1. Hypothalamic Amenorrhea Feb 2, 2011 Grace Yeung

2. CLINICAL SCENARIO 18 yo G0P0 woman referred to your clinic: 18 yo G0P0 woman referred to your clinic: “I haven’t had my period for 6 months” “I haven’t had my period for 6 months” Menarche at age 12, normal 2° sex characteristics, no sexual activity Menarche at age 12, normal 2° sex characteristics, no sexual activity Daily training for National Ballet School audition and has lost 5lbs (BMI 19) Daily training for National Ballet School audition and has lost 5lbs (BMI 19) Home-school, Mother is strict but supportive Home-school, Mother is strict but supportive

3. OBJECTIVES How do you manage this patient? How do you manage this patient? What should you ask further on history? What should you ask further on history? What clinical findings should you look for? What clinical findings should you look for? What investigations do you order? What investigations do you order? How do you diagnose etiology of amenorrhea? How do you diagnose etiology of amenorrhea? Do you need to consult other services? Do you need to consult other services? What are principles of long-term management? What are principles of long-term management?

4. AMENORRHEA The absence or abnormal cessation of menses Transient, intermittent or permanent PrimarySecondary Absence of menses BEFORE menarche Absence of menses BEFORE menarche No period by age 16 No period by age 16 Absence of menses AFTER menarche Absence of menses AFTER menarche No period for > 3 cycles or 6 months No period for > 3 cycles or 6 months

5. H-P-O AXIS & MENSTRUATION Hypothalamus Hypothalamus Pituitary Pituitary Ovaries Ovaries Uterus and outflow tract Uterus and outflow tract

6. HYPOGONADOTROPIC HYPOGONADISM Functional Hypothalamic Amenorrhea Functional Hypothalamic Amenorrhea Anorexia or bulimia nervosa Anorexia or bulimia nervosa Excessive exercise Excessive exercise Excessive weight loss or malnutrition Excessive weight loss or malnutrition Hypothalamic or pituitary destruction Hypothalamic or pituitary destruction Central nervous system tumor Central nervous system tumor Constitutional delay of growth and puberty* Constitutional delay of growth and puberty* Chronic illness Chronic illness Liver disease, Renal insufficiency, Diabetes, Immunodeficiency, Inflammatory bowel disease, Thyroid disease, Severe depression or psychosocial stressors Liver disease, Renal insufficiency, Diabetes, Immunodeficiency, Inflammatory bowel disease, Thyroid disease, Severe depression or psychosocial stressors Cranial radiation Cranial radiation Congenital GnRH deficiency*, Kallmann syndrome* Congenital GnRH deficiency*, Kallmann syndrome* Sheehan’s syndrome *causes of primary amenorrhea only Sheehan’s syndrome *causes of primary amenorrhea only

7. HYPOTHALAMIC AMENORRHEA Secondary amenorrhea due to suppression of H-P-O axis via GnRH pulsatility Secondary amenorrhea due to suppression of H-P-O axis via GnRH pulsatility No anatomic or organic disease = Diagnosis of Exclusion No anatomic or organic disease = Diagnosis of Exclusion STRESS STRESS Energy deficit Energy deficit Wt loss, eating disorder Wt loss, eating disorder Excessive exercise Excessive exercise Psychological Psychological Genetic? Genetic?

9. PATHOPHYSIOLOGY Genetic Basis for FHA (NEJM, Jan 20, 2011) Genetic Basis for FHA (NEJM, Jan 20, 2011) Genes associated with idiopathic hypogonadotropic hypogonadism (Congenital GnRH deficiency) in HA women Genes associated with idiopathic hypogonadotropic hypogonadism (Congenital GnRH deficiency) in HA women FGFR1, PROKR2, GNRHR, KAL1 FGFR1, PROKR2, GNRHR, KAL1 ? Susceptibility genes conferring functional deficiency in GnRH secretion in HA ? Susceptibility genes conferring functional deficiency in GnRH secretion in HA Predisposition to HA Predisposition to HA Triggered by hormonal, nutritional, or psychologic stressor Triggered by hormonal, nutritional, or psychologic stressor Selective advantage for survival in times of stress Selective advantage for survival in times of stress Potential genetic screening tool in familial history Potential genetic screening tool in familial history

10. HISTORY Menstrual cycle Menstrual cycle Menarche, cycle frequency, duration of menses, LNMP, timing of amenorrhea Menarche, cycle frequency, duration of menses, LNMP, timing of amenorrhea Habits/Sports/Hobbies Habits/Sports/Hobbies Wt loss, exercise, eating disorder Wt loss, exercise, eating disorder Psychosocial Psychosocial Loss, family/work/school Loss, family/work/school Meds Meds Antipsychotics Antipsychotics OCP OCP GnRH agonists (Lupron), Depot medroxyprogesterone acetate (DMPA) GnRH agonists (Lupron), Depot medroxyprogesterone acetate (DMPA) PMH Chronic illness Prolactin Galactorrhea, H/A, visual field defect Thyroid Estrogen-deficiency Hot flashes, libido, vaginal dryness, poor sleep Obstetrical event/Instrumentation Hemorrhage, D&C, endometritis Sexual History Infertility FHx - Genetic

11. PHYSICAL EXAM Ht, Wt, BMI Ht, Wt, BMI Tanner Staging Tanner Staging Thyroid exam Thyroid exam Visual Field Visual Field Galactorrhea Galactorrhea Hyperandrogenism Hyperandrogenism Virilization Virilization Vomiting Vomiting Estrogen-deficiency Estrogen-deficiency

12. INVESTIGATIONS 1. Rule out pregnancy – βhCG 2. Hypercortisol – Cortisol AM, ACTH 3. Hypothyroid – TSH, FT3, FT4 4. Prolactinoma – Prl, MRI 5. Ovarian insufficiency – FSH, LH 6. Hyperandrogenism – Free testosterone, DHEAS 7. Chronic systemic illness – CBC, Ferritin, ACE, FBG, HbA1C, Karyotype, BMD, 25-OH Vit D, LFTs, albumin, lipid profile  Estradiol,  /low-normal LH and FSH

13. INVESTIGATIONS

14. INVESTIGATIONS LH and FSH pulsatility study LH and FSH pulsatility study Sampling q 10-15 min for 4-6 h Sampling q 10-15 min for 4-6 h Gonadotropin profile Gonadotropin profile LH pulse type classification LH pulse type classification GnRH test GnRH test LH and FSH pituitary response LH and FSH pituitary response Naloxone test Naloxone test Opioidergic gonadtropic dysfunction Opioidergic gonadtropic dysfunction +ve if LH  2X baseline post-infusion +ve if LH  2X baseline post-infusion BUT, cannot rule-out if –ve as the amount of naloxone may not be enough to effectively counteract high opioidergic hypertone BUT, cannot rule-out if –ve as the amount of naloxone may not be enough to effectively counteract high opioidergic hypertone

15. TREATMENT Lifestyle modification (↓exercise and  diet) Lifestyle modification (↓exercise and  diet) Opiod-R antagonist (Naltrexone cloridrate) Opiod-R antagonist (Naltrexone cloridrate) Acetyl-L-carnitine (ALC) Acetyl-L-carnitine (ALC) Leptin Leptin Bone-density Bone-density Hormonal (low estrogen/OCP, androgens, IGF-1, leptin, bisphosphonates) vs.  Caloric intake to  BMI and resumption of menses Hormonal (low estrogen/OCP, androgens, IGF-1, leptin, bisphosphonates) vs.  Caloric intake to  BMI and resumption of menses

16. MANAGEMENT Psychosocial Psychosocial Stress reduction, CBT Stress reduction, CBT Bone Density Bone Density Combined OCP, Ca 1200 mg/Vit D 1000 IU, baseline BMD Combined OCP, Ca 1200 mg/Vit D 1000 IU, baseline BMD Menstruation Menstruation Wt gain (? cut-off)/ ↓Exercise Wt gain (? cut-off)/ ↓Exercise Infertility Infertility Ovulation induction via pulsatile GnRH or exogenous gonadtropin Poor response to clompiphene citrate

17. CONSULTATION Gynecology Gynecology Psychiatry Psychiatry Pediatrician Pediatrician Family Doctor Family Doctor Sports Medicine Sports Medicine Dietician Dietician Patient’s Family/Coach Patient’s Family/Coach

18. REFERENCES 1. Jean L Chan, Christos S Mantzoros, S.B. 1. Jean L Chan, Christos S Mantzoros, S.B. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. The Lancet, Volume 366, Issue 9479, 2 July 2005-8 July 2005, Pages 74-85 2. 2. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2004;82(suppl 1):S33 3. 3. Alessandro D. et al. Diagnostic and Therapeutic Approach to Hypothalamic Amenorrhea. Annals of the New York Academy of Sciences. 10.1196/annals.1365.009 4. 4. James H. Liu Arthur H. Bill. Stress ‐ Associated or Functional Hypothalamic Amenorrhea in the Adolescent. Annals of the New York Academy of Sciences.10.1196/annals.1429.027 5. 5. Meczekalski B, Podfigurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008 Jan;24(1):4-11. 6. 6. Vescovi JD, Jamal SA, De Souza MJ. Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature. Osteoporos Int. 2008 Apr;19(4):465-78. Epub 2008 Jan 8.

19. THANK-YOU