Pubertal disorders

PUBERTAL
DISORDERS
By Dr. Birhanu A
(paediatrician and assistant professor in paediatrics
and child health at university of Gondar)
8/28/202
0
pubertal disorders 1

CONTENTS
• Objective
• Normal physiology of puberty
• Pubertal growth assessment and physical changes
• Classification of pubertal disorders
• Causes of pubertal disorders
• Approaches of pubertal disorders
• Diagnosis and management of pubertal disorders
8/28/2020pubertal disorders 2

objectives
• At the end of this seminar, you can understand
normal physiology of puberty, assessment, causes,
diagnostic modalities and management approaches
of pubertal disorders (DP and PP).

TERMINOLOGY
• Gonadarche: An increase in the activity of the
hypothalamic-pituitary- Gonadal (HPG) axis during
puberty
• Thelarche: is the onset of breast development;
• Menarche: is the first menstrual period
• Pubarche: is the onset of sexual hair growth.
• Adrenarche: increased adrenal androgen secretion

Physiology of normal puberty
• Puberty is defined as a period of transition from childhood to
adulthood that encompasses physiologic, somatic, and
constitutional changes associated with further development of
the internal and external genitalia and secondary sex characteristics.
• Timing of onset is affected by genetic factors, body mass,
nutritional state, and general health.
• The HPG axis is active during three phases of development: fetal,
neonatal, and adult, with puberty being the period of transition to
mature function.
• Between early childhood and approximately 8-9 yrs. of age the
HPA axis is dormant.

• 1- 3 yr. before the onset of clinically evident puberty, low serum
levels of LH during sleep become demonstrable.
• This sleep-entrained LH secretion occurs in a pulsatile fashion
and reflects endogenous episodic discharge of hypothalamic
GnRH
• Nocturnal pulses of LH continue to increase in amplitude and,
to a lesser extent, in frequency as clinical puberty approaches.
• This pulsatile secretion of gonadotropins is responsible for
enlargement and maturation of the gonads and the secretion of
sex hormones.

Conti….

• The appearance of the secondary sex characteristics in
early puberty is the visible culmination of the sustained,
active interaction occurring among hypothalamus,
pituitary, and gonads in the peri-pubertal period.
• By midpuberty, LH pulses become evident even during
the daytime and occur at approximately 90-120 min
interval.
• A positive feedback mechanism develops whereby
increasing levels of estrogen in midcycle cause a distinct
increase of LH.

• The increasing secretion of hypothalamic GnRH in a
pulsatile fashion thus underlies the onset of pubertal
development.
• The resulting “GnRH pulse generator” is regulated
by multiple neuropeptides
• Stimulatory: glutamic acid, kisspeptin, and neurokinin-B
• Inhibitory: γ-aminobutyric acid, preproenkephalin, and
dynorphin

• GnRH secretion is also regulated by factors produced by
the glial cells, such as transforming growth factor α.
• Increased transforming growth factor α signalling is
associated with the occurrence of central precocious
puberty in patients with hypothalamic hamartoma.
• Loss-of-function mutations of the KISS1 R—also known
as GPR54—gene (the gene encoding a G-protein–coupled
receptor whose ligand is kisspeptin) cause an autosomal
recessive form of hypogonadotropic hypogonadism,
whereas gain-of-function mutations of the gene are
associated with precocious puberty.

Conti….
• Serum levels of dehydroepiandrosterone (DHEA) and its sulfate
(DHEAS) begin to increase at approximately 6-8 yr of age, before
any increase in LH or sex hormones and before the earliest physical
changes of puberty are apparent……...adrenarche
• Although adrenarche typically antedates the onset of gonadal
activity (gonadarche) by a few years, the 2 processes do not seem to
be causally related, because adrenarche and gonadarche are
dissociated in conditions such as central precocious puberty and
adrenocortical failure.
• Estrogens, rather than androgens, are responsible for the process
of bone maturation that ultimately leads to epiphyseal fusion and
cessation of growth

• The effects of gonadal steroids (testosterone in boys,
estradiol in girls) on bone growth and osseous
maturation are critical.
• Both aromatase deficiency and estrogen receptor
defects result in delayed epiphyseal fusion and tall
stature in affected males.

• Estrogens also mediate the increased production of
growth hormone, which along with a direct effect of sex
steroids on bone growth, is responsible for the pubertal
growth spurt.
• The age of onset of puberty varies and is more closely
correlated with osseous maturation than with
chronological age.
• In females, the breast bud (thelarche) is usually the first
sign of puberty (10-11 yrs. of age) followed by the
appearance of pubic hair (pubarche) 6-12 months later.

• The interval to the onset of menstrual activity
(menarche) is usually 2-2.5 yr. but may be as long as
6 yr.
• Peak height velocity occurs early (at breast stages II-
III, typically between 11 and 12 yrs. of age) in girls
and always precedes menarche.
• The mean age of menarche is approximately 12.75
yr.

Pubertal growth assessment
Tanner Stages( Sexual Maturity Rating)
• Conceptually, pubertal maturation can be described
in terms of sequence, timing, and tempo.

Fig. SMR (2-5) of pubic hair changes in
adolescent males
Stage 2. Sparse,
straight pubic hair
along the base of
the penis
Stage 3. Hair is
darker, coarser, and
curlier, extending
over the mid-pubis
Stage 4: Hair is
adult like in
appearance, but
does't extend to
thighs
Stage 5: Hair is adult
in appearance,
extending from thigh
to thigh.

Fig. SMR (2-5) of pubic hair changes in
adolescent males
B Stage 2: Sparse,
straight hair along the
lateral vulva.
Stage 3: Hair is darker,
coarser, and curlier,
extending over the mid-
pubis.
Stage 4: Hair is adult-
like in appearance, but
does not extend to the
thighs.
Stage 5: Hair is adult
in appearance,
extending from thigh
to thigh.

Figure SMR (1-5) of breast changes in
adolescent females.
Stage 1: Prepubertal, with no palpable breast
tissue.
Stage 2: Development of a breast bud, with elevation of the papilla and
enlargement of the areolar diameter.
Stage 3: Enlargement of the breast, without separation of
areolar contour from the breast.
Stage 4: The areola and papilla project above the breast,
forming a secondary mound
Stage 5: Recession of the areola to match the contour of
the breast; the papilla projects beyond the countour of
the areola and breast.

Classification of pubertal disorders
1.Precocious puberty
• Breast development
before age 8 or menarche
before age 10 in females
• Testes volume > 3ml
before 9 years.
• Pubic hair development
before 8 years in females,
and 9 years in males
• Common in girls
2.Delayed puberty
• No breast development
by age 13 in a female
• No menses by age 15 in
a female
• Testicular size < 2.5cm
or 4mL or pubic hair is
not present by age 14 in
a male
• Common in boys

Delayed puberty
• Delayed puberty results from a lack of pubertal
maturation of the neuroendocrine axis or to gonadal
dysfunction.
• Permanent hypogonadism is a consequence of a
defect of GnRH or gonadotropin secretion or
gonadal inability to secrete sex steroids.
• The approach to delayed puberty is to categorize
based on gonadotropin status.

• In boys a period of 3.2+/-1.8 yr. is necessary to achieve
adult testicular volume after the onset of puberty
• In girls the period from breast budding to menarche is
2.4+/-1.1 yr.
• Evaluation is warranted if more than 4-5yr has elapsed
from the puberty to adult testicular size in boys or
menarche in girls
• Causes of hypogonadotropism include the non-
pathologic, i.e., constitutional delay, and the pathologic.
• Hypergonadotropic causes are always pathologic.

Conti….
In girls
• Lack of breast development by 13
yr.
• More than five year b/n breast
growth and mentrual period
• Lack of pubic hair by age 14yr
• Failure to menstruate by age 15-
16yr.
• Less common and often organic
In boys
• Lack of testicular
enlargement by age 14
• Lack of pubic hair by age 15
• More than five years to
complete genital
enlargement
• Often constitutional and
functional

CAUSES OF DELAYED
PUBERTY

1.Hyper gonadotropic
hypogonadism
MALES
Congenital abnormalities
• Klinefelter syndrome
• Other chromosomal
abnormalities
• Mutation in the FSH and LH
receptor genes
• Cryptorchidism
• Disorders of androgen synthesis
• Myotonic dystrophy
Acquired causes
• Infection-mumps, AIDS
• Radiation
• Chemotherapy
• Trauma
• Torsion
• varicocele
• Glucocorticoids excess
• Environmental toxin
• Chronic illness( CRF, CLD)

FEMALES
congenital
• gonadal dysgenesis (Turner
syndrome)
• Aromatase deficiency
• Galactosemia
• Glycoprotein syndrome type 1
• Noonan or pseudo-Turner syndrome
• Ovarian steroid biosynthetic defects
• FSH receptor mutation
acquired
• Radiation therapy
• Chemotherapy
• Autoimmune oophoritis
• Trauma/surgery
• Infection
• Polycystic ovarian disease

2. Hypogonadotropic hypogonadism
Tumours
• Craniopharyngiomas
• Germinomas
• Other germ cell tumors
• Hypothalamic and optic
gliomas
• Astrocytomas
• Pituitary tumors (including
MEN-1, prolactinoma
CNS DISORDERS
Other causes
• Langerhans histiocytosis
• Postinfectious lesions of the CNS
• Vascular abnormalities of the CNS
• Radiation therapy
• Congenital malformations especially
associated with craniofacial anomalies
• Head trauma
• Lymphocytic hypophysitis

Isolated Gonadotropin Deficiency
• Kallmann syndrome
• LHRH receptor mutation
• Isolated LH deficiency
• Isolated FSH deficiency
• Prohormone convertase 1 deficiency (PCI)

Miscellaneous Disorders
• Chronic systemic disease
and malnutrition
• AIDS
• Chronic gastro-enteric
and renal disease
• Anorexia nervosa
• Bulimia
• Female athletes and
ballet dancers (exercise
amenorrhea)
• Hypothyroidism
• Diabetes mellitus

Cont'd
• Cushing disease
• Hyperprolactinemia
• Marijuana use
• Gaucher disease
• Sickle cell disease
• Cystic fibrosis
• Prader-Willi syndrome
• Bardet-Biedl syndromes
• Functional
gonadotropin
deficiency

Approach to delayed puberty
History
• Histroy of birth trauma
• History of cryptochidism and
micropenis during infancy.
• Abnormal of genitalia
• Time gap between telarche and
menarche or duration of of full
genital enlargement to adult size
• Family history of delayed
puberty , infertility, deafness
and anosmia
• History of radiation and
chemotherapy
• History of autoimmune
disease(DM, thyroiditis)
• History of mumps infection
• RVI status

• Testicular injury
• Symptoms of chronic and recurrent illness
• linear growth and nutritional status during the neonatal
period and childhood
• A history of consanguinity
• The presence of congenital defects, including anosmia,
deafness, mirror movements, renal agenesis, dental/digital
anomalies, clefting or coloboma, or findings of CHARGE
syndrome

Physical examination
• Dysmorphic features
• Height, weight and BMI
• Height velocity
• U/L segment ratio and the arm span are measured
and compared with the height
• Length and width of the testes are measured
in boys, or the volume using
an orchidometer, scrotal skin texture.
• The length and diameter of the gently stretched
penis in boys, and the diameter of glandular
breast tissue and areolar size in girls.

• Vaginal mucosa changes( reddish to pink)
• Presence or absence of galactorrhea
• The extent of pubic and axillary hair is assessed, as is the
degree of acne or comedones
• Check the scrotum for the presence of testes
• Neurologic examination including optic disc and visual
field, olfaction.
• Complete physical examination, including the lungs, heart,
kidney, and gastrointestinal tract

Diagnosis

• CBC, electrolyte, RFT, LFT, TFT
• Serum prolactin level
• Serum level of gonadotropin
• Serum inhibin B level
• value over 35 pg/mL ruleout CDP
• Serum level of sex steroids
• 8 AM serum testosterone
 >0.7 nmol/L (20 ng/dL) predicts enlargement of testes to greater than 4 mL
by 12 months in 77% of cases and in 15 months in 100% of cases
 <0.7 nmol/L, only 12% entered puberty in 12 months and only 25% entered
puberty in 15 months.

IHH can be separated from CDP
• Basal LH level <0.3IU/L
• LH level <5.3IU/L after 4hr of 100 μg of triptorelin
acetate stimulations
• inhibin B less than 111 pg/ml had a 100% sensitive and
• Basal LH less than 0.3 IU/L with inhibin B less than 111
pg/mL has a specificity of 98.1% for IHH

• Testestrone/estradiol
• 8 AM serum testestrone >45ng/dl
• Plasma estradiol >9ng/ml is indicative of puberty
• DHEAS level
• Hypogonadotrophic patient undergo adrenarche at a normal age and to have higher
DHEAS concentrations than those with constitutional delay in growth
• Imaging( MRI, CT scan, bone x-ray, u/s)
• Skeletal age correlate smore closely with sexual development than does chronological
age
• Genetic testing for PROP1 mutations
• kayotyping

Management
Aims of treatment
• Determine site and cause of abnormality.
• Induce and maintain secondary sexual characteristics.
• Induce pubertal growth spurt.
• Prevent the potential short-term and long-term
psychological, personality, and social handicaps of delayed
puberty.
• Ensure normal libido and potency.
• Attain fertility

1. Concerned But Not Anxious or Socially Handicapped Adolescent
• Reassurance and follow-up
• Repeat evaluation (including serum testosterone or estradiol) in 6 months
2. Psychosocial Handicaps, Anxiety, Highly Concerned
• Therapy for 4 month
Boys: - testosterone enanthate 100 mg IM q4wk at 14-14.5 years of age, or
- overnight transdermal testosterone patch
Girls: ethinyl estradiol 5-10 mg/day PO or
-conjugated estrogens 0.3 mg/day PO or
- overnight ethinyl estradiol patch at 13 years of age
• No therapy for 4-6 mo;
• reevaluate status including serum testosteroneor estradiol;
• if indicated repeat treatment regimen

Hormonal substitution therapy in
hypogonadism
Boys
• Initial therapy: at 13 years of age, testosterone enanthate
50 mg IM every month for about 9 mo (6-12 mo).
• Over the next 3-4 year: gradually increase dose to adult
replacement dose of 200 mg q2-3wk
• Begin replacement therapy in boys with suspected
hypogonadotropic hypogonadism by bone age ≤14 year
• To induce fertility at appropriate time in hypogonadotropic
hypogonadism: pulsatile GnRH or FSH and hCG therapy

GIRLS
• Initial therapy: ethinyl estradiol 5 mg po or conjugated estrogen 0.3 mg
(or less) po daily for 4-6 mo or preferably estradiol transdermally
• After 6 mo of therapy (or sooner if breakthrough bleeding occurs), begin
cyclic therapy: Estrogen: first 21 days of month Progestagen: (e.g.,
medroxyprogesterone acetate 5 mg PO) 12th to 21st day of month
• Gradually increase dose of estrogen over next 2-3 year to conjugated
estrogen 0.6-1.25 mg or ethinyl estradiol 10-20 mg daily for first 21 days of
month or estradiol patch
• In hypogonadotropic hypogonadism, to induce ovulation at appropriate time:
pulsatile GnRH or FSH and hCG therapy

Precocious Puberty
• Defined by the onset of secondary sexual characteristics
before the age of 8 yr in girls and 9 yr in boys
• Precocious puberty may be classified as central
(gonadotropin dependent, or true) or peripheral (
gonadotropin independent or precocious pseudo
puberty).
• The production of excessive estrogens in males leads to
inappropriate feminization, and the production of
increased androgen levels in females leads to
inappropriate virilization

• Sexual precocity, increased gonadal steroid secretion
increases height velocity, somatic development, and the
rate of skeletal maturation.
• Because of premature epiphyseal fusion, sexual precocity
can lead to the paradox of tall stature in childhood but
short adult height.
• Serum alkaline phosphatase reflects growth, and IGF-1
concentrations reflect the degree of sexual development
rather than chronologic age, as do most chemistry and
haematology values.

• There are 3 main patterns of pubertal progression
1. Rapidly progressive puberty:
• Most girls <= 6 years of age at the onset and a large majority of boys
• Characterized by rapid physical and osseous maturation, leading to a loss of
height potential.
2. Slowly progressive puberty:
• Girls who age >=6yrs. With idiopathic precocious puberty
• characterized by parallel advancement of osseous maturation and linear
growth, with preserved height potential.
3. Spontaneously regressive or unsustained central precocious

Classification of pp
• Completecomplete
Central
gonadotropic
dependent
puberty
peripheral
gonadotropic
independent
puberty
incomplete
Premature
thelarche
Premature
pubarche
Premature
menarche 8/28/2020pubertal disorders 48

Conti…..
Central precocious
puberty
• Always isosexual
• Usually progresses in normal seqeuence
• HPG axis activation with ensuing sex
hormone secretion and progressive sexual
maturation
• 5-10x commonner in girl than boys
• 90% of sexual precocity in girls is
idiopathic
• 75% of boys have structural CNS
abnrmalities
Peripheral precocious
puberty
• Some of the secondary sex
characteristics appear
• No activation of the normal
HPG axis
• Sex characteristics may be
isosexual or heterosexual
(contrasexual)
• Induce maturation of the HPG
axis and trigger the onset of
central puberty.

Causes of PP
Central (Gonadotropin-
dependent PP)
• Idiopathic—most frequent cause
• Tumour-- astrocytoma, glioma,
germinoma
• Congenital anomaly—hydrocephalus,
hamartoma, myelomeningocele
• Infection/postinfection
• Radiation
• Trauma
• Ischemia
Gonadal Steroid-
dependent ( GIPP
• McCune-Albright syndrome—females predominate
• Familial male-limited precocious puberty
• Gonadal neoplasia
• Ovarian follicular cyst
• Leydig cell nodular hyperplasia
• Aromatase excess
• hcG secreting tumour
• Primary hypothyroidism
• Exogenous steroids (oral contraceptive pills, Skin
creams, testosterone

Adrenal Steroid-dependent (Gonadotropin-independent)
• Congenital adrenal hyperplasia
—21 hydroxylase deficiency
—11 hydroxylase deficiency
• 11 hydroxysteroid dehydrogenase deficiency
• Glucocorticoid resistance
• Adrenal tumor (benign, malignant)
• Exogenous steroids (eg, dehydroepiandrosterone)

Incomplete Precocious Puberty (Gonadotropin-
independent)
• Premature thelarche
• Premature adrenarche
• Premature menarche—look for gynecologic cause

Approach to precocious puberty
History
• Onset of age
• Is the precocity central or peripheral?
• Hyperthermia, excessive urination,
unnatural crying or laughing, cachexia,
obesity, proptosis, headache
• Menses regular or irregular?
• Are secondary sexual characteristics
virilising or feminizing?
• Previous CNS disease or
trauma?
• Any exposure to exogenous
sex steroid?
• Pattern of pubertal
development
• Timing of pubertal onset in
his or her parent and sibling?
Family history of similar
symptom
• Irradiation exposure

Physical examination
• Height, weight, calculate height velocity
• Pubertal staging( SMR)
• Abdomina girth, distention,,mass, fluid collection
• Ambigious genitalia, hirsutism,
• Neurologic deficit, fundoscopic examination for
papilledema,
• Café-au-lait spots

DIAGNOSIS
• Sex hormones: testosterone, oestrogen
• serum total T is sensitive to diagnose pp
• serum levels of Etradiol are not used to diagnose CPP, low sensitivity
• estradiol (>50 pg/mL), 20-24 hr. after stimulation with leuprolide
stimulation show pp.
• Determine gonadotropin levels: LH, FSH, FSH/LH ratio
• LH level ≥ 0.3 IU/L was indicative of pubertal progression while basal
LH ≤ 0.2 IU/L indicated no progression with 100% specificity and 90.5%
sensitivity
• LH > 0.6 U/L was able to diagnosis CPP in 62.7% of girls and 71.4% of
boys
• LH/FSH ratio of >=2 is also consistent with CP

• Measurement of ᵦhcG in males
• GnRH agonist stimulation test
• Peak stimulated LH of (8 mIU/mL after GnRH and (5
IU/L after GnRHa are considered indicative of CPP
• TSH,T4 level

Imaging
BONE AGE
• obtained with an X-ray of the non-dominant wrist
• precocious puberty, BA is often advanced, and when the
advancement exceeds either one year or two standard
deviations (SD), it is considered significant.
ULTRASOUND
• An ovarian volume > 1.8 mL and uterine length > 3.4 cm
indicate hormonal stimulation and may be an additional
laboratory parameter to evaluate girls with precocious puberty

Management and Treatment of
True Precocious Puberty
Objectives
• Arrest of premature sexual maturation until the normal
age at onset of puberty
• Regression of secondary sexual characteristics already
present
• Attainment of normal mature height; suppression of the
rapid rate of skeletal maturation
• Detection and treatment of an expanding intracranial
lesion

• Prevention of emotional disorders and handicaps and
alleviation of parental anxiety; promotion of
understanding by counseling, early sex education, and
acceleration of social age
• Reduction of risk of sexual abuse and early sexual debut
• Prevention of pregnancy in girls
• Preservation of future fertility
• Diminishment of the increased risk of breast cancer
associated with early menarche

• Three principal agents have been used in the medical
treatment of idiopathic or neurologic CPP:
1.medroxyprogesterone acetate
2.cyproterone acetate and
3.superactive GnRH agonists

• Treatment with GnRH agonist depends upon the
• Child’s age
• The rate of pubertal progression (sexual maturation),
• Height velocity and the estimated adult height

AGE
• present at a younger age and have a rapid progression of
maturation will have early epiphyseal fusion and reduced adult
height.
• present close to the age of normal puberty or who have a very
slowly progressive variant of precocious puberty may not require
any therapy.
• GnRH agonist treatment results in an average gain in adult height
of
• 9- 10 cm if therapy is begun before the age of six
• 4- 7 cm if begun between six and eight years of age and lower end of this
range if the child’s bone age is advanced

• Indications for Therapy With GnRH Agonists in
True or Central Precocious Puberty
1. In children with clinical and unequivocal endocrine
features of idiopathic true precocious puberty:
• Rapid advancement over a period of 6-12 mo of
secondary sex
• characteristics, height, height velocity, and bone age
(increased >2.5 SD for chronologic age) in affected boys
and girls

• A plasma testosterone concentration sustained >2.5
nmol/L (>75 ng/dL) in boys <8 yr of age
• A plasma estradiol concentration, recurrently ≥36
pmol/L (≥10 pg/mL) .
• Onset of menarche (and recurrent menses) in girls
<9 yr of age

• Psychosocial factors and parental anxiety, including
evidence that the child’s psychosocial well-being is
adversely affected.
2. In children with neurogenic or organic true
precocious puberty, especially those with associated GH
deficiency, the course is almost invariably progressive
and LHRH treatment should not be delayed.

Formulation and administration
• Sustained-release formulations of several GnRH
agonists have been developed for monthly or three-
monthly dosing
• A formulation of histrelin provides long-term
gonadotropin suppression in children with GDPP
for up to one year with a single implantation
• These preparations have not been directly compared
in randomized trials but appear to be comparably
effective in suppressing the gonadotropic axis

monitoring
• Patients should be evaluated every three to six months for
pubertal development and growth, and bone age should
also be measured radiographically every 6 to 12 months
• If treatment is effective, further breast and testicular
development should cease, and height velocity and rate of
bone age advancement should decline.
• Monitor LH and sex steroid concentrations one to two
months after initiating therapy or changing a dose.
• Ensuring adequate intake of calcium and vitamin D
during and after treatment.

• How do we follow adequacy of suppression HPG
axis
• GnRHa stimulation test after 1-2hr
• Serum LH level after therapeutic dose of GnRHa 30-
90min or randomly.
• Generally continue treatment until about age 11 in
girls, and age 12 in boys.

Management of Peripheral pp
• Children with tumors of the testis, adrenal gland, and
ovary are treated by surgery.
• Those with hCG-secreting tumors may require some
combination of surgery, radiation therapy, and
chemotherapy depending upon the site and histologic
type.
• A large functioning follicular cyst of the ovary is the
most common cause of GIPP in girls and can
regress spontaneously.

Summary
• HPG axis is active during foetal, infancy and pubertal
stages.
• After infancy and before puberty HPG axis stay dormant
then GnRH generator will start functioning in pulsatile
manner which induce sex steroid secretion from gonads
• Testicular enlargement ,enlargement of penis, pubic hair
growth, peak height velocity and sperm in the urine are
sequential event happened in boy during puberty.
• Management of CPP depends of age, pubertal
progression and height velocity.

references
• Nelson textbook of paediatrics 20th edition chapter562&563 page2655-2661
• Williams textbook of endocrinology 10th edition chapter 26 page 1090-1203
• Vinícius Nahime Brito, Central precocious puberty: revisiting the diagnosis and
therapeutic management Arch Endocrinol Metab. 2016;60/2; 163-172
• Andrew Muir ,Precocious Puberty AAP Pediatrics in Review 2006;27/10; 373-381
• Brian Bordini, Normal Pubertal Development: Part I&II: Clinical Aspects of
Puberty; AAP Pediatrics in Review ;2011;32 /7 281-292
• Melinda Chen, Erica A. Eugster; Central Precocious Puberty: Update on Diagnosis
and Treatment; Springer International Publishing Switzerland 2015; 274-281
• Uptodate 21.1

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