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Amenorrhea Mayurasakorn N.
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Definitions and Epidemiology
Pregnancy Breast feeding Menopause Not physiologic Primary amenorrhea Normal secondary sex characteristic no manarche by 16 years no periods by 2 years after start of secondary sex changes If No secodary sex characteristic 14 years Secondary amenorrhea If regular menstruation : 3 cycles If irregular mrnstruation : 6 months
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Secondary Amenorrhea Etiology Hypothalamic causes
Pituitary causes Premature ovarian failure(<40 years) Outflow tract Hyperandrogenic anovulation Hypergonadotropic hypogonadism Hypogonadotropic hypogonadism Normogonadotropic hypogonadism
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Hypergonadotropic hypogonadism Hypogonadotropic hypogonadism
Ovary Pituitary Hypothalamus Infection /infiltration Mump Oophoritis TB,syphilis,Encephalitis/menigitis,Sarcoidosis Tumor Ovarian tumor Hyperprolactin Pituitary tumor Empty sella Craniopharyngioma, Germinoma,Hamartoma,Teratoma,Metastasis Trauma Irradiation Chemotherapy Surgery Sheehan sd Metabolic Autoimmune Hemochromatosis Lymphocytic hypophysis Anorexia nervosa Stress Exercise Nutrition-related
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Normogonadotropic hypogonadism
Hyperandrogenic anovulation PCOS Androgen-secreting tumor Cushing’s sd Nonclassical congenital adrenal hyperplasia Thyroid Outflow tract Asherman syndrome cervical stenosis
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Most common causes
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History & Physical examinations
Hypothalamus Stress, wt loss, diet ,exercise, illness Chemotherapy,radiation Galactorrhea Drugs( metoclopramide, anti-psychotics?) Headaches, visual field defects, fatigue, polyuria, polydipsia Hot flashes, vaginal dryness, poor sleep,decreased libido Hyperprolactinemia Pituitary Ovary
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History & Physical examinations
Signs of systemic illness ,cachexia Breast : galactorrhea Bitemporal hemianopia Hypothalamus Hyperprolactinemia Pituitary Ovary
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History & Physical examinations
Hirsutism, acne, history of irregular menses Obstetrical catastrophe, severe bleeding, dilatation and curettage, endometritis PCOS BMI,hirsutism, acne, striae, acanthosis nigricans, vitiligo Virilization, clitorial hypertrophy
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History & Physical examinations
Hirsutism, acne, history of irregular menses Obstetrical catastrophe, severe bleeding, dilatation and curettage, endometritis PCOS
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ข้อใดไม่ใช่ Investigations ของ Amenorrhea
PRL FBS Progesterone estrogen challenge Urine BhCG Karyotype Antithyroid antibody FSH Progesterone challenge DHEA-S and testosterone TSH Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Investigations Hypothalamus MRI hypothalamus, pituitary prolactin
Hyperprolactinemia Pituitary MRI pituitary Ovary FSH,LH, autoimmune PCOS U/S ovary,testosterone Outflow tract Hysterosalpingogram,hysteroscopy Cushing’s sd Dexamethasone supression test Thyroid Thyroid function test
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Normogonadotropic PCOS Outflow Premature ovarian failure
Pregnancy test TSH ,PRL,FSH TSH PRL FSH Hypogonadotropic Normogonadotropic PCOS Outflow Hypothyroid Hyperpro-lactinemia Premature ovarian failure Clinical PRL > 40 mg/dL FSH > 40 mIU/mL
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Progesterone challenge test
High false positive, false negative Delay diagnosis Primolut-N (Norethisterone acetate) 5-10 mg OD Provera (Medroxyprogesterone acetate) 10 mg OD 5 days withdrawal bleed within 2 weeks Estrogen progesterone challenge test Premarin (conjugated E)1.25 mg OD Progynova(Estradial) 21 days followed by provera as above
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Prog.challenge test Testosterone, DHEA-S,17 hydroxyprogesterone
Withdrawal bleeding No withdrawal bleeding Chronic anovulation Testosterone, DHEA-S,17 hydroxyprogesterone T,DHEA-S,LH mild T,DHEA-S marked 17-hydroxyprogesterone Idiopathic anovulation CAH PCOS Androgen-secreting tumor
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No withdrawal bleeding
Prog.challenge test No withdrawal bleeding Est,progest.challenge test Withdrawal bleeding No outflow tract. hypoestrogenic Hypothalamic- pituitary failure
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Premature ovarian failure
1% population 40% autoimmune ass autoimmune Autoimmune thyroiditis IDDM Parathyroid disease MG Addison’s disease(1:million) Polyglandular sd 20-40% develop other autoimmune disease TSH, thyroid autoAb FBS Ca,PO4 Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone Karyotype : if < 30 for Y chromosome remove gonad
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Hyperprolactinemia < 100 ng/mL(µg/L) > 100 ng/mL(µg/L)
Altered metabolism: liver failure, renal failure Ectopic production : BCA,renal cell CA , ovarian dermoid cyst,teratoma Hypothyroid Drugs: OC,antipsychotic, antidepressant,antihypertensive,opiate,cocain,H2 bloker Pituitary stalk irritability Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone > 100 ng/mL(µg/L) Empty sella syndrome Prolactinoma
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Treatment Goals Discovery and treatment of underlying disorder
Hormone 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 induction GnRH pump FSH/LH Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Primary Amenorrhea gonadal failure is most common cause
Low FSH 30% gonadal failure is most common cause 30% have genetic abnormality Gonadal dysgenesis, Turner’s syndrome, mosaicism uterovaginal agenesis is second most common cause Anorexia nervosa Breast 30% High FSH 40%
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History Normal 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? Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Physical 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? Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Secondary sex characteristic
Thelarche (breast devel): average age yrs estrogen exposure Adrenarche (pubic/axillary hair development): average 11 yrs ovarian,adrenal androgen production ,end organ response Decreased breast size or vaginal dryness decreasing estrogen exposure (or increasing androgens) Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Tanner 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 Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Tanner Staging Stage1 : villus hair
Stage 2 : Sparse growth of slightly pigmented hair along labia (11.9 years) Stage 3 : Coarser, curled and pigmented; spreads across pubes (12.7 years) Stage 4 : Adult-type hair but no spread to medial thigh (13.4 years) Stage 5 : Adult-type hair with spread to medial thigh but not up linea alba (14.6 years) Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Secondary sex characteristic
No Yes Pubic hair Yes No PV Androgen insentivity syndrome Uterus Imperforate hymen Yes No Mullerian agenesis As secondary amenorrhea
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Secondary sex characteristic
No ( normal cervix and uterus not include ambiguous) E FSH Primary Gonodal failure Hypothalamus-pituitary Constitutional delay Kallman sd Karyotype XX,XY,XO
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Primary gonodal failure
Gonodal dysgenesis less than 30ykaryotype if Y chromosome exists, excise gonads if 46XX, r/o 17a-hydroxylase deficiency If XOTurner sd Premature ovarian failure Time Before thelarche Before menarche After menopause Autoimmnue Laboratory evidence of autoimmune is much more prevalent than clinically significant disease Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Hypogonadotropic hypogonadism
CNS, hypothalamic, or pituitary failure Constitutional delay Hypothalamic dysfunction Kallmann syndrome Anorexia nervosa, exercise induced; Space-occupying lesion of CNS Pituitary damage (surgery/radiation) Hyperprolactinemia
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Mullerian agenesis normal 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 Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Complete androgen insensitivity syndrome
1:60,000, XR mutation of androgen receptor Karyotype 46, XY Male range testosterone level Normal breasts but no sexual hair Normal looking female external genitalia Occasional present of inguinal mass Absent uterus and upper vagina by AMH Risk gonodal malignancy 20% Raised as girls (XY) remove gonads after breast development and epiphyseal closure replace estrogen
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Imperforate hymen
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Treatment Goals Discovery and treatment of underlying disorder
Remove 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 augmentation Then progestin normal menses every 1-3 months Pregnancy Ovulation induction Pulsatile GnRH FSH/LH Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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17 yo female with primary amenorrhea
Case 1: 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
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Physical Examination Laboratory values
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
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Diagnosis : hypothalamic amenorrhea
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.
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Hypothalamic amenorrhea
Psychological stress, weight changes,exercise Chronic debilitating disease Competitive sport : 3-fold risk of amenorrhea Esp: long distance runners Rx correct causes Adequate intake Less exercise OC??? Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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24 yo woman with secondary amenorrhea
Case 2: 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
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Physical Examination Obese female Acne Normal genitalia Mild hirsutism
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Laboratory findings Urine B-HCG negative TSH, FSH and Prolactin : WNL
Testosterone 180 ng/dL Pelvic U/S
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PCOS : Polycystic Ovarian Syndorme
Etiology unknown Reduce insulin sensitivity 30-40% : Increase secretion LH Hyperinsulin or LH Theca cell androgen disturb hypothalamus& ovary anovulation
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PCOS : Polycystic Ovarian Syndorme
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Hyperandrogenic anovalation
Menstrual disturbance (DUB,oligomenorrhea (76%), amenorrhea(24%) Symptom onset at menarche but sign androgen excess obvious several years later Differential diagnosis : Androgen-secreting tumor(ovarian or adrenal) Cushing’s sd Nonclassical congenital adrenal hyperplasia Thyroid Excess estrogen Increased risk endometrial cancer threefold
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Metabolic complication
Impaired glucose tolerance:31% Impaired fasting glucose 7.5% DM : 2-5 folds test OGTT Cardiovascular risk 2 folds Metabolic syndrome 43%
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NIH criteria 2/3 Chronic anovulation Hyperandrogenism
U/S : polycystic ovaries Exclude other causes 20% of woman with regular menses have polycystic ovary LH/FSH> 2 , not useful in diagnosis
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Treatment Short-term management Infertility Hirsutism Acne Obesity
Miscarriage Long-term management Cardiovascular risks Cholesterol Diabetes blood pressure Endometrial Cancer
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Anovulation & Infertility: Clomiphene , GnRH, Metformin
weight reduction lower androgen level , improve hersutism, normalize menses , decrease insulin resistance Anovulation & Infertility: Clomiphene , GnRH, Metformin Protection endometrial CA: Oral contraceptive or Cyclic progestin to prevent : monthly day regimen Antiandrogen Cyproterone acetate (Diane-35) Drospirenone ( Yasmin) RCOG guidline 2003
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34 Years with secondary amenorrhea 19 years
Case 3: 34 Years with secondary amenorrhea 19 years Menarche at age 15 Only 2 cycles Short stature
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Turner Syndrome Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Classic 45,X other : Time of diagnosis 46,X ,i(Xq) 46,X,Xq- 46,X,Xp-
46,X,r(X) 45,X/46,XX Time of diagnosis
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ข้อใดไม่ใช่ Risks ของผู้ป่วย turner syndrome
Hypothyroidism Coartation of aorta Fracture Type 1 CA colon Hypertension Horseshoe kidney Ischemic heart disease Type 2 DM osteoporosis Cirrhosis Type 1 DM Dilated ascending aorta Thyroiditis Karyotype for patients with premature ovarian failure <30yo If hirsutism is present, consider PCOS, congenital adrenal hyperplasia, Cushing’s, or ovarian tumors: check free testosterone
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Renal and liver function Thyroid status & antibody BMD Aortogram
Cardiovascular Record BP, BMI Echocardiogram q 3-5 years FBS Fasting lipid Renal ultrasound Renal and liver function Thyroid status & antibody BMD Aortogram
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Treatment Children : Growth hormone
adequate height, phychological demand, may spontaneous mense Estrogen maintian secondary sex characteristic Bone mass Cycle progesterone Fertility Oocyte donation Oocyte implantation from cryopreservation
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