Precocious puberty is defined as the development of pubertal signs at a younger age than the accepted lower limits for the onset of puberty. In girls, breast development before the age of 8 years, appearance of sexual pubic hair before the age of 8 years or beginning menses before the age of 9.5 years is traditionally considered as precocious puberty. This is accompanied by rapid growth rate, advanced skeletal maturation and increased levels of gonadotropins and/or sex steroids.

1. Recent Trends in Pubertal Timing and Current Management of
Precocious Puberty in Girls.

2. Review Article
Recent trends in pubertal timing and current management of
precocious puberty in girls
Anjana Hulse*
Consultant Pediatric Endocrinologist, Apollo Hospitals, Bangalore, India
a r t i c l e i n f o
Article history:
Received 28 April 2013
Accepted 15 May 2013
Available online 6 June 2013
Keywords:
Precocious puberty
GnRHa therapy
Early puberty
a b s t r a c t
Precocious puberty is defined as development of pubertal signs at a younger age than the
accepted lower limits for the onset of puberty. Precocious puberty can be classified as
gonadotropin dependent (central or true) and gonadotropin independent (peripheral or
pseudo). Commonest etiology in girls is idiopathic gonadotropin dependent precocious
puberty. Recently, timing of onset of puberty in girls has gained considerable interest
among the professionals and general public. Recent data suggests a decrease in the age of
onset of puberty in girls over the past 2e3 decades which may be attributable to increased
incidence of obesity, improved nutrition and other environmental factors.
Precocious puberty in girls warrants prompt evaluation and early initiation of treatment
to optimize adult height potential and to minimize psychosocial stress to the child.
Treatment is directed at the primary cause. Gonadotropin releasing hormone analog
(GnRHa) is the treatment of choice for gonadotropin dependent precocious puberty. GnRHa
are effective in preventing pubertal progression clinically as well as biochemically. A va-
riety of GnRHa preparations are available and the details are mentioned in the text.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Precocious puberty is defined as the development of pubertal
signs at a younger age than the accepted lower limits for the
onset of puberty. In girls, breast development before the age of
8 years, appearance of sexual pubic hair before the age of 8
years or beginning menses before the age of 9.5 years is
traditionally considered as precocious puberty. This is
accompanied by rapid growth rate, advanced skeletal matu-
ration and increased levels of gonadotropins and/or sex
steroids.
Precocious puberty can be classified as gonadotropin
dependent (central or true) and gonadotropin independent
(peripheral or pseudo). Central precocious puberty (CPP) is due
to premature activation of hypothalamoepituitaryegonadal
(HPG) axis. There is no activation of HPG axis in peripheral
precocious puberty (PPP). Even though organic lesions of the
central nervous system (CNS) are occasionally the cause of
precocious puberty, in the vast majority of the girls, CPP is
idiopathic. The source of sex steroid in PPP is endogenous as in
ovarian cysts or tumors; or adrenal as in adrenal tumors or
CAH; or exogenous such as ingestion of estrogen containing
* TF3, Dhanush Paradise, 10th Cross, 5th Main, Vijaya Bank Layout, Behind IIM-B, Bangalore 76, India. Tel.: þ91 (0) 80 26304050, þ91 (0)
9591382502 (mobile).
E-mail address: anmhulse@gmail.com.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 3 4 e1 3 7
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.05.010

3. pills or other endocrine disruptors (ED) present in food or
cosmetics.
2. Recent trends in pubertal timing
CPP is 10 times (female to male ratio varies from 3:1 to 23:1)
more common in girls than in boys.1,2
During the past 2e3
decades the timing of onset of puberty in girls has been a topic
of debate among pediatric endocrinologists. European data
have shown a sharp decline in age at menarche from 17 years
in the early 19th century to about 13 years in mid 20th cen-
tury.3
In the past 25 years a decrement of 2.5e4 months in age
at menarche has been noticed in both Europe and United
States.4e6
In contrast to menarche, age at onset of breast
development seem to have declined markedly from a mean
age of 11 years to less than 10 years during the past 2 decades.7
Although these findings were reported by two American
studies in 1990s similar findings were confirmed in Europe 15
years later.4,7,8
These studies prompted (LWPES) to recom-
mend a lower age limit for evaluation of precocious puberty in
girls from 8 years to 7 years.9
These recommendations were
based mainly on Pediatric Research in Office Settings network
(PROS)/National Health and Nutrition Examination Survey
(NHANES III) study where only girls up to the age of 12 years
were included. Moreover, NHANES study mainly relied on vi-
sual grading of breast development which may not be the
appropriate way to assess puberty in obese individuals. The
proposal of lowering of the age for evaluation of precocious
puberty in girls by LWPES was criticized by many experts.
More recently Copenhagen Puberty Study reported 12 months
decline in mean age at onset of puberty in Danish girls.4
Further studies clearly suggest a secular trend toward earlier
onset of breast development where as age at menarche has
changed only marginally. However, extrapolation from these
cross sectional findings may not be appropriate to redefine the
age limit for evaluation of precocious puberty and may lead to
possible misdiagnosis of potentially treatable underlying pa-
thology in about 5e10% girls.10
Therefore, cut off values for
age at which diagnostic evaluation is needed should not be
lowered.
Rapid change in pubertal timing in the recent years is a
pointer toward environmental influence on puberty in chil-
dren. Recent increase in the incidence of childhood obesity
has also contributed to early onset of puberty in girls. Genetic
factors, fetal nutrition and physical activity also play a role.
Catch up growth following early fetal or post natal under
nutrition may also be associated with early puberty.11
3. Evaluation of precocious puberty in girls
More than 90% of the girls with precocious puberty have
gonadotropin releasing hormone (GnRH) dependent preco-
cious puberty. Diagnostic evaluation is based on the devel-
opment of physical pubertal changes and laboratory testing
that are consistent with progressive changes of HPG axis
activation. Documentation of history, physical examination
findings and assessing hormonal status make important part
of evaluation. History taking should include growth patterns
since birth, age of onset of physical changes, past medical,
family and psychosocial history. Possibility of exposure to
exogenous hormones should be explored. Past history of CNS
infection, tumors, chemo or radiotherapy should be elicited.
Gelastic seizures may occur with CNS hamartomas. Physical
examination should include careful assessment of growth,
growth velocity, BMI, Tanner staging and systemic examina-
tion including fundus examination. Visualization of vaginal
mucosa to look for the evidence of estrogenization should be
included as a part of the examination.
Initial hormonal evaluation should include assessment of
bone age hormonal assays including luteinizing hormone
(LH), follicle stimulating hormone (FSH), estradiol (E2) and
where indicated dehydroepiandrostenedione (DHEAS) and
thyroid function tests. LH measurements are most valuable
for diagnosing precocious puberty. Pre-pubertal LH levels are
less than 0.1 IU/L. Basal LH level greater than 0.2 IU/L may
have 100% sensitivity and specificity for boys, but there 50% of
the girls in Tanner stage II breast development may have pre-
pubertal LH levels.12
Because of the variations in basal levels
and overlap between pre-pubertal and early pubertal hor-
monal levels, GnRH/GnRHa stimulation test is considered as
the gold standard to confirm the diagnosis of GnRH dependent
precocious puberty. However, there is a lot of debate about the
cut off values of LH and FSH for diagnosis of puberty following
stimulation with GnRH/GnRHa. Moreover, GnRH stimulation
test has low sensitivity, though it is highly specific for con-
firming precocious puberty.13
Conventionally, a peak LH value
more than 4.2e5 IU/L or a greater stimulated peak of LH/FSH is
considered as pubertal response. Peak levels of gonadotropins
are obtained 30 min after GnRH stimulation and 60 min after
GnRHa such as Leuprolide injection.14
Sensitive assays with
pediatric norms should be used.
Pelvic ultrasound in girls determines the ovarian and
uterine size. Uterine length, transverse diameter, endometrial
thickness, ratio of fundus to cervix, ovarian size and volume,
number of follicles and size of the biggest follicle should be
measured. Cut off values for uterine length is considered to be
about 4 cm and fundus to cervix ratio of more than 2:1 is
suggestive of pubertal status. Presence of endometrial echo is
highly specific but less sensitive.15
Cut off for pubertal ovarian
volume is about 1e3 ml.16
MRI of the CNS is usually done to
identify CNS lesions, though this investigation can be omitted
in older girls presenting with typical features of true central
precocious puberty.
4. Treatment
Early treatment of precocious puberty is utmost important. If
untreated, precocious puberty may lead to early epiphyseal
fusion and compromised final height.17,18
In addition early
puberty/menarche can cause significant psychological stress
in young girls.19
Treatment of precocious puberty is directed at
the primary cause.
GnRHa is the treatment of choice for GnRH dependent
precocious puberty. GnRHa suppresses the episodic secretion
of gonadotropins by continued occupation of the GnRH re-
ceptors on the pituitary gonadotropes with high level of
GnRHa. Girls with onset of progressive central precocious
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 3 4 e1 3 7 135

4. puberty before the age of 6 years benefit the most in terms of
height from GnRHa therapy. A variety of GnRHa formulations
are available (monthly and depot preparations for intramus-
cular use; intranasal and sub-cutaneous injections).
Commonly used GnRHa include Goserelin, Buserelin, Leu-
prolide, Triptorelin and Histrelin. GnRHa are expensive and
this may be a limiting factor for its use for patients from lower
socioeconomic status in developing countries. For most chil-
dren, monthly injections in a dose of 0.3 mg/kg/28 days
adequately suppress the gonadotropins. Occasionally more
frequent injections may be required. Depot preparations (3
monthly) also have been tried and shown to be equally effi-
cacious and is useful when compliance in an issue.20
But
larger randomized trials are required to confirm the effec-
tiveness and safety of depot preparations. The choice of
therapy depends on local availability, physician as well as
patient or parents’ choice. GnRHa are generally well tolerated.
Hot flushes, headaches and sterile abscess have been
described in the literature but the incidence is very low.
Anaphylaxis is extremely rare. Vaginal bleeding may occur
after the first injection but, should cease with subsequent
doses. Some pediatric endocrinologists suggest measurement
of stimulated LH and E 2 levels to assess the efficacy of
treatment. However there is no consensus on routine use of
this. Decline in growth velocity and bone age advancement
should occur during treatment. Progression of breast devel-
opment or other pubertal signs (not pubic hair) suggests fail-
ure of treatment and calls for re-evaluation of the patient.
Discontinuation of GnRHa at a chronological age of 11 years
and at a bone age of 12 years has been associated with
maximum adult height.21
Timing of cessation of therapy de-
pends on the parents’ and the child’s wish and also physi-
cian’s assessment. In one study menses began at a mean of 16
months after stopping the treatment with GnRHa.21
Currently
available data does not suggest impairment of gonadal func-
tion in long term after stopping GnRHa therapy.21
Weight gain
and reduction in bone mineral density in children treated with
GnRHa have been mentioned, but these findings are not
objectively supported by the studies.21
GnRHa therapy is also used for hypothalamic hamartoma.
Treatment of PPP is directed against the cause and could be
sometimes challenging. CNS tumors, ectopic gonadotropin
producing gonadal and adrenal tumors require surgery, radio
or chemotherapy. Adrenal suppression in CAH and thyroxine
replacement in hypothyroidism is required. Where there is
autonomous gonadal steroid suppression such as McCune-
eAlbright syndrome aromatase inhibitors or ketoconazole
have been used to reduce the effect of sex steroids.
5. Newer therapies
Histrelin implant has been tried in girls with CPP in some
centers. There was no difference in terms of final height
achievement in children treated with implant or long acting
GnRHa. Menarche occurred sooner after removal of the
implant.22e25
However, long term studies are still awaited.
Orally acting GnRHa are also under development and poten-
tially could be used to treat children with central precocious
puberty in future. Adjunctive therapy with growth hormone
or oxandrolone have been tried, but are not routinely advo-
cated yet.
6. Conclusion
Population based studies have shown a shift towards earlier
mean age at the onset of breast development in girls in the
past two to three decades. These studies have not confirmed
rapid progression of entire sequence of puberty including
menarche. Even then, to avoid overlooking a small subset of
children with rapidly progressive puberty and to avoid
missing the pathological causes of puberty, lowering the
normal age for the evaluation of precocious puberty is not
advisable.
Treatment with GnRHa is reversible, safe and effective for
CPP in girls. Treatment of PPP sometimes is challenging. Long
term studies looking at the use of depot GnRHa preparations
for CPP and newer routes of administration such as implants
are needed. Cost of the treatment is also a limiting factor for
use of GnRHa for treatment of precocious puberty in devel-
oping countries like India.
Conflicts of interest
The author has none to declare.
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