REVIEW

CURRENT
OPINION Precocious puberty
E. Kirk Neely and Stephanie S. Crossen

Purpose of review
Precocious puberty continues to elicit great interest and concern among medical practitioners, as well as
the public.
Recent findings
Studies have elucidated neural regulation of puberty by kisspeptin, neurokinin B, and other factors. Cohort
studies from the North America and Europe suggest that the age of thelarche may be earlier than
determined 2 decades ago, and menarche may be slightly earlier, but the causes are unclear. Long-term
outcomes of gonadotropin-releasing hormone analog therapy demonstrate increases in final height in the
youngest treated patients, with no apparent adverse bone or reproductive consequences.
Summary
Although the appropriate threshold age of onset of central puberty remains uncertain, gonadotropin-
releasing hormone analog therapy is well tolerated and effective in suppressing luteinizing hormone pulses
and ovarian activity.
Keywords
gonadotropin-releasing hormone, histrelin, leuprolide, precocious puberty, thelarche

INTRODUCTION ONSET OF NORMAL PUBERTY

Precocious puberty is a common reason for referral
to a pediatric endocrinologist. Typical clinical
scenarios are as follows: first, a 6–8 year old girl with
pubic or axillary hair only; second, a female infant
or toddler with breast development only; and third,
a 6–8 year old girl with breast development, with or
without pubic hair. The incidence of precocious pub-
erty is much lower in boys than girls, and the liter-
ature on boys is at best fragmentary. This review
focuses on precocious puberty in females and out-
lines the natural history, diagnostic steps, treatment
options, and therapeutic outcomes. Other recent
& &
reviews cover these topics in greater detail [1 –3 ].
‘True’ puberty occurs with reactivation of the
hypothalamic pituitary gonadal axis (HPG) follow-
ing the neonatal surge and long childhood quies-
cence, as the increasing amplitude of gonadotropin-
releasing hormone (GnRH) and luteinizing hor-
mone (LH) pulses signals for increased gonadal
sex steroid production. If this process happens inap-
propriately early, the process is called gonadotropin-
dependent, or ‘central’ precocious puberty (CPP).
Various types of gonadotropin-independent preco-
cious puberty exist as well and are often grouped as
‘peripheral’ or ‘incomplete’ precocious puberty. A
glossary of terms is listed in Table 1, and causes
within each category are delineated in Table 2.
The neuropeptides kisspeptin and neurokinin
B appear to play central roles in initiating GnRH
release from the hypothalamus. Mutations in the
genes-encoding kisspeptin and neurokinin B and
each of their receptors have been associated with
hypogonadotropic hypogonadism [4–6]. GnRH
neurons express kisspeptin receptors [7], and admin-
istration of kisspeptin leads to GnRH release [8–10].
Neurokinin B appears to work upstream of kisspep-
tin in regulating GnRH, and deficiency primarily
&
interferes with release of LH [11,12 ]. These discov-
eries may lead to new therapies for precocious and
delayed puberty [13].
Timing
The definition of normal pubertal timing is essential
to any discussion of precocious puberty, yet it
Division of Pediatric Endocrinology and Diabetes, Stanford University,
Stanford, California, USA
Correspondence to E. Kirk Neely, MD, Division of Pediatric Endocrin-
ology and Diabetes, Rm G-313, Stanford University Medical Center,
Stanford, CA 94305-5208, USA. Tel: +1 650 723 5791; fax: +1 650
725 8375; e-mail: neely@stanford.edu
Curr Opin Obstet Gynecol 2014, 26:332–338
DOI:10.1097/GCO.0000000000000099

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 Precocious puberty Neely and Crossen

Table 2. Causes of precocious puberty (females)

KEY POINTS
 The average age of menarche decreased over the last
century or more, although the decline has more or less
stabilized at approximately 12.5 years old, with
African–American girls earlier than white girls.
 Data suggest that the average onset of thelarche may
have decreased from approximately 11 to 10 years old
over the last few decades, but it is unclear whether this
represents a change in ascertainment or reflects obesity
or possibly environmental estrogens.
 Central precocious puberty with onset prior to 8 years
old in girls should be differentiated from premature
thelarche and confirmed by pubertal LH and estradiol
levels using sensitve pediatric assay methods.
 GnRH analogs, such as multimonth depot leuprolide
and the histrelin implant, are effective therapies for
CPP, may increase final height, and have no apparent
long-term detriment for body composition, bone health,
or reproductive function.
remains a topic of intense debate. Historical analyses
demonstrate that the age of menarche – a reliable
reflection of HPG axis activation – dropped substan-
tially in industrialized nations throughout the late
&
19th century and first half of the 20th century [3 ],
most likely owing to improvements in overall
nutrition and public health. Studies up until the
1990s reported the onset of breast development,
generally the first sign of true puberty, at about
11 years old, and the conventional definition of
precocious puberty was onset prior to 8 years old
in girls. However, the Pediatric Research in Office
Settings study in 1997 reported that puberty (breast
or pubic hair) was evident in 6.7% of White girls
Table 1. Glossary of terms
Precocious puberty: onset prior to 8 years old in girls, deserves
evaluation
Early puberty: normal variant, onset at approximately 8–9 years
old in girls
Thelarche: onset of breast development
Pubarche: onset of pubic hair
Adrenarche: onset of adrenal androgen production
Gonadarche: onset of gonadal activity
CPP: central, true, GnRH-dependent, or Gn-dependent precocious
puberty
Gn-independent PP: Incomplete, peripheral, or GnRH-independent
PP; pseudopuberty
Idiopathic CPP: central precocity without other cause, commonly in
girls
CPP, central precocious puberty; GnRH, gonadotropin-releasing hormone;
Gn, gonadotropin; PP, precocious puberty.
Central precocious puberty
Idiopathic
International adoption
CNS aberrations
 Hypothalamic hamartoma (congenital)
 Astrocytoma and glioma
 Cerebral palsy
 Hydrocephalus
 Irradiation
 Trauma
 Infection
 Subarachnoid cyst
 Pineal cyst
 Neurofibromatosis type 1
 Tuberous sclerosis
 Sturge–Weber syndrome
Gn-independent PP (feminization)
Functional ovarian cysts
McCune–Albright syndrome
Ovarian tumor (granulosa cell)
Exogenous estrogen
Profound primary hypothyroidism
CNS, central nervous system; Gn, gonadotropin; PP, precocious puberty.
and 27.2% of African–American girls less than
8 years of age [14]. This study, along with National
Health and Nutrition Examination Survey data and
&
other surveys [15 ,16], has redefined the mean age
for onset of breast development as 10.0 years or less.
However, age at menarche remained unchanged
except among African–American girls.
This research prompted revision of the Pediatric
Endocrine Society clinical guidelines to reflect a
‘normal’ age at onset of puberty down to 6 years
among African–American girls and 7 years among
White girls [17]. However, the endocrine com-
munity has not fully embraced these guidelines
due to two-fold concerns. First, the Pediatric
Research in Office Settings study relied on visual
inspection alone, and may therefore have detected
adipose tissue from widespread obesity, rather than
&
true breast development [3 ,18]. Second, many
endocrinologists felt that lowering the age limit
for ‘normal’ puberty to this extent would result
in an unacceptable rate of missed abnormality, a
contention that has been supported by later studies
[19–21].
More recent observations of only European
cohorts have also reported a drop in the age of
thelarche since the 1990s but could not support this
by a significant change in age-based gonadotropin
levels [22,23]. These results raise the possibility that

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 Adolescent and pediatric gynecology
secondary sexual characteristics may be occurring
earlier in some children – whether due to obesity or
environmental triggers of estrogenization – without
&
activation of the HPG axis [3 ,24].
DIFFERENTIATING CENTRAL PRECOCIOUS
PUBERTY AND NORMAL VARIANTS
Premature adrenarche and premature thelarche
are common pubertal presentations generally not
requiring intervention.
Premature adrenarche
Control of adrenarche is poorly understood, but
premature low-level secretion of adrenal androgens
at 6–8 years old commonly causes mild virilization
(but not clitoromegaly) without feminization. The
features of adrenarche are onset of pubic hair, axil-
lary hair, mild acne, and body odor. An increase in
growth rate and bone age advancement can be
observed, but in general premature adrenarche is
considered benign, aside from a possible association
with later menstrual irregularities or polycystic
ovarian syndrome [25,26]. Differential diagnosis
includes the rare adrenalvirilizing tumor, which
would usually progress rapidly and exhibit high
androgen levels, and late-onset, or rather late diag-
nosis, congenital adrenal hyperplasia (CAH).
Although the most likely cause of early
pubarche, premature adrenarche is a diagnosis of
exclusion [27]. Measurement of serum 17-OH pro-
gesterone excludes the most common form of CAH,
21-OH deficiency, while dehydroepiandrosterone
(DHEA), androstenedione, and testosterone can
gauge the level of adrenal androgen production
and rule out an adrenal tumor. Mild elevation of
DHEA and androstenedione (for age) support, but
are not necessary for, the diagnosis of premature
adrenarche. Bone age is often obtained but is
unlikely to influence clinical decisions except
whether to treat a mild form of CAH.
Premature thelarche
Female infants and toddlers may present with breast
development alone. This is not due to maternal or
placental estrogens, but instead is likely to be sec-
ondary to follicle-stimulating hormone (FSH)-
driven enlargement of the ovaries, with cyst for-
mation and granulosa cell secretion of estradiol
resulting in feminization. This may represent an
exaggeration of the standard postnatal FSH surge
in females [28] and is generally ‘benign’ and self-
limited, although occasionally of dismayingly long
duration [29]. The pediatric endocrinologist will
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often follow these patients clinically. Progression
to pubic hair is inconsistent with premature the-
larche and instead suggests an LH-driven process. A
congenital hypothalamic hamartoma may present
as CPP in this age-group. In some girls, FSH-driven
premature thelarche may eventually convert to LH
predominance and CPP. Several studies have tried to
predict which girls will progress from premature
thelarche to CPP [30,31], but at this time clinical
signs, such as pubic hair and increasing growth
velocity, are the most reliable indicators.
Vaginal bleeding suggests an ovarian tumor
(usually granulosa cell) or functional ovarian cyst.
Recurrent breast enlargement from intermittent
ovarian cysts with or without bleeding might be
associated with McCune–Albright syndrome
(MAS). This gonadotropin-independent precocious
puberty is part of the ‘classic triad’ along with
mosaic cafe-au-lait skin pigmentation and fibrous
dysplasia of bone [32]. MAS is caused by sporadic
mutation of the GNAS gene, resulting in constitu-
tively activated G-protein-coupled adenyl cyclase,
which affects the signaling of many types of hor-
mone receptors [33]. Unresponsive to gonado-
tropin-releasing hormone analog (or agonist)
(GnRHa) because it is gonadotropin-independent,
the precocious puberty of MAS has been treated with
partial success using medroxyprogesterone, tamox-
ifen, and aromatase inhibitors [33,34].
Central precocious puberty
The girl with CPP typically follows the standard
pubertal progression that begins with breast budding,
an increase in growth velocity from rising estrogen
and insulin-like growth factor-1, and progressive
breast enlargement culminating in menarche around
&
2.5 years later [1 ]. Pubic hair and axillary hair are
generally not observed until girls reach Tanner breast
stage 3, therefore many girls in central puberty
exhibit thelarche alone at the time of evaluation,
and the clinician must determine whether this
represents a variant of FSH-predominant premature
thelarche or early LH-predominant CPP. Typically,
girls less than 6 years will have nonprogressive pre-
mature thelarche [31], and 6–8 year olds will have
CPP that represents the leading edge of normal vari-
ation in timing of central puberty. A strong genetic
component exists [35], and familial CPP is well
described. Many central nervous system (CNS) aber-
rations predispose to CPP [36] (Table 2).
DIAGNOSTIC CONFIRMATION OF CPP
Early LH and estradiol radioimmunoassays (RIAs)
could not measure throughout pediatric ranges
Volume 26  Number 5  October 2014

and to some extent still cannot. Tests using GnRH
stimulation to release a large gonadotropin pulse
were in part developed to overcome this impedi-
ment. Assessment of LH and FSH was later enhanced
by double-antibody, or ‘sandwich’ RIA and can now
accurately measure pediatric levels [37], although
application of the technology is variable in com-
mercial and hospital laboratories. RIAs for estradiol
improved by the 1990s but were often unreliable
[38]. Liquid chromatography-tandem mass spec-
trometry has revolutionized our ability to measure
pediatric estradiol levels, but even assays down to
1 pg/ml are not measuring prepubertal levels. We
use an informal threshold of less than 5 pg/ml to
indicate prepubertal status, but childhood norms for
estradiol are not well established.
Random luteinizing hormone
Diagnosis of CPP relies upon clinical signs – at
minimum, breast development – and laboratory
confirmation, specifically rising LH and sex steroid
levels. Because prepubertal unstimulated LH is very
low (< 0.1 U/l), ascertainment of rising LH by an
accurate RIA can suffice for diagnosis in a girl with
physical signs. However, sensitivity and specificity
are imperfect [39,40]. Girls in the early phase of CPP
may have borderline or normal random levels, as the
‘trough’ between endogenous LH pulses may not yet
be elevated. The problem with specificity occurs in
FSH-predominant premature thelarche, in which
LH may be slightly elevated as well, but intervention
is unnecessary.
GnRHa-stimulation tests
The historic ‘gold standard’ for diagnosis of CPP was
measurement of pituitary LH 15–60 min after GnRH
stimulation. A prepubertal LH pulse reaches
approximately 1.5–2 U/l, in comparison with an
adult female response of 30–40 U/l [40,41]. Any
level greater than 4 or 5 U/l suggests that puberty
has begun [40,41]. This provocative test has been
modified to utilize the GnRHa leuprolide instead of
GnRH (which is not readily available) [30]. Levels
achieved poststimulation by the two agents are
comparable, although sustained for a longer
duration postanalog. We and others have adapted
the test for convenient clinic use by administering
aqueous leuprolide 10–20 mcg/kg2 and measuring
LH and FSH with estradiol in a single sample at
30–60 min [42,43]. A random FSH is not useful to
confirm entry into true puberty, but the poststimu-
lation LH/FSH ratio is helpful in differentiating
premature thelarche from CPP [43], as the initiation
of CPP represents a transition from FSH to LH
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Precocious puberty Neely and Crossen
predominance. We use a threshold LH/FSH ratio
greater than 1 to confirm CPP, although the ratio
is more typically 3–4 [43].
Imaging
Pelvic ultrasound can be used to assess pubertal
status. The prepubertal ovary is generally less than
1 cc, although some studies argue for a threshold of
less than 3 cc [44]. The presence of an ‘endometrial
stripe’ is consistent with CPP but is more specific
than sensitive [45]. A left-hand radiograph is often
performed to appraise the degree of bone age
advancement, although we do not typically obtain
either an ultrasound or bone age, instead using
physical and laboratory parameters for diagnosis.
Because most CPP is idiopathic, we tend to limit
brain MRI to girls under 7 years old, but the require-
ment for MRI in evaluation remains contentious
[11].
GNRHA THERAPY
Modifications of the decapeptide GnRH have
resulted in super-agonists that interfere with GnRH
pulse periodicity and downstream gonadotropin
release. Originally tested as short-acting nasal and
daily injectable forms, long-acting depot formu-
lations or implants are now predominantly used.
Goserelin and buserelin are available in long--
acting form, and depot triptorelin is used widely
in Europe, but the primary agents used in the USA
are depot leuprolide and the histrelin annual
&
implant [1 ,46,47]. GnRH analogs work superbly
to suppress gonadotropin-dependent precocious
puberty [46,47]. It is less clear how effective they
are in achieving the long-term goals of therapy,
namely preservation of adult height potential and
avoidance of psychosocial sequelae.
Depot leuprolide
Long-term details of the original multicenter
monthly depot leuprolide trial in the USA were
recently published [48,49]. Infrequent side-effects
include local or systemic reactions to the depot
polymer and withdrawal bleeding approximately
2 weeks after the initial dose. Doses range from
3.75 mg monthly, as used in Europe and Asia, to
7.5–15 mg in the USA, without any direct compari-
son suggesting superiority. After 3 -month depot
leuprolide preparations were approved for adult
use, they were adopted off-label in pediatrics [50].
We and others demonstrated that the 22.5 or 30 mg
dose resulted in better suppression of LH than the
11.25 mg dose, but with no differences in estradiol
www.co-obgyn.com 335
 Adolescent and pediatric gynecology
level, growth velocity, or any other treatment
parameters [51,52]. The 30 mg dose is approved
for CPP and is the most commonly used.
Histrelin implant
The histrelin implant is reimplanted annually in the
inner upper arm. Long-term outcome data are lim-
ited, but 1 and 2 year results have shown good
suppression of puberty [53,54]. Although no direct
comparisons with 3-month depot leuprolide have
been reported, in our experience stimulated LH
levels are lower during implant therapy, usually less
than 1 U/l. Treatment failures are extremely rare, but
occasionally the device is difficult to remove. A
recent study reported that effective suppression con-
tinued for 2 years after a single implant [55].
Monitoring therapy
There is no standard protocol for monitoring depot
leuprolide or histrelin implant therapy. We and
others have shown that the depot leuprolide injec-
tion contains free leuprolide that acts as a stimulat-
ing agent to release gonadotropin [56,57], allowing
for covenient measurement of LH and estradiol
30–60 min after injection to ensure adequate sup-
pression. Assessment of LH suppression during
implant therapy uses the aqueous leuprolide test
instead (mentioned above). We perform routine
monitoring tests in the first year only, as later treat-
ment failures with either agent are unlikely. Studies
of monthly and 3-month depot leuprolide and the
implant have all demonstrated progressive decline
in stimulated and random LH levels over the first
2 years of therapy [48]. However, random LH levels
remain in the pubertal range during therapy, pre-
sumably due to tonic low-level release in spite of
pulse suppression, and should not be used to
monitor GnRHa therapy in CPP [58,59].
LONG-TERM OUTCOMES AFTER GNRHA
THERAPY
Height, bone density, and return of ovarian func-
tion have been the key outcomes evaluated in long-
term follow-up.
Height
Almost all studies of GnRHa therapy for CPP have
&
been open-label [1 ,46]. Height gain is usually
reported as the difference between final height
and pretreatment predicted adult height (PAH)
based on bone age. PAH tends to overestimate final
height by a few centimeters, and final height is
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almost always less than PAH reported at the end
of treatment. These issues aside, trials from the past
2 decades have reported final heights up to 9.8 cm
&
greater than pretreatment predictions [46,60 ]. In
large trials, children with younger ages at onset of
puberty have shown the greatest gains [61–63] One
trial stratified by age showed gains of 8.2, 4.2, and
1.1 cm with mean ages at treatment initiation of
6.4, 7.5, and 8.9 years, respectively [63]. Random-
ized trials have been undertaken only in girls at
marginal ages (onset of puberty >7.5 years old)
and did not demonstrate a gain in final height [64].
Psychosocial studies
Psychological studies have demonstrated that girls
entering puberty earlier than normal are vulnerable
to behavioral issues [65,66]. However, no studies
have shown that intervention with GnRHa therapy
affects these outcomes or quality of life [46].
Bone health and body composition
At the onset of treatment for CPP, most girls are tall
and have above-average bone mineral density
(BMD), but not when volumetrically adjusted for
body size. During GnRHa treatment, BMD is gener-
ally stable or declines [62]. However bone mineral
continues to accrue in the teenage years, and post-
treatment BMD or volumetric BMD measures are
&
within normal ranges [60 ]. Studies are inconsistent
regarding BMI during and after GnRHa treatment.
Most report BMI slightly above normal at the begin-
&
ning and end of GnRHa therapy [60 ,67], although
others have reported a decline during or after
therapy [68,69]. Most studies demonstrate normal
&
BMI at long-term follow-up [60 ,62,69,70].
Reproductive function
Multiple trials have followed female individuals
&
through menarche [60 ]. Studies consistently report
return of normal gonadotropin pulsatility and
pubertal estradiol levels within the first year follow-
&
ing discontinuation of therapy [48,60 ]. Mean time
&
to menses varies from 9 to 20 months [60 ] after
1-month or 3-month depot GnRHa and falls in
the early part of that range following removal of
the histrelin implant [71]. Long-term follow-up
studies show menstrual regularity comparable with
untreated or normal controls. Pregnancies have
been documented by several studies, without any
apparent increase in difficulty conceiving [48,72].
In fact, a recent follow-up study into adulthood
suggested that GnRHa or cyproterone therapies
for CPP enhanced fertility rates compared with
Volume 26  Number 5  October 2014

women with a history of untreated CPP [63]. The
literature is inconsistent regarding the likelihood of
hyperandrogenism following GnRHa therapy.
Although recent papers have reported up to a 32%
prevalence of hyperandrogenism or positive PCOS
scores in previously treated girls [73–75], other
studies found a much lower prevalence and no
difference between patients with treated CPP versus
untreated CPP or age-matched controls [76].
CONCLUSION
Precocious puberty continues to elicit great interest
and concern among medical practitioners, as well as
the public. The clinician must consider a broad
differential of central and peripheral causes and
pursue appropriate testing to confirm common
variants, CPP, or more unusual diagnostic altern-
atives. GnRHa therapy is a well tolerated and
highly effective treatment for CPP.
Acknowledgements
E.K.N. has participated in advisory boards for Endo
Pharma and Abbott.
Funding disclosure: nothing to disclose.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Fuqua JS. Treatment and outcomes of precocious puberty: an update. J Clin
& Endocrinol Metab 2013; 98:2198–2207.
A good recent review.
2. Willemsen RH, Elleri D, Williams RM, et al. Pros and cons of GnRHa treatment
& for early puberty in girls. Nat Rev Endocrinol 2014; 10:352–363.
An expert discussion of the decision whether or not to treat with GnRH analogs.
3. Sorensen K, Mouritsen A, Aksglaede L, et al. Recent secular trends in pubertal
& timing: implications for evaluation and diagnosis of precocious puberty. Horm
Res Paediatr 2012; 77:137–145.
A sophisticated discussion of the onset of puberty controversy.
4. Topaloglu AK, Tello JA, Kotan LD, et al. Inactivating KiSS1 mutation and
hypogonadotropic hypogonadism. N Engl J Med 2012; 366:629–635.
5. Young J, Bouligand J, Francou B, et al. TAC3 and TACR3 defects cause
hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin
Endocrinol Metab 2010; 95:2287–2295.
6. De Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to
loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl
Acad Sci USA 2003; 100:10972–10976.
7. Irwig MS, Fraley GS, Smith JT, et al. Kisspeptin activation of gonadotropin
releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat.
Neuroendocrinology 2004; 80:264–272.
8. Messager S, Chatzidaki EE, Ma D, et al. Kisspeptin directly stimulates
gonadotropin-releasing hormone release via G protein-coupled receptor
54. Proc Natl Acad Sci USA 2005; 102:1761–1766.
9. Shahab M, Mastronardi C, Seminara SB, et al. Increased hypothalamic
GPR54 signaling: a potential mechanism for initiation of puberty in primates.
Proc Natl Acad Sci USA 2005; 102:2129–2134.
10. Smith JT, Dungan HM, Stoll EA, et al. Differential regulation of KiSS-1 mRNA
expression by sex steroids in the brain of the male mouse. Endocrinology
2005; 146:2976–2984.
1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Precocious puberty Neely and Crossen
11. Topaloglu AK, Reimann F, Guclu M, et al. TAC3 and TACR3 mutations in
familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in
the central control of reproduction. Nat Genet 2009; 4:354–358.
12. Young J, George JT, Tello JA, et al. Kisspeptin restores pulsatile LH secretion
& in patients with neurokinin B signaling deficiencies: physiological, pathophy-
siological and therapeutic implications. Neuroendocrinology 2013; 97:193–
202.
This study demonstrates the interaction and relative positions of kisspeptin and
neurokinin B in the neuroendocrine cascade-regulating GnRH secretion.
13. Millar RP, Newton CL. Current and future applications of GnRH, kisspeptin
and neurokinin B analogues. Nat Rev Endocrinol 2013; 9:451–466.
14. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual
characteristics and menses in young girls seen in office practice: a study from
the Pediatric Research in Office Settings network. Pediatrics 1997; 99:505–
512.
15. Biro FM, Greenspan LC, Galvez MP, et al. Onset of breast development in a
& longitudinal cohort. Pediatrics 2013; 132:1019–1027.
The most recent publication from a series of studies redefining the onset of
thelarche.
16. Euling SY, Herman-Giddens ME, Lee PA, et al. Examination of US puberty-
timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics
2008; 121 (Suppl 3):S172–S191.
17. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when
puberty is precocious in girls in the United States: implications for evaluation
and treatment. Drug and Therapeutics and Executive Committees of the
Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999; 104:936–
941.
18. McDowell MA, Brody DJ, Hughes JP. Has age at menarche changed? Results
from the National Health and Nutrition Examination Survey (NHANES) 1999–
2004. J Adolesc Health 2007; 40:227–231.
19. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age
8 benign? Pediatrics 2003; 111:47–51.
20. Mogensen SS, Aksglaede L, Mouritsen A, et al. Diagnostic work-up of 449
consecutive girls who were referred to be evaluated for precocious puberty. J
Clin Endocrinol Metab 2011; 96:1393–1401.
21. Mogensen SS, Aksglaede L, Mouritsen A, et al. Pathological and incidental
findings on brain MRI in a single-center study of 229 consecutive girls with
early or precocious puberty. PLoS One 2012; 7:e29829.
22. Aksglaede L, Sorensen K, Petersen JH, et al. Recent decline in age at breast
development: the Copenhagen Puberty Study. Pediatrics 2009; 123:e932–
e939.
23. Susman EJ, Houts RM, Steinberg L, et al., Eunice Kennedy Shriver NICHD
Early Child Care Research Network. Longitudinal development of secondary
sexual characteristics in girls and boys between ages 9 1/2 and 15 1/2 years.
Arch Pediatr Adolesc Med 2010; 164:166–173.
24. Euling SY, Selevan SG, Pescovitz OH, Skakkebaek NE. Role of environmental
factors in the timing of puberty. Pediatrics 2008; 121:S167–S171.
25. Ibanez L, Diaz R, Lopez-Bermejo A, Marcos MV. Clinical spectrum of pre-
mature pubarche: links to metabolic syndrome and ovarian hyperandrogen-
ism. Rev Endocr Metab Disord 2009; 10:63–76.
26. Ibanez L, Lopez-Bermejo A, Diaz M, et al. Early metformin therapy to delay
menarche and augment height in girls with precocious pubarche. Fertil Steril
2011; 95:727–730.
27. Williams RM, Ward CE, Hughes IA. Premature adrenarche. Arch Dis Child
2012; 97:250–254.
28. Brown DB, Loomba-Albrecht LA, Bremer AA. Sexual precocity and its
treatment. World J Pediatr 2013; 9:103–111.
29. Pescovitz OH, Hench KD, Barnes KM, et al. Premature thelarche and central
precocious puberty: the relationship between clinical presentation and the
gonadotropin response to luteinizing hormone-releasing hormone. J Clin
Endocrinol Metab 1988; 67:474–479.
30. Ibanez L, Potau N, Zampolli M, et al. Use of leuprolide acetate response patterns
in the early diagnosis of pubertal disorders: comparison with the gonadotropin-
releasing hormone test. J Clin Endocrinol Metab 1994; 78:30–35.
31. De Vries L, Guz-Mark A, Lazar L, et al. Premature thelarche: age at presenta-
tion affects clinical course but not clinical characteristics or risk to progress to
precocious puberty. J Pediatr 2010; 156:466–471.
32. Zacharin M. The spectrum of McCune Albright syndrome. Pediatr Endocrinol
Rev 2007; 4:412–418.
33. Eugster EA. Peripheral precocious puberty: causes and current management.
Horm Res 2009; 71:64–67.
34. Feuillan P, Calis K, Hill S, et al. Letrozole treatment of precocious puberty in
girls with the McCune-Albright syndrome: a pilot study. J Clin Endocrinol
Metab 2007; 92:2100–2106.
35. Elks CE, Perry JR, Sulem P, et al. Thirty new loci for age at menarche identified
by a meta-analysis of genome-wide association studies. Nat Genet 2010;
42:1077–1085.
36. Soriano-Guillen L, Corripio R, Labarta JI, et al. Central precocious puberty in
children living in Spain: incidence, prevalence, and influence of adoption and
immigration. J Clin Endocrinol Metab 2010; 95:4305–4313.
37. Neely EK, Hintz RL, Wilson DM, et al. Normal ranges for immunochemilumi-
nometric gonadotropin assays. J Pediatr 1995; 127:40–46.
38. Albrecht L, Styne D. Laboratory testing of gonadal steroids in children. Pediatr
Endocrinol Rev 2007; 5:599–607.
www.co-obgyn.com 337
 Adolescent and pediatric gynecology
39. Resende EA, Lara BH, Reis JD, et al. Assessment of basal and gonadotropin-
releasing hormone-stimulated gonadotropins by immunochemiluminometric
and immunofluorometric assays in normal children. J Clin Endocrinol Metab
2007; 92:1424–1429.
40. Neely EK, Wilson DM, Lee PA, et al. Spontaneous serum gonadotropin
concentrations in the evaluation of precocious puberty. J Pediatr 1995;
127:47–52.
41. Bordini B, Littlejohn E, Rosenfield RL. Blunted sleep-related luteinizing
hormone rise in healthy premenarcheal pubertal girls with elevated body
mass index. J Clin Endocrinol Metab 2009; 94:1168–1175.
42. Sathasivam A, Garibaldi L, Shapiro S, et al. Leuprolide stimulation testing for
the evaluation of early female sexual maturation. Clin Endocrinol 2010;
73:375–381.
43. Chi CH, Durham E, Neely EK. Pharmacodynamics of aqueous leuprolide
acetate stimulation testing in girls: correlation between clinical diagnosis and
time of peak luteinizing hormone level. J Pediatr 2012; 61:757–759.
44. Sathasivam A, Rosenberg HK, Shapiro S, et al. Pelvic ultrasonography in the
evaluation of central precocious puberty: comparison with leuprolide stimula-
tion test. J Pediatr 2011; 159:490–495.
45. Battaglia C, Mancini F, Regnani G, et al. Pelvic ultrasound and color Doppler
findings in different isosexual precocities. Ultrasound Obstet Gynecol 2003;
22:277–283.
46. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of
gonadotropin-releasing hormone analogs in children. Pediatrics 2009;
123:e752–e762.
47. Bertelloni S, Baroncelli GI. Current pharmacotherapy of central precocious
puberty by GnRH analogs: certainties and uncertainties. Expert Opin Phar-
macother 2013; 14:1627–1639.
48. Neely EK, Lee PA, Bloch CA, et al. Leuprolide acetate 1-month depot for
central precocious puberty: hormonal suppression and recovery. Int J Pediatr
Endocrinol 2010; 2010:398639.
49. Lee PA, Neely EK, Fuqua J, et al. Efficacy of leuprolide acetate 1-month depot
for central precocious puberty (CPP): growth outcomes during a prospective,
longitudinal study. Int J Pediatr Endocrinol 2011; 2011:7.
50. Badaru A, Wilson DM, Bachrach LK, et al. Sequential comparisons of one-
month and three-month depot leuprolide regimens in central precocious
puberty. J Clin Endocrinol Metab 2006; 91:1862–1867.
51. Fuld K, Chi C, Neely EK. A randomized trial of 1- and 3-month depot leuprolide
doses in the treatment of central precocious puberty. J Pediatr 2011;
159:982–987.
52. Lee PA, Klein K, Mauras N, et al. Efficacy and safety of leuprolide acetate
3-month depot 11.25 milligrams or 30 milligrams for the treatment of central
precocious puberty. J Clin Endocrinol Metab 2012; 97:1572–1580.
53. Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin
subdermal implant in children with central precocious puberty: a multicenter
trial. J Clin Endocrinol Metab 2007; 92:1697–1704.
54. Rahhal S, Clarke WL, Kletter GB, et al. Results of a second year of therapy
with the 12-month histrelin implant for the treatment of central precocious
puberty. Int J Pediatr Endocrinol 2009; 2009:812517.
55. Lewis KA, Goldyn AK, West KW, Eugster EA. A single histrelin implant is
effective for 2 years for treatment of central precocious puberty. J Pediatr
2013; 163:1214–1216.
56. Bhatia S, Neely EK, Wilson DM. Serum luteinizing hormone rises within
minutes after depot leuprolide injection: implications for monitoring therapy.
Pediatrics 2002; 109:E30.
57. Brito VN, Latronico AC, Arnhold IJ, Mendonca BB. A single luteinizing
hormone determination 2 h after depot leuprolide is useful for therapy mon-
itoring of gonadotropin-dependent precocious puberty in girls. J Clin Endo-
crinol Metab 2004; 89:4338–4342.
58. Lewis KA, Eugster EA. Random luteinizing hormone often remains pubertal
in children treated with the histrelin implant for central precocious puberty.
J Pediatr 2013; 162:562–565.
338 www.co-obgyn.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
59. Neely EK, Silverman LA, Geffner ME, et al. Random unstimulated pediatric
luteinizing hormone levels are not reliable in the assessment of pubertal
suppression during histrelin implant therapy. Int J Pediatr Endocrinol 2013;
2013:20.
60. Thornton P, Silverman LA, Geffner ME, et al. Review of outcomes after
& cessation of gonadotropin-releasing hormone agonist treatment of girls with
precocious puberty. Pediatr Endocrinol Rev 2014; 11:306–317.
A good review of therapeutic outcomes.
61. Klein KO, Barnes KM, Jones JV, et al. Increased final height in precocious
puberty after long-term treatment with LHRH agonists: the National Institutes
of Health experience. J Clin Endocrinol Metab 2001; 86:4711–4716.
62. Pasquino AM, Pucarelli I, Accardo F, et al. Long-term observation of 87 girls
with idiopathic central precocious puberty treated with gonadotropin-releas-
ing hormone analogs: impact on adult height, body mass index, bone mineral
content, and reproductive function. J Clin Endocrinol Metab 2008; 93:190–
195.
63. Lazar L, Padoa A, Phillip M. Growth pattern and final height after cessation of
gonadotropin-suppressive therapy in girls with central sexual precocity. J Clin
Endocrinol Metab 2007; 92:3483–3489.
64. Cassio A, Cacciari E, Balsamo A, et al. Randomised trial of LHRH analogue
treatment on final height in girls with onset of puberty aged 7.5–8.5 years.
Arch Dis Child 1999; 81:329–332.
65. Downing J, Bellis MA. Early pubertal onset and its relationship with sexual risk
taking, substance use and antisocial behaviour: a preliminary cross-sectional
study. BMC Public Health 2009; 9:446.
66. Blumenthal H, Leen-Feldner EW, Babson KA, et al. Elevated social anxiety
among early maturing girls. Dev Psychol 2011; 47:1133–1140.
67. Colmenares A, Gunczler P, Lanes R. Higher prevalence of obesity and
overweight without an adverse metabolic profile in girls with central preco-
cious puberty compared to girls with early puberty, regardless of GnRH
analogue treatment. Intl J Pediatr Endocrinol 2014; 2014:5.
68. Arrigo T, De Luca F, Antoniazzi F, et al. Menstrual cycle pattern during the
first gynaecological years in girls with precocious puberty following gonado-
tropin-releasing hormone analogue treatment. Eur J Pediatr 2007; 166:
73–74.
69. Paterson WF, McNeill E, Young D, Donaldson MD. Auxological outcome and
time to menarche following long-acting goserelin therapy in girls with central
precocious or early puberty. Clin Endocrinol (Oxf) 2004; 61:626–634.
70. Poomthavorn P, Suphasit R, Mahachoklertwattana P. Adult height, body mass
index and time of menarche of girls with idiopathic central precocious puberty
after gonadotropin-releasing hormone analogue treatment. Gynecol Endocri-
nol 2011; 27:524–528.
71. Gillis D, Karavani G, Hirsch HJ, Strich D. Time to menarche and final height
after histrelin implant treatment for central precocious puberty. J Pediatr
2013; 163:532–536.
72. Heger S, Muller M, Ranke M, et al. Long-term GnRH agonist treatment for
female central precocious puberty does not impair reproductive function. Mol
Cell Endocrinol 2006; 254–255:217–217.
73. Chiavaroli V, Liberati M, D’Antonio F, et al. GNRH analog therapy in girls with
early puberty is associated with the achievement of predicted final height but
also with increased risk of polycystic ovary syndrome. Eur J Endocrinol 2010;
163:55–62.
74. Franceschi R, Gaudino R, Marcolongo A, et al. Prevalence of polycystic ovary
syndrome in young women who had idiopathic central precocious puberty.
Fertil Steril 2010; 93:1185–1191.
75. Magiakou MA, Manousaki D, Papadaki M, et al. The efficacy and safety of
gonadotropin-releasing hormone analog treatment in childhood and adoles-
cence: a single center, long-term follow-up study. J Clin Endocrinol Metab
2010; 95:109–117.
76. Cassio A, Bal MO, Orsini LF, et al. Reproductive outcome in patients treated
and not treated for idiopathic early puberty: long-term results of a randomized
trial in adults. J Pediatr 2006; 149:532–536.
Volume 26  Number 5  October 2014