Amenorrhea Mayurasakorn N.

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

Secondary Amenorrhea Etiology Hypothalamic causes Pituitary causes Premature ovarian failure(<40 years) Outflow tract Hyperandrogenic anovulation Hypergonadotropic hypogonadism Hypogonadotropic hypogonadism Normogonadotropic hypogonadism

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

Normogonadotropic hypogonadism Hyperandrogenic anovulation PCOS Androgen-secreting tumor Cushing’s sd Nonclassical congenital adrenal hyperplasia Thyroid Outflow tract Asherman syndrome cervical stenosis

Most common causes

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

History & Physical examinations Signs of systemic illness ,cachexia Breast : galactorrhea Bitemporal hemianopia Hypothalamus Hyperprolactinemia Pituitary Ovary

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

History & Physical examinations Hirsutism, acne, history of irregular menses Obstetrical catastrophe, severe bleeding, dilatation and curettage, endometritis PCOS

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

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

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

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

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

No withdrawal bleeding Prog.challenge test No withdrawal bleeding Est,progest.challenge test Withdrawal bleeding No outflow tract. hypoestrogenic Hypothalamic- pituitary failure

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

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

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

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%

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

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

Secondary 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 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

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

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

Secondary sex characteristic No Yes Pubic hair Yes No PV Androgen insentivity syndrome Uterus Imperforate hymen Yes No Mullerian agenesis As secondary amenorrhea

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

Primary gonodal failure Gonodal dysgenesis less than 30ykaryotype if Y chromosome exists, excise gonads if 46XX, r/o 17a-hydroxylase deficiency If XOTurner 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

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

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, hydronephrosisIVP 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

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

Imperforate hymen

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

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

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

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.

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

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

Physical Examination Obese female Acne Normal genitalia Mild hirsutism

Laboratory findings Urine B-HCG negative TSH, FSH and Prolactin : WNL Testosterone 180 ng/dL Pelvic U/S

PCOS : 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 Syndorme

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

Metabolic complication Impaired glucose tolerance:31% Impaired fasting glucose 7.5% DM : 2-5 folds test  OGTT Cardiovascular risk 2 folds Metabolic syndrome 43%

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

Treatment Short-term management Infertility Hirsutism Acne Obesity Miscarriage Long-term management Cardiovascular risks Cholesterol Diabetes blood pressure Endometrial Cancer

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 10-14 day regimen Antiandrogen Cyproterone acetate (Diane-35) Drospirenone ( Yasmin) RCOG guidline 2003

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

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

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

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

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

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