多囊性卵巢症候群患者 施行人工協助生殖技術時之 藥物及手術協助誘導排卵新策略

1. 多囊性卵巢症候群患者施行人工協助生殖技術時之藥物及手術協助誘導排卵新策略多囊性卵巢症候群患者施行人工協助生殖技術時之藥物及手術協助誘導排卵新策略 台中榮總 婦產部 生殖醫學科 陳明哲醫師

2. PCO(S)多囊性卵巢(症候群) Diagnosis • PCO: Readily based on ovarian morphology • Polycystic ovaries:ten or more cysts 2-8 mm in diameter, arranged around a dense stroma or scattered throughout an increased amount of stroma • Prevalence of polycystic ovaries: 20-25% in young adults • PCOS: polycystic ovaries found in association with menstrual disturbance, the complications of hyperandrogen and obesity.

3. PCOS 診斷之演進 • Laparotomy and histological confirmation of PCO Stein and Leventhal 1935 • Biochemical criteria Raised LH or LH/FSH Raised Testosterone, androstenedione Abnormal estrogen secretion • Clinical presentation Menstrual cycle disturbance Obesity Hyperandrogenism (hirsutism, acne, androgen -dependent alopecia)

4. US consensus on the diagnosis of PCOS 美國定義- NIH 1990 Two criteria: • Chronic oligo-/anovulation • Hyperandrogenism Hirsutism Hyperandrogen Total testosterone > 89 ng/dl Free testosterone > 0.66 ng/dl Androstenedione > 2.97 ng/ml SHBG Excluding: Hyperprolactinemia, Thyroid dysfunction, LOCAH, Cushing’s, Androgen secreting tumor

5. UK definition of the diagnosis of PCOS 英國定義 • Polycystic ovaries (PCO) Ovarian area > 5.5 cm2 Ovarian volume > 11 ml 12 Follicles: 2-9 mm (mean of both ovaries) • Associated clinical or biochemical features Oligo-/amenorrhea Hyperandrogenism Obesity Elevated serum testosterone Elevated serum LH

6. PCO without PCOS 如何重要 • Incidence: around 20% • Normally ovulatory women with PCO Increased incidence of subfertility and miscarriage Frequently develop typical symptoms after gaining significant weight Exaggerated response to gonadotropin Degree of insulin resistance ranked between PCOS and normal

7. Proposed protocol 流程 for the diagnosis of PCOS Homburg 2002 HR • 1. Symptoms menstrual disturbance, hirsutism, acne anovulatory infertility •  2. Ultrasound examination : If (+) Dx confirmed > 8 follicles (<10mm) in one plane stroma > 25% volume or > 34% area If (-): proceed to •  3. Biochemical examination elevated serum testosterone, elevated LH, elevated free androgen, fasting glucose: insulin < 4.5 If any one (+): Dx confirmed

8. New consensus on diagnosis of PCOS 2003 最新診斷共識 At least two out of the following three criteria • (1) Chronic oligo-/anovulation • (2) Hyperandrogenism • (3) Polycystic ovaries Subsets: (1)+(2); (3)+(2); (3)+(1); (1)+(2)+(3) Excluding hyperprolactinemia, thyroid dysfunction, LOCAH, Cushing’s , androgen secreting tumor

9. PCOS多囊性卵巢症候群 Treatment policy • PCOS: elevated LH, chronic hyperandrogen, insulin resistance (hyperinsulinemia) • CC remains the first-line therapy, ovulation 70~85%, PR 40~50% • Standard (conventional) OI: CC, Gn (hMG, u-FSH, r-FSH), pulsatile GnRH • If fail (refractory to OI in vivo) IVF-ET • Or have coexisting infertility factors

10. Prevalence 盛行率 of PCO(S) in ART Polycystic ovaries • 87% in oligomenorrhea, 26% in amenorrhea, 22% in ‘normal’ population (Polson, 1988) PCO referred for IVF: not so well known • 33% to 50% in IVF cycles: common finding with or without clinical symptoms(MacDougall, 1994) • If there is no other cause for infertility, try ovulation induction first. • OI for pure PCOS and IVF for other causes or after OI has failed(>= 6 ovulatory cycles)

11. Relevance 關聯性 of PCOS to fertility Implication of PCOS to fertility Cause of infertility: anovulation and hypersecretion of LH Elevated basal (follicular phase) LH. Debate: • Adverse effect (Regan, Lancet: 1990) - Midfollicular phase LH > 10 IU/L vs normal : dropped PR (67% vs 88%), increased SAR (65% vs 12%) • No deleterious effect (Thomas, BJOG: 1989) - LH above 75 percentile: no adverse effect on FR Premature endogenous LH surge • LH surge identified at its initiation: abandoned or augmented with HCG • LH surge is established: cancelled • Canceling cycles with spontaneous surge, unless it is caught within 12 h onset, intensive monitoring required

12. COS控制性誘導排卵in PCO(S) Response to stimulation • OI for unifollicular development: slow response, risk of hyperstimulation & cyst formation • OI for multifollicular recruitment: explosive follicle production • Increased number of follicles, oocytes, and estrogen with decreased FR • Prone to OHSS

13. ART人工協助生殖技術 in PCOS Efficacy / Outcome of IVF-ET therapy in PCOS • higher peak E2, • lower hMG requirement, • greater number of follicles, oocytes • reduced FR (57.3% vs 65.7%), CR, • comparable PR/aspiration, PR/ET (22.6~25.4% vs 26.5~23%), or LBR with other diagnosis • more MPR, increased miscarriage (SAB) rate, • no increased congenital abnormalities • 10.5% OHSS (moderate ~ severe)

14. Preconceptional counseling 孕前諮詢 • Importance of the diagnosis of PCO morphology prior to COS • Preconceptional counseling • Explanation the behavior and drugs chosen • Advice about potential problems – OHSS and multiple pregnancies • Miscarriage rate increased. Congenital abnormalities not increased • Reducing the risk of pregnancy loss by weight reduction before ART

15. Preconceptional counseling • Hyperinsulin (obesity) associated with hypertension, pre-eclampsia and GDM (prevalence 8.1%). • Attain ideal BW before conception to avoid pre-eclampsia • Screening women with PCOS for glucose intolerance • Obesity leads to increased UTI, malpresentation, dystocia, PPH, thromboembolism, PNM • Increased risk of HT, NIDDM and CVD, endometrial hyperplasia in later life • The most effective management is advice on diet and weight loss (Obese become slim, non-obese stay slim)

16. COS Strategy for ART in PCOS COS in PCOS for IVF: multifollicular developmentwithout causing OHSS CC with hMG/FSH: premature luteinization and premature LH surge may occur • with deleterious effect on developing oocytes or ovulation prior to OR, these problems are more common in PCOS • COS resulting in collection of large number of oocytes (>10) results in poor prognosis - the optimum number being between 7 and 9 Move toward pituitary desensitization with a GnRH-a • suppression of endogenous LH by GnRH-a is of particular relevance and advantage to women with PCOS

17. COS Strategy for ART in PCOS 壹：Influence of adding GnRH-a in COS • Trends toward reduced cancellation (24%->15%), improved cycle fecundity(16%->27%) (Dodson, 1989) • Longer (30Ds) desensitization: lower androgen, similar PR, SAB, OHSS (Salat-Baroux, 1988) • Reduced P, A, by GC cells, but no difference in number of oocytes, FR, PR (Dor, 1992) • Improved FR (62 vs 51%), improved PR (27 vs 16%), reduced SAB (18 vs 39%) in PCOS (Homburg, 1993)

18. GnRH-a for COS in PCOS • Hughes E, Cochrane review (1996 Feb): Gonadotrophin-releasing hormone analogue as an adjunct to gonadotropin therapy for clomiphene-resistant polycystic ovarian syndrome. Similar conception rates were demonstrated in women receiving GnRHa/hMG/FSH versus hMG/FSH alone common odds ratio 1.50, (95% CI 0.72 – 3.12) No significant difference was noted in the rates of OHSS: common odds ratio 1.40 (95% CI 0.5 - 3.92).

19. GnRH-a for COS in ART in PCOS Bourn Hall data 1060 preg/7623 IVF cycles (6Ys) 1984-1990 Ongoing : 68.3% (724/1060); Spontaneous miscarriage 26.6%; EP: 5.1% Miscarriage rate • No difference in age group: 20-24, 25-29, 30-34 y/o • increased significantly in 35-39 y/o age group: 31.9% • normal ovaries vs PCO: 23.6% vs 35.8% (p=0.0038) • no difference between hMG or FSH with clomiphene (30.2% vs 36.8%) • short buserelin (28%), ultrashort (24.7%) no difference with clomid • highly significant decreased by long buserelin regimen (19.1%) • no difference between hMG or FSH with long buserelin (21% vs 17%)

20. GnRH-a for COS in ART in PCOS

21. GnRH-a for COS in ART in PCOS • Higher rate of miscarriage in CC group: R/O deleterious effects of elevated LH • The use of short or ultrashort GnRHa exposes the patient to the same adverse effects as CC • Pituitary desensitization is the important factor in reducing miscarriage rate in PCO, rather than the CC being the adverse factor • There appears to be no beneficial effect on miscarriage rate for women with normal ovaries. • Pretreatment USG is important in order to select the treatment regimen to optimize outcome

22. Gn for COS in ART in PCOS hMG vs FSH 沒什麼差別 • purified FSH does not substantially improve ovulation rates compared with hMG • incidence of OHSS not reduced with FSH therapy • duration of therapy or amount of gonadotropin required: no difference • no difference in duration, ampoules, oocyte numbers, % mature oocytes, FR,CR,PR and incidence of OHSS (Tanbo, 1990)

23. Gn for COS in ART in PCOS • Daya S Cochrane review (1995 Dec): Follicle-stimulating hormone and human menopausal gonadotropin for ovarian stimulation in assisted reproduction cycles. Among the GnRHa studies, the respective overall odds ratios for clinical pregnancy per cycle started, per oocyte retrieval procedure and per embryo transfer procedure were 1.48 (95% CI, 0.93, 2.34), 1.51 (95% CI, 0.95, 2.40) and 1.54 (95% CI, 0.96, 2.45)

24. Gn for COS in PCOS • Nugent DCochrane review (2000 May): Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome. The beneficial effect of FSH versus hMG for OHSS was only present where no analogue was used (OR 0.20; 95% CI 0.08-0.46), halving the incidence from 12% to 6%. Higher overstimulation rates (OR 3.15; 95% CI 1.48-6.70) were found with the addition of a GnRHa without a significantly higher OHSS rate (OR 1.41; 95% CI 0.50-3.95) although the direction of effect remains. Insufficient data were available to draw conclusions on miscarriage and multiple pregnancy rates.

25. COS Strategy (not for ART) in PCOS Pulsatile GnRH pump 並不適合 • Poor response unless pretreatment with GnRH-a • Prolonged suppression 8 ~ 12 wks followed by pulsatile GnRH at dosage of 5 ~ 20 ug IV/SC at 60~90 min intervals monofollicular ovulation Modification from high-dose step-up regimen • Low-dose step-up regimen • Step-down regimen • Step-up-step-down regimen • Intend to allow selection and dominance to occur

26. COS Strategy for ART in PCOS 貳：Dual suppression (OCP and GnRH-a) Dual suppression improves IVF outcome in high responders (mostly PCOS) Damario HR 1997:2359 • OCP taken for 25 days followed by SC Leuprolide acetate 1 mg/day, overlapped with the final 5 days of OCP. hMG or FSH 150 IU/day since DOC3. • 99 cycles (73 patients in 5 Ys) • Cancellation 13.1% • CPR/initiated cycle 46.5% • OGPR/initiated cycle 40.4% (Miscarriage 13.1%) • OHSS: mild-moderate 8/99 • Improvement in FR, IR, CPR, OGPR

27. Dual suppression (OCP and GnRH-a)

28. Dual suppression (OCP and GnRH-a)

29. COS Strategy for ART in PCOS Prevention of OHSS 風險規避計劃 • Frequent complication in COS for PCOS • Oocyte aspiration imparts partial protection • Recognizing the risk factors: young age and PCOS etc and clinical profile • Individualize the medication regimen, start at lowest Std dose, close monitoring, even low dose of hMG may be associated with severe OHSS • GnRH-a suppression confers no protection but risk for OHSS, not necessary to deviate in PCOS • At risk sign: decrease medication or mid-cycle coasting

30. Prevention of OHSS • Withholding Gn for 1 ~ 8 days (controlled drift period) - Incidence of OHSS: 2.5%, PR: 25%/cycle (~1996) • Trigger ovulation with GnRH-a in lieu of HCG (cycles without prior desensitization) - Buserelin acetate 250 ~ 500 ug IN at Q12H for 2 doses - LA 500 ug SC • Administration of albumin at the time of OR - 25 g human albumin IV st + 25 gm at recovery room or - Single dose of 50 gm human albumin diluted in 500 ml crystalloid st • Use of exogenous P as opposed to hCG for LPS • Cryopreservation of all embryos - re-administration of GnRH-a till subsequent menstruation

31. Administration of albumin Debate: Ben-Chetrit RCT HR 2001: 1880 • OHSS incidence no difference: relative risk (RR) = 1.49, 95% CI = 0.59-3.73 • Conception rates no difference: RR = 0.78, 95% CI = 0.44-1.39) • Albumin appears to have no positive effect on OHSS or conception rates, while its use carries the risk of undesirable side effects, including exacerbation of ascites in OHSS, nausea, vomiting, febrile reaction, allergic reaction, anaphylactic shock and risk of virus and prion transmission. We suggest that this form of treatment should not be included in the prevention of OHSS.

32. COS Strategy for ART in PCOS 參：Coasting 靠岸策略 HR 2003:937, Levinsohn-Tavor • Coasting: withdrawing exogenous Gn / postponing hCG • First described by Rabinvici in 1987, first applied in IVF by Sher 1993 • Variable application, heterogeneous criteria, inconsistent efficacy • What is the best formula / recommended protocol? - Should be initiated when ? - But not unless the leading follicles reach ? - Duration should be limited to ? - Administration of hCG withheld till serum E2 falls to ? - Incidence of severe OHSS ?, FR: ?, PR: ?

33. COS Strategy for ART in PCOS 參：Coasting 靠岸策略 • What is the best formula / recommended protocol? - Should be initiated when serum E2 > 3000 pg/ml - But not unless the leading follicles reach 15-18 mm - Duration should be limited to < 4 days - Administration of hCG withheld till serum E2 falls < 3000 pg/dl - Incidence of severe OHSS: < 2%, FR: 55-71%, PR: 37-63%

34. Coasting

35. Coasting 何時該靠岸休息呢？ When? • Excessive response, at risk of severe OHSS • ~ Size of active granulosa cell population • Serum E2 > 3000 pg/ml; more than 30 follicles • Serum E2 > 6000 pg/ml: 38%; Fs > 30: 23%; Both: 80% SOH (Asch, 1991)

36. Coasting When to initiate / terminate? • Factors: serum E2, number of follicles, diameter of leading follicle • E2: 2500-3000 pg/ml; high cut-off associated with higher OHSS / longer coasting • Additional subsequent rise • hCG administration with E2 < 2500-3000, - not be allowed to fall too low below it • when leading F >= 15 mm, follicular growth continued to a size of > 18 mm - oocytes in smaller follicles -> maturation arrest and atresia - too many larger follicle -> cystic follicles and poor quality oocytes

37. Coasting 該休息多久呢？ Duration? • >= 4 days reduces the IR and PR (Ulug, 2002; Isaza 2002) • <= 4 days did not influence outcome (Waldenstrom, 1999) • Interval of coasting mainly affects EM receptivity!? • Prolonged coasting: reduction of OR rate and embryo quality!? • Coasting is initiated when F not more than 17-18 mm, E2 not more than 6000 pg/ml, period of > 4 days can be avoided (Egbase 2000)

38. Coasting How successful? • Severe OHSS 0.5-2% in IVF • < 2% in high-risk patients managed with coasting • 20% if too early hCG / too late coasting • 80% if non-coasting • No significant difference in oocyte maturity / quality, fertilizability, cleavage embryo quality (Isaza, 2002) and PR (37~63%). • More specific marker for prediction?

39. Early coasting早點休息吧！ HR 2002: 1212, Egbase Early coasting: consistent with good clinical outcome • 102 obese PCOS • Fixed period of 3 days • Leading follicle 15 mm • > 10 follicles per ovary • E2 > 1500 but < 3000 pg/ml • Mean hpFSH: 23.2 ampoules • E2 coasting D1: 1943, hCG day: 2169 • FR 73.9%, CR: 87.7% CPR:45.1% • No severe OHSS

40. Modified Coasting Strategy 有些複雜！ HR 2001:24, Al-Shawaf : based on ultrasound and E2 • E2 <3000 pmol/l (817 pg/ml), the Gn dose maintained; • E2 > 3000 pmol/l but <13200 pmol/l (3595 pg/ml) and 25% of the follicles had a diameter of 13 mm, the Gn dose halved; • E2 > 13200 pmol/l and 25% of the follicles had a diameter of 15 mm, patients were coasted, hCG 10000 IU was administered when at least three follicles 18 mm and E2 <10000 pmol/l (2724 pg/ml) • MOH 0.7%, SOH 0.2% • PR: 39.6-40%; IR: 30.7-25.6% (reduced-coasting group)

41. Auxiliary Strategy for ART in PCOS 肆：早期(?)單側濾泡抽吸術〈EUFA〉 Egbase HR, 1999:1421 EUFA vs coasting • E2 > 6000 pg/ml and > 15 Fs (>=18mm) each ovary • EUFA 10-12 hours after hCG vs coasting 4.9 Ds till E2 < 3000 pg/ml • Similar E2 & Fs at starting: 9911 vs 10055 & 43.3 vs 41.4 • Higher oocytes retrieved: 15.4 vs 9.6 • Higher % OR/F: 91.4% vs 28.3% • Similar FR and CR • Similar CPR: 40% vs 33% • Similar OHSS: 26.6% vs 20%

42. 早期單側濾泡抽吸術〈EUFA〉

43. COS Strategy for ART in PCOS 伍：有限度卵巢刺激策略〈LOS〉 Limited ovarian stimulation without IVM El-Sheikh, EJOGRB 2001:245 LOS prevent SOH in PCOD (EJOGRB 1999:81 LOS preliminary report 5 patients) • 20 patients with prior SOH • Long protocol (Suprefact, nasal) with daily hMG (150IU) injection • hCG 10000 IU administered when the leading F reached a diameter of 12 mm • OR 36 hours later (120 mm Hg, 15G, no flushing) followed by ICSI and ET - HMG ampoules decreased (21.5 vs 28.4); Duration decreased (10.4 vs 13.9 Ds) - E2 decreased (1978 vs 2754); Fs decreased (27.6 vs 34.3) - Oocytes retrieved decreased (15.7 vs 25.5); MII oocytes: 12.3+6.3 (4-25) **!! - FR: 70.5% by ICSI; 8 clinical pregnancies (40%) and none recurrent SOH • No need to be stimulated until leading F reaches 18 mm!!

44. COS Strategy for ART in PCOS 陸：體外培育成熟之策略(IVM) Cha 1991-2000 FS 2000:978 IVM in PCOS Oocytes were retrieved by a US-guided oocyte aspiration technique either 10–13 days after spontaneous menses or withdrawal bleeding induced by IM injection of P • 64 patients, 94 cycles • 13.6 oocytes per patients • 89% morphologically normal • 62.2% matured in vitro • 68% FR after ICSI (62.2%x68%=42%) • PR 27.1% (23/94 cycles) IR: 6.9%

45. COS Strategy for ART in PCOS 陸：體外培育成熟之策略(IVM after priming) Lin & Hwang HR 2003:1632 60 PCOS 68 IVM cycles rFSH 75 IU for 6 Ds then hCG (35 cycles) vs hCG alone (33 cycles) hCG 10000 IU, OR (usual needle with flush) -> IVM -> ICSI -> D2 or D3 ET • E2 level: 377.2 pmol/l vs 143.8 pmol/l (102.7 pg/ml vs 39.2 pg/ml) • Oocytes retrieved: 21.9 vs 23.1 • Maturation rate 74.2% (48 hours): 76.5% vs 71.9% • Fertilization rate 72.8%: 75.8% vs 69.5% (74.2%x72.8%=54%) • PR 33.8 %: 31.4% vs 36.4% • IR: 9.7% vs 11.3% Confirm the beneficial effect of hCG priming FSH priming has no additional beneficial effect on IVM IVM for PCOS is a feasible treatment

46. 體外培育成熟策略(LOS/priming+IVM)Lin & Hwang HR 2003:1632 好棒！

47. 體外培育成熟之策略(priming+IVM) Son (Korea) HR 2002:134 • BC development and pregnancies after IVM-ICSI/IVF from unstimulated PCOS with in-vivo HCG priming • Maturation medium: YS medium with 30% hFF + 1IU/ml rFSH+10 IU/ml hCG+10 ng/ml rhEGF Son HR 2002:2963 • Ongoing twin pregnancy after vitrification of BCs produced by IVM for PCOS • Coculture with cumulus cell with above maturation medium system Bagele (Austria) HR 2002:373 • Successful pregnancy resulting from IVM oocytes retrieved at LSC surgery in PCOS • DOC 12 10000 IU hCG given, Combined LSC retrieval of immature oocytes and ovarian electrocautery (using monopolar needle 40W at the puncture sites of OR 有點麻煩 有些複雜

48. Auxiliary Strategy for ART in PCOS 柒：經陰道卵巢鑽孔術 (TVOD) Tranvaginal ovarian drilling Feraretti, FS 2001:812 TVOD improves outcome of ART in PCOS TVOD was performed under anesthesia with Propofol using a 17-gauge, 35-cm long needle. Each ovary was repeatedly punctured from different angles, and all the small follicles visible by US were aspirated and scraped. Patients were discharged after 2–3 hours and followed up with by US, • Higher FSH required 52.2 vs 33.5 ampoules • Higher FR (66% vs 27%) & CR (72% vs 54%) • CPR 58% and IR 26% • TVOD is effective in difficult PCOS • TVOD less invasive and expensive as compared to LOD

49. 柒：經陰道卵巢鑽孔術 (TVOD)

50. Auxiliary Strategy for ART in PCOS 捌：經腹腔鏡卵巢熱療(灼洞)術(LOD) LOD Laparoscopic ovarian diathermy (drilling) Tozar HR 2001:91: may be beneficial • 31 patients : 15 (22 cycles) with LOD; 16 (24 cycles) without LOD • Oocytes retrieved: no difference • Decreased embryos available for transfer (4.6 vs 7.1) • CPR decreased (41.2% vs 63.2%) • Miscarriage rate decreased (28.6% vs 66.7%) • OGPR/ET improved (29.4% vs 10.5%) not statistically significant • OHSS decreased (0% vs 4.2%) • No deleterious effect, may be beneficial!