1. Puberty Disorders Dr. Sarar Mohamed
MBBS, FRCPCH(UK), MRCP (UK), MRCPCH(UK), DCH(Ire), CCST(Ire), CPT(Ire), MD
Consultant Pediatric Endocrinologist & Metabolic Physician
Assistant Professor of Pediatrics
King Saud University

3. Definition of puberty What is puberty?
It is the transitional period of development during which an individual mature from childhood to physical, psychosocial, sexual & reproductive maturity

4. FERTILITY AND FINAL HEIGHT
PUBERTY
Gonadal maturation with acquisition of secondary sexual characteristics and associated growth spurt
FERTILITY AND FINAL HEIGHT

5. Endocrine Regulation Negative feedback: Insert fig. 20.9 Female: Male:
Inhibits GnRH from hypothalamus.
Inhibits anterior pituitary response to GnRH.
Inhibin secretion inhibits anterior pituitary release of FSH.
Female:
Estrogen and progesterone.
Male:
Testosterone.
Insert fig. 20.9

6. Onset of puberty The age of onset of puberty -Females ----8-13
Average age of onset:
GIRLS 10 to 11 years (range 8 to 13 years)
BOYS 11 to 12 years (range 9 to 14 years)
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

7. Duration of puberty The time from onset to completion of puberty
Average Y
Range Y

8. Factors That Affect Puberty
Genetics
Race/Ethnicity
Previous nutrition
Subcutaneous fat
Birth weight
Obesity
Increased leptin and estrogen production
Insulin stimulation of ovaries & uterus

9. Initial signs of puberty
GIRLS – Breast Development
BOYS – Testicular Enlargement
Volume > 3.0 cm³
Length > 2.5 cm

10. Growth in puberty
Insert fig

11. Evaluation of disorder of puberty
CLINICAL ASSESSMENT
History
Behavioural changes
Pubertal staging
Skin examination
Height measurement / Growth velocity
Bone age assessment
Hormone study if needed

12. Assessment of Puberty History Parents
onset of puberty
Menarche
Male Age of first shaving regularly
Parental heights (MPH)
prenatal and perinatal (exposure to exogenous sex steroids in intrauterine period; birth weight, perinatal asphyxia)
Concomitant illnesses, postnatal exposure to sex steroids
time of first sign of puberty
Thelarche (galactorrhea)
Adrenarche/pubarche (body odor, axillary & pubic hair, acne)
Gonadarche

13. History Important to include:
Past medical history (history of brain tumor, radiation, chemotherapy, known genetic disorder, chronic disease affecting growth)
Eating habits
Any evidence of disordered eating
Activity level
Is exercise excessive or is this an athlete with a high level of training
Growth history
Previous growth chart can be extremely helpful

14. History Review of Systems
CNS: visual changes/visual field abnormalities, headaches, anosmia
Cardiac: congenital anomaly
Respiratory: asthma
Renal:
GI: diarrhea, blood in stools

15. Physical Examination Examination of Growth
Height
Weight
Pubertal Assessment (Tanner staging)
Axillary hair
Pubic hair & staging
Breast development & staging
Genital development & staging
skin, hair, thyroid
Neurological assessment

16. Growth charts

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

18. Staging of pubertal development in boys
(Tanner)
G1-5, Pu 1-5, A 1-5, testicular volum > 4 ml – first sign of male puberty

20. Diagnostic evaluation
Laboratory
gonadotropins (FSH, LH) basal and peak after LHRH stimulation (prepubertal LH/FSH<1)
estradiol
testosteron (basal value and value after LH stimulation)
adrenal androgens (17-OHP, A-dion,...) and ACTH
bone age
Pelvic US (ovarian and uterine size)
CT or MRI of adrenals, Brain
Vaginoscopy
Genetic – karyotype, DNA analysis

21. Bone age
2 yrs 6 m.
10 yrs
12 yrs

22. Summary:Variants of puberty
Premature thelarché
exclude the start of precocious puberty!
Premature adrenarché
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
Reassurance & f/u

23. PRECOCIOUS PUBERTY

25. Landmark Case of Precocious Puberty
5 year old Lina Medina of Peru
Menses onset age 8 months
Breast development age 4
Advanced bone maturation age 5
Was evaluated for abdominal tumor due to increasing abdominal size at age 5
On 5/14/1939 gave birth to a 2.9 kg baby boy

26. Definition of Precocious Puberty
ONSET OF PUBERTY BEFORE
-Females years
-Males years
Lawson Wilkins Pediatric Endocrine Society recommended 7 for white girls/ 6 for back
The prevalence
is estimated to be between one in 5,000 to 10,000 children annually in the United States.

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

28. True precocious puberty (central, GnRH dependent)
Idiopatic, constitional sporadic or familial (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

29. True precocious puberty (central, gonadotropin-dependent)
Bone age is accelerated
FSH and LH elevation after LH-RH is diagnostic test
(LH/FSH > 2)
LH  LH/FSH ratio < 1  Prepubertal
 LH  LH/FSH ratio > 1  Pubertal
MRI of CNS is necessary to exclude the neoplasia

32. Treatment of true precocious puberty
Purpose of treatment
To prevent psychosocial distress
To improve final height outcome
Treat the underlying cause
GnRH analogue
Lupron depot ped, leuprolide acetate
Desensitizes the pituitary
Blocks LH and FSH secretion
Prevents continued sexual development for the duration of the treatment
Growth may almost stop while on therapy
± addition of growth hormone remains controversy

33. Precocious pseudopuberty in girls (gonadotropin-independent)
McCune - Albright syndrome
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)
McCune Albright Syndrome
Acceleration of bone age
FSH and LH are low after LH-RH stimulation
Testicular or adrenal steroids are elevated

36. 21-OH CAH: DeHydroEpiAndrosterone Desmolase Cholesterol Desmolase
17 a OH
Pregnenlolone
17 OH Pregnenlolone
DeHydroEpiAndrosterone
3 B HSD
3 B HSD
3 B HSD
Androstendione
17 a OH
Progesterone
17 OH Progesterone
Testosterone
Estradiol
21 OH
21 OH
90 % of CAH
50-70 % salt wasting
Female =
ambiguous, Hyperpig
Male =
virlization
Desoxycorticosterone
11 Desoxycortisol
11 OH
Depend on the degree
11 OH
Treatment
Hydrocortisone
Fludrocortisone
Corticosterone
Cortisol
18 OH
18 OH Corticosterone
Aldosterone

37. Non classic CAH .

38. Precoccious puberty-treatment
Gonadotropin-dependent PP
Idiopathic
GnRH (LH-RH) analog to block LH-RH receptor of pituitary gland
Organic – tumor or cysts
Surgery
Gonadotropin independent (pseudopuberty)
-treat underline cause
testicular, ovarian or adrenal tumors –surgery
CAH – substitution of corticosteroids

39. Delayed puberty .

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

41. Types of delayed puberty
Gonadotropin dependent
Hypogonadotropic hypogonadism
Low LH/FSH
Central, chronic disease
Gonadotropin independent
Hypergonadotropic hypogonadism
High LH/FSH
Peripheral cause (gonads)

42. GnRH or gonadotropin dependent
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

43. GnRH or gonadotropin dependent
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....

44. Kallmann Syndrome

45. Kallman Syndrome A syndrome of isolated gonadotropin deficiency
1/10,000 males, 1/50,000 females
KAL-1 gene
Present with ANOSMIA or HYPOSMIA
Can also be associated with harelip, cleft palate, and congenital deafness

46. Syndromes Associated with Pubertal Delay
Prader-Willi syndrome
Laurence Moon syndrome
Septo-optic dysplasia
Bardet-Biedl syndrome

47. Gonadotropin independent (hypergonadotrophic)
Boys
Congenital
Anorchia
Chromosomal abnormalities (Klinefelter syndrome, Noonan syndrome…)
Disorders in androgen synthesis or action
Acquired
Autoimunne inflamation (APS)
Radio or chemotherapy
Traumatic
Surgery

48. Klinefelter’s Syndrome
45 XXY most common (2/3),
Tall in childhood, with euchanoid body habitus
More female type fat distribution
puberty is delayed
Small testicles & gynecomastia
90-100% are infertile

49. Klinefelter's syndrome
A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter's syndrome). The karyotype was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low normal. Note normal virilization with long legs and gynecomastia (B, C). The testes were small and firm and measured 1.8 × 0.9 cm. Testicular biopsy revealed a severe degree of hyalinization of the seminiferous tubules and clumping of Leydig cells. D, A 48-year-old male with 47,XXY Klinefelter's syndrome with severe leg varicosities.
(Williams Textbook of Endocrinology, 10th ed, 2003)

50. 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

51. Turner syndrome Karyotype 45,X (60%)
(45,X/46,XX, structural abnormalities of X chromosome)
Incidence 1/2000
Short stature (final height cm)/
web neck
Gonadal dysgenesis - streak gonad
Autoimmune : Hashimoto’s thyroditis, Addison’s ds
Mild insulin resistance &
Essential hypertension
hearing loss /No mental defect
Impairment of cognitive function : mathematical ability↓
Visual–motor coordination, spatial-temporal processing↓
Y chromosome predisposed to gonadoblastoma
H. Turner, 1938

52. Investigation of Delayed Puberty
Investigations depend on clinical presentation, but may include
Bone age
Hormone levels (IGF-1, FSH, LH, estradiol, testosterone, DHEAS, prolactin, TSH)
Karyotype
Hormone stimulation tests
GnRH stimulation test
GH stimulation test
Imaging
MRI brain if gonadotropins low & no obvious cause of hypogonadotropic hypogonadism
US or MRI pelvis

53. Treatment of delayed Puberty
Treat underline cause
Time of therapy initiation may vary and individualized
Testosterone supplementation
Estrogen for girls