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) F 2- Pubic hair is the first visible physical sign of puberty T 3- The maximum growth velocity occurs ar 12 years T 4- The age of menarche has decreased over the last 3-4 decades due to improved nutrition, general health & life style F 5-Menarche marks the attainment of reproductive maturity

AGES OF GIRLS AT VARIOUS STAGES 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  T 3- At the onset of puberty GnRH/ LH pulses occur during sleep F 4-With further maturation pulse frequency & amplitude decrease

PLASMA LH CONC MEASURED EVERY 20 MIN FOR 24 HRS 1-PREPUBERTAL 2-EARLY PUBERTAL 3-LATE PUBERTAL

INITIATION OF PUBERTY FACTORS 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  T 5-Frisch theory relates a critical body fat & body weight to the initiation of puberty

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 Adrenarche & gonadarche F 1-Adrenarche & gonadarche are dependent on each other T 2-Adrenarche means increased adrenal androgen secretion leading to the development of pubic hair, adult type body odor, acne & oily skin & hair

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 T 3- Reactivation of the HPO axis results in increased gonadotropins pulses & follicular development with significant estrogen production

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 F 4-Ovulatory cycles occur during the first 6-18 months after menarche

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 F 5- Ovulatory menstrual cycles requires the development of positive feed back on the hypothalamus resulting in decreased LH & FSH secretion

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 DEVELOPMENT THELARCHE 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 STAGING OF PUBIC HAIR DEVELOPMENT Stage 1 : No pubic hair Stage 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 (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 disorders Precoccious puberty B. Delayed puberty C. Child with ambiguous genitalia (intersex)

Classification Early stimulation of hypothalamic-pituitary-gonadal Central (true), gonadotropin-dependent Early stimulation of hypothalamic-pituitary-gonadal axis. Periferal, GnRH independent (precocious pseudopuberty) The source of sex steroid may be endogenous or exogenous, gonadal or extragonadal, independent of gonadotropins stimulation.

True precocious puberty (central, GnRH dependent) Idiopatic, sporadic or familial (most common) CNS abnormalities Congenital (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 developping countries - 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 girls (gonadotropin-independent) McCune - Albright syndrome (polycystic osseous dysplasia, café au lait spots and one or more endocrinopathies – i.e. autonomous ovarian activity, pituitary gigantism,..) Abnormal function of LH receptor-mutation in α-subunit of the G-protein Ovarian cysts Isolated follicular cysts with E2 production. Self-limiting with spontaneous regression. Ovarian tumors Acceleration of bone age FSH and LH are low after LH-RH stimulation Estrogens are elevated

Precocious pseudopuberty in boys (gonadotropin-independent) Congenital adrenal hyperplasia (CAH) Undiagnosed or inadequately treated simple virilising form of CAH caused by 21-hydoxylase deficiency. Neonatal screening? Testotoxicosis Activating mutation of LH receptor. AD inheredited. Tumors Gonadal (testosterone-secreting Leydig cell tumor) Adrenal (adenoma, carcinoma) Exogenous androgens (anabolic steroids – iatrogene, doping) Acceleration of bone age FSH and LH are low after LH-RH stimulation Testicular or adrenal steroids are elevated

Heterosexual pubertal development in girls Clinical findings Hirsutisms, acne, virilisation of external genitalia, amonorhoe or menstrual cycle disturbance Elevation of androgens - Adrenal (congenital adrenal hyperplasia, tumors) - Ovarian (polycystic ovary syndrome, tumors) - Exogenous (anabolic steroids – doping?) Bone age is accelerated Elevation of testosteron or adrenal androgens

Heterosexual pubertal development in boys Clinical findings Gynecomastia, hypogenitalism, eunuchoid body proportions Elevation of estrogens Adrenal or testiscular tumors Administration of Exogenous estrogens Drugs – amfetamin, canabis, tricyclic antidepresives Primary hypogonadism or syndromes with androgen insensitivity or testosteron synthesis disorders (related to ambigous genitalia)

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-treatment Gonadotropin-dependent PP Idiopathic GnRH (LH-RH) analog (triptorelin) to block LH-RH receptor in gonadotroph of pituitary gland Organic – tumor or cysts Surgery Gonadotropin independent (pseudopuberty) testicular, ovarian or adrenal tumors –surgery CAH – substitution of corticosteroids autonomous steroid secretion-estrogens receptor antagonists (tamoxifen), steroid synthesis inhibitors (ketoconasole), aromatase inhibitors (testolacton)

Delayed puberty - definition Initial physical changes of puberty are not present by 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 I. 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 dependent II. Hypogonadotropic hypogonadism Gonadotropin deficiency LH 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 independent (hypergonadotrophic hypogonadism) Girls Congenital Billateral ovarian torsion Chromosomal abnormalities (Turner syndrome, pure gonadal dysgenesis, Noonan syndrome…) Acquired Autoimunne inflamation (APS) Radio or chemotherapy Traumatic Surgery

Turner syndrome Turner syndrome H. Tuner, 1938 Karyotype 45,X (45,X/46,XX, structural abnormalities of X chromosome) Short stature (final height 144-146 cm) Gonadal dysgenesis Skletal abnormalities Cardiac and kidney malformation Dysmorfic face No mental defect Impairment of cognitive function) Therapy: growth hormone, sex hormone substitution H. Tuner, 1938

Congenital 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 puberty Boys: precoccious puberty Simple virilising form (without metabolic disorder)(SV) Simple virilising form – partial enzymatic block – late onset (LO SV)