Puberty and its disorders

1. Puberty and its disorders

2. Puberty A stage of human development when sexual maturation and growth are completed and result in ability to reproduce. Accelerated somatic growth Maturation of primary sexual characteristics (gonads and genitals) Appearance of secondary sexual characteristics (pubic and axillary hair, female breast development, male voice changes,...) Menstruation and spermatogenesis begin

3. Puberty � hormonal changes Hormonal changes procede physical changes Increased stimulation of hypothalamo-pituitary-gonadal axis gradual activation of the GnRH (LHRH) increases frequency and amplitude of LH pulses. gonadotropins stimulate secretion of sexual steroids (estrogenes and androgenes) extragonadal hormonal changes (elevation of IGF-I, and adrenal steroids)

4. Extrahypothalamic region - neurotransmiters, stress, nutrition serotonin, dopamin, GABA norepinefrin, neuropeptid Y, glutamic acid Ventromedial region of hypothalamus LH-RH (gonadoliberin) Adenohypophysis LH FSH Gonads Inhibin Estrogens Estrogens Androgens Androgens

5. Staging of pubertal development(Tanner) Pubertal development is classified according to the Tanner standard � 5 different stages Girls: breast (B1-5), pubic hair (Pu1-5), axillary hair (A1-5), menarche Boys: testicular volume > 4 ml (Te), penis enlargement (G1-5), pubic hair (Pu1-5), axillary hair (A1-5), spermarche Monitoring of the pubertal growth acceleration growth velocity is 2-3 times greater than prepubertal sexual dimorfism in pubertal growth

8. Normal pubertal development

9. Diagnostic evaluation History pubertal history of other family members prenatal and perinatal (exposure to exogenous sex steroids in intrauterine period; birth weight, lenght, mechanism of delivery, perinatal pathology - resuscitation,..) concomitant illnesses, postnatal exposure to sex steroids time of first sign of puberty Physical examination - auxologic parameters (height, weight, arm span, upper/lower segment ratio,...) skin, hair, thyreoid, neurologic findings staging of pubertal signs, inspection of external genitalia

10. Growth charts

11. 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 Skeletal maturity (bone age) Pelvic sonography (ovarian and uterine size) CT or MRI of adrenals, CNS Vaginoscopy and vaginal cytology Genetic � karyotype, DNA analysis

12. X-ray film of the left hand and wrist Radius Ulna Small bones (RUS) (X-ray of knee � important examination for final height prediction) Different methods of bone age evaluation � radiographic atlas of skeletal development Greulich Pyle Tanner-Whitehouse II Tanner-Whitehouse III Semp� Bone age (Assessment of biologic maturation)

13. Bone age

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

15. Precocious puberty

16. Precocious puberty Traditional limits for PP are the age of 8 years in girls the age of 9 years in boys

17. Classification 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.

18. General terminology Complete PP Incomplete PP (isolated pubertal sign) Isosexual precocity early pubertal development appropriate for sex Contrasexual (heterosexual) precocity inappropriate for sex or appropriate for opposite sex

19. 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

20. 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

21. Precocious pseudopuberty in girls(gonadotropin-independent) McCune - Albright syndrome (polycystic osseous dysplasia, caf� au lait spots and one or more endocrinopathies � i.e. autonomous ovarian activity, pituitary gigantism,..) Abnormal function of LH receptor-mutation in a-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

22. 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

23. 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

24. 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)

25. Variants of normal development Premature thelarch� (isolated breast enlargement) exclude the start of precocious puberty! Premature adrenarch� (pubic and axillary hairs) exclude simple virilising form of CAH! Premature menarch� 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

26. Gynecomastia Breast enlargement in boys Physiologic (Testosteron is converting to estrogenes in liver. Increased sensitivity of E receptors in breast to slighly elevated E level) in 40 � 50% boys at the start of puberty unilateral or bilateral Pathologic Unilateral � breast tumor (very rare) Billateral elevated prolactin (PRL) � prolactinoma or subclinical hypothyreosis with elevation of TSH elevated estrogen/testosteron (47,XXY)

27. 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)

28. Delayed puberty

29. 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

30. 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

31. GnRH or gonadotropin dependentII. 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....

32. Gonadotropin independent(hypergonadotrophic) Boys Congenital Anorchia Chromosomal abnormalities (Klinefelter syndrome, Noonan syndrome�) Acquired Autoimunne inflamation (APS) Radio or chemotherapy Traumatic Surgery

33. 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

34. Turner syndrome 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

35. 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)