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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

Hypothalamic Amenorrhea

Feb 2, 2011

Grace Yeung

clinical scenario
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
objectives
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?
amenorrhea
AMENORRHEA
  • The absence or abnormal cessation of menses
  • Transient, intermittent or permanent
h p o axis menstruation
H-P-O AXIS & MENSTRUATION
  • Hypothalamus
  • Pituitary
  • Ovaries
  • Uterus and outflow tract
hypogonadotropic hypogonadism
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
hypothalamic amenorrhea1
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?
pathophysiology
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
history
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
physical exam
PHYSICAL EXAM
  • Ht, Wt, BMI
  • Tanner Staging
  • Thyroid exam
  • Visual Field
  • Galactorrhea
  • Hyperandrogenism
  • Virilization
  • Vomiting
  • Estrogen-deficiency
investigations
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

investigations2
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
treatment
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
management
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
consultation
CONSULTATION
  • Gynecology
  • Psychiatry
  • Pediatrician
  • Family Doctor
  • Sports Medicine
  • Dietician
  • Patient’s Family/Coach
references
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.