Hypothalamic Hypothalamic AmenorrheaAmenorrhea

Feb 2, 2011Feb 2, 2011

Grace YeungGrace Yeung

CLINICAL SCENARIOCLINICAL SCENARIO 18 yo G0P0 woman 18 yo G0P0 woman

referred to your clinic:referred to your clinic: ““I haven’t had my I haven’t had my

period for 6 months”period for 6 months” Menarche at age 12, Menarche at age 12,

normal 2° sex normal 2° sex characteristics, no characteristics, no sexual activitysexual activity

Daily training for Daily training for National Ballet School National Ballet School audition and has lost audition and has lost 5lbs (BMI 19)5lbs (BMI 19)

Home-school, Mother is Home-school, Mother is strict but supportivestrict but supportive

OBJECTIVESOBJECTIVES

How do you manage this patient?How do you manage this patient? What should you ask further on What should you ask further on historyhistory? ? What What clinical findingsclinical findings should you look should you look

for?for? What What investigationsinvestigations do you order? do you order? How do you How do you diagnosediagnose etiology of etiology of

amenorrhea?amenorrhea? Do you need to Do you need to consult other servicesconsult other services?? What are principles of What are principles of long-term long-term

managementmanagement??

AMENORRHEAAMENORRHEA• The absence or abnormal cessation of menses

• Transient, intermittent or permanentPrimaryPrimary SecondarySecondary

Absence of menses Absence of menses BEFOREBEFORE menarche menarche No period by age 16No period by age 16

Absence of menses Absence of menses AFTERAFTER menarche menarche No period for > 3 No period for > 3 cycles or 6 months cycles or 6 months

H-P-O AXIS & H-P-O AXIS & MENSTRUATIONMENSTRUATION

HypothalamusHypothalamus

PituitaryPituitary

OvariesOvaries

Uterus and outflow Uterus and outflow tracttract

HYPOGONADOTROPIC HYPOGONADOTROPIC HYPOGONADISMHYPOGONADISM

Functional Hypothalamic AmenorrheaFunctional Hypothalamic Amenorrhea Anorexia or bulimia nervosaAnorexia or bulimia nervosa Excessive exerciseExcessive exercise Excessive weight loss or malnutritionExcessive weight loss or malnutrition

Hypothalamic or pituitary destructionHypothalamic or pituitary destruction Central nervous system tumorCentral nervous system tumor Constitutional delay of growth and puberty*Constitutional delay of growth and puberty* Chronic illnessChronic illness

Liver disease, Renal insufficiency, Diabetes, Immunodeficiency, Liver disease, Renal insufficiency, Diabetes, Immunodeficiency, Inflammatory bowel disease, Thyroid disease, Severe depression or Inflammatory bowel disease, Thyroid disease, Severe depression or psychosocial stressorspsychosocial stressors

Cranial radiationCranial radiation Congenital GnRH deficiency*, Kallmann syndrome*Congenital GnRH deficiency*, Kallmann syndrome* Sheehan’s syndromeSheehan’s syndrome *causes of primary amenorrhea only*causes of primary amenorrhea only

HYPOTHALAMIC HYPOTHALAMIC AMENORRHEAAMENORRHEA

Secondary amenorrhea due to Secondary amenorrhea due to suppression of H-P-O axis via GnRH suppression of H-P-O axis via GnRH pulsatilitypulsatility

No anatomic or organic disease = No anatomic or organic disease = Diagnosis of ExclusionDiagnosis of Exclusion

STRESSSTRESS Energy deficitEnergy deficit Wt loss, eating disorderWt loss, eating disorder Excessive exerciseExcessive exercise PsychologicalPsychological

Genetic?Genetic?

PATHOPHYSIOLOGYPATHOPHYSIOLOGY Genetic Basis for FHAGenetic Basis for FHA (NEJM, Jan 20, 2011) (NEJM, Jan 20, 2011)

Genes associated with idiopathic hypogonadotropic Genes associated with idiopathic hypogonadotropic hypogonadism (Congenital GnRH deficiency) in HA hypogonadism (Congenital GnRH deficiency) in HA women women

FGFR1, PROKR2, GNRHR, KAL1FGFR1, PROKR2, GNRHR, KAL1 ? Susceptibility genes conferring functional ? Susceptibility genes conferring functional

deficiency in GnRH secretion in HAdeficiency in GnRH secretion in HA Predisposition to HA Predisposition to HA Triggered by hormonal, nutritional, or psychologic Triggered by hormonal, nutritional, or psychologic

stressorstressor Selective advantage for survival in times of stressSelective advantage for survival in times of stress Potential genetic screening tool in familial historyPotential genetic screening tool in familial history

HISTORYHISTORY Menstrual cycleMenstrual cycle

Menarche, cycle frequency, Menarche, cycle frequency, duration of menses, LNMP, duration of menses, LNMP, timing of amenorrheatiming of amenorrhea

Habits/Sports/HobbiesHabits/Sports/Hobbies Wt loss, exercise, eating Wt loss, exercise, eating

disorderdisorder PsychosocialPsychosocial

Loss, family/work/schoolLoss, family/work/school MedsMeds

AntipsychoticsAntipsychotics OCPOCP GnRH agonists (Lupron), GnRH agonists (Lupron),

Depot Depot medroxyprogesterone medroxyprogesterone acetate (DMPA)acetate (DMPA)

PMHPMH Chronic illnessChronic illness

ProlactinProlactin Galactorrhea, H/A, Galactorrhea, H/A,

visual field defectvisual field defect ThyroidThyroid Estrogen-deficiencyEstrogen-deficiency

Hot flashes, libido, Hot flashes, libido, vaginal dryness, poor vaginal dryness, poor sleepsleep

Obstetrical Obstetrical event/Instrumentationevent/Instrumentation Hemorrhage, D&C, Hemorrhage, D&C,

endometritisendometritis Sexual HistorySexual History InfertilityInfertility FHx - FHx - GeneticGenetic

PHYSICAL EXAMPHYSICAL EXAM Ht, Wt, BMIHt, Wt, BMI Tanner StagingTanner Staging Thyroid examThyroid exam Visual FieldVisual Field GalactorrheaGalactorrhea HyperandrogenismHyperandrogenism VirilizationVirilization VomitingVomiting Estrogen-Estrogen-

deficiencydeficiency

INVESTIGATIONSINVESTIGATIONS1.1. Rule out pregnancy – Rule out pregnancy – ββhCGhCG

2.2. Hypercortisol – Cortisol AM, ACTHHypercortisol – Cortisol AM, ACTH

3.3. Hypothyroid – TSH, FT3, FT4Hypothyroid – TSH, FT3, FT4

4.4. Prolactinoma – Prl, MRIProlactinoma – Prl, MRI

5.5. Ovarian insufficiency – FSH, LHOvarian insufficiency – FSH, LH

6.6. Hyperandrogenism – Free testosterone, Hyperandrogenism – Free testosterone, DHEASDHEAS

7.7. Chronic systemic illness – CBC, Ferritin, Chronic systemic illness – CBC, Ferritin, ACE, FBG, HbA1C, Karyotype, BMD, 25-ACE, FBG, HbA1C, Karyotype, BMD, 25-OH Vit D, LFTs, albumin, lipid profileOH Vit D, LFTs, albumin, lipid profile

Estradiol, /low-normal LH and FSH

INVESTIGATIONSINVESTIGATIONS

INVESTIGATIONSINVESTIGATIONS LH and FSH pulsatility studyLH and FSH pulsatility study

Sampling q 10-15 min for 4-6 hSampling q 10-15 min for 4-6 h Gonadotropin profileGonadotropin profile LH pulse type classificationLH pulse type classification

GnRH testGnRH test LH and FSH pituitary responseLH and FSH pituitary response

Naloxone testNaloxone test Opioidergic gonadtropic dysfunctionOpioidergic gonadtropic dysfunction +ve if LH +ve if LH 2X baseline post-infusion2X baseline post-infusion BUT, cannot rule-out if –ve as the amount of BUT, cannot rule-out if –ve as the amount of

naloxone may not be enough to effectively naloxone may not be enough to effectively counteract high opioidergic hypertone counteract high opioidergic hypertone

TREATMENTTREATMENT

Lifestyle modification (↓exercise and Lifestyle modification (↓exercise and diet)diet)

Opiod-R antagonist (Naltrexone Opiod-R antagonist (Naltrexone cloridrate)cloridrate)

Acetyl-L-carnitine (ALC)Acetyl-L-carnitine (ALC) LeptinLeptin Bone-density Bone-density

Hormonal (low estrogen/OCP, androgens, Hormonal (low estrogen/OCP, androgens, IGF-1, leptin, bisphosphonates) vs. IGF-1, leptin, bisphosphonates) vs. Caloric Caloric intake to intake to BMI and resumption of mensesBMI and resumption of menses

MANAGEMENTMANAGEMENT

PsychosocialPsychosocial Stress reduction, CBTStress reduction, CBT

Bone DensityBone Density Combined OCP, Ca 1200 Combined OCP, Ca 1200 mg/Vit D 1000 IU, baseline BMDmg/Vit D 1000 IU, baseline BMD

MenstruationMenstruation Wt gain (? cut-off)/ ↓ExerciseWt gain (? cut-off)/ ↓Exercise

InfertilityInfertility Ovulation induction via pulsatile GnRH or exogenous gonadtropin Poor response to clompiphene citrate

CONSULTATIONCONSULTATION

GynecologyGynecology PsychiatryPsychiatry PediatricianPediatrician Family DoctorFamily Doctor Sports MedicineSports Medicine DieticianDietician

Patient’s Family/CoachPatient’s Family/Coach

REFERENCESREFERENCES1.1. Jean L Chan, Christos S MantzorosJean L Chan, Christos S Mantzoros, S.B. , 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. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea.  Fertil Steril.  2004;82(suppl 1):S33

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. 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. 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. 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.

THANK-YOUTHANK-YOU