Disorders of Early Sexual Maturation

1. Disorders of Early Sexual Maturation Assunta Albanese St George’s Hospital London

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

3. Normal Puberty GIRLSBOYS - Thelarche - Testarche - Pubarche - Pubarche - Growth spurt - Growth spurt - Menarche - Spermarche

4. PUBERTY Average age of onset: • 11.4 years in girls • 12.0 years in boys First signs of pubertal maturation: • breast budding in girls • increase in testicular volume in boys

5. Tanner’s Staging of Puberty in Girls

6. Tanner’s Staging of Puberty in Boys

8. "Consonance" of Puberty • Close relationship between secondary sexual characteristics and pubertal growth spurt • In girls the pubertal growth spurt occurs early in puberty (B2-3) • In boys the pubertal growth spurt occurs late in puberty (G3-4 10 ml testicular volume)

10. Classification of Premature Sexual Maturation • Gonadotrophin-Dependent (True Precocious Puberty) • Gonadotrophin-Independent (Pseudo Precocious Puberty) • Variants of Precocious Sexual Maturation (Premature thelarche / adrenarche; isolated menarche)

11. Gonadotrophin-Dependent Precocious Puberty Onset of puberty before: • 8 yrs in girls • 9 yrs in boys Early Puberty Onset of puberty between: • 8 - 9 yrs in girls • 9 - 10 yrs in boys Primary Hypothyroidism

12. Central Precocious Puberty • 1 in 5000 children; F>M (x5-6) • Idiopathic • Secondary to CNS abnormalities • Congenital anomalies (hydrocephalus) • Tumours • Acquired (infections, surgery, irradiation)

13. Central Precocious Puberty Sexual Dimorphism • Usually idiopathic in girls (~90%) • Almost always secondary to lesions in CNS in boys

14. Central Precocious/Early Puberty • Pulsatile gonadotrophin secretion, especially overnight • High LH : FSH ratio • Gonadal activation with sex steroid production • Development of secondary sexual characteristics • Normal "Consonance" • Bone age acceleration • Final height impairment

15. Patterns of LH Secretion During Pubertal Development

16. Central Precocious/Early Puberty • Pulsatile gonadotrophin secretion, especially overnight • High LH : FSH ratio • Gonadal activation with sex steroid production • Development of secondary sexual characteristics • Normal "Consonance" • Bone age acceleration • Final height impairment

17. LH, FSH and E2 and Pubertal Stage in Girls

18. Central Precocious/Early Puberty • Pulsatile gonadotrophin secretion, especially overnight • High LH : FSH ratio • Gonadal activation with sex steroid production • Development of secondary sexual characteristics • Normal "Consonance" • Bone age acceleration • Final height impairment

21. Primary Hypothyroidism • Loss of "Consonance" between sexual maturation and growth spurt • Absence of pubertal growth spurt • Isolated breast development in girls • Isolated testicular enlargement, with inadequate virilization

22. Variants of Precocious Sexual Maturation • Isolated premature thelarche and thelarche variants • Isolated menarche • Premature adrenarche

23. Isolated Premature Thelarche • Isolated cyclic breast enlargement • Absence of other signs of puberty • Absence of behavioural problems • Normal growth and bone maturation • Predominant FSH pulsatility • Development of follicular ovarian cysts

24. Sexual Spectrum mixedcharacteristics Isolated thelarche Precocious puberty

25. Spectrum Of Sexual Development Between Isolated Premature Thelarche and CPP “Unsustained central precocious puberty” “Intermediate sexual precocity” “Slowly progressive variant of sexual precocious puberty” “Thelarche variant” “Exaggerated thelarche” INTERMEDIATE CONDITIONS

26. Variants of Precocious Sexual Maturation • Isolated premature thelarche and thelarche variants • Isolated menarche • Premature adrenarche

27. Isolated Menarche • Absence of other signs of sexual maturation • Menses can occur regularly for several yrs and then stop • Puberty usually occurs at a normal time • All causes of premature oestrogen secretion and local causes of vaginal bleeding must be excluded • Due to ? increased sensitivity of endometrium to oestrogens • Secondary to oestrogen production from a follicular cyst

28. Variants of Precocious Sexual Maturation • Isolated premature thelarche and thelarche variants • Isolated menarche • Premature adrenarche

29. Premature Adrenarche (Pubarche) • Usually begins at around 6-8 years of age • Early appearance of pubic hair, with or without axillary hair • Puberty usually occurs at a normal time • Slight growth spurt and advance in bone maturation • Final height prognosis is not compromised

30. Premature Adrenarche • Increased adrenal production of sex hormones • Links with PCOS and hyperinsulinism in older age Clitoral virilization in girls and phallic enlargement in boys together with excessive bone age maturation should suggest excessive production of sex hormones due to CAH or an adrenal tumour

31. Gonadotrophin-independent • Sex steroid production from gonads or adrenal gland or exogenous source • Suppressed LH and FSH levels • Secondary sexual characteristics or virilization without testicular enlargement in boy • Growth acceleration • Bone age acceleration with final height impairment

32. Gonadotrophin-independent • Adrenal disorders Tumours secreting sex steroids Congenital adrenal hyperplasia • Gonadal disorders Ovarian cyst/tumours secreting sex steroids Leydig cell tumour • Exogenous sex steroids • McCune-Albright Syndrome • Testotoxicosis

34. McCune - Albright Syndrome • Fibrous dysplasia of skull and long bone • "Cafe-au lait" patches with serrated edges • Autonomous endocrine overactivity : • Precocious puberty • Hyperthyroidism • Hypercortisolism • Pituitary adenomas secreting GH/ PRL • Hyperparathyroidism

36. McCune - Albright Syndrome • PPP most common presenting feature: • autonomous, gonadotropin-independent ovarian function • large ovarian cysts E2 secretion • Acute breast enlargement • sudden onset of vaginal bleeding from cyst resolution and E2 • Natural history sporadic and unpredictable • Concerns: Continued 2o sexual development, freq. menstrual bleeds, GV and early fusion of epiphyses

37. McCune - Albright Syndrome • Gene mutation for the α-subunit of the G protein, which stimulate cAMP formation • Activation of receptors that operate with a cAMP-dependent mechanism • The somatic mutationoccurs early in embriogenesis

38. Testotoxicosis • Occurs in boys, Familial, Autosomic Dominant • Normal "Consonance" between sexual maturation and growth spurt • Extreme degree of virilization compared to the testicular enlargement • Prepubertal values of FSH and LH • Failure to respond to GnRH analogue treatment • Due to a mutation of LH receptor with constant activation of the G protein even without ligand

39. Investigation of Premature Sexual Maturation • The purpose of investigating precocious puberty is to distinguish between: • conditions that are benign (isolated thelarche or premature adrenarche) and • those that require treatment (adrenal/gonadal adrenal tumours, CAH, central precocious puberty)

40. Evaluation of Premature Sexual Maturation CLINICAL ASSESSMENT • History • Behavioural changes • Pubertal staging • Skin examination • Height measurement / Growth velocity • Bone age assessment

41. Investigation in Suspected CPP • Basal gonadotrophins • Basal oestradiol in girls and testosterone • GnRH stimulation test • (Spontaneous overnight LH profile) • TFT • Pelvic USS in girls • Neuroradiological imaging

42. Gn-RH Stimulation Test LH and FSH response to Gn-RH: • LH predominance or • a peak LH to FSH ratio of more than 0.66 or • a LH peak more than 5 IU/L consistent with central activation of puberty

43. Diagnostic Value of Pelvic USS • Depend on experience of examiner! • Size and shape of uterus and ovarian volume and appearance are a indicator of the degree of pubertal development

44. Main Findings on Pelvic USS • Ovarian enlargement with a volume more than 2 ml • Larger bilateral ovarian cysts (> 9 mls) • Uterine length greater than 3.5 cm • Fundus to cervix ratio of more than 1 • Endometrium thickness ARE INDICATIVE OF EARLY PUBERTY

45. Investigations in Isolated Premature Thelarche In girls with breast development only, without acceleration of growth or bone age advancement: • Regular clinical follow-up to monitor growth velocity • Investigation required only if precocious puberty is suspected

46. Investigations in Isolated Adrenarche In children with early pubic/axillary hair and mild growth acceleration and bone age advancement: • Clinical monitoring • 24 hour urine steroid profile • Adrenal androgens and 17-OH P

47. Investigations in Adrenarche • Extensive andprogressive virilization, as well as young age, requires investigation • Urinary steroid profile (CAH/adrenal tumour) • Basal A4, DHEA-S, 17-OH-P, Testosterone • ACTH stimulation test (CAH) • Dexamethasone suppression test (adrenal tumour) • Adrenal imaging (adrenal tumour)

48. Why treat precocious puberty?

49. Concerns Raised by Precocious Puberty • Possibly sinister underlying cause • Psychologically unacceptable embarrassment of inappropriate early sexual changes, excessively tall stature, early onset of periods in girls, vulnerability of young girls • Long term sequelae: short stature

50. Why treat precocious puberty? • To prevent psychosocial distress • To improve final height outcome