1. NORMAL PUBERTAL DEVELOPMENT

2. NORMAL PUBERTAL DEVELOPMENT
WHAT IS PUBERTY?
-It is the transitional period of development during which an individual mature from childhood to sexual & reproductive maturity

3. 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

4. NORMAL PUBERTAL DEVELOPMENT
-WHAT IS THE AGE OF ONSET OF PUBERTY?
-Females
-Males
-WHAT IS THE USUAL SEQUANCE OF SOMATIC CHANGES OF PUBERTY?
1-Beast development (mean 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

5. AGES OF GIRLS AT VARIOUS STAGES OF PUBERTAL DEVELOPMENT

6. 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 

7. NORMAL PUBERTAL DEVELOPMENT
-WHAT IS THE TIME FROM ONSET TO COMPLETION OF PUBERTY?
Average Y
Range Y

8. 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

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

10. 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

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

12. 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

13. 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

14. 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

15. 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 Y
-----Maximum at 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

16. 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

17. 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

18. 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

19. PHYSICAL EVENTS OF PUBERTY

20. I-Maturation of the genital organs
PREPUBERTAL
1-UTERUS
-Ratio of corpus : cx  1:2
-Tubular shape
-Length cm
-Volume Endometrium  single layer of cuboidal cells
2-OVARIES
-Volume ml
-Non functional
PUBERTAL ---ADULT
1-UTERUS
-Ratio of corpus :cx 2:1
-Pear shape
-Length
-Volume Endometrium  
thickness
2-OVARIES
-Volume ml
-Multicystic

21. Maturation of the genital organs
PREPUBERTAL
3-VAGINA
-Reddish in color
-Thin atrophic columnar epithelium
PH ---neutral
Length—
PUBERTAL ---ADULT
3-VAGINA
-Thickening of the epithelium
Cornification of the superficial layer  stratified squamous
Epithelium
-Dulling of the reddish color
-PH ----acidic
-Secretion of clear whitish discharge  in the months before menarche
-Length cm

22. 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

23. II-BREAST DEVELOPMENT THELARCHE
The first visible change of puberty
Thelarche is induced by estrogen
Starts at 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

24. 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

25. 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

26. Staging of pubertal development in girls
(Tanner)
B 1-5, Pu 1-5, A 1-5. (B2 – first sign of female puberty)

27. 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

28. GROWTH RATE VERSUS AGE IN GIRLS

29. 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

30. Pubertal disorders Precoccious puberty B. Delayed puberty
C. Child with ambiguous genitalia (intersex)

31. 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.

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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)

38. 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

39. 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)

40. Delayed puberty - definition
Initial physical changes of puberty are not present
by age 13 years in girls
(or primary amenorhoe at y)
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

41. 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

42. 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....

43. 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

44. Turner syndrome Turner syndrome H. Tuner, 1938
Karyotype 45,X (45,X/46,XX, structural abnormalities of X chromosome)
Short stature (final height 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

45. 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)