OBJECTIVES

Tanner staging &

Physiology of
puberty

schedule puberty
H-P-G axis of
puberty

Abnormal puberty
Classification & etiology
Diagnostic approach

INTRODUCTION
Hormonal
Hormonal
Adrenarche
Adrenarche
Gonadarche
Gonadarche
Gonadotropin
Gonadotropin
Sex
Sexsteroid
steroid
Growth
Growthhormone
hormone

Physical
Physical
Reproduction
Reproductionorgans
organs
2nd
2ndcharacteristics
characteristics
Growth
Growthspurt
spurt

Reproductive
Reproductivematuration
maturation
fertility
fertility
Final
Finalheight
height

Onset & Definition

Female: 8-13 years old
Male : 9.5-13.5 years old
Delayed and precocious puberty

Basic
Basic changes
changes
Adrenarche
Adrenarche
Gonadarche
Gonadarche

PHYSIOLOGY OF PUBERTY

1. Infancy
Midgestation in the fetus LH + FSH
At birth Negative feed back is released level of FSH
+ LH fall rapidly until 6-8 years.

2. Prepubertal
FSH + LH remain low but do show some pulsatile
activity

Adrenarche

means increased activity of the suprarenal

cortex at puberty with increased production
of adrenal androgens which lead to
appearance of pubic and

axillary hair.

 ADRENARCHE (MINI PUBERTY)

2-3 years before gonadarche age 6-8 yrs
cortex adrenal activity adrenal androgens production
(DHEA, DHEAS & androstenedione) pubic and axillary
hair

GONADARCHE
Activation of the gonad at the end of prepuburtal sex
steroids & completion of gametogenesis maturation
reproductive organs.

GONADOSTAT HYPOTHESIS

Prepubertal: negative feedback regulation

of FSH/LH secretion low threshold & sensitive to
low levels of steroids

Puberty: sensitivity gonadotropins &

sex steroids

Definition of Puberty
The period from the earliest signs
of sexual maturation until the
attainment of physical, mental
and emotional maturity
Pubertal changes result directly or
indirectly from maturation of the
hypothalamic-pituitary gonadotropin
unit, stimulation of the ovaries or testes,
and the secretion of sex steroids

PUBERTY
Average age of onset:
11.4 years in girls
12.0 years in boys

First signs of pubertal maturation:

breast budding in girls
increase in testicular volume in boys

PUBERTY
The first sign of pubertal development is usually breast
growth (thelarche), followed by appearance of pubic hair

(pubarche), then (axillary hair), then (menarche).

The mean interval between breast budding and menarche is
2.5 years with a standard deviation of about one year.

PHYSIOLOGY OF PUBERTY
Activation of the hypothalamopituitary- gonadal axis

From Forest MG et al., 1973.

HORMONAL CHANGES IN PUBERTY

frequency & amplitude GnRH pulses
progressive FSH & LH
Episodic peaks of estradiol
Onset of puberty
activity GnRH
pulse generator

Nocturnal gonadotropin pulses

daytime

Manifestations of puberty in the female include:

Physical
development
Psychological
changes

Appearance of
secondary sex
characters
Menarche,

TANNERS STAGING OF
PUBERTY IN GIRLS
STAGE

BREAST DEVELOPMENT (B)

PUBIC HAIR (PH)

Prepubertal; no breast tissue

None

Areolar enlargement with

breast bud

A few darker hairs

along labia

Enlargement of breast and

areola as single mound

Curly pigmented hairs

across pubes

Projection of areola above

breast as double mound

Small adult
configuration

Mature adult breast with single Adult pubic hair

contour
distribution

PUBERTAL STAGES (TANNER) FEMALE

LH, FSH and E2 and PUBERTAL

STAGE in GIRLS

Patterns of LH
secretion during
pubertal development

Cause of puberty :
During childhood , the
hypothalamus is
extremely sensitive to
the negative feedback
exerted by the small
quantities of estradiol &
testosterone produced
by the child's ovaries .

As puberty approaches ,
the sensitivity of the
hypothalamus is
decreased and
subsequently , it
increase the pulsatile
GnRH secretion .

Factors affecting the initiation of

pubertal development :
1.1.Height
Heightand
andweight
weight
ratio
ratio(nutritional
(nutritional
factors).
factors).
4.4.Onset
Onsetof
ofadrenal
adrenal
androgen
androgenactivity
activity

2.2.Maturation
Maturationof
ofthe
the
hypothalamus
hypothalamus
3.3.Increased
Increased
neurotransmitter
neurotransmitteroutput
output
ininCNS
CNS

MENARCHE
Average
Average
age
age of
of
menarche
menarche

12,7 yrs (white)

12,1 yrs (black)

Varies with race, nutrional status, body fat, maternal age at menarche
Occur 2 2,5 yrs after thelarche
Occur 1 yrs after growth spurt

Adolescence :
Is the period of life during which the
child becomes an adult person
i.e. the physical , sexual and psychological
development are complete .
Puberty represents the first part of adolescence .

Abnormalities of puberty
Precocious puberty .
Delayed puberty .
Growth problems :

During adolescence e.g. short

stature or tall stature , marked
obesity and menstrual disorders at
puberty .

Classification Precocious Puberty

1. Gonadotrophin dependent/central precocious puberty
(most common)
2. Gonadotrophin independent/peripeheral precocious
puberty
3. Pseudoprecocious puberty/variant
Premature thelarche
Premature adrenarche

Classification Precocious Puberty

 GnRH dependent activation H-P-O axis called true, central,

complete
due to GnRH in pituitary
GnRH independent called false/peripheral, incomplete.
Due to secretion of sex hormones
Isosexual or heterosexual
A girl who feminizes early is defined as having isosexual
precocious puberty.
A girl who virilize early is defined as having heterosexual
precocious puberty. (female pseudohermaphrodite)

GONADOTROPHIN-DEPENDENT
Pulsatile gonadotrophin secretion, especially overnight
LH : FSH ratio > 1
Gonadal activation with sex steroid production
Development of secondary sexual characteristics
Normal "Consonance"
Bone age acceleration
Final height impairment

Central Precocious Puberty

Idiopathic
It is due to increased production of pituitary
gonadotrophins.
CNS dysfunction

Congenital
Destructive tumors
Excessive pressure hydrocephalus
Previous or current infection/inflammation
Injury
Irradiation
GnRH secreting hypothalamic hamartoma

Precocious Puberty

GONADOTROPHIN-INDEPENDENT
Adrenal disorders

Tumours secreting sex steroids

Congenital adrenal hyperplasia

Gonadal disorders

Ovarian cyst/tumours secreting sex steroids

Leydig cell tumour

Exogenous sex steroids

McCune-Albright Syndrome
Testotoxicosis

GONADOTROPHIN-INDEPENDENT
Sex steroid production from gonads or adrenal gland or exogenous
source
Suppressed LH and FSH levels
Secondary sexual characteristics or virilization
Growth acceleration
Bone age acceleration with final height impairment

ItItisisof
ofperipheral
peripheral
origin.
origin.

ItItisisdue
dueto
tosecretion
secretionof
ofsex
sexhormones;
hormones;
(estrogen
(estrogenor
orandrogen)
androgen)which
whichisisnot
not
dependent
dependent

GONADOTROPHIN-INDEPENDENT

From Grumbach MM et al.

Williams Textbook of
Endocrinology 10th edition.
Modified from Sklar CA et
al. JCEM 1980.

ETIOLOGYOF PRECIOUS PUBERTY

1. Idopathic
Most case about 90%
There is normal menstruations and ovulation
Pregnancy can occur at young age

2. Organic lession of the brain

Second cause
Brain injury, meningitis, brain tumor, brain abscess

ETIOLOGYOF PRECIOUS PUBERTY

3. Adrenal causes

Adenoma
Congenital adrenal hyperplasia
Cushing syndrome

4. Ovariann causes

Tumors of Granulosa and theca cell

5. Mc Cune-Albright syndrome

Only 5% of female precocity

Multiple disseminated cystic bone lesions that can easy fracture
Can be associated: ovarian cysts, adenoma, hyperthyroidism,
osteromalacia

Diagnosis of precocious puberty

1. History:
It excludes iatrogenic source of estrogen or
androgen.
It differentiates between isosexual and
heterosexual precocious puberty.

2. Physical examination:
It diagnoses McCune-Albright syndrome.
Neurologic and ophthalmologic examinations
exclude organic lesions of the brain.

:Special investigations. 3
a.

X-ray examination of the hand and

wrist

to determine bone age.

Estrogen stimulates growth of bone but causes

early fusion of the epiphysis.
So the child is taller than her peers during
childhood, but she is short during adult life.

Hormonal assay:

b.

including serum FSH, LH,

prolactin, estradiol, testosterone, 17-hydroxy
progesterone,
TSH,
and
human
chorionic
gonadotrophin to diagnose Choriocarcinoma.

c.

Ultrasonography

to diagnose ovarian or adrenal

tumor.
d. CT or MRI : to diagnose an organic lesion of the
brain, or adrenal tumor.

Idiopathic precocious puberty:

is
is diagnosed
diagnosed
after
after excluding
excluding
all
all other
other causes
causes..

McCune-Albright Syndrome:

The disease is found more frequently in girls.

It consists of a triad of :
1. Precocious puberty,
2. Cystic changes in bones, and
3. Cafe-au lait patches of the skin.
The cause of precocious puberty is autonomous
production of estrogen by the ovaries.
FSH and LH levels are low.

McCune-Albright Syndrome:
The treatment is testolactone oral tablets which inhibit
ovarian steroidogenesis.
is treated with testolactone oral tablets.
The drug inhibits the formation of estrogen from its
precursors, so reduces estrogen level.
The dose is 20 mg/kg body weight in 4 divided doses and
increased to 40 mg/kg body weight during a 3 week interval.

Treatment of precocious puberty

1.1. Arrest
Arrestmaturation
maturation

until
untilnormal
normalpubertal
pubertal
age
age

4.4. Avoid
Avoidabuse,
abuse,reduce
reduce
emotional
emotional&&social
social
problems
problems

Objectives:

2.2. Attenuate
Attenuate&&

3.
3. Maximize
Maximizeadult
adult
height
height

diminish
diminishestablished
established
precocious
precocious
characteristics
characteristics

IDIOPATHIC TYPE
is treated by explanation and reassurance and by giving one of the
following drugs which inhibit the secretion of gonadotrophins:

(a) Gonadotrophin releasing hormone analogues which are given as daily

nasal spray, intramuscular, or subcutaneous injections every 4
weeks.
(b) Medroxyprogesterone acetate tablets (Provera tablets) or intramuscular
injection (Depo-Provera);
(c) Danazol capsules;
(d) Cyproterone acetate tablets (Androcur).

Gonadotrophin releasing
hormone analogues

Drug of choice because it achieves all objectives:

1.

It acts by binding to the anterior pituitary receptors causing

down-regulation & desensitization of the pituitary.

2.

Regression of symptoms occurs in the first year

3.

Delayed epiphyseal fusion; treatment more effective if begun

before bone age >12 yrs.

4.

Maintain E2 at <10 pg/mL.

5.

Children require higher doses than adults for suppression.

6.

Adrenarche will continue.

DELAYED PUBERTY
Secondary
Secondary Sexual
Sexual
Characters
Characters do
do not
not
develop
develop by
by the
the age
age of
of 14
14 yy
or
or
no
no menstruation
menstruation till
till age
age of
of
16y
16y

DELAYED PUBERTY
It is either :
* Delayed onset: Breast bud does not appear till 13
years or menarche does not occur till 16 years .
or
* Delayed progreession : Menarche does not occur
within 5 years after breast bud .

DELAYED PUBERTY
Absence of secondary sexual characteristics by age
14 or
Absence of menarche two years after apprearance of
secondary sexual characteristics
Classification
Hypergonadotrophic hypogonadism or gonadal failure
Hypogonadotrophic hypogonadism
Eugonadism

Girl, 13 years old, with constitutional delay in growth and puberty

ETIOLOGY OF DELAYED PUBERTY

1 - Constitutional with +ve family history , short stature & normal
fertility .
2 - Hypergonadotropic hypogonadism (FSH > 40) = ovarian causes
of Iry amenorrhea = primary ovarian failure & 2ry ovarian
failure (if occurs before puberty).
3 - Hypogonadtropic hypogonadism = hypothalamic & pituitary
causes of Iry amenorrhea e.g. Kallman's syndrome , Anorexia
nervosa .

4 - Normogonadtropic hypogonadism = end organ defects =

uterine causes (Mullerian agenesis and testicular feminization
syndrome), imperforate hymen (c/o = delayed menarche +
normal other aspects of puberty), PCOD and Virilizing ovarian
adrenal tumors .
5 - General causes of amenorrhea (endocrinal or non-endocrinal
especially malnutrition) if occurred before puberty &GH &
steroid synthesis defects .

INVESTIGATIONS OF DELAYED PUBERTY

History :
1 - Family history , nutritional history , any systemic
diseases (e.g. history of endocrinal disturbance).
2 - Clinical picture of space occupying lesion in the
ovary , adrenal, pituitary & hypothalamus.
3 - Periodic pain and +ve 2ry sexual characteristics in
imperforate hymen .

Special Investigations :
1 - FSH & LH assay important to differentiate level of
the lesion & progesterone assay in 17 OH deficiency
.
2 - Chromosomal study if short stature or
hypergonadotropic type .

3 - Radiological bone age study &

radiologic study for pituitary
adenoma

TREATMENT OF DELAYED PUBERTY

* Constitutional : Reassurance .
* Treatment of the cause (if treatable) or cyclic estrogenprogesterone hormone replacement therapy if the cause is
not treatable , for 3 cycles: Norethistrone acetate 5 mg twice
daily for 21 d or OCP
* Patient with

Y chromosome cell line : Gonadectomy +

hormone replacement therapy

CONCLUSION
A good understanding of normal puberty is
necessary to fully assess disorders of growth and
puberty
The commonest disorders of precocious/delayed
puberty are idiopathic
Psychological disturbances is the commonest
indication for intervention

THANK YOU

SECONDARY SEX
CHARACTERISTICS

FEMALE
From Marshall WA, Tanner JM, ArchDis Child 1969.

DELAYED PUBERTY

Absence of a clear pattern of pulsatile gonadotrophin secretion

Pre-pubertal LH and FSH levels

Development of secondary sexual characteristics

Normal "Consonance"

Bone age delay

Final height is not impaired except if severe degree of delay

Treatment of precocious puberty

1. Treatment of the cause, e.g., thyroxin for
hypothyroidism, removal of ovarian and
adrenal tumors.
2. Incomplete forms of precocious puberty
do not require treatment, as estrogen
production is not increased.

Etiology of precocious puberty

1.Constitutional or idiopathic:
In most cases of precocious puberty (90%) , no
cause is found.
For some unknown reason the hypothalamus
stimulates the pituitary gland to secrete its
gonadotrophic hormones.
There is normal menstruation and ovulation.
Pregnancy can occur at young age.

Etiology of precocious puberty

2. Organic lesions of the brain:

The next common cause.

Organic lesions affecting the midbrain, hypothalamus, pineal
body, or pituitary gland may lead to premature release of
pituitary gonadotrophins.
Examples include traumatic brain injury, meningitis,
encephalitis, brain abscess, brain tumor as glioma,
craniopharyngioma, and hamartomas.

Etiology of precocious puberty

3. McCune-Albright syndrome.
4. Adrenal causes:
(a) Hyperplasia, adenoma, or carcinoma of
suprarenal cortex.
Congenital adrenal hyperplasia and Cushing
syndrome lead to precocious puberty in the male
direction, i.e. heterosexual precocious puberty;
(b) Estrogen secreting adrenal tumor which is very
rare.

Etiology of precocious puberty

5. Ovarian causes :
(a) Estrogen producing tumors as granulosa and theca cell
tumor;
(b) Androgen producing tumors as androblastoma;
(c) Choriocarcinoma because it secretes human chorionic
gonadotrophin (HCG) which may stimulate the ovaries to
secrete estrogen;
(d) Dysgerminoma if it secretes HCG.

3. Incomplete precocious puberty

In this case only one pubertal change as breast
development is present before the age of 8 years
without the presence of any other pubertal
changes and in absence of increased estrogen
production.
The other pubertal changes occur at the normal
age.

3. Incomplete precocious puberty

Incomplete forms of precocious puberty
include premature thelarche (unilateral
or bilateral), premature pubarche and
premature adrenarche with appearance
of pubic and axillary hair.

2. False (peripheral) precocious puberty

False precocious puberty may be isosexual or
heterosexual.
A girl who feminizes early is defined as having
isosexual precocious puberty.
A girl who virilize early is defined as having
heterosexual precocious puberty. (female
pseudohermaphrodite)

HORMONAL CHANGES:
Gonadotropin-Releasing Hormone 2 One of the important
neuroendocrine mechanisms that control the onset of puberty is
probably an increase in the frequency of GnRH pulse
stimulation of the pituitary. Whatever the mechanism, the
process is not abrupt but develops over several years, as
evidenced by slowly rising plasma concentrations of the
gonadotropins and testosterone or estrogens.

HORMONAL CHANGES:
Gonadotropin-Releasing Hormone 1 In prepubertal children, no
significant luteinizing hormone (LH) or follicle-stimulating
hormone (FSH) response to intravenous or subcutaneous
administration of GnRH is observed. During adolescence, the LH
response to GnRH increases progressively in both sexes. The
increase of FSH is much less marked than that of LH. The
primary triggering mechanism that initiates the activation of the
hypothalamic-pituitarygonadal
hypothetical.

axis

at

puberty

is

still

LEPTIN in PUBERTY
Peptide hormone
Regulates food intake and energy expenditure at the
hypothalamic level (satiety factor)
Expressed predominantly in adipocytes
Regulated by body weight and nutrition
Involved in the regulation of GnRH secretion
Permissive factor for puberty (48kg)
Interacts with insulin, IGF1, GH and glucocorticoids

Types:
1 - True precocious puberty .
2 - False
(pseudoprecocious puberty).
3 - Incomplete precocious puberty .

PRECOCIOUS/DELAYED PUBERTY
Puberty is considered precocious if these
changes are noted prior to 8 years of age in
girls and 9 years of age in boys and is
considered delayed when such changes do not
occur prior to 13 years of age in girls and 14
years of age in boys (Europe).

EVALUATION OF UTERUS AT USS

Shape depends on the age of child:
During neonatal period and infancy drop shaped
By 8 yrs tubular form
During puberty pear shape

Cervix to corpus ratio:

2:1 pre-puberty
1:2 post-puberty

Angle between corpus and cervix only seen after puberty

Endometrium thickness not seen in prepuberty

PERIPHERAL PRECOCIOUS
PUBERTY
Exogenous sex steroids or gonadotrophins

Chronic primary hypothyroidism

Ovarian tumors
Granulosa cell= 60 per cent
Benign ovarian cysts (sexual maturation wanes as cyst
regresses)
Feminising adrenal tumours
Virilizing adrenal tumours
CAH late onset or non classical
Mc Cune albright sysndrome

EVALUATION OF OVARIES AT USS

Shape is oval. If smaller than 1 ml prepubertal. In young
adult ~6.5 ml
Ovarian follicles can be detected from any age of early
infancy onward
Follicles increase progressively in size and number after 8.5
yrs.
3-4 small cysts (~ diameter 5 mm) normal at any age

OVULATION
Plasma testosterone levels also increase at puberty
although not as markedly as in males. Plasma
progesterone remains at low levels even if secondary
sexual characteristics have appeared. A rise in
progesterone after menarche is, in general, indicative
that ovulation has occured. The first ovulation does not
take place until 6-9 months after menarche because the
positive feedback mechanism of estrogen is not
developed.

PHYSICAL CHANGES OF PUBERTY

Puberty proceeds through five stages from childhood to full
maturity (P1 to P5) as described by Marshall and Tanner. In both
sexes, these stages reflect the progressive modifications of the
external genitalia and of sexual hair. Secondary sex
characteristics appear at a mean age of 10.5 years in girls and
11.5 to 12 years in boys.

FEMALE SECONDARY SEXUAL

CHARACTERISTICS

If breast development, pubic and/or axillary hair,

and menses occur earlier than normal
variations from the mean, the terms premature
thelarche, pubarche and/or adrenarche, and
menarche are used.

PHYSIOLOGY OF PUBERTY
Activation of the hypothalamic- hipofisis- gonadal axis:
Induces and enhances the progressive ovarian and testicular
sex hormone secretion
Responsible for the profound biological, morphological, and
psychological changes to which the adolescent is subjected sex
steroid production:
appearance and maintenance of sexual characteristics
capacity for reproduction

Genital organs changes:

Mons pubes, labia majora & minora:
increase in size.
Vagina:
1. length: increase, appearance of the rugae
2. Epithelium: thick, stratified squamous.,
containing glycogen
3. pH: acidic.

PUBERTAL STAGES (TANNER)

FEMALE
P1

Prepubertal

P2

Early development of subareolar breast bud +/-small amounts

of pubic hair and axillairy hair

P3

Increase in size of palpable breast tissue and areolae,

increased amount of dark pubic hair and of axillary hair

P4

Further increase in breast size and areolae that protrude

above breast level adult pubic hair

P5

Adult stage, pubic hair with extension to upper thigh

Genital organs changes:

Uterus:
enlarge, Uterus / Cervix :2 / 1

Ovaries:
1.Increase in size, almond shape
2.300 thousands primary follicle at
menarche ( 2 million at birth)

Definition:
It means menarche or
appearance of any of the
secondary sexual characters
before the age of 8 years.

Secondary sex characters include:

Development
Development of
of the
the
breast,
breast, appearance
appearance of
of
pubic
pubic and
and axillary
axillary
hair.
hair.

PUBERTAL STAGING
Breast budding: earliest sign of puberty in

Breast

Pubic hair

girls
Breast enlargement

Androgen influenced

MENARCHE
During puberty, plasma estradiol levels fluctuate
widely, probably reflecting successive waves of
follicular development that fail to reach the ovulatory
stage. The uterine endometrium is affected by these
changes and undergoes cycles of proliferation and
regression, until a point is reached when substantial
growth occurs so that withdrawal of estrogen results in
the first menstruation ( menarche).

At the conclusion of this presentation,

participants should be able to:

Detail the physical and hormonal changes that

occur at puberty.
Classify girls with abnormalities of puberty.
Outline appropriate schema for the evaluation
of girls with delayed and precocious puberty.

Declining Age of Menarche?

 Schematic Sequence
of Events at Puberty
(After Tanner, 1974)

Gonadotropin Secretion during the Life of

Women

Changes in FSH and LH during Puberty

Interactions in the Hypothalamic-PituitaryGonadal Unit

Evaluation of Delayed or Interrupted

Puberty

Precocious Puberty
Differentiation from the benign conditions
precocious pubarche and precociousthelarche
is most important.
The major aim of evaluation is to rule out a
serious cause of the precocious development.

Evaluation of Precocious Puberty

Precocious Adrenarche
6 1/12 years

Precocious Puberty