review

Central precocious puberty:

revisiting the diagnosis and
therapeutic management

Vinícius Nahime Brito1, Angela Maria Spinola-Castro1,

Cristiane Kochi2, Cristiane Kopacek2,
Paulo César Alves da Silva1, Gil Guerra-Júnior2

ABSTRACT 1
Departamento de Endocrinologia
Clinical and laboratory diagnosis and treatment of central precocious puberty (CPP) remain chal- Pediátrica, Sociedade Brasileira
de Endocrinologia e Metabologia
lenging due to lack of standardization. The aim of this revision was to address the diagnostic and
(SBEM), Rio de Janeiro, RJ, Brasil
therapeutic features of CPP in Brazil based on relevant international literature and availability of the 2
Departamento de Endocrinologia,
existing therapies in the country. The diagnosis of CPP is based mainly on clinical and biochemical Sociedade Brasileira de Pediatria
parameters, and a period of follow-up is desirable to define the “progressive” form of sexual precoc- (SBP), Rio de Janeiro, RJ, Brasil
ity. This occurs due to the broad spectrum of pubertal development, including isolated premature
thelarche, constitutional growth and puberty acceleration, progressive and nonprogressive CPP, and
Correspondence to:
early puberty. Measurement of basal and stimulated LH levels remains challenging, considering that Gil Guerra-Júnior
the levels are not always in the pubertal range at baseline, short-acting GnRH is not readily available Departamento de Pediatria,
in Brazil, and the cutoff values differ according to the laboratory assay. When CPP is suspected but Faculdade de Ciências Médicas,
basal LH values are at prepubertal range, a stimulation test with short-acting or long-acting monthly Universidade Estadual de Campinas
GnRH is a diagnostic option. In Brazil, the treatment of choice for progressive CPP and early puberty Rua Tessália Vieira de Camargo, 126
Cidade Universitária “Zegferino Vaz”
is a long-acting GnRH analog (GnRHa) administered once a month or every 3 months. In Brazil, for-
13083-887 – Campinas, SP, Brasil
mulations of GnRHa (leuprorelin and triptorelin) are available and commonly administered, includ- [email protected]
ing 1-month depot leuprorelin 3.75 mg and 7.5 mg, 1-month depot triptorelin 3.75 mg, and 3-month
depot leuprorelin 11.25 mg. Monthly or 3-month depot GnRHa are effective and safe to treat CPP. Arch Received on Feb/12/2016
Endocrinol Metab. 2016;60(2):163-72 Accepted on Mar/10/2016

Keywords DOI: 10.1590/2359-3997000000144

Precocious puberty; sexual maturation; gonadotropin-realising hormone; luteinizing hormone; long-acting GnRH analog

anterior pituitary gland. This process is named gonad-

INTRODUCTION arche (1-3).

P uberty is a period of physical, hormonal, and psy- Gonadarche is often preceded by adrenarche, a
chological transition from childhood to adult- process ACTH-independent (adrenocorticotropic hor-
hood, with accelerated linear growth and achievement mone) and responsible for the secretion of androgens
of reproductive function. It is a complex and multifac- (DHEA = dehydroepiandrosterone and DHEAS =
torial process that includes genetic, metabolic, environ- DHEA sulfate) by the adrenal zona reticularis. Adrenar-
mental, ethnic, geographic, and economic factors and che is clinically characterized by development of axillary
results in reactivation of the hypothalamic-pituitary-go- odor, pubic hair, and skin oiliness, whereas in gonadar-
nadal (HPG) axis. An effective pubertal onset requires che the initial clinical manifestation is thelarche in girls
pulsatile hypothalamic secretion of GnRH stimulating and a bilateral increase in testicular volume in boys (4).
the secretion of gonadotropins by the anterior pituitary The classical definition of precocious puberty is the
gland (LH = luteinizing hormone and FSH = follicle- development of secondary sexual characteristics before
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stimulating hormone). Gonadotropins stimulate the the age of 8 years or menarche before the age of 9 years
gonads and exert a negative feedback effect on the hy- in girls and any secondary sexual characteristic before
pothalamus, whereas gonadal steroids (T = testoster- the age of 9 years in boys. However, recent epidemiolo-
one, produced by the testis, and E2 = estradiol, pro- gical studies have suggested that the initial pubertal age
duced by the ovaries) inhibit both hypothalamus and is decreasing mainly in girls (5-7), but also in boys (8,9).

Arch Endocrinol Metab. 2016;60/2 163

 Guideline of central precocious puberty

CLASSIFICATION OF PRECOCIOUS PUBERTY Table 1. Etiologies of central precocious puberty

Idiopathic
Precocious puberty is classified according to the un-
Genetic causes
derlying physiopathological process (10) in:
• Variants of normal pubertal development: iso- Activating mutations in the KISS1R and KISS1 genes

lated forms of thelarche, pubarche, or vaginal Inactivating mutations in the MKRN3 gene (familial CPP)

bleeding due or not to a hormonal etiology; Chromosomal abmormalities

• Central precocious puberty (CPP), gonadotro- Secondary to chronic exposure to sex steroid hormones (late treatment of
simple virilizing congenital adrenal hyperplasia, following ressection of tumors
pin-dependent precocious puberty, or true preco- secreting sex steroid hormones, testoxicosis, McCune-Albright syndrome) or
cious puberty: early maturation of the HPG axis; endocrine disruptors
• Peripheral precocious puberty, or gonadotro- International adoption
pin-independent precocious puberty, or pseu- CNS abnormalities
doprecocious puberty: excessive secretion of Hypothalamic hamartoma
gonadal sex hormones or adrenal hormones Tumors: astrocytoma, ependymoma, optic or hypothalamic glioma,
from a genetic or tumoral etiology, germ cell LH-secreting adenoma, pinealoma, neurofibroma, non-hCG secreting
tumors secreting hCG (human chorionic go- dysgerminoma, craniopharyngioma*

nadotropin – exclusively in boys), or an exoge- Other congenital malformations: suprasellar cyst, arachnoid cyst, septo-optic
dysplasia, hydrocephalus, spina bifida, vascular malformation,
nous source. meningomyelocele, ectopic posterior pituitary lobe, pituitary duplication
Acquired diseases*: inflammatory processes (abscess, meningitis,
encephalitis, sarcoidosis, tuberculosis), radiation, perinatal asphyxia, trauma
PARTICIPANTS AND OBJECTIVE
CNS: central nervosus system. * May also progress to pituitary dysfunction.
There were 6 participants chosen for their expertise in
pediatric and adult endocrinology. Therefore, a meeting
was organized in Sao Paulo, Brazil, in October 2015,
with representation from Brazilian Society for Endocri- lopment of breasts, enlargement of labia majora and
nology and Metabolism and Brazilian Pediatric Society, minora, and increase and redistribution of body fat
Departments of Pediatric Endocrinology, to examine predominantly in the hips. Another important aspect
current data relevant to the diagnosis and therapeutic is the estrogenization of the vaginal epithelium, with
management of children with CPP. This revision pre- acidification of the vaginal pH and mucus discharge. In
sents a summary of essential issues on this topic. response to testosterone, boys present testicular, penile,
The aim of this revision was to address the diagnosis and cricoid cartilage growth (leading to voice change),
and therapeutic management of CPP based on relevant facial hair development, changes in body fat distribu-
international literature and availability of the existing tion, and increase in muscle mass. In 40% of the boys,
medications in Brazil. transient pubertal gynecomastia may occur. In both
genders, development of pubic hair is associated with
adrenarche (10,16-19). The stage of female and male
CENTRAL PRECOCIOUS PUBERTY pubertal development is determined by Marshall and
Tanner’s classification (20,21).
Etiology
To evaluate a patient with precocious puberty, the
The main etiologies of CPP are listed in Table 1 (10- clinician must know the normal chronology of pubertal
15). Idiopathic CPP represents 90% of the cases in girls, events and growth rate, and the progression of bone
whereas organic etiologies are more frequent (60% to maturation (Figure 1) (22). A progression from one
70%) in boys. However, these epidemiological data are stage to another in less than six months and a height
currently being revised with the new genetic and ima- velocity above 6 cm/year characterize a progressive
ging diagnostic methods (8). condition. Height, weight, and height velocity should
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be plotted in reference curves, and height is generally

Clinical diagnosis found to be above the familial pattern (10,16-19).
From a clinical standpoint, puberty onset and rate of The main objective of evaluating patients with pre-
progression are determined by the observation of phy- cocious puberty is to identify benign conditions from
sical changes. In girls, estrogen determines the deve- others caused by diseases like tumors, which require

164 Arch Endocrinol Metab. 2016;60/2

 Guideline of central precocious puberty

Female Male
Event Event

Growth velocity ± 2 years Growth velocity ± 2 years

Menarche Penis 1 5

Breast 2 3 4 5 Testes 2 3 4 5

Hair Hair 2 3 4 5

10 11 12 13 14 15 16 17 10 11 12 13 14 15 16 17

Age (years) Age (years)

Figure 1. Chronology of sexual maturation and growth spurt during puberty in both genders according to Marshall & Tanner (20,21) stages. Adapted from
Tanner (22).

immediate and objective management. Patients with ment of secondary sexual characteristics between the
the following characteristics must always be evaluated: ages of 8 and 9 years in girls and 9 and 10 years in
• Early onset and/or accelerated development boys) (23,24). In boys, testicular development is of-
of secondary sexual characteristics in both gen- ten indicative of activation of the HPG axis, whereas
ders; in peripheral puberty, penile growth occurs without
• Height velocity above the expected value for concomitant testicular development, or the size of the
gender and age and/or height above the fami- testis is disproportional to the virilization of the geni-
lial genetic channel. talia. Other important assessments during physical exa-
The clinical history must always be the initial diag- mination that may help in the differential diagnosis of
nostic step, and investigation should include the birth idiopathic and neurogenic CPP include neurological
conditions, history of perinatal trauma, previous infec- examination, measurement of head circumference, and
tions, accidental ingestion of drugs, and use of creams funduscopic evaluation. The physical examination must
or ointments. It is also very important to identify prior also investigate the presence of neurofibromas and
neurological diseases and information such as the oc- café-au-lait spots with regular edges, which are sug-
currence of headache and psychological, visual, or appe- gestive of type 1 neurofibromatosis and related to CPP
tite changes. The age at onset of signs and symptoms is (associated with optic glioma). Café-au-lait spots with
not helpful in differential diagnosis. However, clinical irregular and often jagged edges may indicate the diag-
manifestations below the age of 4 years suggest orga- nosis of McCune-Albright syndrome, which is associa-
nic etiologies, particularly hypothalamic hamartomas. ted with peripheral precocious puberty of ovarian etio-
Information about family history, including the age at logy (10,16-19).
pubertal onset and similar cases in the family, may be
useful in the diagnosis of familial CPP (10,16-19). Differential diagnosis of precocious puberty
The physical examination must include informa- It is essential to discriminate between CPP and com-
tion about height, weight, and pubertal stage. In girls, mon variants of precocious puberty, such as isolated
the differential diagnosis of CPP may be challenging
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premature thelarche or adrenarche and prepubertal

because the spectrum of pubertal development is very vaginal bleeding due or not to a hormonal etiology.
broad and includes isolated premature thelarche, cons- These conditions occur independent of the reactivation
titutional growth and puberty acceleration, progressive of gonadotropic axis. Premature thelarche refers to the
and nonprogressive CPP, and early puberty (develop- isolated development of breast tissue, without other pu-

Arch Endocrinol Metab. 2016;60/2 165

 Guideline of central precocious puberty

bertal signs, such as accelerated linear growth and ad- their progression, a stimulation test with short-acting
vanced bone age, without impairment of adult height. GnRH (intravenous gonadorelin, 100 µg) may be re-
It usually regresses over several months. In the largest commended. When short-acting GnRH is unavailab-
cohort on outcome of girls with premature thelarche, le (which is frequent in Brazil), LH measurement 30
13% of them developed progressive CPP (independent to 120 minutes after the first application of a monthly
of the age of initial clinical presentation), which reinfor- long-acting GnRH analog (GnRHa) may be an alter-
ce the need for long-term follow-up (25). Premature nativeto confirm the biochemical diagnosis of CPP in
adrenarche is defined by the development of pubic or clinically suspected cases (29,30). The disadvantages
axillary hair growth due to increased concentrations of of this strategy are the high cost, risk of local reaction
adrenal-derived androgens (mainly DHEA and DHEA and unavailability of GnRHa in some centers. For this
sulfate). In this condition, adrenal disease (adrenal con- reasons, the importance of basal LH in the diagnosis of
genital hyperplasia, adrenocortical tumors) and other CPP must be highlighted. A Canadian study demons-
causes, such as contact with transdermal testosterone, trated the ability of basal LH, assessed by sensitive as-
topical corticosteroids cream, must be excluded. Ad- say (ICMA), to predict clinical pubertal progression
vanced bone age might be present. Isolated prepubertal in 57 girls (31). Based on an algorithm, the authors
vaginal bleeding, with no other signs of puberty, are found that a basal LH level ≥ 0.3 IU/L was indicative
generally benign, acyclic and must be differentiated if of pubertal progression while basal LH ≤ 0.2 IU/L in-
it is dependent or not of hormonal action. Of note, dicated no progression with 100% specifity and 90.5%
prepubertal vaginal bleeding rarely represents the first sensitivity (31). The authors stated that basal LH levels
manifestation of CPP. In addition, recurrent or conti- in the diagnosis of CPP should be interpreted using
nuous bleeding requires further investigation. Clinical local normative data and this approach may facilitate
indicators of pubertal progression should be carefully change in clinical practice avoiding the necessity of
conducted in these patients with isolated forms. Labo- GnRH test, which is unfeasible in many centers, with
ratory and imaging assessment of isolated variants of cost savings (31). We demonstrated that basal LH >
puberty can be limited to basal hormonal levels, bone 0.6 U/L, measured by IFMA, was able to diagnosis
age and pelvic ultrasound in girls (10,16,26). CPP in 62.7% of girls and 71.4% of boys (31). Using
ICMA and ECLIA, we suggest consider the cutoff of
Laboratory diagnosis basal LH of 0.3 U/L as indicative of CPP, avoiding the
necessity of GnRH stimulation test. The distinct cutoff
Hormonal assessment values of basal or GnRH-stimulated LH that indicate
Laboratory measurement of gonadotropins (mainly activation of the HPG axis are summarized in Table 2
LH) at baseline and/or after stimulation with short- (27,28,30-38).
-acting GnRH is recommended to document the ac- In girls, serum levels of E2 are not used to diagnose
tivation of the gonadal axis (10,15). The sensitivity of CPP, considering their low sensitivity and large over-
serum LH at baseline morning for diagnosis of CPP, lap between normal prepubertal and pubertal children
mainly in girls, varies between 60 and 100%, depen- (26). In boys, serum total T is sensitive to diagnose
ding on the cutoff value and laboratory methodology precocious puberty but insufficient to determine the
(16). Several laboratory methods with high sensitivity differential diagnosis between central and peripheral
to measure gonadotropins levels are available, inclu- CPP, which is established from LH levels. Also in the
ding immunofluorometric (IFMA), immunochemilu- male gender, measurement of β-hCG is always recom-
minescence (ICMA), and electrochemiluminescence mended. Measurement of basal or GnRH-stimulated
(ECL). Of these, ICMA and ECL are the most com- FSH is not useful in the diagnosis of CPP, but when the
monly used. Basal LH values > 0.6 IU/L (IFMA) or levels are low or suppressed, they strongly suggest the
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> 0.3 IU/L (ICMA, ECL) in both genders are consi- diagnosis of peripheral precocious puberty (10). Levels
dered pubertal (16,27,28). Although a basal LH value of gonadotropins and sex steroid hormones in children
in the prepubertal range does not exclude the diag- below the age of 2 years should be interpreted with
nosis of CPP, GnRH stimulation test is not warran- caution since they are often increased at this age in as-
ted in most cases. Depending on clinical variables and sociation with the physiological minipuberty.

166 Arch Endocrinol Metab. 2016;60/2

 Guideline of central precocious puberty

Table 2. Cutoff values of basal and GnRH-stimulated LH for diagnosis of central precocious puberty
Author Method Basal LH (IU/L) GnRH LH peak after GnRH (IU/L)
Neely and cols., 1995 (32) ICMA 0.15 Gonadorelin 100 ug IV 5.0
Brito and cols., 1999 (27) IFMA 0.6 Gonadorelin 100 ug IV 6.9 (F)
9.6 (M)
Brito and cols., 2004 (30) IFMA 0.6 Leuprorelin acetate 3.75 mg 10.0
Houk and cols., 2009 (33) ICMA 0.83 N/A N/A
IFMA 1.05
Pasternak and cols., 2012 (34) ICMA 0.1 Gonadorelin 100 ug IV 4.9
Sathasivam and cols., 2010 (35) ICMA 0.3 Leuprorelin acetate 20 ug/kg SC 5.0
Resende and cols., 2007 (28) ICMA 0.2 Gonadorelin 100 ug IV 4.1 (M); 3.3 (F)
IFMA 0.6 3.3 (M); 4.2 (F)
Lee and cols., 2013 (36) ECLIA 0.1 Gonadorelin 100 ug IV 5.0 (F)
Freire and cols., 2013 (37) IFMA N/A Triptorelin 7.0
ECLIA 0.1 mg/m2, maximum of 0.1 mg SC 8.0
Bizarri and cols., 2014 (38) ICMA > 0.2 Gonadorelin 100 ug IV 5.0
ICMA: immunochemiluminescence; IFMA: immunofluorimetric; ECLIA: eletrochemiluminescence; SC: subcutaneous; IV: intravenous; F: female; M: male; N/A: not available.

Imaging (43). After laboratory confirmation of CPP, anatomical

Bone age (BA) is obtained with an X-ray of the nondo- assessment of the central nervous system (CNS) should
minant wrist and hand and estimated by different me- be performed in all patients, preferably by magnetic
thods, of which Greulich and Pyle’s is the most com- resonance imaging (MRI) (10,44). Computed tomo-
monly used (39). In patients with precocious puberty, graphy of the brain may identify CNS tumors, mainly
BA is often advanced, and when the advancement ex- calcified ones, but it has low sensitivity to detect small
hamartomas.
ceeds either one year or two standard deviations (SD),
it is considered significant. BA is used to predict adult
height by the Bayley-Pinneau method (40), although
Molecular studies
this method has low accuracy. Bayley-Pinneau tables for In all cases of idiopathic CPP with or without familial
average BA should be preferred over those that use ac- history, molecular study of the makorin ring-finger 3
celerated BA, since the latter overestimate adult height (MKRN3) gene, recently implicated in the genetic etio-
(41,42). Pelvic ultrasonography is not used in the diag- logy of CPP, is indicated and may elucidate the genetic
nosis of precocious puberty, but in girls, it helps deter- basis of the CPP, with no implication on diagnosis and
mine the uterine and ovarian volume, and is a sensitive therapeutic management (26). MKRN3 has a potential
method to detect cysts and neoplastic lesions. An ova- inhibitory effect on GnRH secretion and inactivating
rian volume > 1.8 mL and uterine length > 3.4 cm in- MKRN3 mutations have been identified in families from
dicate hormonal stimulation and may be an additional several geographical origins (12). In fact, MKRN3 repre-
laboratory parameter to evaluate girls with precocious sents the most common genetic cause of CPP (Table 1).
puberty (16). Microcysts and ovarian follicles are nor- In familial CPP, MKRN3 defects were found in about
mal findings in approximately 40% of prepubertal girls. 30% of families (45) while in patients with apparently spo-
Some studies have demonstrated that pelvic ultrasono- radic CPP, MKRN3 defects were detected in about 8% of
graphy and uterine artery Doppler findings are useful cases (12). In theses cases, genetic counseling should be
to establish a differential diagnosis between isolated considered in affected patients and their families.
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premature thelarche and progressive CPP. This asses-

sment is based on the pulsatility index (PI) of the ute- Objectives and indications of pubertal arrest
rine artery (a difference between the peak systolic and The treatment of precocious puberty aims to interrupt
end-diastolic flow divided by the flow velocity). Ho- the sexual maturation until the normal age for pubertal
wever, this method requires an experienced examiner development is reached, revert or stabilize the sexual

Arch Endocrinol Metab. 2016;60/2 167

 Guideline of central precocious puberty

characteristics, delay the skeletal maturation, preserve higher GnRHa doses (200-300 µg/kg), a monthly 7.5 mg
the normal height potential (within the range of the dose has failed to show superior clinical results to ini-
target height), avoid body disproportions, and promo- tiate pubertal arrest (49). In recent years, more conve-
te the psychosocial adjustment of the patient and his or nient preparations with trimonthly dosing became avai-
her family. It also helps to prevent pregnancy at an early lable, such as LA 11.25 mg, 22.5 mg, and 30 mg, with
age, and reduce the risk of sexual abuse, early initia- several studies demonstrating their efficacy and safety
tion of sexual activity, and estrogen-dependent cancer compared with those of monthly GnRHa. However,
(mainly breast cancer) related to the occurrence of early long-term follow-up results are still lacking (49-51). In
menarche (10,44,46). Brazil, the recent approval of 3-month depot LA 11.25
Pubertal arrest is indicated in patients with progres- mg to treat CPP has improved dosing convenience and
sive precocious puberty of any etiology, accelerated adherence, and brought satisfactory therapeutic results.
pubertal development (progression from one puber- Pubertal arrest may be initially obtained with 1-month
tal stage to another in a shorter period than normal), depot (3.75 mg or 7.5 mg) or 3-month depot (11.25
potential of abnormal final stature [prediction of final mg) dosages. A flowchart of CPP treatment is presen-
height below the 2.5th percentile; prediction of final ted in Figure 2.
height below the target height (± 8.5 cm); height SD A subdermal implant of prolonged action that re-
for BA below -2; loss of height potential during fol- leases therapeutic doses of GnRHa for 12 to 24 mon-
low-up (44)]. Clinical and anthropometric data and ths (histrelin 50 mg) has advantages and disadvantages
BA advance are crucial for the decision to treat or not over 1-month and 3-month depot GnRHa (52). The
CPP. A period of 3-6 months follow-up can be useful advantages include the abolishment of periodic subcu-
to evaluate the “progressive” pattern of CPP. There is taneous or intramuscular administration, but the risk
no consensus about the recommendation of pubertal of reactions at the implant site, spontaneous extrusion,
arrest exclusively for psychosocial reasons (behavioral and local infection are the main undesirable side effects
disorders, emotional immaturity, mental retardation, of this therapy. This treatment option is still unavailable
seizures) (44). In early and fast puberty, pubertal arrest in Brazil.
may be beneficial (24,47). GnRHa are generally well tolerated, and their side
effects are infrequent and include local allergic reac-
tions (5%-10% of the cases), headache, abdominal pain,
Treatment of central precocious puberty
vaginal bleeding after the first GnRHa dose, nausea,
The treatment of choice for CPP is GnRHa (15,44), a vasomotor symptoms due to hypoestrogenism and
synthetic decapeptide that binds to the GnRH receptor hyperprolactinemia, and rarely, anaphylaxis (10,44).
in the pituitary with more stability and duration, and These effects may be mild to severe in intensity. Atten-
is resistant to protease degradation, which prolongs its tion should be given to local allergic reaction, charac-
half-life. GnRHa acts on the anterior pituitary, com- terized by the development of a sterile abscess, which
peting for GnRH receptor with endogenous GnRH, impairs the absorption of GnRHa that fails to suppress
promoting endocytosis and reducing the amount of the hormonal secretion (53). In these cases, medro-
GnRH receptors (“down-regulation”) (46-48). Ini- xyprogesterone acetate (MPA) or cyproterone acetate
tially, GnRHa stimulates the synthesis and secretion of (CPA) represent therapeutic options. Both MPA and
LH and FSH but when it is administered chronically, CPA are useful in blocking puberty progression, but
GnRHa suppresses the production of these hormones, have no beneficial impact on final height. MPA inhi-
which in turn suppress the production of sex steroid bits central gonadotropin release by acting on hypo-
hormones by the gonads (28,48). Of the available thalamic pulse generator, and it also directly inhibits
GnRHa, leuprorelin acetate (LA) and triptorelin are the gonadal steroidigenesis by inhibiting 3 betahydroxys-
most commonly used, and their efficacy and safety on teroid dehydrogenase 2 enzyme (16,19). In addition,
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the treatment of CPP has been demonstrated by several MPA has a glucocorticoid mimetic action resulting in
studies. The dose of GnRHa used to treat CPP is 75- adrenocorticotrophic hormone (ACTH) suppression,
100 µg/kg. In practice, this corresponds to a 3.75 mg hypertension, development of cushingoid habitus, and
administered intramuscularly or subcutaneously every bone mineral loss. MPA dosage varies from 50 mg to
28 days. Although some American groups recommend 150 mg per month (depot intramuscular injection)

168 Arch Endocrinol Metab. 2016;60/2

 Guideline of central precocious puberty

Clinical and laboratorial diagnosis of progressive CPP

1-month depot GnRHa 3.75 mg 28/28 days

3 – 6 months

3-month depot GnRHa 11.25 mg 12/12 weeks (84 days)

Trimonthly clinical and laboratorial monitoring

Adequate control Inadequate control

1-month depot GnRHa 3.75 mg

Inadequate control

1-month depot GnRHa 7.5 mg

Figure 2. Treatment flowchart of progressive central precocious puberty (CPP) with a long-acting GnRH analog (GnRHa).

Advantages of MPA include its low cost, easily admi- rare cases of tumor growth, when a differential diag-
nistration, and established efficacy in blocking puberty nosis must be established with other lesions, such as
progression (16,19). CPA has antiandrogenic activity, astrocytoma and glioma (55).
competing with testosterone for its receptor in peri-
pheral tissues and an additional progestational action at Treatment monitoring in central precocious puberty
the pituitary level, partially suppressing gonadotropin
The treatment of CPP with GnRHa is monitored by cli-
secretion. The usual CPA daily oral doses are 50 to 100
nical and laboratory evaluations (10,15). Parameters of
mg/m2 (16). CPA side effects include gastrointestinal
good clinical control include stabilization or regression
symptoms and gynecomastia in the male. Due to its
of secondary sexual characteristics, decrease in height
ACTH and cortisol suppressing effect, laboratory hy-
velocity, and improvement in final height prediction.
poadrenalism can occur with CPA use, deserving special
BA must be monitored annually in cases with adequa-
attention in stressful situation (16,19). Of note, these
therapeutic options must be considered only when Gn- te clinical and hormonal control, or semiannually in
RHa are not available or, as above-mentioned, in case cases suggesting inadequate control. The laboratory
of local reaction. parameter of choice is the measurement of LH values
Surgical treatment of CNS lesions associated with after monthly or trimonthly GnRHa, aiming at levels
CPP is indicated for both congenital and acquired mal- below 4 IU/L (determined by IFMA, ICMA, or ECL)
formations (11,54). Other treatment modalities, such (10,16,28,29,50). Levels of E2 or T should be suppres-
as chemotherapy or radiotherapy, are reserved for germ sed before GnRHa administration (16,26,50). Patients
with inadequate clinical and laboratory control that
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cell tumors. Treatment with surgery does not preclude

clinical therapy with GnRHa (10,11,15,54). Surgical persists after an increase in GnRHa dose must have the
therapy for hypothalamic hamartomas is reserved for etiological diagnosis of the precocious puberty carefully
large lesions associated with epilepsy refractory to cli- reevaluated (10). When the height velocity reduces mar-
nical treatment, signs of intracranial hypertension, or kedly (below 4 cm/year), recombinant human growth

Arch Endocrinol Metab. 2016;60/2 169

 Guideline of central precocious puberty

hormone (rGH) may be added to the treatment (56). that GnRHa therapy is effective in preserving the po-
This measure aims at increasing the height velocity and tential genetic height in girls older than 6 yr (42). In
promoting height gain. The recommended rGH dose fact, the main factors determining normal final height
in this circumstance is 0.15 IU/kg/day administered in girls with CPP treated with depot GnRHa were shor-
subcutaneously. Few studies have assessed the impact ter interval between the onset of puberty and onset of
of rGH administration on final height in patients with therapy, higher height SDS at the onset and end of the-
CPP (56-58). Two studies showed a benefit effect from rapy, and target height (42). Finally, no benefits on final
adding rGH to GnRHa therapy in children with de- height was demonstrated in those girls with early or fast
creased growth during GnRHa therapy. In these non- puberty, although benefits on psychosocial profile and
randomized studies, the mean final height was around in delay menarche should be considered (24,44,47).
7.5 cm greater than the pretreatment predicted height Transitional changes in body composition and bone
(56,57). In addition, 46 girls with early or precocious mass may occur without consequences in adulthood
puberty adopted from developing countries were ran- (44,47,59). With regard to reproductive function, stu-
domized for treatment for 2-4 y with GnRHa, or with dies indicate that menstruation occurs on average 16
a combination of rGH and GnRHa. During treatment, months after the treatment of CPP is withdrawn (with
the mean growth velocity in the rGH/GnRHa group a variation of 2 to 61 months). Regular ovarian cycles
was significantly higher and resulted in a higher final occur in 60% to 96% of the patients, and infertility has
height (58). All in all, based on available literature, the not been reported (44,59). In females, an increased pre-
association of rGH to GnRH cannot sistematically be valence of polycystic ovary syndrome has been reported,
recommended and the subset of CPP patients whose although the findings are controversial (44,60). In ma-
take some advantage with rGH addition was not de- les, a few studies that have been carried out have shown
termined so far (44,58). Treatment withdrawal should normal gonadal function (43). The few studies that have
take into account the chronological age of the patient evaluated the psychosocial impact of CPP suggest that
and his or her psychosocial adequacy and desire. A BA antisocial behavior is limited to adolescence and that
around 12.5 years in girls and 13.5 years in boys indi- there are no differences in psychosocial adjustment (44).
cate the best moment to withdraw the therapy aiming However, there are no controlled studies evaluating the
at reaching a normal final height within the genetic po- short- and long-term effects of the therapeutic interven-
tion with GnRHa on psychosocial characteristics.
tential (10,15,44,46).

Long-term follow-up CONCLUSIONS

Final height, body composition, bone mineral density, Puberty is a multifactorial process. The clinical diagnosis
reproductive function, and psychological characteristics of precocious puberty is not always easy, particularly in
are parameters of interest in the long-term follow-up females and among variants of normal development (pre-
of patients treated with GnRHa. Evidence shows that mature thelarche and constitutional growth and puberty
the GnRHa treatment is beneficial in preserving the po- acceleration) with progressive and nonprogressive pa-
tential genetic height, mainly in those girls who started thological conditions. The decision to treat CPP, mainly
treatement before 6 years of age (42,44,46,47). Con- in girls, is based on clinical and anthropometric data,
versely, CPP diagnosed after the age of 6 yr had redu- and bone age advance. Sometimes these data obtained
ced post treatment height gain and compromised final at short-term follow-up do not recommend CPP treat-
height, probably due to pre treatment intrinsic changes ment. Although the biochemical diagnosis has shown
in the growth plate according Lazar and cols. (24,47). significant improvement with more sensitive and specific
In a Brazilian study involving 45 girls, we found no sig- immunoassays, standardization is still required due to the
nificant association between chronological age at the availability of several methods and protocols to measure
Copyright© AE&M all rights reserved.

start of therapy and posttreatment linear growth (42). basal and GnRH-stimulated LH. This fact results in dif-
Although cronological age at the onset of therapy was ferent cutoff values to confirm the activation of the go-
significantly and negatively associated with final height, nadal axis. Treatment with GnRHa has shown significant
most of the girls who achieved normal adult height advances in recent years, with more convenient, effective,
started GnRHa therapy after the age of 6 yr, indicating and safe dosages in the short- and long-term.

170 Arch Endocrinol Metab. 2016;60/2

 Guideline of central precocious puberty

Disclosure: all authors received lecture fees from Abbvie. No po- 19. Kumar M, MukhopadhyayS, Dutta D. Challenges and controver-
tential conflict of interest relevant to this article was reported. sies in diagnosis and management of gonadotropin dependent
precocious puberty: an Indian perspective. Indian J Endocrinol
Metab. 2015;19(2):228-35.
20. Marshall WA, Tanner JM. Variations in pattern of puberal changes
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172 Arch Endocrinol Metab. 2016;60/2

 erratum

Central precocious puberty: revisiting the

diagnosis and therapeutic management
Vinícius Nahime Brito, Angela Maria Spinola-Castro, Cristiane Kochi,
Cristiane Kopacek, Paulo César Alves da Silva, Gil Guerra-Júnior

Arch Endocrinol Metab. 2016;60(2):163-72

DOI: 10.1590/2359-3997000000144

Where you read: Should read:

INTRODUCTION INTRODUCTION

P uberty is a period of physical, hormonal, and

psychological transition from childhood to
adulthood, with accelerated linear growth and
P uberty is a period of physical, hormonal, and
psychological transition from childhood to
adulthood, with accelerated linear growth and
achievement of reproductive function. It is a complex achievement of reproductive function. It is a complex and
and multifactorial process that includes genetic, multifactorial process that includes genetic, metabolic,
metabolic, environmental, ethnic, geographic, and environmental, ethnic, geographic, and economic
economic factors and results in reactivation of the factors and results in reactivation of the hypothalamic-
hypothalamic-pituitary-gonadal (HPG) axis. An pituitary-gonadal (HPG) axis. An effective pubertal
effective pubertal onset requires pulsatile hypothalamic onset requires pulsatile hypothalamic secretion of
secretion of GnRH stimulating the secretion of GnRH stimulating the secretion of gonadotropins
gonadotropins by the anterior pituitary gland (LH = by the anterior pituitary gland (LH = luteinizing
luteinizing hormone and FSH = follicle-stimulating hormone and FSH = follicle-stimulating hormone).
hormone). Gonadotropins stimulate the gonads and Gonadotropins stimulate the gonads, whereas gonadal
exert a negative feedback effect on the hypothalamus, steroids (T = testosterone, produced by the testis,
whereas gonadal steroids (T = testosterone, produced by and E2 = estradiol, produced by the ovaries) inhibit
the testis, and E2 = estradiol, produced by the ovaries) both hypothalamus and anterior pituitary gland. This
inhibit both hypothalamus and anterior pituitary gland. process is named gonadarche (1-3).
This process is named gonadarche (1-3).

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DOI: 10.1590/2359-3997000000198

Arch Endocrinol Metab. 2016;60/4