pubic hair development before this age, and extensive evaluation and treatment may not be required. If the evaluation leads to a diagnosis of progressive precocious puberty, treatment may be considered.

The treatment of precocious puberty, which depends upon the underlying cause, will be discussed in this topic. The definition, etiology, and evaluation of precocious puberty are reviewed separately. (See "Definition, etiology, and evaluation of precocious puberty".)

CLASSIFICATION — Precocious puberty can be classified based upon the underlying pathologic process.

●Central precocious puberty – Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. It is characterized by sequential maturation of breasts and pubic hair in females, and of maturation of the testes, penis, and pubic hair in males. The sexual characteristics are appropriate for the child's sex (isosexual). CPP is idiopathic in 80 to 90 percent of cases in females, whereas intracranial lesions are detected in 20 to 75 percent of males with CPP (table 1A). (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of central precocious puberty'.)

●Peripheral precocity – Peripheral precocity (also known as gonadotropin-independent precocious puberty or peripheral precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) derived either from the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropins from a germ cell tumor (eg, human chorionic gonadotropin [hCG]) (table 1B). We use the term precocity instead of puberty because puberty implies activation of the hypothalamic-pituitary-gonadal axis, as occurs in CPP, whereas precocity refers only to the secondary sexual characteristics. Peripheral precocity is most commonly either isosexual (concordant with the child's sex), or contrasexual (with virilization of females and feminization of males), but can also present with both virilizing and feminizing features in rare cases. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

●Benign or nonprogressive pubertal variants – Benign pubertal variants include isolated breast development in females (premature thelarche) or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) in males or females that result from early activation of the hypothalamic-pituitary-adrenal axis (premature adrenarche) (table 1C). Both of these conditions can be a variant of normal puberty. However, repeat evaluations may be warranted in these children to be certain that the diagnosis is correct. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Types of benign or nonprogressive pubertal variants'.)

TREATMENT FOR CENTRAL PRECOCIOUS PUBERTY — When warranted, pubertal progression in central precocious puberty (CPP) can be treated by administration of a gonadotropin-releasing hormone (GnRH) agonist. GnRH agonists work by providing continuous stimulation to the pituitary gonadotrophs, instead of physiologic pulsatile stimulation from hypothalamic GnRH. Continuous stimulation leads to desensitization of the gonadotroph cells and suppression of gonadotropins, resulting in decreased sex steroid production [1], a phenomenon referred to as pituitary-gonadal axis suppression. This treatment can be used for patients with idiopathic or neurogenic CPP [2,3], or for secondary activation of CPP, which may occur in patients who initially present with peripheral precocity. However, not all patients with CPP require treatment, as outlined in the following section.

When CPP is caused by an identifiable central nervous system (CNS) lesion (neurogenic CPP), therapy is also directed toward the underlying pathology when possible. Benign hypothalamic hamartomas are often left in situ and monitored neuroradiologically over time [4], unless associated with significant generalized epileptic activity [5].

Decision to treat — The decision of whether to treat CPP with a GnRH agonist depends upon the child's age, the rate of pubertal progression (sexual maturation), height velocity, and the estimated adult height as determined from the rate of bone age advancement. Pubertal progression would be considered slow if there is no change in stage of breast, pubic hair, or genital development during six or more months of observation (table 2) [6]. Height velocity is considered accelerated if it is more than 6 cm per year. The relationship between pubertal stages and height velocity in normally developing children is outlined in the figure (figure 1A-B) and discussed in detail elsewhere. (See "Normal puberty", section on 'Pubertal changes'.)

Clinical decision-making related to height preservation is guided by the following considerations (decision-making related to psychosocial concerns is described below (see 'Goals of treatment' below)):

●Age – Children with CPP who present at a younger age and have a rapid progression of maturation benefit the most from therapy because they have early epiphyseal fusion and reduced adult height if they are not treated [7,8]. In contrast, children who present close to the age of normal puberty or who have a very slowly progressive variant of precocious puberty may not require therapy, particularly if their adult height without treatment is concordant with their midparental height range [9-12]. Treatment decisions should be individualized, and initiation of GnRH agonist therapy may be indicated for some children with onset of precocious puberty closer to the normal range [13].

•For females with onset of CPP before the age of six years, GnRH agonist treatment results in an average gain in adult height of 9 to 10 cm, whereas for those with onset of CPP between six and eight years, treatment results in an average gain in adult height of 4 to 7 cm [8,13,14]. The degree of bone age advancement prior to treatment initiation can, however, attenuate this height gain [14].

•For males, fewer data are available. One study estimated that GnRH treatment beginning at an average age of 7.6 years resulted in a mean height gain of 6.2±8.7 cm [15]. Two expert panels concluded that it is reasonable to consider GnRH agonist treatment for males with progressive CPP if they present before nine years of age [7,8]. As in females, the height gain conferred by GnRH agonist therapy is less robust for patients who have more advanced bone age at the initiation of therapy.

●Rate of maturation (pubertal progression) – If precocious puberty is slowly progressive, it is unlikely to compromise adult height and in that instance we do not suggest therapy [8,16]. In a study of 16 such children who were followed for 12 years without treatment, all reached normal adult height [9]. Despite the early onset of breast development in this group, menarche occurred at a normal age (average age 11 years). Similarly, in a group of 35 males with slowly progressive puberty (defined as progression from sexual maturity rating [Tanner] stage 2 to 3 over more than 18 months) who were not treated, adult height was within the range of their target height [11]. Clinical experience has shown that many cases of precocious puberty, particularly in females with onset after six years of age, will be slowly progressive.

●Estimated adult height – If the predicted adult height approximates the mid-parental height, therapy is probably not needed and a conservative approach is therefore warranted [17]. A variety of methods can be used to predict adult height. A common method developed by Bayley and Pinneau employs a table to predict adult height based upon the child's bone age and chronologic age. Height prediction methods have, however, often been found to overpredict the adult height in children with precocious puberty.

Based upon the data described above, we suggest initiation of GnRH agonist therapy for a female presenting with CPP before the age of six with progressive breast and pubic hair development, advanced bone age, and accelerated height velocity. Conversely, in an individual with somewhat later onset of CPP and/or historically slow progression of pubertal development without a substantial increase in height velocity or advancement of bone age, we suggest monitoring without treatment for three to six months to establish the pace of the pubertal progression before making treatment decisions [7,8]. For males, we treat all those presenting with CPP before the age of nine years, unless there is evidence of slow pubertal progression and/or acceptable height prediction, in which case, we monitor clinically to assess the pace of pubertal progression before making treatment decisions [11].

Goals of treatment

●A primary goal of treatment for CPP is to allow a child to grow to a normal adult height. Therefore, as noted above, the decision to treat should include analysis of the predicted height benefit from treatment. (See 'Decision to treat' above.)

●Another goal of therapy is to relieve psychosocial stress. Parents are often concerned about the prospect of early menses, which might be distressing to a young girl. However, the data regarding the psychosocial impact of CPP are limited. A study of 19 females with CPP prior to treatment initiation found no difference in psychological distress as compared with females with normal puberty [18]. A study of 10 females with CPP demonstrated reduced stress levels following one year of GnRHa therapy [19]. However, another study of 36 females with CPP demonstrated improvement in psychological scores irrespective of GnRHa treatment [20]. Because of scant data in this area, treatment primarily to address perceived psychosocial consequences of precocious puberty should be approached with caution [7]. This caution is especially true for females with pubertal onset at the edge of the normal range, whereas treatment of a very young child may be warranted even in the absence of strong data. In females with developmental disabilities where the goal of treatment may be suppression of menses rather than height preservation, alternate treatment approaches such as intramuscular (depot) medroxyprogesterone, continuous oral contraceptive pills, or intrauterine devices can be considered [16,21] (see "Hormonal contraception for menstrual suppression"). It is important to take a family-centered approach to the decision to initiate therapy for CPP by ensuring that the caregivers are fully informed about the pros and cons of the therapy.

GnRH agonist therapy — For children with CPP, GnRH agonist administration results in an initial transient stimulation of gonadotropin secretion from the pituitary, followed by a complete, but reversible, suppression of the pituitary-gonadal axis. The initial stimulation of gonadotropins is the basis for using these drugs in a stimulation test to distinguish CPP from peripheral precocity or benign pubertal variants. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Serum LH concentrations after GnRH agonist stimulation'.)

Formulations and dosing — Sustained-release formulations of several GnRH agonists have been developed: depot preparations for monthly, three-, or six-monthly dosing and a subcutaneous implant that is surgically inserted every 12 months (table 3) [6]. The choice of GnRH agonist formulation depends on patient and clinician preference and local regulatory approvals [8]. These preparations have not been directly compared in randomized trials but appear to be similarly effective in suppressing the pituitary-gonadal axis [22-32].

Short-acting GnRH agonist formulations are also available, including daily subcutaneous injections and multiple daily dosing intranasal sprays (nafarelin acetate). Depot preparations are preferable because of improved compliance and thus better pituitary-gonadal axis suppression [33]. However, in certain clinical situations, such as the development of sterile abscesses with depot GnRH agonist therapy, these daily preparations can be used as an alternative.

The different GnRH agonist preparations and typical starting doses used in various countries are outlined in the table (table 3). Our typical approach to GnRH agonist depot dosing is described below. (See 'Our approach' below.)

Monitoring — After GnRH agonist therapy has begun, follow-up monitoring should be performed to ensure that the goals of GnRH agonist therapy are being achieved (eg, suppression of the pituitary-gonadal axis, slowing of development of secondary sexual characteristics, slowing of bone age advancement, and, ultimately, increases in predicted adult height). If treatment is effective, further breast and testicular development and menses should cease and height velocity and rate of bone age advancement should decline. Therefore, routine monitoring should include:

●Evaluation of pubertal development and growth every three to six months. Effective GnRH agonist therapy should result in a decrease in height velocity, cessation of menses, and arrest pubertal progression.

●Periodic bone age measurements (eg, every 6 to 12 months), looking for a reduction in the bone age advancement [2,7]. Once this has been documented, bone age measurements can be performed less frequently (eg, every one to two years).

In our practice, we do not routinely monitor serum LH and sex steroid concentrations during GnRH agonist therapy, because we believe there are insufficient data to demonstrate that using such measurements to adjust therapy improves adult height outcomes [8]. However, we recognize that this is a controversial topic and that other clinicians prefer to monitor biochemically for evidence of pituitary-gonadal axis suppression and adjust treatment accordingly. Such measurements include basal LH and sex steroid concentrations (estradiol in females and testosterone in males) or stimulated LH and sex steroid levels (after GnRH or a GnRH agonist administration). Native GnRH is not available in the United States; therefore, some clinicians use the next scheduled GnRH agonist injection for the stimulated LH sample.

Regardless of whether biochemical monitoring is performed, ongoing careful clinical assessment is paramount. If there is evidence of ongoing pubertal progression once therapy has begun, then the above biochemical measurements may be used to assess whether there is complete suppression of the pituitary-gonadal axis [34,35]. If this testing shows incomplete suppression of the pituitary-gonadal axis, the GnRH agonist dose should be increased or the interval between doses decreased. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Basal serum luteinizing hormone' and "Definition, etiology, and evaluation of precocious puberty", section on 'Serum LH concentrations after GnRH agonist stimulation'.)

Within the first weeks after the initial dose of the GnRH agonist, vaginal bleeding may occur due to estradiol withdrawal because the treatment initially stimulates estradiol production before suppressing the pituitary-gonadal axis. If vaginal bleeding occurs later in the course of treatment, this either indicates lack of suppression of the pituitary-gonadal axis or an alternative diagnosis to CPP (eg, a cause of peripheral precocity). Pubic hair stage may advance due to adrenarche despite effective treatment with GnRH agonists because these agents have no effect on adrenal androgen production [36].

Treatment duration — The duration of GnRH agonist therapy should be long enough to optimize final adult height, yet still allow progression of pubertal characteristics at an age that is concurrent with the individual's peers. When GnRH agonist therapy with monthly depot preparations is stopped, normal puberty returns, on average, within 12 to 18 months.

In one study, menarche occurred 17.5±11.2 months after the last injection of GnRH. It was somewhat earlier in females who had menstruated prior to GnRH treatment (mean age of resuming menses 12.7±1.3 years, approximately nine months after the last GnRH injection), compared with those who had not previously menstruated (mean age of menarche 13.1±1.5 years, approximately 19 months after the last GnRH injection) [37]. In males, the interval between the last injection of GnRH and achievement of adult testosterone levels was 11±10.9 months. If histrelin implants are used, reports suggest that the average length of time between removal of the implant and resumption of menses is approximately 12 months, with wide variability [29,30].

Safety

●Short-term – Potential adverse effects of GnRH agonist therapy include:

•Localized adverse effects of the one-, three-, and six-monthly depot injections include transient pain and local reactions at the injection sites, and, although uncommon, sterile abscess formation [38].

•For histrelin implants, the extraction procedure can be complicated by breakage of the implant in 15 to 39 percent of cases, with a higher likelihood of breakage if the implant is left in for two years rather than shorter periods of time [39,40].

•Systemic hypersensitivity reactions have been reported in <4 percent of patients [41].

•Pseudotumor cerebri (idiopathic intracranial hypertension) has been described in a few case reports [42-44]. This appears to be rare, but patients should be monitored for suggestive symptoms, including headache, papilledema, or blurred vison.

•A risk of prolonged QT interval has been raised because this complication has been reported for GnRH agonist therapy in a small number of men with prostate cancer. As a result, the Pediatric Endocrine Society recommended that risk factors for prolonged QT interval be identified prior to initiating GnRH agonist therapy, including concomitant medications known to prolong the QT interval or a family history of long QT syndrome, congenital heart disease, arrhythmia, or sudden death [45,46]. Patients with these risk factors should be monitored by electrocardiogram prior to commencement of GnRH agonist therapy and again when the GnRH agonist dose has reached steady state. The frequency of this complication and whether it occurs in children/youth have yet to be determined.

●Long-term – No long-term adverse effects of GnRH agonist therapy have been demonstrated:

•Treatment with GnRH agonists appears to have no significant long-term effects on the pituitary-gonadal axis [47]. In long-term follow-up of females who were treated with GnRH agonists, the rate of regular menstrual cycles and fertility was not different from the general population [48-50]. For males, small studies show normal gonadal function after completing treatment with GnRH agonists [51].

•Although earlier pubertal development is associated with obesity, long-term treatment with GnRH agonists does not appear to cause or exacerbate obesity in adolescence or adulthood [8,52,53].

•While bone mineral density may slightly decrease during GnRH agonist administration, these changes are not sustained, with preservation of peak bone mass accrual after discontinuation of therapy [54,55].

•Overall, there is no clear evidence that GnRH agonist treatment increases the risk for polycystic ovary syndrome [7,8,47]. The reported incidence of polycystic ovary syndrome in females with CPP is variable, with some series reporting up to a 32 percent incidence [56], while others report rates of 0 to 12 percent, an incidence not different from the general population [7].

Our approach — After a progressive form of CPP has been identified and discussion with the family has resulted in a decision to treat, the choice of GnRH agonist formulation depends upon patient and clinician preference, insurance company coverage, and local regulatory approvals. Families should be counseled that some vaginal bleeding may occur after the initiation of GnRH agonist therapy due to transient stimulation of the pituitary-gonadal axis with the first dose. Similarly, males can experience a transient increase in erections.

A variety of dosing schemes are effective. Starting doses used in Europe tend to be somewhat lower than those in the United States (as outlined in the table (table 3)); additionally, other products are available worldwide but not in the United States. Our approach includes the following:

●Given the GnRH agonist preparations available to us, we typically use the three-month preparation of leuprolide depot (Lupron Depot PED [three month]) at a starting dose of 11.25 mg. If puberty is not adequately suppressed, we decrease the interval between doses or titrate up the dose. Triptorelin and histrelin can be substituted for Lupron Depot PED where available if preferred.

●For young children (under two years of age) or children with hypothalamic hamartomas (groups in which control of puberty may be more difficult), we often instead use leuprolide depot (Lupron Depot PED [one month]), given intramuscularly every 28 days, with a starting dose of 7.5 mg. After suppression is achieved, we typically switch to three-monthly preparations if desired by the family. (See 'Formulations and dosing' above.)

●We monitor the response to the GnRH agonist by assessing pubertal development and height velocity every three to six months and bone age initially every 6 to 12 months. If pubertal progression is not suppressed, the dose of GnRH agonist is adjusted upward or the interval between doses is shortened. (See 'Monitoring' above.)

●We generally continue treatment until approximately age 11 years in females and age 12 years in males. The decision of when to discontinue GnRH agonist therapy is individualized [13]; contributing factors include the age of the child, bone age and height age, predicted height, and desire to have pubertal progression concurrent with their peers. (See 'Treatment duration' above.)

TREATMENT FOR PERIPHERAL PRECOCITY — Peripheral sexual precocity (also referred to as gonadotropin-independent precocious puberty or peripheral precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) derived from the gonads, adrenal glands, or exogenous sources or driven by ectopic production of gonadotropin from a germ cell tumor (eg, human chorionic gonadotropin [hCG]) (table 1B). The causes and evaluation of peripheral precocity are discussed in a separate topic review. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

General approach — Peripheral precocity does not respond to gonadotropin-releasing hormone (GnRH) agonist therapy. Instead, treatment is directed at blocking the production of and/or response to the sex steroids, depending on the cause:

●Tumors of the testis, adrenal gland, or ovary – These are treated by surgery. hCG-secreting tumors may also require radiation therapy and chemotherapy, depending upon the site and histologic type.

●Functioning follicular cysts of the ovary – These develop and regress spontaneously, so conservative management without surgery is generally appropriate [57-59]. Patients should be followed clinically to document regression in the clinical signs of precocity. If there is no clinical evidence of pubertal regression, ultrasonography of the ovaries should be performed. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Ovarian cysts'.)

●Exposure to exogenous sex steroids – The source should be identified and removed. After removal, the pubertal changes are likely to regress. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Exogenous sex steroids and endocrine-disrupting chemicals'.)

●Defects in adrenal steroidogenesis, such as classic congenital adrenal hyperplasia – These should be treated with glucocorticoids. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Definition, etiology, and evaluation of precocious puberty", section on 'Adrenal pathology'.)

●McCune-Albright syndrome and familial male-limited precocious puberty – These disorders require a different approach because they are caused by mutations resulting in overstimulation of the tissues that produce sex steroids. (See 'McCune-Albright syndrome' below.)

Children with peripheral precocity with exposure to high serum sex steroid levels are at risk for developing secondary central precocious puberty (CPP) once the cause of peripheral precocity has been treated. Clinical monitoring for signs of progressive breast or testicular development is therefore important after treating a child with peripheral precocity. Addition of a GnRH agonist may be warranted if CPP has developed. (See 'GnRH agonist therapy' above.)

McCune-Albright syndrome — McCune-Albright syndrome (MAS; MIM #174800) is a rare genetic disorder defined as the triad of peripheral sexual precocity, café-au-lait skin pigmentation, and fibrous dysplasia of bone. It is caused by a somatic (postzygotic) mutation of the gene encoding the alpha subunit of the Gs protein that results in constitutive activation of adenylyl cyclase in affected tissues [60].

Affected females tend to form recurrent ovarian cysts, resulting in estradiol secretion and intermittent vaginal bleeding. The ovarian enlargement is sometimes mistaken for an ovarian tumor, leading to unnecessary oophorectomy [61]. Affected males produce excess testosterone, but they are less likely to develop sexual precocity. Testicular abnormalities on ultrasound that most likely represent Leydig cell hyperplasia are common [62]. To preserve fertility, children with MAS should be treated with drugs that inhibit gonadal steroidogenesis or gonadal steroid action, rather than surgery.

The clinical presentation and diagnosis of MAS is discussed separately (see "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'). More detailed information, including evaluation and management of associated skeletal abnormalities, renal phosphate wasting, and other endocrine abnormalities, is described in a guideline from an international consortium [63].

Females — Approximately 85 percent of females with MAS develop precocious puberty [60]. One goal of treatment is to reduce the potential for compromised adult height due to early epiphyseal fusion from sustained estrogen exposure in young females. A second goal is to reduce the psychological impact of recurrent vaginal bleeding [64]. Treatment for females with MAS has included strategies to block estrogen biosynthesis with aromatase inhibitors or block estrogen action (figure 2). While there is no consensus on the optimum treatment, we use an aromatase inhibitor (letrozole); this practice is based upon the limited clinical experience outlined below:

●Aromatase inhibitors – Treatment with letrozole has become one of the commonly used therapeutic approaches for females with MAS [63]. In a pilot study of nine females treated with letrozole, the episodes of vaginal bleeding either ceased or decreased and there was a decrease in bone age advancement [65]. One patient, however, developed a large ovarian cyst with clinical symptoms suggestive of torsion. A follow-up study of 28 females treated with letrozole for a mean of 4.1 years demonstrated further improvement in predicted adult height, without any further cases of ovarian torsion [66]. More data on the long-term safety and impact of letrozole on adult height from larger cohorts of patients are still needed.

Clinical experience suggests that other aromatase inhibitors are less effective. Testolactone, a first-generation aromatase inhibitor, is partially effective for reducing the recurrence of ovarian cysts and slowing pubertal progression [67], but there is a loss of efficacy over time [68]. For reasons that are not clear, the newer-generation aromatase inhibitors, fadrozole and anastrozole, are largely ineffective for long-term treatment [69-71].

●Blockers of estrogen action – Drugs that block estrogen action appear to have some efficacy, but their clinical role remains unclear because evidence is limited to small case series. Treatment with tamoxifen, a selective estrogen receptor modulator (SERM), has been shown to decrease the vaginal bleeding episodes and slow the rate of bone age advancement in a study of 28 females [72]. However, uterine and ovarian volumes increased by the end of the study, raising concerns about long-term safety. In a retrospective study of eight females treated with tamoxifen, the predicted adult height improved during treatment [73]. However, in the four females who had completed their growth during the follow-up period, the gain in adult height was modest (average of 4.3 cm).

In a one-year open-label trial of fulvestrant, a pure estrogen receptor antagonist, most subjects who had vaginal bleeding at baseline experienced either a substantial reduction or cessation of bleeding, and rates of bone age advancement decreased significantly [74]. These results are promising but long-term safety or efficacy outcomes for fulvestrant treatment of MAS are not yet available.

A few patients with MAS will develop a component of central precocious puberty (CPP). This is probably caused by prolonged fluctuating exposure to elevated levels of sex steroids and is most often found in patients with advanced bone age. Such patients may respond to adjuvant treatment with a GnRH agonist, as do other children with CPP [75]. (See 'GnRH agonist therapy' above.)

Males — MAS is less common in males than females [76], and approximately 15 percent of affected males develop precocious puberty, which is due to overproduction of testosterone [60,62].

Due to the rarity of this disorder in males, information about treatment outcomes is very limited. A few case reports describe successful treatment of these individuals with an antiandrogen in combination with an aromatase inhibitor to prevent conversion to estradiol and subsequent bone age advancement, similar to the regimen used for familial male-limited precocious puberty described below [62,63,75,77]. (See 'Familial male-limited precocious puberty' below.)

The pathogenesis and presentation of MAS are outlined in a separate topic review. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

Familial male-limited precocious puberty — Familial male-limited precocious puberty, also called familial gonadotropin-independent precocious puberty or familial testotoxicosis, is a rare genetic condition in males that is caused by an activating mutation in the gene encoding the luteinizing hormone (LH) receptor, which results in premature Leydig cell maturation and testosterone secretion.

The disorder is treated with a combination of an antiandrogen (an androgen receptor antagonist; eg, spironolactone, bicalutamide) and an aromatase inhibitor, eg anastrozole, which inhibits the conversion of testosterone to estradiol, thereby slowing further epiphyseal maturation (figure 2) [78-80]. The resulting decrease in sex steroid levels may lead to CPP. If so, CPP is treated with a GnRH agonist [61,75].

The optimal treatment regimen has not been established, because data are limited to small case series and direct comparisons are lacking. Based upon available published data, we use the combination of spironolactone and anastrozole (testolactone is no longer available). Preliminary results of such combination therapy are promising. Results of published case series are:

●In the largest case series to date, 25 subjects with familial male-limited precocious puberty were treated with a combination of spironolactone and either testolactone or anastrozole (once testolactone was no longer available) and followed to adult height. GnRH agonist therapy was introduced if there was evidence of secondary activation of CPP. This treatment regimen resulted in an increased adult height compared with the predicted adult height at the time of initial assessment of 12.4 cm (1.3 standard deviations) [81] and is consistent with initial findings from a smaller case series published by the same investigators [80].

●In a case report of two males with familial male-limited precocious puberty, a regimen of bicalutamide and anastrozole was effective in reducing height velocity and decreasing secondary sexual characteristics without serious adverse effects [82]. In an open-label study in 14 males, the same combination effectively reduced height velocity and bone age maturation; gynecomastia and breast tenderness were the most common side effects [83]. Further data on final adult height and safety are needed for this combination of medications.

●Other regimens have included ketoconazole, an inhibitor of steroid synthesis, which was effective in two small series [84,85] but may cause hepatotoxicity and adrenal insufficiency [86].

BENIGN OR NONPROGRESSIVE PUBERTAL VARIANTS — For patients presenting with idiopathic isolated premature thelarche or premature adrenarche, clinical reexamination and follow-up are important to confirm the diagnosis because some patients with an initial presentation that is consistent with a benign pubertal variant will turn out to have a progressive disorder such as central precocious puberty (CPP) or peripheral precocity. If reexamination confirms lack of rapid progression in secondary sexual characteristics, these children need no therapy and can be discharged from clinical care. Similarly, intermittent or slowly progressive precocious puberty does not warrant therapy. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Types of benign or nonprogressive pubertal variants'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and puberty-related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Early puberty (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Types of precocious puberty – The etiology of precocious puberty is classified by the underlying pathogenesis into three categories: central precocious puberty (CPP; also known as gonadotropin-dependent precocious puberty or true precocious puberty), peripheral precocity (also known as gonadotropin-independent precocious puberty or peripheral precocious puberty), and benign or nonprogressive pubertal variants (table 1A-C). (See 'Classification' above.)

●CPP

•Decision to treat – The primary goal of treatment for CPP is to allow a child to grow to a normal adult height; relieving psychosocial distress, if present, is an additional goal. For patients with CPP, the decision about whether to treat largely depends on the age of onset of CPP, the rate of sexual maturation, and the estimated adult height as determined by the rate of bone age advancement (table 2). In general, treatment is most likely to be beneficial for children who are younger, have rapid pubertal progression, and shorter predicted adult height. Children with slowly progressive forms of CPP do not require treatment, because they reach their height potential without treatment. (See 'Decision to treat' above.)

•Gonadotropin-releasing hormone (GnRH) agonist therapy – If treatment for CPP is indicated, GnRH agonists are used. Clinically significant increments in height potential are achieved with a variety of GnRH agonists, and outcome data are insufficient to recommend one form over another; several preparations are listed in the table (table 3). The choice of GnRH agonist formulation depends on patient and clinician preference and local insurance and regulatory approvals; in our practice, we use either the one-month or three-month preparation of leuprolide depot given intramuscularly. (See 'Formulations and dosing' above and 'Our approach' above.)

•Monitoring – During treatment with a GnRH agonist, patients should be monitored periodically for pubertal development, height velocity, and bone age to determine whether the dose and interval are adequate. (See 'Monitoring' above.)

●Peripheral precocity

•Causes – Peripheral precocity is caused by excess secretion of sex hormones either from the gonads or adrenal glands, by exogenous sources of sex steroids, or driven by ectopic human chorionic gonadotropin (hCG) production by a germ cell tumor; in these cases, the precocity is GnRH independent. Causes of peripheral precocity are listed in the table (table 1B). (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

•Management – Treatment for peripheral precocity is directed at blocking the production of and/or response to the excess sex steroids; these patients do not respond to GnRH agonist therapy, unless they have developed secondary CPP (figure 2). (See 'Treatment for peripheral precocity' above.)

●Benign or nonprogressive variants – Benign or nonprogressive pubertal variants include isolated breast development (premature thelarche) or isolated characteristics such as pubic hair development mediated by androgens produced by early maturation of the adrenal glands (premature adrenarche). Either of these patterns usually is a variant of normal puberty and requires no intervention. However, clinical reexamination and follow-up are important to confirm the diagnosis because some patients with an initial presentation that is consistent with a benign pubertal variant will turn out to have a progressive disorder. (See 'Benign or nonprogressive pubertal variants' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Saenger, MD, MACE, who contributed to an earlier version of this topic review.