산 부 인 과 김 진 영 Preconceptional care in PCOS

Diagnostic criteria of PCOS (2003) Previous ) Previous ) 1. clinical or biochemical hyperandrogenism 2. chronic anovulation and exclusion of other disorders Revised ) 2 out of 3 Revised ) 2 out of 3 1. oligo or anovulation 1. oligo or anovulation 2. clinical or biochemical signs 2. clinical or biochemical signs of hyperandrogenism of hyperandrogenism 3. Polycystic ovaries and exclusion of other 3. Polycystic ovaries and exclusion of other disorders disorders

PCO >12 follicles in 2-9 mm and/or increased ovarian volume (> 10ml) >12 follicles in 2-9 mm and/or increased ovarian volume (> 10ml) Only one ovary is sufficient to define PCO Only one ovary is sufficient to define PCO Evaluation in MCD#3-5 (early follicular phase) Evaluation in MCD#3-5 (early follicular phase) Clinical Clinical - Hirsutism - Hirsutism - Acne, androgenic alopecia - Acne, androgenic alopecia Biochemical Biochemical - Testosterone, free testosterone - Testosterone, free testosterone - DHEA-S - DHEA-S - Free androgen index (FAI): T/SHBG ratio - Free androgen index (FAI): T/SHBG ratio Hyperandrogenism

증상 (%patients affected) 내분비적 양상장기적 합병증 비만 (38%) 안드로젠 증가 (testosterone, free testosterone, androstenedione, DHEA, DHEA-S) 당뇨 월경 불순 (66%)LH 증가심혈관질환 고안드로젠혈증 (48%)LH:FSH 비율 증가고지혈증 불임 ( 배란요인의 73%)Estrone, Free estradiol 증가자궁내막암 무증상 (20%) 인슐린 증가 유즙분비호르몬 (prolactin) 증가 성호르몬 결합 단백 (SHBG) 증가 PCOS 의 임상적 양상

An-, oligo-ovulation An-, oligo-ovulation obesity obesity Endometrial hyperplasia or cancer Endometrial hyperplasia or cancer Spontaneous abortion Spontaneous abortion Gestational DM Gestational DM DM, dyslipidemia, CVD DM, dyslipidemia, CVD PCOS – reproductive and metabolic dysfunction Infertilit y Pregnancy complication Long-term risk

PCOS and Obesity ~50% of women with PCOS are obese ~50% of women with PCOS are obese Central obesity (waist >88cm, WH ratio 증가 ) Central obesity (waist >88cm, WH ratio 증가 ) BMI > 27 BMI > 27 Insulin resistance, Hyperinsulinemia Insulin resistance, Hyperinsulinemia Weight loss  decrease insulin, increase SHBG,free testosterone, restore ovulation Weight loss  decrease insulin, increase SHBG,free testosterone, restore ovulation

Insulin resistance 근육, 지방조직 hyperinsulinemia Obesity Ovary 유전 ? Association of Insulin resistance and PCOS theca cell 의 androgen 생성 증가 IGF-I, II anovulation

Granulosa GnRH pulse frequency  LH pulse amplitude, frequency  CYP17 IGF-I, IGF-II  Theca Androstenedione  Follicle atresia hirsutism Insulin resistance, Insulin  SHBG  IGFBP-1  obesity Insulin action defect Testosterone  Free-T  estradiol estrone  Pathophysiology of PCOS

Evaluations for PCOS Oligo-,amenorrhea Oligo-,amenorrhea BP, BMI(Kg/m2), WH ratio, BP, BMI(Kg/m2), WH ratio, Sx. for hyperandrogenism or insulin resistance Sx. for hyperandrogenism or insulin resistance ( acne, hirsutism, alopecia, acanthosis nigricans) ( acne, hirsutism, alopecia, acanthosis nigricans) US for ovary (PCO, endometrial evaluation ) US for ovary (PCO, endometrial evaluation ) Testosterone (total, free) ---( hyperandrogenemia) Testosterone (total, free) ---( hyperandrogenemia) TSH, prolactin,17-OHP --- (exclusion for other cause) TSH, prolactin,17-OHP --- (exclusion for other cause) E2, LH, FSH E2, LH, FSH 75gm OGTT, fasting lipid, lipoprotein, 2 hr insulin (Cholesterol,HDL/LDL,TG) --- (metabolic eval.) 75gm OGTT, fasting lipid, lipoprotein, 2 hr insulin (Cholesterol,HDL/LDL,TG) --- (metabolic eval.) Consider EM biopsy Consider EM biopsy Physical Lab

Test for insulin resistance Fasting test2hr test normal<110mg/dL  140mg/dL IFG or IGT mg/dL mg/dL DM  126mg/dL  200mg/dL 75gm OGTT ( IDC, Staged Diabetes Management, 2003 ) IFG : impaired fasting glucose IGT : impaired glucose tolerance 2 hr insulin Insulin resistance very likely :  U/mL Insulin resistance :  U/mL Severe insulin resistance : 300  U/mL

Metabolic Syndrome (NCEP ATP-III) Risk factorDefining level Abdominal obesity Waist circumference Waist circumference Men> 102 cm (40 inch) Women> 88 cm (35 inch) Triglycerides≥150 mg/dl HDL-cholesterol Men< 40 mg/dl Men< 40 mg/dl Women< 50 mg/dl Women< 50 mg/dl Blood pressure≥130/85 mmHg Fasting glucose≥110 mg/dl

Anovulation/oligoovulation  subfertility Anovulation/oligoovulation  subfertility Associated endometrial hyperplasia or cancer Associated endometrial hyperplasia or cancer Increased risk of miscarriage Increased risk of miscarriage 불임에 대한 검사와 전문적 치료가 필요. 불임에 대한 검사와 전문적 치료가 필요. PCOS- infertility

Higher miscarriage rate in PCOS Higher miscarriage rate in PCOS Pathogenesis Pathogenesis 1) high LH (premature oocyte maturation, receptivity?) 1) high LH (premature oocyte maturation, receptivity?) 2) high androgen (follicular atresia) 2) high androgen (follicular atresia) 3) high insulin 3) high insulin 4) obesity 4) obesity 5) Plasminogen activator inhibitor 증가, HOXA-10 suppression 5) Plasminogen activator inhibitor 증가, HOXA-10 suppression Higher LH  lower pregnancy rate and higher miscarriage rate (65% vs.12%) (Regan et al., 1990) Higher LH  lower pregnancy rate and higher miscarriage rate (65% vs.12%) (Regan et al., 1990) Tx : Life style modification (esp. in obesity) Tx : Life style modification (esp. in obesity) Insulin sensitizer during pregnancy (Glueck et al., 2001) Insulin sensitizer during pregnancy (Glueck et al., 2001) PCOS- risk of miscarriage

Increased risk for IGT/type 2 DM (3-7 times) (Legro 1999) Increased risk for IGT/type 2 DM (3-7 times) (Legro 1999) Increased Gestational DM Increased Gestational DM - pre-gestational insulin resistance - pre-gestational insulin resistance - prevalence of GDM ; 7.7 (PCOS) vs. 0.6% (control) (Bjercke 2002) - prevalence of GDM ; 7.7 (PCOS) vs. 0.6% (control) (Bjercke 2002) CVD CVD Risk of endometrial hyperplasia, endometrial cancer ( consider EM biopsy) Risk of endometrial hyperplasia, endometrial cancer ( consider EM biopsy) Tx)  lifestyle modification, insulin sensitizer PCOS - Long term risk

Insulin resistance IGTT DM dyslipidemia Metabolic - DM, Dyslipidemia, CVD Cancer - endometrial cancer Abnormal Glucose metabolism Antilipolysis (lipoprotein lipase, hepatic lipase) genetic environmental LDL HLD TG PAI-1 obesity AS CVD thrombosis

Management of PCOS Tx of amenorrhea/oligomenorrhea Tx of amenorrhea/oligomenorrhea - oral contraceptives : suppress LH and androgen - oral contraceptives : suppress LH and androgen increase SHBG increase SHBG - cyclic progestin : depot or oral provera 10mg,10days - cyclic progestin : depot or oral provera 10mg,10days suppress LH and androgen, prevent EM ca. suppress LH and androgen, prevent EM ca. - insulin sensitizing agent : 3-6mo. Tx - insulin sensitizing agent : 3-6mo. Tx androgen decrease, ovulation, glucose tolerance androgen decrease, ovulation, glucose tolerance

Tx of infertiliy Tx of infertiliy - life style modification (if obesity  Wt. loss !) - life style modification (if obesity  Wt. loss !) - Insulin sensitizer (metformin) - Insulin sensitizer (metformin) - clomiphene citrate, aromatase inhibitor, gonadotropin, - clomiphene citrate, aromatase inhibitor, gonadotropin, - ovarian drilling - ovarian drilling - ART - (risk of OHSS) - ART - (risk of OHSS) recombinant FSH, GnRH antagonist, recombinant FSH, GnRH antagonist, cryopreservation cryopreservation In Vitro maturation of immature oocyte In Vitro maturation of immature oocyte

Prevention and Tx for dyslipidemia Prevention and Tx for dyslipidemia - screening for - screening for 1) lipoprotein  cholesterol control 1) lipoprotein  cholesterol control 2) OGTT  control glucose and insulin 2) OGTT  control glucose and insulin - life style modification (low carbohydrate diet and exercise ) - life style modification (low carbohydrate diet and exercise ) - insulin sensitizer - insulin sensitizer  insufficient data in use in PCOS to prevent DM, but, many trials favor in IGT  metformin can prevent the develop of DM in IGT (Knowler et al., NEJM, 2002) (Knowler et al., NEJM, 2002) - OC, progestin : little effect for DM - OC, progestin : little effect for DM

Metformin (glucophage) - biguanide - biguanide - inhibit hepatic gluconeogenesis, - inhibit hepatic gluconeogenesis, glucose utilization -- not induce hypoglycemia glucose utilization -- not induce hypoglycemia - metabolized in kidney - metabolized in kidney 투여 mg/d, alone or combine with Clomiphen, 투여 mg/d, alone or combine with Clomiphen, gonadotropin gonadotropin side effect : GI trouble (  dose adaptation), side effect : GI trouble (  dose adaptation), lactic acidosis lactic acidosis 검사 : Kidney function test, LFT 검사 : Kidney function test, LFT Insulin sensitizing agent

effect - increase ovulatory frequency effect - increase ovulatory frequency - decrease early pregnancy loss - decrease early pregnancy loss - prevention of develping IGT/DM - prevention of develping IGT/DM - decrease GDM, preeclampsia in PCOS - decrease GDM, preeclampsia in PCOS (Tx during pregnancy ) (Glueck, 2003) (Tx during pregnancy ) (Glueck, 2003) Use in adolescent Use in adolescent pros - safety of metformin, esp.in insulin resistant pros - safety of metformin, esp.in insulin resistant cons - low CHO diet, Wt. loss is enough cons - low CHO diet, Wt. loss is enough OC is better in reducing androgen OC is better in reducing androgen

Reduction of type 2 DM with lifestyle intervention or metformin (NEJM, 2002)

다낭성난소증후군 --- 비만과 관련 다낭성난소증후군 --- 비만과 관련 초기 체중의 5% 만 감량해도 효과가 있다. 초기 체중의 5% 만 감량해도 효과가 있다. ( 예, 60kg 이라면 3Kg 정도 감량목표 ) ( 예, 60kg 이라면 3Kg 정도 감량목표 ) 1 주에 약 3 시간 정도가 적당하다. 1 주에 약 3 시간 정도가 적당하다. ( 예, 하루 30 분 걷기, 10 분씩 3 회 걷기 ) ( 예, 하루 30 분 걷기, 10 분씩 3 회 걷기 ) 갑작스런 감량보다는 점진적인 감량과 유지 갑작스런 감량보다는 점진적인 감량과 유지 체중의 감소가 없더라도 운동을 꾸준히 하면 체중의 감소가 없더라도 운동을 꾸준히 하면 호르몬과 건강에 좋은 효과를 준다. 호르몬과 건강에 좋은 효과를 준다. Exercise for the management of PCOS

균형적인 식사 (30% 지방, 20% 단백질, 나머지 탄수화물 ) 균형적인 식사 (30% 지방, 20% 단백질, 나머지 탄수화물 ) 저탄수화물 식이 - 단백질과 지방의 적절한 섭취 저탄수화물 식이 - 단백질과 지방의 적절한 섭취 ( 단, 극도의 탄수화물 제한 식이는 좋지 않으며, 올리브유, 견과류, 생선의 지방은 건강에 도움이 된다.) 저 인슐린식이 - 당지수가 낮은 음식 저 인슐린식이 - 당지수가 낮은 음식 적은 양씩 나눠서 섭취 적은 양씩 나눠서 섭취 칼슘, 비타민, 충분한 수분 칼슘, 비타민, 충분한 수분 Dietary managenent in PCOS

주스, 시럽과일 주스, 시럽과일 감자, 정제된 곡물 감자, 정제된 곡물 가당 씨리얼, 도너츠 가당 씨리얼, 도너츠 탄산음료, 당분 음료 탄산음료, 당분 음료 과자, 케익, 사탕 과자, 케익, 사탕 신선한 과일, 야채 정제되지 않은 현미, 잡곡밥 섬유소 함유식품 무가당 음료, 다이어트 소다 무가당 요구르트 식이섬유가 많고, 가공되지 않은 음식, 당지수가 낮은 음식 ! 인슐린 저하 음식 선택의 예

당지수가 높은 음식 당지수가 낮은 음식 혈당, 인슐린 빨리 증가 공복감도 빨리 살찌기 쉽다. 혈당, 인슐린 천천히 증가 현미밥 버터 통밀빵 메밀국수두부 마요네즈 팥 우유 달걀소, 돼지, 닭고기 새우, 오징어, 명란 크래커 바케트빵 흰식빵 딸기쨈 쌀밥라면 감자 후추 벌꿀우동 초콜릿 옥수수당근

Conclusion PCOS : reproducitve and metabolic dysfunction with genetic susceptibility PCOS : reproducitve and metabolic dysfunction with genetic susceptibility insulin resistance – major role in pathogenesis insulin resistance – major role in pathogenesis related to infertility, miscarriage, pregnancy complication related to infertility, miscarriage, pregnancy complication ( 특히 obesity 경우 ) ( 특히 obesity 경우 ) High risk of GDM, type II DM -- screening for OGTT, lipid profile High risk of GDM, type II DM -- screening for OGTT, lipid profile Management of PCOS Management of PCOS - Life style modification - Life style modification (regular exercise / Wt control / low carbohydrate diet) (regular exercise / Wt control / low carbohydrate diet) - Insulin sensitizer (Metformin) : for ovulation and preventing DM - Insulin sensitizer (Metformin) : for ovulation and preventing DM 다각적인 치료와 관리 - 무월경, 불임, 대사성 질환예방 (obesity 등 ) 다각적인 치료와 관리 - 무월경, 불임, 대사성 질환예방 (obesity 등 )

감사합니다

인슐린 저항성, 고인슐린 호르몬 불균형, 남성호르몬 증가 무월경, 생리불순, 여드름, 다모증, 자궁내막이상 비만, 당뇨, 지질이상, 고혈압, 자궁내막암 운동, 다이어트 인슐린 - 조절 약물 무배란 피임약 배란촉진제 피임약 황체호르몬주사 운동, 다이어트, 규칙적인 생리유발 병인과 증상에 따른 치료방법

식이섬유와 각종 영양소가 많은 복합탄수화물이 좋다 당과 인슐린을 높이지 않는 식이. 서서히 소화되어 천천히 당을 높인다. 빨리 분해되어 당을 빨리 높임 복합 탄수화물단순 탄수화물

Oral contraceptives Oral contraceptives - Estrogen  suppress LH and androgen - Estrogen  suppress LH and androgen - Progestin ; endometrial shedding, prevent endometrial proliferation, - Progestin ; endometrial shedding, prevent endometrial proliferation, Cyclic progesterone Cyclic progesterone Tx of Oligo/Amenorrhea

청소년기의 치료는 다른점이 있나요 ? 균형적인 식사 균형적인 식사 - 무리한 다이어트는 금물 - 탄수화물, 단백질, 지방을 골고루 섭취 - 당이 적고 섬유소가 많은 음식, 채소, 과일 - 적은양을 자주 먹는다. 규칙적이고 꾸준한 운동 규칙적이고 꾸준한 운동 경구용 피임약, 주기적 황체호르몬 제재를 경구용 피임약, 주기적 황체호르몬 제재를 이용한 규칙적인 생리 유발 이용한 규칙적인 생리 유발 Insulin sensitizer Insulin sensitizer

배란 자궁내막의 증식 생리 생리출혈 정상생리주기와 호르몬 변화

? 여성호르몬 양이 매우 적다 규칙적인 생리 유발 질환의 치료 장기간 복용의 안전성 입증 피임약을 장기간 복용한 경우에서 오히려 심혈관 질환의 위험성은 감소된다 (2004. 미국불임학회 ) 피임약을 오래 복용하면 위험하지 않을까 ….? NO!!

규칙적인운동 체중감량 / 인슐린감소 호르몬 상태 호전 배란, 생리 유발 운동이 치료에 도움이 되나요 ?

?. 저탄수화물, 저인슐린식이를 하되 그 대신 칼로리를 충분히 섭취. 체중감량은 안해도 운동은 도움이 된다. 날씬한 사람도 운동과 다이어트를 하나요 ? YES!

Pathophysiology skeletal m.- resistant skeletal m.- resistant hypoth. hypoth. adrenal -sensitive adrenal -sensitive ovary ovary SHBG Ovary, adrenal Compensatory insulin Testosterone “Selective insulin resistance ---- resulting in hyperandrogenism ” Genetic? Pituitary LH pulse /frequency (Insuin -> androgen )