precocious puberty is one of the grey areas for pediatricians and gyenecologists. this is an attempt to answer some of the questions the content is references taken from authorative textbooks

1. PRECOCIOUS PUBERTY
DR SANTOSH MOGALI

2. INTRODUCTION-
• onset of secondary sexual characters before the age of 8
years in girls and 9 years in boys.
• Two types-central-gonadotropin dependent or true. Is
always isosexual and stems from hypothalamic-pituitary-
gonadal activation with ensuing sex hormone secretion and
progressive sexual maturation.
• Peripheral- gonadotropin independent or pseudo. some of
the secondary sex characters appear, but no activation of
the normal hypothalamic-pituitary-gonadal interplay. May
be isosexual or heterosexual (contrasexual)

3. Causes of central precocious puberty-
• Idiopathic
Organic brain lesions- Hypothalamic hamartoma
Brain tumors, hydrocephalus, severe head
trauma, myelomeningocele
Hypothyroidism, prolonged and untreated

4. CENTRAL PRECOCIOUS PUBERTY-
• Defined by the onset of breast development before the age of 8
years in girls and by the onset of testicular development
(volume ≥ 4 mL) before the age of 9 years in boys, as a result of
the early activation of the HPG axis.
• 5- to 10-fold more often in girls than in boys and is usually
sporadic.
• A high prevalence of idiopathic central precocious puberty has
been reported in girls adopted from developing countries, with
the limitation that the exact date of birth may be uncertain.
• 90% of girls have an idiopathic form,
• 75% of boys have structural central nervous system (CNS)
abnormality. Beyond its etiology, which thus needs to be
specifically addressed, central precocious puberty can affect
linear growth and the child's growth potential.

5. ILLUSTRATIONS-

6. CLINICAL FEATURES-
• Sexual development begins at any age and generally in
normal sequence.
• In girls- early menstrual cycles are more irregular and
anovulatory. Pregnancy is reported as early as 5.5 years.
• In boys, testicular biopsies have shown stimulation of all
elements of the testes, and spermatogenesis as early as 5-6
years.
• In affected girls and boys, height, weight, and osseous
maturation are advanced. The increased rate of bone
maturation results in early closure of the epiphyses, and
the ultimate stature is < normal

7. • In hypothalamic hamartoma remain static in size or grow
slowly, - no signs other than precocious puberty.
• For symptomatic , manifestations may be present for 1-2
yr before the tumor can be detected radiologically.
• Include diabetes
insipidus, adipsia, hyperthermia, unnatural crying or
laughing (gelastic seizures), obesity, and cachexia.
• Visual signs (proptosis, decreased visual acuity, visual field
defects) may be the first manifestation of an optic glioma.

8. • Mental development is usually compatible with
chronological age. Emotional behavior and mood swings
are common, but serious psychological problems are rare.
• Natural course- rapid- most common pattern.
characterized by rapid physical and osseous
maturation, leading to a loss of height potential.
• Slow-this pattern characterized by parallel advancement
of osseous maturation and linear growth, with preserved
height potential.
• spontaneously regressive or unsustained central
precocious puberty – marks the need for longitudinal
observation

9. LAB. INVESTIGATIONS-
• With sensitive assays, serum LH concentrations are
undetectable in prepubertal children but become
detectable in 50-75% of girls and a higher percentage of
boys with central sexual precocity.
• Measurement during sleep increases diagnostic power and
reveals the pulsatile LH secretion.
• GnRH stimulation test. Predominant LH response over FSH
after iv administration of GnRH or agonist like Leuprolide.
However in girls, LH:FSH ratio can remain low until mid-
puberty. In such girls with “low” LH response, the central
nature of sexual precocity can be proved by detecting
pubertal levels of estradiol (>50 pg/mL), 20-24 hr after
stimulation with leuprolide.

10. • Pelvic ultrasound reveals progressive enlargement of
ovaries followed by uterus to pubertal size.
• Osseous maturation advances.
• An MRI scan usually shows normal enlargement of the
pituitary gland, during puberty; it may also reveal CNS
pathology.

11. TREATMENT-
• Long term GnRH agonists In the USA, the most commonly
used preparation is leuprolide acetate (Lupron Depot Ped),
in a dose of 0.25-0.3 mg/kg (minimum, 7.5 mg) i.m. once
every 4 wk. Other preparations (D-Trp6-GnRH [Decapeptyl],
goserelin acetate [Zoladex]) are approved for treatment of
precocious puberty in other countries.
• Alternatively, histrelin (Supprelin LA), a subcutaneous 50
mg implant with effects lasting 12 mo, is approved by the
FDA .
• Intranasal and subcutaneous injection formulae are also
available.
• IUGR at greater risk of short stature as adults and require
more-aggressive treatment of precocious puberty, possibly
in conjunction with human growth hormone (hGH) therapy.

12. PERIPHERAL PUBERTY-ETIOLOGY
• PERIPHERAL (GONADOTROPIN INDEPENDENT, PRECOCIOUS
PSEUDOPUBERTY) Girls Isosexual (feminizing) conditions- McCune-
Albright syndrome
Autonomous ovarian cysts
Ovarian tumors-Granulosa-theca cell tumor with Ollier disease
Teratoma, chorionepithelioma
SCTAT associated with Peutz-Jeghers syndrome
Feminizing adrenocortical tumor
Exogenous estrogens
Heterosexual (masculinizing) conditions- Congenital adrenal
hyperplasia
Adrenal tumors
Ovarian tumors
Glucocorticoid receptor defect
Exogenous androgens

13. ETIOLOGY IN BOYS-
• Boys Isosexual (masculinizing) conditions -Congenital adrenal hyperplasia
Adrenocortical tumor
Leydig cell tumor
Familial male precocious puberty Isolated
Associated with pseudohypoparathyroidism
hCG-secreting tumors Central nervous system
Hepatoblastoma
Mediastinal tumor associated with Klinefelter syndrome
Teratoma
Glucocorticoid receptor defect
Exogenous androgen
Heterosexual (feminizing) conditions- Feminizing adrenocortical tumor
SCTAT associated with Peutz-Jeghers syndrome
Exogenous estrogens

14. MAC CUNE ALBRIGHT SYNDROME-
• A rare disorder prevalence 1 in 100000 to 1000000. Is
associated with patchy cutaneous pigmentation and fibrous
dysplasia of the skeletal system.
• a missense mutation in the gene encoding the α-subunit of
GS, the G protein that stimulates cAMP formation, resulting
in the formation of the putative gsp oncoprotein. Activation
of receptors (corticotropin [ACTH], TSH, FSH, and LH
receptors) that operate via a cAMP-dependent
mechanism, as well as cell proliferation, ensue.
• expressed differently in different tissues, accounts for
variability of clinical expression.

15. PRESENTATION-
• GIRLS- The average age at onset girls is about 3 yr, vaginal
bleeding as early as 4 mo of age and secondary sexual
charecters at 6 mo of age.
• Estradiol levels vary from normal to markedly elevated
(>900 pg/mL), are often cyclic, and can correlate with the
size of the cysts.
• BOYS- Precocious puberty is less common but has been
reported in several instances.
• At Pubertal age, Central precocious puberty overrides the
antecedent precocious pseudopuberty.

16. LAB. INVESTIGATIONS-
• . Estradiol levels vary from normal to markedly elevated
(>900 pg/mL), are often cyclic, and can correlate with the
size of the cysts.
• Testicular histology has demonstrated large seminiferous
tubules and no or minimal Leydig cell hyperplasia; these
findings might simply reflect the fact that biopsy specimens
were obtained at an early stage of pubertal development.

17. TREATMENT-
• Pubertal progression is variable in these patients. In
girls- Functioning ovarian cysts often disappear
spontaneously; aspiration or surgical excision of cysts is
rarely indicated.
• Aromatase inhibitors such as letrozole (1.25-2.5 mg/d
orally) or antiestrogens (such as tamoxifen; fulvestrant
is currently being investigated).
• in boys, in combination with antiandrogens (such as
spironolactone 50-100 mg bid, or flutamide 125-250
mg bid). Long-acting analogs of GnRH is indicated only
for patients whose puberty has shifted from a
gonadotropin-independent to a predominantly
gonadotropin-dependent mechanism.

18. INCOMPLETE(PARTIAL) VARIANTS-
•
Isolated manifestations of precocity without development
of other signs of puberty.
• Premature thelarche- isolated breast development that
most often appears < 2 yr of life. Sporadic and asymmetric.
; activating mutations of the GNAS1 gene encoding the α-
subunit of the GS protein have been described in some
patients without other signs of McCune-Albright syndrome.
• Menarche occurs at the expected age, and reproduction is
normal. Basal serum levels of FSH and the FSH response to
GnRH stimulation >normal girls
Plasma LH and estradiol are consistently < limits of
detection. Ultrasound examination of ovaries show a few
small (<9 mm) cysts.

19. • However, In some girls, breast development is associated
with definite evidence of systemic estrogen effects, such
as growth acceleration or bone age advancement. Pelvic
sonography shows enlarged ovaries or uterus. This
condition, referred to as exaggerated or atypical
thelarche, differs from central precocious puberty
because it spontaneously regresses.
• PREMATURE PUBARCHE(ADRENARCHE)-appearance of
sexual hair before the age of 8 yr in girls or 9 yr in boys
without other evidence of maturation.
• Girls >boys. Associated with reduced 3β-hydroxysteroid
dehydrogenase activity, and an increase in C-17,20-lyase
activity. Leads to increased DHEA, androstenedione and
17HOP

20. Exaggerated form is atypical premature adrenarche. May develop
one or more features of systemic androgen effect, such as marked
growth acceleration, clitoral (girls) or phallic (boys)
enlargement, cystic acne, or advanced bone age (>2 SD above the
mean for age).

21. • Although it has been considered a benign
condition, longitudinal observations suggest that approximately
50% of girls with premature adrenarche are at high risk for
hyperandrogenism and polycystic ovary syndrome, alone or
more often in combination with other components of the
metabolic syndrome (insulin resistance possibly progressing to
type 2 diabetes mellitus, dyslipidemia, hypertension, increased
abdominal fat) as adults.
• Premature Menarche-is a diagnosis of exclusion. In girls with
isolated vaginal bleeding in the absence of other secondary
sexual characters, more common causes such as
vulvovaginitis, a foreign body, or sexual abuse, and uncommon
causes such as urethral prolapse and sarcoma botryoides must
be carefully excluded.

22. • The majority of idiopathic premature menarche have
only 1-3 episodes of bleeding; puberty occurs at the
usual time, and menstrual cycles are normal. Plasma
levels of gonadotropins are normal, but estradiol levels
may be elevated, probably owing to episodic ovarian
estrogen secretion. Occasional patients are found to
have ovarian follicular cysts on ultrasound.

23. Approach to a girl with precocious puberty
Early breast development
Increased height velocity and advanced yes
bone age
Associated sec.sexual characters ,
axillary and pubic hair
no yes
age
<2years >2 year
Infantile
Pelvic ultrasound evaluation of
mamoplasia
gonads and uterus
Prepubertal Pubertal
GnRH stimulation test
Premature thelarche

24. GnRH stimulation test
LH response
Suppressed
GnRH dependent CPP GnRH independent PP
TSH, T4, hCG,ovarian, adre
nal imaging
MRI CNS imaging
no Abnormal
yes
Idiopathic CPP Organic CPP

25. Approach to a boy with penile enlargement<9years
Penile enlargement < 9 years
Increased height velocity and
advanced bone age
Increased testicular size
yes
no
Adrenal etiology
symmetrica
l asymmetrical
Raised
Raised 17-OHP levels
• yes no cortisol, cortic Glucocorticoid
otropin resistance
DHEAS high
CAH
Adrenal tumour

26. Continued…..
Asymmetrical enlargement
Symmetrical testicular
enlargement
yes Raised 17 OHP levels no
Adre.CAH
Raised
GnRH stimulation test, S.testosterone, and testoster.
hCG
LH raised, absent
hCG Testicul.
LH suppressed, hCG LH suppressed, Tumour
hCG absent
present
GnRH dependent PP
hCG secreting testotoxicosis
tumour