NORMAL PUBERTAL DEVELOPMENT

NORMAL PUBERTAL DEVELOPMENT

WHAT IS PUBERTY?

-It is the transitional period of development during which an individual mature from childhood to sexual & reproductive maturity

NORMAL PUBERTAL DEVELOPMENT

WHAT ARE THE MAJOR CHARECTERISTICS OF THIS PERIOD?

1-Maturation of the 1ry sexual chct ?

Hypothalamic Pituitary Ovarian Axis

2-Development of 2ry sexual chct ?

-Sexual hair

-Breasts

-Genitalia

3-Dramatic growth spurt

4-Phycological changes mental & emotional maturity

NORMAL PUBERTAL DEVELOPMENT

-WHAT IS THE AGE OF ONSET OF PUBERTY?

-Females ----8-13

-Males -----9-14

-WHAT IS THE USUAL SEQUANCE OF SOMATIC CHANGES OF PUBERTY?

1-Beast development (mean 10.6 Y)

2-Pubic & axillary hair (11.2)

3-Maximal growth velocity (12)

onset of growth spurt (9.6)

4-Menarche (12.7)

AGES OF GIRLS AT VARIOUSSTAGES OF PUBERTAL DEVELOPMENT

NORMAL PUBERTAL DEVELOPMENT

-DOES MENARCHE MARK THE ATTAINMENT OF REPRODUCTIVE MATURITY?

• No, the reproductive system continues to mature for around 3-4 years

• No. of ovulatory cycles from 10% to 90%• Duration of menstrual cycle

NORMAL PUBERTAL DEVELOPMENT

-WHAT IS THE TIME FROM ONSET TO COMPLETION OF PUBERTY?

Average 4.2 Y

Range 1.5-6 Y

MECHANISM CONTROLLING FSH & LH SECRETION IN INFANTS

1-THE MAIN MECHANISM IS THE LEVELOF SEX STEROIDS

▲Peak FSH & LH 1-2 years

2- THE INTRINSIC CNS INHIBITORY MECHANISM

▲Gradually develops with continued growth & maturation of the CNS Minimum FSH & LH level 6-8 years

▲The principal CNS inhibitor of GnRH is GABA

LEVELS OF LH & FSH DURING FETAL LIFE, INFANCY CHILDHOOD & PUBERTY

MATURATION OF THE HPO AXIS

THE SEQUENCE OF MATURATION

☻At the onset of puberty GnRH pulses occur during sleep LH pulses

☻The frequency of LH pulses with further maturation

☻LH pulses appear during day time & in amplitude

☻As menarche approaches the pulses are detected all the time (no diurnal variation)

☻Similar changes occur in FSH pulses

☻LH/FSH ratio

PLASMA LH CONC MEASURED EVERY 20 MIN FOR 24 HRS

1-PREPUBERTAL

2-EARLY PUBERTAL

3-LATE PUBERTAL

INITIATION OF PUBERTYFACTORS RESPONSIBLE FOR THE INITAIATION OF

PUBERTY

***UNKNOWN

*FRISCH THEORY

• A critical body fat & body wt are required for the initiation of menarche

• Supported by :

1-Highly competitive athletic training

delayed puberty

2-Delayed menarche in malnutrition

3-Overwt girls have early menarche

4-Pt with anorexia nervosa revert to prepubertal pattern of gonadotropin secretion as body wt

INITIATION OF PUBERTY

AGAINST THE THEORY

Changes in body composition occurs simultaneously with

gonadortopin increase & does not precede it

*LEPTIN

An adipose derived protein may play a role in the initiation of puberty

INITIATION OF PUBERTY

☻Gonadostat begins to loose its sensitivity to the –ve

feedback by estrogen reactivation of GnRH pulsatility puberty

☻ CNS inhibitory mechanism (on the hypothalamus) wane GnRH FSH & LH estrogen (gonadarche)

☻ sensitivity of the pituitary to GnRH

☻ sensitivity of the ovary to LH & FSH esrtogen secretion

ADRENARCHE

• The maturational in adrenal androgen secretion • DHEA , DHEAS, AND

development of pubic & axillary hair

adult type body odor

acne

oily skin & hair• DHEAS -----First detected at 7 Y

-----Maximum at 15 Y • The mechanism of initiation is unknown• Adrenal androgens bone age & linear growth• Premature adrenarche adult height• Adrenarche & gonadarche are not associated

GONADARCHE

• The onset of pubertal gonadal activity due to reactivation

of HPO axis estrogen

• The process of ovarian follicular growth & atresia is initiated in utero & continues from birth to puberty

It is independent of gonadotropin secretion & results in only minimal estrogen secretion

• Reactivation of HPO axis gonadotropin pulses sustained follicular development to antral stage

significant estrogen production• There is direct relationship between follicular size &

estrogen secretion

MENARCHE

• When there is sufficient gonadotropin stimulation of the ovaries follicular growth (~16mm) estrogen

proliferation of the endometrium untill it outgrows the estrogen capacity to maintain it or the follicle undergo

atresia estrogen menstruation (MENARCHE)

• Anovulatory cycles occur during the first 6-18 months

“endometrium is not exposed to progestrone” irregular unpredictable menstrual flow

OVULATORY MENSTRUAL CYCLES

• Requires further maturation of the HPO axis development of the +ve feedback mechanism LH surge ovulation & corpus luteum formation progestron production

• Early ovulatory cycles have short or inadequate luteal phase HPO axis has not achieved full maturity

PHYSICAL EVENTS OF PUBERTY

I-Maturation of the genital organs

PREPUBERTAL

1-UTERUS

-Ratio of corpus : cx 1:2

-Tubular shape

-Length --- 2-3 cm

-Volume ----- 0.4-1.6 -Endometrium single layer of cuboidal cells

2-OVARIES

-Volume -----0.2-1.6 ml

-Non functional

PUBERTAL ---ADULT

1-UTERUS

-Ratio of corpus :cx 2:1

-Pear shape

-Length ----5-8

-Volume ----- 3-15 --- -Endometrium thickness

2-OVARIES

-Volume ------2.8-15 ml

-Multicystic

Maturation of the genital organs

PREPUBERTAL

3-VAGINA

-Reddish in color

-Thin atrophic columnar epithelium

-PH ---neutral

-Length—2.5-3.5

PUBERTAL ---ADULT

3-VAGINA

-Thickening of the epithelium

Cornification of the superficial layer stratified squamous

Epithelium

-Dulling of the reddish color

-PH ----acidic 3.8-4.2

-Secretion of clear whitish discharge in the months before menarche

-Length ---7.5 cm

Maturation of the genital organs

EXTERNAL GENITALIA

Under the effect of estrogens 1-Labia majora & minora in size & thickness

Rugation & change in color of the labia majora

2-The hymen thickens

3-Clitoris enlarge

4-Vestibular glands begin secretion

Under the effect of adrenal androgens & ovarian androgens growth of pubic & axillary hair

II-BREAST DEVELOPMENTTHELARCHE

• The first visible change of puberty• Thelarche is induced by estrogen• Starts at 10.6 completed in ~ 3 years• Effects of estrogen on the breast 1-Ductal proliferation 2-Site spicific adipose deposition 3- Enlargement of the areola & nipple• Breast development may be unilateral for several

months• Other hormones that play a role in breast development

prolactin, glucocoricoids & insulin• In normal girls the stage of breast development is

consonant with the stage of pubic hair development

TANNER STAGING OF BREAST DEVELOPMENT

Stage 1 : Prepubertal

Stage 2 : Breast bud

Stage 3 :Enlargement of breast &

areola

Stage 4 :Areola &nipple form

a mound atop breast

tissue

Stage 5 :Adult configuration

areola &beast having

smooth contour

TANNER STAGINGOF PUBIC HAIR DEVELOPMENT

Stage 1 : No pubic hairStage 2 : Sparse downy hair on the medial aspect of the labia majora

Stage 3 : Darkening, coarsening & curling of hair which extends upwards & laterally

Stage 4 : Hair of adult consistency limited to the mons

Stage 5 :Hair spreads to medial aspect of thighs

Staging of pubertal development in girls Staging of pubertal development in girls (Tanner)(Tanner)Staging of pubertal development in girls Staging of pubertal development in girls (Tanner)(Tanner)

B 1-5, Pu 1-5, A 1-5. (B2 – first sign of female puberty)

III-GROWTH SPURT

• A global process involving skeletal growth rate

muscle mass

growth of all internal organs• Dependent on mainly on estrogen & growth hormone

however adrenal androgens also play a role • Estrogen has :

direct anabolic effect

growth hormone

insulin like growth factors• The onset of growth spurt antedates thelarche &

pubarche

GROWTH RATE VERSUS AGE IN GIRLS

GROWTH SPURT

Peak Height Velocity

-8.1 cm/year (before puberty 3-6 cm/y)

-by the time PHV is achieved 90% of

adult height has been achieved

-the average in height from the onset

of growth spurt to cessation of growth

25 cm

-girls who start the growth spurt early

will have a shorter adult height

Bone age is more closely correlated with pubertal events than chronological age

Pubertal disordersPubertal disordersPubertal disordersPubertal disorders

Precoccious puberty

B. Delayed puberty

C. Child with ambiguous genitalia (intersex)

ClassificationClassificationClassificationClassification

Central (true), gonadotropin-dependentCentral (true), gonadotropin-dependent

Early stimulation of hypothalamic-pituitary-gonadalEarly stimulation of hypothalamic-pituitary-gonadal

axisaxis..

Periferal, GnRH independent (precocious pseudopubertyPeriferal, GnRH independent (precocious pseudopuberty))

The source of sex steroid may be endogenous or exogenous,The source of sex steroid may be endogenous or exogenous, gonadal or extragonadal, independent of gonadotropins gonadal or extragonadal, independent of gonadotropins

stimulation.stimulation.

True precocious puberty(central, GnRH dependent)

Idiopatic, sporadic or familial (most common)

CNS abnormalitiesCongenital (hydrocephalus, arachnoid cysts, ...)Acquired pathology (posttraumatic, infections, radiation,..Tumors (LH secreting pituitary microadenoma, glioma – may

be associated with neurofibromatosis, hamartoma,..Reversible forms - space occuping or pressure-associated

lesion (abscess, hydrocephalus,...)

Adopted children or children emigrating from developpingcountries

- Improved nutrition, environmental stability and psychosocial support

True precocious puberty(central, gonadotropin-dependent)

Always isosexual!

Bone age is accelerated

FSH and LH elevation after LH-RH is diagnostic test

(LH/FSH > 2)

MRI of CNS is necessary to exclude the neoplasia

Precocious pseudopuberty in girlsPrecocious pseudopuberty in girls(gonadotropin-independent)(gonadotropin-independent)

Precocious pseudopuberty in girlsPrecocious pseudopuberty in girls(gonadotropin-independent)(gonadotropin-independent)

McCune - Albright syndrome McCune - Albright syndrome (polycystic osseous dysplasia, café au lait spots and one or more (polycystic osseous dysplasia, café au lait spots and one or more endocrinopathies – i.e. autonomous ovarian activity, pituitary endocrinopathies – i.e. autonomous ovarian activity, pituitary

gigantism,..)gigantism,..)Abnormal function of LH receptor-mutation in Abnormal function of LH receptor-mutation in αα-subunit of the G-protein-subunit of the G-protein

Ovarian cystsOvarian cystsIsolated follicular cysts with E2 production. Self-limiting with Isolated follicular cysts with E2 production. Self-limiting with

spontaneousspontaneousregression.regression.

Ovarian tumors Ovarian tumors

Acceleration of bone ageAcceleration of bone ageFSH and LH are low after LH-RH stimulationFSH and LH are low after LH-RH stimulationEstrogens are elevatedEstrogens are elevated

Precocious pseudopuberty in boysPrecocious pseudopuberty in boys(gonadotropin-independent)(gonadotropin-independent)

Precocious pseudopuberty in boysPrecocious pseudopuberty in boys(gonadotropin-independent)(gonadotropin-independent)

Congenital adrenal hyperplasia (CAH)Congenital adrenal hyperplasia (CAH)

Undiagnosed or inadequately treated Undiagnosed or inadequately treated simple virilising formsimple virilising form of CAH of CAH caused by 21-hydoxylase deficiency.caused by 21-hydoxylase deficiency.

Neonatal screening?Neonatal screening?TestotoxicosisTestotoxicosis

Activating mutation of LH receptor. AD inheredited.Activating mutation of LH receptor. AD inheredited.TumorsTumors

Gonadal (testosterone-secreting Leydig cell tumor)Gonadal (testosterone-secreting Leydig cell tumor)Adrenal (adenoma, carcinoma)Adrenal (adenoma, carcinoma)

Exogenous androgensExogenous androgens (anabolic steroids – iatrogene, doping) (anabolic steroids – iatrogene, doping)

Acceleration of bone ageAcceleration of bone ageFSH and LH are low after LH-RH stimulationFSH and LH are low after LH-RH stimulationTesticular or adrenal steroids are elevatedTesticular or adrenal steroids are elevated

Heterosexual pubertal development in girls

Clinical findings Hirsutisms, acne, virilisation of external genitalia, amonorhoe or menstrual Hirsutisms, acne, virilisation of external genitalia, amonorhoe or menstrual cycle disturbancecycle disturbance

Elevation of androgensElevation of androgens

- - Adrenal Adrenal (congenital adrenal hyperplasia(congenital adrenal hyperplasia, tumors), tumors)

- Ovarian (polycystic ovary syndrome, tumors)- Ovarian (polycystic ovary syndrome, tumors)- Exogenous (anabolic steroids – doping?)- Exogenous (anabolic steroids – doping?)

Bone age is acceleratedBone age is acceleratedElevation of testosteron or adrenal androgensElevation of testosteron or adrenal androgens

Heterosexual pubertal development in boys

Clinical findingsClinical findingsGynecomastia, hypogenitalism, eunuchoid body proportionsGynecomastia, hypogenitalism, eunuchoid body proportions

Elevation of estrogensAdrenal or testiscular tumors

Administration of

Exogenous estrogensDrugs – amfetamin, canabis, tricyclic antidepresives

Primary hypogonadism or syndromes with androgen insensitivityor testosteron synthesis disorders (related to ambigous genitalia)

Variants of normal development Variants of normal development

Premature thelarché (isolated breast enlargement)

exclude the start of precocious puberty!Premature adrenarché (pubic and axillary hairs)

exclude simple virilising form of CAH!Premature menarché

exclude vaginal bleeding due to trauma of vagine or rare ovarian cyst!

Bone age is not accelerated!

FSH and LH levels after LH-RH are normal

Gonadal and adrenal steroid levels are normal

Pelvic and adrenal ultrasonography is normal

Precoccious puberty-treatmentPrecoccious puberty-treatmentPrecoccious puberty-treatmentPrecoccious puberty-treatment

Gonadotropin-dependent PPIdiopathic

GnRH (LH-RH) analog (triptorelin) to block LH-RH receptor in gonadotroph of pituitary gland

Organic – tumor or cystsSurgery

Gonadotropin independent (pseudopuberty)testicular, ovarian or adrenal tumors –surgeryCAH – substitution of corticosteroidsautonomous steroid secretion-estrogens receptor

antagonists (tamoxifen), steroid synthesis inhibitors (ketoconasole), aromatase inhibitors (testolacton)

Delayed puberty - definitionDelayed puberty - definitionDelayed puberty - definitionDelayed puberty - definition

Initial physical changes of puberty are not presentby age 13 years in girls

(or primary amenorhoe at 15.5-16y)

by age 14 years in boys

Pubertal development is inappropriate

the interval between first signs of puberty and menarche in girls/completition genital growth in boys is > 5 years

GnRH or gonadotropin dependent GnRH or gonadotropin dependent II..

GnRH or gonadotropin dependent GnRH or gonadotropin dependentII..

Idiopathic sporadic or familial (associated with constitutional growth delay)

Chronic diseases with bone age delay and growth retardation due to different pathophysical mechanismes (malnutrition, anemia, acidosis, hypoxia,...anorexia nervosa, cystic fibrosis, chronic renal insuficiency,..)

Psychosocial deprivation

GnRH or gonadotropin dependentGnRH or gonadotropin dependentIIII . .

GnRH or gonadotropin dependentGnRH or gonadotropin dependentIIII . .

Hypogonadotropic hypogonadism

Gonadotropin deficiencyLH only (fertile eunuch syndrome)FSH and LH - Congenital (genetic, syndromes) - Kallman syndrome –mutation of KAL

gene, mutation of DAX1 gene, Prader-Willi syndrome ,...

- Acquired - cranial irradiation, hemosiderosis, granulomtous disease

Associated with others pituitary hormones deficiencies - Congenital – empty sella syndrome, genetic-transcription factors,

disruption of pituitary stalk (breech delivery),... - Acquired – tumors, inflamation, irradiation, trauma....

Gonadotropin independentGonadotropin independent(hypergonadotrophic hypogonadism)(hypergonadotrophic hypogonadism)

GirlsCongenitalBillateral ovarian torsion

Chromosomal abnormalities (Turner syndrome, pure gonadal dysgenesis, Noonan syndrome…)

AcquiredAutoimunne inflamation (APS)

Radio or chemotherapy

Traumatic

Surgery

GirlsCongenitalBillateral ovarian torsion

Chromosomal abnormalities (Turner syndrome, pure gonadal dysgenesis, Noonan syndrome…)

AcquiredAutoimunne inflamation (APS)

Radio or chemotherapy

Traumatic

Surgery

Turner syndrome

Karyotype 45,X (45,X/46,XX, structural abnormalities of X chromosome)Short stature (final height 144-146 cm)Gonadal dysgenesisSkletal abnormalitiesCardiac and kidney malformationDysmorfic face

No mental defectImpairment of cognitive function)

Therapy: growth hormone, sex hormone substitution

Turner syndromeTurner syndrome

H. Tuner, 1938

Congenital adrenal hyperplasiaCongenital adrenal hyperplasiaCongenital adrenal hyperplasiaCongenital adrenal hyperplasia

Autosomal recessive disorder (1: 500 – 4000)

The block (complete or partial) in the adrenal production of corticosteroids (and mineralocorticoids) mostly due to deficiency of 21 hydroxylase Adrenal androgenes (17-OHP, A-dion) elevated but they cannot block ACTH

Adrenal glands are often enlarged

Clinical symptomatology

Salt wasting form (life threatenig disease) (SW)hyperkalemia, hyponatremia (dehydratation, shock)Girls: virilisation of genitalia, heterosexual precoccious

pubertyBoys: precoccious puberty

Simple virilising form (without metabolic disorder)(SV) Simple virilising form – partial enzymatic block – late onset (LO

SV)