PCOS & Pregnancy - 임옥룡 박사


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PCOS & Pregnancy - 임옥룡 박사

  1. 1. Polycystic Ovarian Syndrome 2012.04.03 임옥룡
  2. 2. Prevalence Most common female endocrinopathy 5-10% of reproductive(3% in adolescent) 90% with oligomenorrhea 70% with hirsutism 20% with polycystic ovary 20-40% with persistent acne only 10% with alopecia only 75% of anovulatory infertility(M/C)
  3. 3. Rotterdam criteria(2003) Oligo-(>35days) or anovulation Hyperandrogenism(biochemical or clinical) : hirsutism, testosterone Polycytic ovaries(US) - ≥ 12 follicles in either ovary measuring 2-9mm in diameter - >10mL ovarian volume
  4. 4. Pathogenesis
  5. 5. Pathophysiology Insulin resistance 20-50% Compensatory hyperinsulinemia -65-70% of women with PCOS -70-80% of obese -30-40% of normal weight Hyperinsulinemia result in increased ovarian theca androgen production and decreased production of SHBG by liver Disorder of androgen excess or hyperandrogenism
  6. 6. Manifestations Multiple manifestations -cutaneous -reproductive -metabolic Peripubertal(12-13y) in onset
  7. 7. Cutaneous manifestations Hirsutism ; mFG ≥ 6 Acne, persistent acne Baldness
  8. 8. Reproductive manifestations oligomenorrhea >35 days secondary amenorrhea anovulation infertility early pregnancy loss
  9. 9. Metabolic and endocrine manifestations increased Testosterone(total,free) Androstenedione decreased SHBG increased Insulin increased LH/FSH ratio Dyslipidemia
  10. 10. lab Baseline blood sample ; LMP 3-7 day FSH, LH Prolactin, TSH, free thyroxine(FT4) Testosterone(total) Testosterone(free) ; gold standard FAI=100xTestosterone(ng/mLx3.467)/SHBG(nmol/L) Androstenedione >2.57ng/mL 17-HP, DHEAS, SHBG 75g OGTT, Insulin(fasting) TG(N<150mg/dL) HDL(N>50mg/dL)
  11. 11. Insulin resistance Insulin(fasting) >20mU/mL(10) Homeostasis model assessment of IR (HOMA-IR) >2.5 fasting insulin(mIU/L) x glucose(mg/dL)/405 C-peptide >4.6(2.5)
  12. 12. DDx Thyroid disease(hypo- or hyperTH) ; less Hyperprolactinemia ; 30% of secondary amenorrhea Ovarian failure Congenital adrenal hyperplasia ; 21-OH-deficient nonclassic-CAH(M/C) 17-HP >2.0ng/mL(synacthen test) Cushing’s syndrome ; amenorrhea(80- 100%),hirsutism(60-100%), acne(40-50%) Androgen secreting tumor ; rare Severe insulin resistance and hyperinsulinemia (fasting insulin 80uIU/mL, 2hr >300uIU/mL) Idiopathic hirsutism
  13. 13. General risk on PCOS Infertility Dysfunctional bleeding Endometrial carcinoma OR 2.7 Obesity(50%) Type2 diabetes mellitus(T2DM) Dyslipidemia Hypertension Cardiovascular disease
  14. 14. Menopause on PCOS Improve many manifestations of PCOS(ovarian size, morphology, T levels) Increased rates of obesity, insulin resistance, hyperinsulinemia, T2DM, dyslipidemia, cardiovascular events
  15. 15. Obstetric risk of PCOS Early pregnancy loss GDM 40-50% OR2.94 Pregnancy-induced hypertension OR3.67 Preeclampsia OR3.47 Premature delivery OR1.75 Increased perinatal mortality OR3.07 SGA 10-15% Delivery by cesarean section
  16. 16. Risk of PCOS for female offspring Higher risk of developing PCOS Daughters of women with PCOS -increased LH and testosterone -hyperinsulinemia -increased in ovarian size during puberty Genetic component, supported by strong familial association Environmental component, including programming from intrauterine hyperandrogenemia
  17. 17. Risk of metabolic disorders for the female offspring Timing of fetal androgen exposure seems to be important factor in determining phenotypic presentation of offspring -Offspring of female monkeys that treated early(gestational day 40) had impaired insulin secretion -offspring of late-treated(gestational day 100- 115) females show decrements insulin sensitivity with increasing adiposity, but preserved normal insulin secretory function
  18. 18. Risk of male offspring Increased body hair growth, premature male balding, and insulin resistance Increased risk of coronary heart disease Mechanism not clear, but may involve insulin resistance that develop because of exposure to intrauterine hyperandrogenemia
  19. 19. Genetic counseling Strong familial clustering Lack of reliable association between genotype and phenotype raises possibility that inheritance of PCOS modified by environmental factors Multifactorial
  20. 20. Therapies No Treatment Weight loss Oral contraceptives Metformin Hirsutism Acne Anovulation and infertility
  21. 21. No treatment Spontaneous ovulation in PCOS occur, but infrequently Although ovulation frequently increases as PCOS women age, less likely to conceive and deliver a baby
  22. 22. Weight loss Lifestyle changes(diet/exercise) effective treatment 500-1000kcal daily reduction Loss of 5-10% of body weight in 6 months reduce hirsutism, acne, restore ovulation and improve obstetric outcomes Fasting insulin, androstenedione, dihydrotestosterone decreased. Although LH, FSH, DHEA, DHEAS, testosterone, estrogen level unchanged Protect T2DM and improve dyslipidemia
  23. 23. Oral contraceptives Reduce hyperandrogenism via suppression of LH secretion and by stimulating SHBG production First-line therapy for hirsutism Yasmin(drospirenone ; antiandrogenic) after 3month, efficacy assessed OCP continues until gynecologically mature (5y post menarche) Progesterone only ; if estrogen contraindication or periodic progestogen withdrawal requested(7-10d every 3months often in four withdrawal bleeds annually)
  24. 24. Metformin Metformin introduced in late 1950s In USA, metformin(insulin sensitizer) available in 1990s Reduce insulin resistance and insulin secretion by reduction of ovarian androgen Inhibit hepatic glucose production Reduce plasma TG concentration Reduced weight and centripetal obesity Begin at 500mg daily/wk(1000-2500mg/d) Improve menstrual frequency and restore ovulation In PCOS, Protect against development of GDM and reduce later development of T2DM
  25. 25. Factors affecting response to metformin Higher BMI ; poor response <4wks metformin pretreatment suboptimal Insulin-resistant PCOS with low BMI ; good response Higher insulin, low androstenedione, less severe menstrual irregularity ; good response
  26. 26. Metformin on ovulation Combination of CC and metformin or metformin alone After 6-8wks of metformin, letrozole plus metformin Either 6wks before or at GnRH agonist long protocol Ovarian drilling plus metformin CC resistant, Obese, Glucose intolerance
  27. 27. Metformin on cancer Because insulin promotes growth and has mitogenic effects, suggested that metformin might reduce risk of cancer in diabetic patients Evans et al. in T2DM patients, metformin had a 23% reduced risk of cancer compared to patients on sulfonylureas Bowker et al. show that cancer-related mortality rate significantly lower in metformin group compared to sulfonylureas Decreased breast cancer Reduction in risk of pancreatic cancer OR0.38 Lower risk of prostate cancer
  28. 28. Duration of metformin use Metformin for at least 8 weeks(PCOS) -reduced weight, fasting glucose, triglycerides and LDL by 4.5-5.6% -fasting insulin by 14% -calculated HOMA-IR by 22% -reduced new onset diabetes by 40% In PCOS metformin for up to 6 months reduced hirsutism and reduced androgen , with reductions in testosterone 25-50%
  29. 29. Metformin indication Metformin as a first line therapy -T2DM(PCOS) -IFG and IGT(PCOS) -as it is in general population -GDM(12wks, 32wks?, term?)
  30. 30. Hirsutism modified Ferriman-Gallwey ≥ 6 Loss of 5-10% of weight improve hirsutism within 6 months Prolonged(>6months) medical Tx
  31. 31. Hirsutism treatment Diane 35(cyproterone acetate ; block androgen receptor 2mg/d) -improve acne(3M), hirsutism(9M) -add of CPA 10-100mg/d on first 10days Yasmin(drospirenone 3mg/d) Spironolacton(competitive inhibitor of androgen receptor) 100mg/d -widely used for hirsutism in USA where CPA not available -40% reduction after 6months Finasteride 1-5mg/d(inhibit 5a-reductase) -30-60% reduction in hirsutism score
  32. 32. Acne Isotretinoin beneficial, in severe cases Eflornithine hydrochloride(inhibitor of ornithine decarboxylase) topical apply
  33. 33. Anovulation and infertility Clomiphene citrate Metformin Tamoxifen Aromatase inhibitor(letrozole) Low-dose gonadotrophin therapy Glucagon like peptide-1(GLP-1) Laparoscopic ovarian drilling In-vitro fertilization
  34. 34. Clomiphene citrate Block estrogen receptor(hypothalamus). Induce pulsatile release of GnRH and induce FSH from anterior pituitary CC 50-150mg/d starting on Day 2, 3, 4 or 5 Restore ovulation 49% and pregnancy 23%(PPCOS trial) Substitution of CC with tamoxifen(20mg for every 50mg of CC) avoid anti-estrogenic effect CC resistance 20% of PCOS
  35. 35. CC and Metformin In PPCOS trial, ovulation 52% in first month and 60% over 6 months Live birth rate over 6 months 27% Benefit of combined therapy on live birth rates debated
  36. 36. Tamoxifen No anti-estrogenic effect Not licensed for ovulation Used in a similar way to CC(5 days in early follicular phase) with starting daily dose of 20mg-40mg if ovulation not
  37. 37. Aromatase inhibitor Letrozole, anastrazole Block action of aromatase that convert androstenedione and testosterone to estrogen(no anti-estrogenic effect) Increased release of FSH Half life 2 days 2.5-5mg/d for 5 days on Day2, 3, 4 or 5 Questions of possible teratogenicity(locomotor and heart)
  38. 38. Low dose gonadotrophin therapy Gonadotropin typically offered to not ovulated with oral therapies Live birth rates over 6 cycles 60% Multiple pregnancy rates 16% Cancellation rate 16-40% Low dose gonadotropin 37.5 to 75 units
  39. 39. Glucagon like peptide-1 agonist Glucagon like peptide-1(GLP-1) ; incretin, which enhances glucose-dependent insulin secretion, delays gastric emptying, and centrally controls appetite, therefore producing weight loss GLP-1 agonist exenatide, metformin, and their combination in obese patients with PCOS after 24wks of intervention, ovulation rates improved by 50%, 29%, and 86%. Suggest that GLP-1 agonists may have a role in therapy for PCOS
  40. 40. Adolescence(13-19y) All three of Rotterdam criteria make diagnosis of PCOS 85% anovulatory during the first year after menarche 59% still anovulatory during the third year after menarche
  41. 41. In adolescent girls, Androgen Excess Society(AES) 2006 criteria anovulation frequently occurs in the first 2 y after menarche(physiologic anovulation) multifollicular ovaries can be a normal finding in adolescence defining biochemical androgen excess in adolescence girls difficult as normative ranges fluctuate during puberty and acne and mild hirsutism are common and obesity becoming more prevalent
  42. 42. Adolescence treatment Many of pediatric colleagues have already adopted metfomin as a standard treatment in light of difficulties of maintaining diet and life style restrictions in younger age group
  43. 43. conclusion Weight loss(diet, exercise) Oral contraceptives(yasmin, diane35) Metformin Clomiphen citrate Tamoxifen Letrozole Low dose gonadotrophin therapy Glucagon like peptide-1 agonist