Secondary amenorrhoea in adolescence

1. Secondary amenorrhoea in adolescence Dr. KL Ng United Christian Hospital

2. Case history • 13 year-old girl • Admitted with secondary amenorrhoea in Jan/2004

3. History of Present Illness • Features of anorexia nervosa since Feb 03 • Distorted body image • Dietary manipulation • Intentional restriction of dietary • Pre-occupied by food • Excessive exercise • Purging • Physical symptoms • Fatigue easily • Poor exercise tolerance • Cold extremities • Constipation

4. Secondary Amenorrhea • Menarche at the age of 12 • Regular cycle of 28 – 30 days • Last 6-7 days • Normal flow, no clot / flooding • No menses since July 2003

5. Puberty started at 8yrs • Consonant • growth spurt

6. Insignificant past medical history / drug use • Normal development • Excessive weight loss • Pre-morbid weight : 53 kg (March 03) • Weight on admission : 30.3 kg • Excessive exercise • Basketball, badminton, rope-jumping, hula loops • 3-4 hr daily

7. No sexual history • No symptoms of androgen excess • hirsuitism • Acne • Stressful • Self-demanding in academic result and appearance • Felt depressed if goal not met

8. Family History • Paternal height : 158 cm Maternal height : 150 cm • Mother’s age of menarche : 13 yrs • No family history of • Thyroid disease • AN • Father got DM

9. Physical Examination • Stable vital signs • Wt 30.3 kg (~ 1 kg below 3rd percentile) Ht 149 cm ( 25th percentile) • BMI : 13.64 • % of body fat: 7.09%

10. Thinning of subcutaneous fat • Loss of muscle bulk • Loose skinfolds • Lanugos hair over the back • Normal systemic review

11. Pubertal stage • B4, P3, A3 • No signs of androgen excess • Thryoid status : euthyroid • No signs of gonadal dysgenesis • No anosmia • No visual defect

12. Laboratory / Imaging ResInvestigations • CBC } L/RFT } all normal Bone profile } • Thyroid function test • Prolactin 5.9 (1.4 – 24.2)

13. LHRH stimulation test • Ultrasound abdomen • Uterus normal configuration • Normal ovaries with no adnexal masses

14. Provera withdrawal test • No menses on withdrawal of drug Diagnosis: Anorexia nervosa (DSM-IV diagnostic criteria)

17. Normal menstrual physiology • Menstrual cycle is defined at 3 levels: • Endometrial response (proliferative & secretory phases) • Ovarian response (follicular & luteal phases) • Pituitary responses (FSH & LH levels)

18. Follicular phase • Corpus luteum involution occurs with resulting low levels of estradiol and progesterone, in turn, increases FSH & LH • FSH stimulates maturation of ovarian follicles, one follicle predominating • Under the influence of estrogen, “proliferative phase” of endometrium occurs • In mid- and late-follicular phase, FSH begins to fall

19. Ovulation • Preovulatory estradiol surge leads to a midcycle LH surge • A mature follicle releases an oocyte and becomes corpus luteum

20. Luteal phase • Corpus luteum produces large amount of progesterone and increased levels of estrogen, lead to falling levels of LH & FSH • Progesterone stimulates endometrial differentiation into “secretory” endometrium • Corpus luteum involutes with decreased levels of estrogen & progesterone. Sloughing of endometrium

21. Feedback systems • Negative feedback: estradiol and progesterone suppress LH and FSH • Positive feedback: rising estradiol >200pg/ml during preovulation leads to positive feedback surge of LH, causing ovulation

22. Amenorrhoea • Absence of menstrual bleeding • First menarchal year, 95th percentile for cycle length is 90 days • Primary amenorrhoea, Secondary amenorrhoea

23. Primary Amenorrhoa • Absence of menses by age 14 yrs + absence of secondary sexual characteristics • Absence of menses by age 16 yrs + normal secondary sexual characteristics • Developmental abnormalities of ovaries, genital tracts or ext. genitalia • Gonadal dysgenesis (50%) • Associated with delayed puberty

24. Secondary Amenorrhoea • Cessation of mens. for at least 6 mons • At least 3 of the previous 3 cycle intervals • Distinction between primary and secondary amenorrhoea not absolute

27. Clinical Assessment (history) • Systemic diseases (Thyroid) • Family history • Past medical history • Pubertal growth and development • Emotional status • Medications (heroin, methadone)

28. Clinical Assessment (history) • Nutritional status, recent wt. changes • Exercise history • Sexual history • Past menstrual history • History of androgen excess (PCOS, ovarian or adrenal tumours)

29. C. Assessment (examination) • Signs of systemic dis. or malnutrition • Sexual maturity rating • Genitalia • Bw / Bh / BMI • Signs of androgen excess

30. C. Assessment (examination) • Signs of thyroid dysfunction • Signs of gonadal dysgenesis • Breast examination • Visual field / Fundi

31. Lab. Studies • Pregnancy test* • CBP / LRFT / urinalysis • TSH / FT4 • Prolactin • BA • FSH / Estradiol /LH

32. Hyperprolactinaemia • Pituitary tumour or lesion disrupting the pit. stalk • >200ng/mL suggests macroprolactinoma • High blood and CSF prolactin levels • Serum level correlates with tumour’s size • Psychiatric drugs, hypothyroidism, stress, eating disorder can also raise prolactin level • Functional gonadotrophin defic.

33. FSH • Elevated FSH level (40mIU/L) ovarian failure • 2 exceptions • Bone age </= 11ys • Partial ovarian failure

34. Elevated FSH • Chromosomal studies (Turner syndrome variants) • Autoimmune endocrinopathies • Functional ovarian failure (17 hydrolylase defic.) • Ovarian resistance syndromes (Gn receptor’s mutation) • Ovarian biopsy (no diagnostic value)

35. LH • Non specific for ovarian failure • Elevated in 60-70% of patients with PCOS • Elevated in cases of 17-20 lyase deficiency, 17-hydroxylase deficiency

36. FSH not elevated, BA >11yrs • Assess degree of estrogenization • Plasma estradiol level • Progestin withdrawal test

37. Estradiol • Simplest test • Diurnal and cyclical variations • Normal serum levels despite well documented ovarian failure (Partial ovarian failure)

38. Progestin withdrawal test • Estrogen effect at the level of endometrium • Vaginal bleeding after a course of medroxyprogesterone acetate, 5mg daily PO for 5 days, • Endometrial thickness > 5mm by scanning

39. Progestin withdrawal test • + ve response indicates serum estradiol levels greater than 40pg/mL • + ve response  hyperprolactinemia, thyroid dysfunction, androgen excess(PCOS) • - ve response  hypothalamic-pituitary failure, ovarian failure • Anorexia nervosa, drug abuse, heavy exercise may or may not withdraw to progesterone

40. - Withdrawal bleeding (hypoestrogenic) • GnRH test - FSH hyperresponseive  partial ovarian failure - brisk LH response (>/= 7 IU/L)  delayed puberty - FSH & LH not hyperresponsive  delayed puberty or Gonadotrophin def. • Gonadotrophin defic.may not be established until 16yrs of age

41. + Withdrawal bleeding (normoestrogenic) • Hypothalamic anovulation (athletic, psychogenic, post-pill) • Nonhypothalamic extraovarian disorders (pregnancy, Cushing syndrome, hypothyroidism, endometritis, drug abuse) • Hyperprolactinemia • Hyperandrogenism (PCOS)

42. Imaging studies • Pelvis US: hypoplastic ovaries, endometrial disorders, polycystic ovaries • MRI hypothalamus-pituitary area: gonadotrophin deficiency, hyperprolactinemia

43. FSH ELEVATED Chromosome studies Electrolytes abnormal normal Turner syndrome variants Hereditary ovarian failure Acquired ovarian failure FSH NOT ELEVATED Pubertal stage & Bone age Estradiol, Progestin withdrawal hypoestrogenic normoestrogenic GnRH or GnRH agonist test Prolactin Androgens Ultrasound Thyroid / Cortisol FSH hyperresponsive FSH & LH not hyperresponsive Prolactin excess normal abnormal Partial primary Ovarian failure Delayed puberty Gonadotropin deficiency Hypothalamic anovulation Androgen excess Endometrial disorder Extra-HPG disorder

44. Anorexia nervosa • Childhood psychiatric disorder • 0.5-1% amongst adolescents • DSM-IV and ICD-10 criterion • Syndrome of amenorrhoea, undernutrition from voluntary starvation and psychosocial dysfunction

45. Endocrine disturbances in AN • Amenorrhoea-oligomenorrhoea (wt. change 10-15%) • Delayed puberty • Hypothyroidism • Hypercortisolism • Hypoglycaemia • Osteopenia & osteoporosis

46. Amenorrhoea in AN • Weight changes of 10-15% of body weight • Fat stores <17% • Return of menses within 6 mons of reaching 90% of ideal body weight or 23% of fat store

47. Hypoth.-Pit.-Ovar. axis in AN • Isolated hypogonadotrophic hypogonadism • Hypothalamic origin • Low basal Gns, low estradiol levels • Blunted Gns response to GnRH • 24h LH profile: Decrease in both frequency & amplitude • Normalized with weight recuperation

48. Aetiology of hypo-hypog. In AN • Malnutrition (Leptin) • Hypothalamic dysfunction • Neurotransmitter alternation • Melatonin

49. Leptin and amenorrhoea • Synthesized by adipose tissue • Regulate food intake & energy expenditure • Receptors expressed in anterior pituitary and gonads • Regulate GnRH secretion • Initiation and maintenance of gonadal function • Loss of adipose tissue in AN  Decreases leptin level  GnRH def.

50. Management of amenorrhoea in AN • Rehydration and metabolic stabilization • Psychotherapy • Behavior modification • Family counseling