Amenorrhea

Mayurasakorn N.

Not physiologic

Primary amenorrheaNormal secondary sex characteristic

no manarche by 16 yearsno periods by 2 years after

start of secondary sex changesIf No secodary sex characteristic

14 years

Secondary amenorrhea

Definitions and EpidemiologyDefinitions and Epidemiology

If regular menstruation : 3 cyclesIf irregular mrnstruation : 6 months

PregnancyBreast feedingMenopause

Hypothalamic causesPituitary causes

Premature ovarian failure(<40 years)

Outflow tractHyperandrogenic anovulation

EtiologyEtiologyHypergonadotropic

hypogonadism

Hypogonadotropic hypogonadism

Normogonadotropic hypogonadism

Secondary AmenorrheaSecondary Amenorrhea

Ovary Pituitary Hypothalamus

Infection /infiltration

Mump Oophoritis

TB,syphilis,Encephalitis/menigitis,Sarcoidosis

Tumor Ovarian tumor

HyperprolactinPituitary tumorEmpty sella

Craniopharyngioma, Germinoma,Hamartoma,Teratoma,Metastasis

Trauma Irradiation Chemotherapy

SurgeryIrradiationSheehan sd

Metabolic Autoimmune AutoimmuneHemochromatosisLymphocytic hypophysis

Anorexia nervosaStressExercise Nutrition-related

Hypergonadotropic hypogonadismHypergonadotropic hypogonadismHypogonadotropic hypogonadismHypogonadotropic hypogonadism

Hyperandrogenic anovulationPCOSAndrogen-secreting tumorCushing’s sdNonclassical congenital adrenal hyperplasiaThyroid

Outflow tractAsherman syndromecervical stenosis

Normogonadotropic hypogonadismNormogonadotropic hypogonadism

Hypothalamus :25-35%

PCOS: 20-25%

Ovarian : 12%

Hyperprolactinemia : 13%

Pituitary : 7-16%

Uterine : 7%

other

Most common causesMost common causes

Hypothalamus

Stress, wt loss, diet ,exercise, illnessChemotherapy,radiation

GalactorrheaDrugs( metoclopramide,

anti-psychotics?)

Headaches, visual field defects, fatigue, polyuria, polydipsia

Chemotherapy,radiation

Hot flashes, vaginal dryness, poor sleep,decreased libido

Hyperprolactinemia

Ovary

History & Physical examinationsHistory & Physical examinations

Pituitary

Hypothalamus

Hyperprolactinemia

Ovary

History & Physical examinationsHistory & Physical examinations

Pituitary

Signs of systemic illness ,cachexia

Breast : galactorrhea

Bitemporal hemianopia

PCOS

History & Physical examinationsHistory & Physical examinations

Hirsutism, acne, history of irregular menses

Obstetrical catastrophe, severe bleeding, dilatation and curettage, endometritisBMI,hirsutism, acne, striae, acanthosis nigricans, vitiligo

Virilization, clitorial hypertrophy

PCOS

History & Physical examinationsHistory & Physical examinations

Hirsutism, acne, history of irregular menses

Obstetrical catastrophe, severe bleeding, dilatation and curettage, endometritis

PRL FBSProgesterone estrogen challengeUrine BhCG KaryotypeAntithyroid antibody FSHProgesterone challengeDHEA-S and testosterone TSH

ข้�อใดไม่�ใช่� Investigations ข้อง Amenorrheaข้�อใดไม่�ใช่� Investigations ข้อง Amenorrhea

HypothalamusHyperprolactinemia

Ovary

Pituitary

PCOS

Outflow tract

Cushing’s sd

Thyroid

MRI hypothalamus, pituitary

FSH,LH, autoimmune

MRI pituitary

U/S ovary,testosterone

Dexamethasone supression testThyroid function test

prolactin

Hysterosalpingogram,hysteroscopy

InvestigationsInvestigations

Pregnancy test

TSH ,PRL,FSH

TSH

Hypothyroid

PRL

Hyperpro-lactinemia

FSH

Premature

ovarian failure

Hypogonadotropic Normogonadotropic PCOS

Outflow

Clinical

PRL > 40 mg/dL

FSH > 40 mIU/mL

High false positive, false negativeDelay diagnosis

Primolut-N (Norethisterone acetate) 5-10 mg ODProvera (Medroxyprogesterone acetate) 10 mg OD 5 days

withdrawal bleed within 2 weeks

Progesterone challenge test

Estrogen progesterone challenge test

Premarin (conjugated E)1.25 mg OD Progynova(Estradial) 21 days followed by provera as above

Prog.challenge test

Withdrawal bleeding

No withdrawal bleeding

Chronic anovulation

Testosterone, DHEA-S,17 hydroxyprogesteroneTestosterone, DHEA-S,17 hydroxyprogesterone

T,DHEA-S,LH

mild

PCOS

T,DHEA-S

marked

Androgen-secreting

tumor

17-hydroxyprogesterone

CAH Idiopathic anovulation

No withdrawal bleeding

Est,progest.challenge test

Hypothalamic-

pituitary failure

Hypothalamic-

pituitary failure

hypoestrogenic

outflow tract .

Withdrawal bleeding

No

Prog.challenge test

1% population40% autoimmune ass autoimmune

Autoimmune thyroiditisIDDMParathyroid diseaseMGAddison’s disease(1:million)

Polyglandular sd20-40% develop other autoimmune disease

Premature ovarian failurePremature ovarian failure

TSH, thyroid autoAb FBS Ca,PO4

Karyotype : if < 30 for Y chromosome remove gonad

HyperprolactinemiaHyperprolactinemia< 100 ng/mL(µg/L)

Altered metabolism: liver failure, renal failureEctopic production : BCA,renal cell CA , ovarian dermoid cyst,teratomaHypothyroidDrugs: OC,antipsychotic, antidepressant,antihypertensive,opiate,cocain,H2 blokerPituitary stalk irritability

> 100 ng/mL(µg/L)Empty sella syndromeProlactinoma

Discovery and treatment of underlying disorderHormone replacement

for maintain secondary sex characteristic Normal menses every 1-3 months

reduce risk of osteoporosis

Adequate caloric intake

Calcium 1200 to 1500 mg/D

Vitamin D (400 IU daily)Pregnancy

Ovulation inductionGnRH pumpFSH/LH

Treatment GoalsTreatment Goals

Chromosomal abnormality:20%Ovarian failure: 15%

46 XY :5%

Mullerian agenesis : 10%

Androgen insensitivity : 9%

Constitutional delay: 8%

Constitutional delay

Prolactinoma: 5%

Kallman, Stress, PCOS

Breast

30%

High FSH

40%

Low FSH

30%

Primary AmenorrheaPrimary Amenorrhea

HistoryHistoryNormal physical & pubertal development?

Family history of delayed/absent menarche?Short stature compared to family members?

Neonatal/childhood health normal? any recent increase in stress, or change in weight, diet, or exercise habits?

Hypothalamic-pituitary disease (headaches, visual field defects, fatigue, polyuria or polydipsia?)

Drugs?

Physical examinationPhysical examination

Height, weight

Secondary sex characteristic (Tanner staging)

PV for cervix, uterus, ovaries (may need ultrasound)

Androgen excess (acanthosis nigras, hirsutism, acne, & striae)

Turner syndrome (low hair line, web neck, shield chest, and widelyspaced nipples)

Galactorrhea?

Secondary sex characteristicSecondary sex characteristic

Thelarche (breast devel): average age 10.8 yrs estrogen exposure

Adrenarche (pubic/axillary hair development): average 11 yrs ovarian,adrenal androgen

production ,end organ responseDecreased breast size or vaginal dryness

decreasing estrogen exposure (or increasing androgens)

Tanner StagingTanner Staging

Stage 1 : prepubertal

Stage 2 : breast bud

Stage 3 : further enlarge of breast

& areolar ,no seperation

Stage 4: areolar & papilla form

second mound

Stage 5 : mature, only projection of

papilla

Tanner StagingTanner StagingStage1 : villus hair

Stage 2 : Sparse growth of slightly

pigmented hair along

labia (11.9 years)

Stage 3 : C oarser, curled and pigmented;

spreads across pubes (12.7 years)

Stage 4 : - Adult type hair but no spread to medial thigh

(1 3 .4 years)

Stage 5 : - Adult type hair with spread to medial thigh but not up linea alba (14.6 years)

Secondary sex characteristic

No Yes

Pubic hair

Yes

Uterus

No

Androgen insentivity syndrome

Androgen insentivity syndrome

Imperforate hymen

Imperforate hymen

Yes NoMullerian agenesis

Mullerian agenesisAs secondary

amenorrhea

PV

Secondary sex characteristic

No ( normal cervix and uterus

not include ambiguous )FSH

E

Primary Gonodal failure

Primary Gonodal failure

Constitutional delay

Kallman sd

Hypothalamus-pituitary

Hypothalamus-pituitary

Karyotype

XX,XY,XO

Primary gonodal failurePrimary gonodal failure

Gonodal dysgenesis

less than 30ykaryotypeif Y chromosome exists, excise gonadsif 46XX, r/o 17a-hydroxylase deficiencyIf XOTurner sd

Premature ovarian failure

Time Before thelarche Before menarche After menopause

AutoimmnueLaboratory evidence of autoimmune is much more prevalent than clinically significant disease

CNS, hypothalamic, or pituitary failureConstitutional delayHypothalamic dysfunction

Kallmann syndromeAnorexia nervosa, exercise induced; Space-occupying lesion of CNS

Pituitary damage (surgery/radiation)Hyperprolactinemia

Hypogonadotropic hypogonadismHypogonadotropic hypogonadism

Mullerian agenesisMullerian agenesisnormal gonad hormone

but no uterus and upper vagina

Embryonal activation of antimullerian hormone

15-30% ass. urogenital malformation : unilateral renal agenesis, pelvic kidney, horseshoe kidney, hydronephrosisIVP

Cyclic breast tenderness or pain in rudimentary uterus

karyotype R/O male pseudohermaphrodism

1:60,000, XR mutation of androgen receptorKaryotype 46, XYMale range testosterone levelNormal breasts but no sexual hairNormal looking female external genitaliaOccasional present of inguinal massAbsent uterus and upper vagina by AMHRisk gonodal malignancy 20%Raised as girls (XY)

remove gonads after breast development and epiphyseal closurereplace estrogen

Complete androgen insensitivity syndromeComplete androgen insensitivity syndrome

Imperforate hymenImperforate hymen

Discovery and treatment of underlying disorderRemove gonadal streaks if XY or mosaic

Increased (52%) risk of gonadoblastomas, dysgerminomas, and yolk sac tumors

Hormone replacement for maintain secondary sex characteristic and reduce risk of osteoporosis

adolescent: low dose E breast augmentationThen progestin normal menses every 1-3 monthsPregnancy

Ovulation inductionPulsatile GnRH FSH/LH

Treatment GoalsTreatment Goals

17 yo female with primary amenorrhea

Normal pubertal development

Normal health

No family history of delayed puberty

Not involved in athletics

Does well in school

Not taking any meds

Case 1:Case 1:

Physical Examination

Thin young woman )10% below IBW)

Normal genitalia

No galactorrhea

Tanner stage 4

Laboratory values

Urine and serum B-HCG negative

Prolactin, FSH, TSH all normal

Further history

Patient’s parents concerned about her eating habits (very low fat intake and restricting calories)

Diagnosis : hypothalamic amenorrhea

Etiology is most likely inadequate caloric and fat intake.

referred for evaluation for an eating disorder.

Psychological stress, weight changes,exerciseChronic debilitating diseaseCompetitive sport : 3-fold risk of amenorrhea

Esp: long distance runnersRx

correct causesAdequate intakeLess exerciseOC???

Hypothalamic amenorrheaHypothalamic amenorrhea

24 yo woman with secondary amenorrhea

Menarche at age 12

Periods have always been irregular

Now amenorrhea x 10 months

Overweight

Wants to get pregnant

Case 2:Case 2:

Physical Examination

Obese femaleAcneNormal genitaliaMild hirsutism

Urine B-HCG negativeTSH, FSH and Prolactin : WNL Testosterone 180 ng/dLPelvic U/S

Laboratory findings

PCOS : Polycystic Ovarian SyndormePCOS : Polycystic Ovarian Syndorme

Etiology unknown Reduce insulin sensitivity 30-40% : Increase secretion LH

Hyperinsulin or LH Theca cell androgen disturb hypothalamus& ovary anovulation

PCOS : Polycystic Ovarian SyndormePCOS : Polycystic Ovarian Syndorme

Menstrual disturbance (DUB,oligomenorrhea (76%), amenorrhea(24%)

Symptom onset at menarche but sign androgen excess obvious several years laterDifferential diagnosis :

Androgen-secreting tumor(ovarian or adrenal)Cushing’s sdNonclassical congenital adrenal hyperplasia

Thyroid Excess estrogen

Increased risk endometrial cancer threefold

Hyperandrogenic anovalationHyperandrogenic anovalation

Metabolic complicationMetabolic complication

Impaired glucose tolerance:31%Impaired fasting glucose 7.5%DM : 2-5 folds test OGTTCardiovascular risk 2 folds Metabolic syndrome 43%

2/3Chronic anovulation HyperandrogenismU/S : polycystic ovaries

Exclude other causes20% of woman with regular menses have polycystic ovaryLH/FSH> 2 , not useful in diagnosis

NIH criteriaNIH criteria

TreatmentTreatmentShort-term management

InfertilityHirsutismAcneObesityMiscarriage

Long-term managementCardiovascular risks

CholesterolDiabetesblood pressure

Endometrial Cancer

weight reductionlower androgen level , improve hersutism, normalize menses , decrease insulin resistance

Anovulation & Infertility: Clomiphene , GnRH, Metformin

RCOG guidline 2003

Protection endometrial CA: Oral contraceptive or Cyclic progestin to prevent : monthly 10-14 day regimen

AntiandrogenCyproterone acetate (Diane-35)Drospirenone ( Yasmin)

34 Years with secondary amenorrhea 19 years

Menarche at age 15

Only 2 cycles

Short stature

Case 3:Case 3:

Turner SyndromeTurner Syndrome

Classic 45,X other :

46,X ,i(Xq)46,X,Xq-46,X,Xp-46,X,r(X)45,X/46,XX

Time of diagnosis

Ischemic heart diseaseType 2 DMosteoporosisCirrhosisType 1 DMDilated ascending aortaThyroiditis

ข้�อใดไม่�ใช่� Risks ข้องผู้��ป่�วย turner syndromeข้�อใดไม่�ใช่� Risks ข้องผู้��ป่�วย turner syndrome

HypothyroidismCoartation of aortaFracture Type 1 CA colonHypertensionHorseshoe kidney

CardiovascularRecord BP, BMIEchocardiogram q 3-5 yearsFBSFasting lipid

Renal ultrasoundRenal and liver functionThyroid status & antibodyBMDAortogram

TreatmentTreatmentChildren : Growth hormone

adequate height, phychological demand, may spontaneous menseEstrogen maintian secondary sex characteristicBone massCycle progesteroneFertility

Oocyte donationOocyte implantation from cryopreservation