Precocious puberty diagnosis management

1. By Dr. ANIRUDH RAO
Moderator Dr. V.R. ANAND

2. INTRODUCTION
 Onset of secondary sexual characteristics before the age
of 8 yr in girls & 9 yr in boys
CLASSIFICATION:
 central or gonadotropin dependent or true – always
isosexual
 Peripheral or gonadotropin independent or precocious
pseudopuberty – may be isosexual or heterosexual
 Combined peripheral and central : peripheral precocious
puberty can induce maturation of the HPG axis & trigger
the onset of central puberty

3. CAUSES
CENTRAL PRECOCIOUS PUBERTY
 Idiopathic
 Organic brain lesions
 Hypothalamic hamartoma
 Brain tumours, hydrocephalus, head trauma,
myelomeningocele
COMBINED PERIPHERAL & CENTRAL
 Treated CAH
 McCune- Albright syndrome
 Familial male precocious puberty

4. PERIPHERAL PRECOCIOUS PUBERTY
CAUSES
GIRLS
ISOSEXUAL CONDITIONS
 McCune Albright syndrome
 Ovarian cysts / tumours
 Granulosa theca cell tumour
 Teratoma,
chorionepithelioma
 SCTAT associated with PJS
 Feminising adrenocortical
tumour
 Exogenous estrogens
HETEROSEXUAL
CONDITIONS
 CAH
 Adrenal tumours
 Ovarian tumours
 Glucocorticiod receptor
defect
 Exogenous androgens

5. PERIPHERAL PRECOCIOUS PUBERTY
CAUSES
BOYS
ISOSEXUAL CONDITIONS
 CAH
 Adrenocortical tumour
 Leideg cell tumour
 Familial male precocious
puberty
 Pseudohypoparathyroidism
 HCG secreting tumours
 Mediastinal tumor
 Teratoma
 GC receptor defect
 Exogenous androgens
HETEROSEXUAL
CONDITIONS
 Feminising adrenocortical
tumour
 SCTAT associated with PJS
 Exogenous estrogens

6. INCOMPLETE/PARTIAL
PRECOCIOUS PUBERTY
 Premature thelarche
 Premature adrenarche
 Premature menarche

7. CENTRAL PRECOCIOUS PUBERTY
DEFINITION:
 Onset of breast development before the age of 8yr in
girls & by the onset of testicular development before
the age of 9 yrs in boys, as a result of early activation of
HPG axis
 5 to 10 times more common in girls than in boys
 In girls – 90% cases idiopathic
 In boys – 75% of cases structural CNS abnormality

8. CLINICAL MANIFESTATIONS
 Sexual development may begin at any age & follows the
sequence observed in normal puberty
 In girls early menstrual cycles more irregular
 The initial cycles are usually anovulatory
 In boys testicular biopsies shown stimulation of all
elements of the testes & spermatogenesis observed as
early as 5-6 yrs of age

9. CLINICAL MANIFESTATIONS
 In affected girls & boys height, weight & osseous
maturation are advanced
 Early closure of the epiphyses & ultimate stature is less
 Mental development is usually compatible with
chronological age
 Emotional behaviour & mood swings common

10. CLINICAL FEATURES
3 patterns of pubertal progression
 Rapid – most common pattern. characterised by rapid
physical & osseous maturation, leading to loss of
height potential
 Slow - parallel advancement of osseous maturation &
linear growth, with preserved height potential
 Spontaneously regressive/unsustained - rare

11. CLINICAL MANIFESTATIONS
 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 tumour can be detected radiologically
 Hypothalamic signs or symptoms include diabetis
insipidus , adipsia , hyperthermia, unnatural crying or
laughing, obesity & cachexia
 Visual signs may be the first manifestation of optic
glioma

14. LAB INVESTIGATIONS
 Sex hormone levels usually appropriate for the stage of
puberty in both sexes
 Measurement of LH in serial blood samples obtained
during sleep is best & reveals pulsatile LH secretion
 GnRH stimulation test: predominant LH response over FSH
after i.v administration of GnRH or GnRH 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
precocious puberty can be proved by detecting pubertal
levels of estradiol (>50 pg/ml), 20-24 hr after stimulation
with leuprolide

15. INVESTIGATIONS
 USG pelvis: in girls reveals progressive enlargement of
ovaries f/b enlargement of uterus to pubertal size
 MRI: physiologic enlargement of the pituitary gland
 May also reveal CNS pathology

16. TREATMENT
 Virtually all boys and the large subgroup of girls with
rapidly progressive precocious puberty are candidates for
treatment.
 Girls with slowly progressive idiopathic central precocious
puberty do not seem to benefit in terms of height prognosis
from GnRH -agonist therapy.
 Former SGA infants may be at greater risk of short stature
as adults & may require more aggressive treatment of
precocious puberty, possibly in conjunction with human
growth hormone therapy.
 Certain patients require treatment solely for psychologic or
social reasons , including children with special needs and
very young girls at risk of early menarche

17. TREATMENT
 The observation that the pituitary gonadotropic cells
require pulsatile rather than continuous, stimulation by
GnRH to maintain the ongoing release of gonadotropins
provides the rationale for using GnRH agonists for
treatment of central precocious puberty
 Long-acting formulations of GnRH agonists which
maintain fairly constant serum concentrations of the
drug for weeks or months , constitute the preparations of
choice for treatment of central precocious puberty.

18. TREATMENT
The available preparations include
 (1) leuprolide acetate (Lupron Depot- Ped) in a dose of
0.25-0.3 mg/kg (minimum 7.5 mg) intramuscularly once
every 4 wk
 (2) longer-acting preparations of depot leuprolide
allowing for injections 11.35- 30.0 mg IM every 90 days
 (3) histrelin (Supprelin LA) , a subcutaneous 50 mg
implant with effects lasting 12 months
 Other preparations Decapeptyl , goserelin acetate
( Zoladex ) are approved for treatment of precocious
puberty in other countries

19. TREATMENT
Other available treatment options include
 Subcutaneous injections of aqueous leuprolide, given
once or twice daily (total dose 60 μg/kg/24 hr)
 Intranasal administration of GnRH agonist nafarelin
(Synarel) 800 μg bid.
 The potential for irregular compliance with daily
administration, as well as the variable absorption of
the intranasal route for nafarelin may limit the long
term benefit of these preparations on adult height.

20. TREATMENT
 Treatment results in decrease of the growth rate,
generally to age appropriate values
 Treatment results in enhancement of the predicted
height
 In girls, breast development may regress in those with
Tanner stages II-III development
 Most commonly the size of the breasts remains
unchanged in girls with stages III-V development or
may even increase slightly because of progressive
adipose tissue deposition

21. TREATMENT
 Pubic hair usually remains stable in girls, or may
progress slowly during treatment, reflecting the
gradual increase in adrenal androgens.
 Menses, if present, cease.
 Pelvic sonography demonstrates a decrease of the
ovarian and uterine size.
 In boys, there is decrease of testicular size, variable
regression of pubic hair , and decrease in the
frequency of erections.

22. TREATMENT
 If treatment is effective, the serum sex hormone
concentrations decrease to pre pubertal levels
(testosterone <10-20 ng/dL in boys ; estradiol <5-10
pg/ml in girls).
 The serum LH and FSH concentrations decrease to less
than 1 IU/L in most Patients
 The incremental FSH and LH responses to GnRH
stimulation decrease to less than 2-3 IU/L.
 Serum LH and sex hormone levels remain suppressed
for as long as therapy is continued but puberty resumes
promptly when therapy is discontinued, typically at a
“pubertal” chronological age

23. TREATMENT
 In patients with hypothalamic hamartoma and
associated intractable gelastic or psychomotor seizures
stereotactic radiation therapy (gamma knife surgery)
is effective and less risky than neurosurgical
intervention.
 Combined growth hormone therapy should be
considered for patients with associated GH deficiency

24. McCune – albright syndrome
 A rare disorder pevalence 1 in 1 lakh to 1 in 10 lakh. Is
associated with patchy cutaneous pigmentation & fibrous
dysplasia of the skeletal system
 A classical cause of peripheral precocious puberty, it can
also induce pituitary, thyroid, and adrenal aberrations
 characterized by autonomous hyper function of many
glands and caused by a missense mutation in the gene
encoding the α-subunit of GS, the G protein that stimulates
c AMP formation, resulting in the formation of the putative
gsp oncoprotein.
 Activation of receptors (corticotropin ,ACTH, TSH, FSH,
and LH receptors) that operate via a cyclic AMP dependent
mechanism as well as cell proliferation ensue.

25. PRESENTATION
GIRLS- average age at onset is about 3 yrs
 Young girls have suppressed levels of LH and FSH,
and there is no response to GnRH or leuprolide
stimulation.
 Estradiol levels vary from normal to markedly elevated
(>900 pg/ml) & often cyclic may correlate with the size
of the recurrent ovarian cysts.
BOYS- precocious puberty is less common but has been
reported in several instances.
 At pubertal age, central precocious puberty over rides
the antecedent precocious pseudopuberty

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

28.  TREATMENT : Pubertal progression is variable in these
patients. Functioning ovarian cysts often disappear
spontaneously; aspiration or surgical excision of cysts is
rarely indicated
 For girls with persistent estradiol secretion aromatase
inhibitors such as letrozole (1.25-2.5 mg/day orally) or
anti estrogens such as tamoxifen (5-20 mg/day orally)
 The same compounds have also been used in boys, in
combination with anti androgens such as
spironolactone 50-100 mg bid , flutamide 125-250 mg
bid or bicalutamide 25-50 mg daily

29. INCOMPLETE (PARTIAL) VARIANTS
 Isolated manifestations of precocity without development of
other signs of puberty
 Premature thelarche - sporadic, transient condition of
isolated breast development that most often appears in the
1st 2 yr of life.
 In some girls, breast development is present at birth and
persists.
 Growth and osseous maturation are normal or slightly
advanced.
 The genitalia show no evidence of estrogenic stimulation.
 Breast development may regress after 2 yr, often persists for
3-5 yr, and is rarely progressive.
 Menarche occurs at the expected age , and reproduction is
normal.

30. PREMATURE THELARCHE
 Basal serum levels of FSH and the FSH response to GnRH
stimulation may be greater than that seen in normal
controls
 Plasma levels of LH and estradiol consistently less than
the limits of detection.
 Ultrasound examination of the ovaries reveals normal size,
but a few small cysts may seen
 In some girls, breast development may be associated with
definite evidence of systemic estrogen effects, such as
growth acceleration or bone age advancement.
 Pelvic sonography may reveal enlarged ovaries or uterus.
This condition, referred to as exaggerated or atypical
thelarche differs from central precocious puberty because
it spontaneously regresses.

31. PREMATURE PUBARCHE
 The 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 3 beta HSD activity& increase
in C- 17,20-lyase activity. Leads to increased DHEA,
androstenidione & 17 HOP

32.  Idiopathic premature adrenarche is a slowly
progressive condition that requires no therapy.
 ATYPICAL PREMATURE ADRENARCHE : some
patients with precocious pubarche has 1 or more
features of systemic androgen effect, such as marked
growth acceleration, clitoral or phallic enlargement,
cystic acne, or advanced bone age
 About 50% of girls with premature adrenarche are at
high risk for hyperandrogenism and polycystic ovary
syndrome, alone or in combination with other
components of the metabolic syndrome

33. PREMATURE MENARCHE
 It is a diagnosis of exclusion.
 In girls with isolated vaginal bleeding in the absence of
other secondary sexual characteristics, 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.
 The majority of girls with 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 low, but estradiol levels
may be occasionally elevated, probably owing to episodic
ovarian estrogen secretion associated with ovarian follicular
cysts that can be detected on ultrasound

34. Thank you