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Hypothalamic Amenorrhea

Hypothalamic Amenorrhea. Feb 2, 2011 Grace Yeung. CLINICAL SCENARIO. 18 yo G0P0 woman referred to your clinic: “I haven’t had my period for 6 months” Menarche at age 12, normal 2° sex characteristics, no sexual activity

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Hypothalamic Amenorrhea

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  1. Hypothalamic Amenorrhea Feb 2, 2011 Grace Yeung

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

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

  4. AMENORRHEA • The absence or abnormal cessation of menses • Transient, intermittent or permanent

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

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

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

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

  9. Menstrual cycle Menarche, cycle frequency, duration of menses, LNMP, timing of amenorrhea Habits/Sports/Hobbies Wt loss, exercise, eating disorder Psychosocial Loss, family/work/school Meds Antipsychotics OCP 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 HISTORY

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

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

  12. INVESTIGATIONS

  13. INVESTIGATIONS • LH and FSH pulsatility study • Sampling q 10-15 min for 4-6 h • Gonadotropin profile • LH pulse type classification • GnRH test • LH and FSH pituitary response • Naloxone test • Opioidergic gonadtropic dysfunction • +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

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

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

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

  17. REFERENCES • 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 • The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea.  Fertil Steril.  2004;82(suppl 1):S33 • Alessandro D. et al. Diagnostic and Therapeutic Approach to Hypothalamic Amenorrhea.Annals of the New York Academy of Sciences.10.1196/annals.1365.009 • 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 • 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. • 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.

  18. THANK-YOU

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