PCOS Non-IVF'te Gonadotropin Tedavisinde Kritik Noktalar Dr Batuhan Özmen Ankara Üniversitesi KHD AD USAUM, Üreme Sağlığı Merkezi

PCOS: OI Amaç: Anovulatuar PCOS hastalarında fertilitenin sağlanması ve tek canlı doğuma ulaşılması,

İnsidans %6-7 Female İnfertilite: %40 sebep anovulasyon Anovulatuar infertilite: %75-80 sebep PCOS PCOS’a sekonder anovulatuar infertilitede ilk-basamak tedavi halen CC

PCOS:OI Klomifen Sitrat Homburg R, Hum Reprod, 2005

PCOS:OI Klomifen Sitrat Imani et al Fertil Steril 2002

CRA ? Birçok merkez 150-mg CC’ye rağmen ovulasyon yoksa CCR The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2007. Hum Reprod 2008

CC / Ovulasyon Oranları 50 mg  %46 100mg  %21 150mg  %8 %75 %25 olguda CRA Anovulation is estimated to cause 40% of female infertility, and many cases are due to the polycystic ovary syndrome (PCOS). In these cases of euestrogenic anovulation, clomiphene citrate (CC) remains the primary therapy to induce ovulation; 75% of patients ovulate in response to CC treatment (1). Approximately 70% of patients who respond do so at a dose of 50 or 100 mg of CC (2); the maximum dose is usually 250 mg. However, we and many other infertility specialists consider patients who do not ovulate while receiving the 150-mg dose of CC to be resistant to the drug. Homburg R, Hum Reprod, 2005 7

CC rezistan olguda kabul edilmiş standart bir yaklaşım yok … PCOS / ESHRE – ASRM Tanı: Rotterdam kriterleri, 2003 Tedavi: Selanik, 2007 First-line tedavi CC Second-line tedavi LOS Gn CC rezistan olguda kabul edilmiş standart bir yaklaşım yok … The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2007. Hum Reprod 2008

SOGC Clinical Practice Guideline 2010 Gonadotropin Oİ 2nd-line tedavi olarak anovülatuar PCOS hastalarında önerilmektedir. Tedavi ultrason ve laboratuar olarak takip gerektirir. Yüksek maliyet ve çoğul gebelik ile OHSS en önemli risklerdir. (II-2A) J Obstet Gynaecol Can 2010

%71 Kümülatif Gebelik CC takiben Gnd OI Eijkemans et al Hum Reprod 2003

GONADOTROPİN Ovulatuar siklus % 70-98 Kümülatif gebelik oranı % 35-70 van Santbrinket al., 1995 White et al., 1996 Mulders et al., 2003 DEZAVANTAJ Çoğul gebelik >%10-30 OHSS %1-10 Siklus iptali %3-10 Fauser and Van Heusden, 1997.

PCOS OI: Gonadotropin Kritik Noktalar Hasta seçimi Protokol tipi Gonadotropin tipi GnRH Ant ? Adjuvant Ajanlar İptal kriterleri Sonuçlar Coğul Gebelik OHSS Siklus başarısı

Ovulasyon İndüksiyon Protokolleri Standart doz step-up Düşük doz protokoller Kronik düşük doz step-up Düşük doz step-down Ardışık düşük doz step-up/ step-down Kronik ultra düşük doz step up

Klasik (Konvansiyonel) Protokol 18 mm hCG 5000-10000 IU 16 mm 14 mm E 2 12 mm 10 mm 300 ıu 225 IU 150 IU 1 2 7 14 21 28 35 Başlangıç dozu 150 IU, 2-4. günü USG sonucuna göre doz artışı 75 IU Doz artışı her 5-7 günde

Klasik (Konvansiyonel) Protokol Ovulasyon %62-98 Konsepsiyon (siklus başına) %10-20 Çoğul gebelik %15-36 Abortus %24-42 OHSS %1.1-14

Düşük Doz Step-down Protokolü 150 IU FSH 5 gün süre ile, follikül > 10 mm olana kadar 3 gün aralıklarla 37.5 IU doz artımı, daha sonra hCG kriterleri sağlanana kadar 3 günde bir 37.5 doz azaltımı

van Santbrink,European Journal of Endocrinology (2002)

Klasik ve Düşük Doz Klasik Protokol Düşük Doz Protokol 94 %16 %27 %6.3 Siklus Gebelik Çoğul gebelik OHSS Homburg, 95 48 6 2 5 59 10 Hedon, 98 46 9 1 42 14 Total 94 %16 %27 %6.3 101 %24 %8 %0.9

Düşük doz Step-down OHSS↑ Stimülasyon süresi ↓ Kötü cevaplı hastalarda uygun yöntem olabilir. These regimens have proved to be successful in reducing the risk of ovarian hyperstimulation while maintaining a satisfactory pregnancy rate (7, 10). However, these protocols were imprecise, as it was necessary for the patient to self-administer half or two-thirds of a 75-IU ampoule of urinary gonadotropins. With the availability of recombinant FSH (rFSH) preparations in vials containing 50 IU (follitropin beta) or 37.5 IU (follitropin alfa), it was easier for patients to use smaller doses. The hCG was withheld if there was an insufficient ovarian response after 35 days of treatment or in the case of ovarian hyperresponse (3 follicles of 15 mm). In the latter instance, conversion to IVF-ET was allowed. Stimulation is cancelled when multifollicular growth is apparent and more than three folliclesO12 mmin diameter are present. 20

Kronik Düşük Doz Step-up Protokolü hCG gününe kadar follikül > 10 mm sağlayan dozda devam

Düşük Doz Step-up Protokolü Ovulasyon (monofoliküler) %70-92 Konsepsiyon (siklus başına) %20 Çoğul gebelik %5.7 Abortus %11-28 OHSS %0.14

Step-up versus step down protocols in PCOS (Messinis,2005)

Christin-Maitre S, Hum Reprod 2003

CRA olgularda Gnd CC dirençli hastalarda düşük doz step-up protokolü daha güvenilirdir Takip eden sikluslarda step-up protokollere başlangıç dozu, cevap alınan dozun 25 veya 37.5 IU altı olmalıdır Düşük doz step-down protokol dirençli hastalar için uygun yaklaşım olabilir İptal kriterlerini belirlemek gerekli

Düşük Doz Step-up: Kritik Noktalar Başlangıç Dozu (37.5, 50, 75) Doz artım süresi (7 vs 14, 3 vs 7) Doz artım düzeyi (25, 37.5, 50) Doz düşüş gerekli mi İptal kriterleri

FSH Eşik Yaş BMI, Önceki CC siklus cevabı, IGF-1 düzeyi Bazal FSH konsantrasyonu Imani B,Fertil Steril 2002

Probability Increased İnfertilty duration < 2 years FAI < 9 Cumulative ongoing pregnancy rate over time expressed per cycle in 85 women with clomiphene citrate-resistant PCOS. Presented at each treatment cycle is the number of pregnancies attained at that treatment cycle per number of women still under treatment. Probability Increased İnfertilty duration < 2 years FAI < 9 Oligomenorrhea Cumulative ongoing pregnancy rate over time expressed per cycle in 85 women with clomiphene citrate-resistant PCOS. Presented at each treatment cycle is the number of pregnancies attained at that treatment cycle per number of women still under treatment. van Wely M et al. Hum. Reprod. 2005;20:1827-1832 © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Düşük doz step-up Folikül çapı < 10 mm Folikül çapı > 18 mm hCG These regimens have proved to be successful in reducing the risk of ovarian hyperstimulation while maintaining a satisfactory pregnancy rate (7, 10). However, these protocols were imprecise, as it was necessary for the patient to self-administer half or two-thirds of a 75-IU ampoule of urinary gonadotropins. With the availability of recombinant FSH (rFSH) preparations in vials containing 50 IU (follitropin beta) or 37.5 IU (follitropin alfa), it was easier for patients to use smaller doses. The hCG was withheld if there was an insufficient ovarian response after 35 days of treatment or in the case of ovarian hyperresponse (3 follicles of 15 mm). In the latter instance, conversion to IVF-ET was allowed. 52.5 IU 75 IU 112.5 IU 150 IU 187.5 IU 225 IU WHITE ET AL. 1996 JCE 30

Düşük doz step-up Ovulasyon başarısızlığı < %5 hasta Ciddi OHSS (-) ,İkiz gebelik %6 75 IU başlangıç dozunda %20 siklus iptali 52.5 başlangıç dozuna Ovulatuar siklus %72 Ovulatuar siklus %71 % 50 (37-79) monofoliküler %84 monofoliküler Gebelik %45 Gebelik %57 Düşük %35 Düşük %20 WHITE ET AL. 1996 JCE Balash et al 2001 Hum Reprod

Low dose step up 37.5 vs 50 FSH Başlangıç dozu 37.5 IU n=12 Gün 13.5 ± 0.9 12.47 ± 0.72 NS IU 522.5 ± 45.9 623.3 ± 35.8 <0.05 EŞİK IU 40.0 ± 2.5 50 ± 0 <0.005 hCG günündeki Fol 10-13mm 0.33 ±0.16 0.2 ±0.14 Fol 13-17mm 0.27 ±0.12 0.53±0.17 Fol >17mm 1.7 ±0.24 1.7 ±0.24 E2 286 ± 22.7 296 ± 24.7 Unifoliküler % 67 % 60 Bifoliküler % 33 % 40 Prospective, randomized, crossover study including 15 women with clomiphene citrate-resistant chronic anovulatory infertility. Patients were treated with subcutaneous recombinant FSH at starting doses of 37.5 IU and 50 IU, respectively, according to a low-dose step-up protocol. Each woman received both treatments, in a randomized order, with an interval of 1 month between treatments. Balasch 2000. Journal of Assisted Reproduction and Genetics, 32

Düşük doz step-up önceki siklus ovulasyon(+) gebelik (-) Folikül çapı < 10 mm Folikül çapı > 10 mm Folikül çapı > 18 mm hCG 52.5 IU 75 IU 112.5 IU Folikül çapı > 10 mm In women who developed multiple follicles, the treatment protocol was amended so that either a smaller starting dose was used (some patients will respond to 37.5 IU) or the increment in dose was less than usual (i.e. 25 Folikül çapı > 18 mm Folikül çapı < 10 mm hCG 75 IU 112.5 IU 33

%36 siklus iptal oranı Folikül çapı > 18 mm Folikül çapı < 10 mm hCG 50 IU 100 IU 150 IU 200IU All the patients exhibited a follicular response: 6 (54%) of 11 ovulated, of whom 2 conceived. Four had their cycles cancelled because of overstimulation. Three of these had an explosive response, and 1 underwent diffuse ovarian enlargement and was discontinued from treatment because of a failure of unifollicular domination and a high risk of hyperstimulation. One patient did not ovulate despite the development of a follicle. One had an ovulatory cycle with the initial dose of 50 IU without any increase. %36 siklus iptal oranı Hayden 1999. Fertil Steril 34

%13 siklus iptali % 84 ovülasyon % 6.8 OHSS (minimal-mild) % 14 gebelik /siklus % 36.5 gebelik /hasta % 5.8 çoğul gebelik (ikiz) % 1.5 ektopik gebelik Alsina 2003, BJOG

Düşük doz step-up Folikül çapı < 12 mm Folikül çapı > 18 mm hCG These regimens have proved to be successful in reducing the risk of ovarian hyperstimulation while maintaining a satisfactory pregnancy rate (7, 10). However, these protocols were imprecise, as it was necessary for the patient to self-administer half or two-thirds of a 75-IU ampoule of urinary gonadotropins. With the availability of recombinant FSH (rFSH) preparations in vials containing 50 IU (follitropin beta) or 37.5 IU (follitropin alfa), it was easier for patients to use smaller doses. The hCG was withheld if there was an insufficient ovarian response after 35 days of treatment or in the case of ovarian hyperresponse (3 follicles of 15 mm). In the latter instance, conversion to IVF-ET was allowed. 50 IU 75 IU 100 IU 125 IU 150IU 175 IU Leader et al. Fertil Steril 2006 36

(Fertil Steril 2006; In total, 118 women completed the trial (68 in the 25-IU dose increment group and 50 in the 50-IU dose increment group). The mean (SD) total dose of follitropin beta administered was lower in the 25-IU group than in the 50-IU group (886.6 491.3 IU vs. 984.3 572.4 IU). The estimated treatment difference (adjusted for center) was also statistically significant (160.7 IU; P .013; 95% CI of difference, 287.2 to 34.3). 37

Leader et al. Fertil Steril 2006 No statistically significant differences were found for the cancellation rate due to low response, the total number of treatment days, and the mean serum FSH level. Nor was the difference in ongoing pregnancy rate (20.0% in the 25-IU group vs. 12.8% in the 50-IU group) statistically significant. Leader et al. Fertil Steril 2006 38

%20.5 %5.0 Leader et al. Fertil Steril 2006 Figure 3 shows the cancellation rate due to ovarian hyperresponse by treatment period. A considerably higher number of women in the 50-IU group developed an ovarian hyperresponse: 20.5 % versus 5.0% in the 25-IU group (P .004). In the present study, one woman (1.3%) in each group was hospitalized because of OHSS. This indicates that both dose regimens are adequate to minimize the risk of OHSS in a group of patients particularly sensitive to it. The low occurrence of multiple gestations (only two cases) supports the importance of careful monitoring of follicle development during ovarian stimulation in PCOS patients. A surprising finding was the relatively low incidence of miscarriage (11.1% of pregnancies) in our 25-IU group. Most large series of pregnant patients with PCOS report an early miscarriage rate of 20%–30% (7). However, a similarly low miscarriage rate (15%) was also observed in a small study of the sequential step-up and step-down regimen (20). Leader et al. Fertil Steril 2006 39

Step-up sonrası Step-down protokol İlk siklus step-up protokol ile FSH eşik değeri belirlenir Takip eden siklusta eşik değerin 37.5 IU fazlası ile step down siklusu başlanır. kümülatif gebelik oranı % 82 devam eden gebelik oranı %58 Tekil canlı doğum %43 Çoğul canlı doğum % 5 Mulders, et al. 2003. Reprod. Biomed Online 41

Step-Up / Down Protokolü Sequential Protocol 10 mm hCG 5000-10000 IU 18 mm 14 mm 16 mm 12 mm E 2 150 IU 112.5 IU 112.5 IU 75 IU 75 IU 35 1 2 6 12 step-up 14 mm foll. sonra step-down

Doz Düşürülmesi Hugues, et al. Hum Reprod 2006

GnRH Ant: OI, PCOS

Metformin + FSH vs FSH: OI POS CLD step-up Moll E et al. Hum. Reprod. Update 2007;13:527-537 Yarali et al., 2002; Tasdemir et al., 2004; Palomba et al., 2005; van Santbrink et al., 2005

Metformin + FSH vs FSH: OI POS CLD step-up Figure 3 Results of FSH ovulation induction using a low-dose step-up protocol in 17 normogonadotropic insulin-resistant anovulatory subfertile patients after randomization and co-treatment with metformin or placebo (n = 7). Results of FSH ovulation induction using a low-dose step-up protocol in 17 normogonadotropic insulin-resistant anovulatory subfertile patients after randomization and co-treatment with metformin or placebo (n = 7). van Santbrink E J P et al. Eur J Endocrinol 2005;152:611-617

5. Recombinant FSH versus urinary Gonadotrophins ( van Wely et al

rFSH vs uFSH: PCOS OI Outcome or subgroup title Statistical method Studies Participant Statistical method Effect size 1 Ovulation rate (per cycle) 2 457 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.19 [0.78, 1.80] 2 Pregnancy rate (per patient) 3 445 0.95 [0.64, 1.41] 3 Miscarriage rate (per pregnancy) 172 1.26 [0.59, 2.70] 4 OHSS rate (per patient) 1.55 [0.50, 4.84] 5 Multiple pregnancy rate (per pregnancy) 0.44 [0.16, 1.21] 6 Mean duration of stimulation (days) 1 96 Mean Difference (IV, Fixed, 95% CI) -0.32 [-2.95, 2.31] Bayram et al 2001-2009 Cochrane Review

Siklus İptal Endikasyonları > 2 follikül >16 mm >1 folliküle >16 mm + 2 follikül >14 mm, >Serum E2 1200 pg/mL

Sonuç-I CC dirençli hastalarda düşük doz step-up protokolü daha güvenilirdir. PCOS’ lu hastalarda FSH eşik değerini belirlemek için gonadotropin uygulamalarında düşük doz step-up protokolü ilk seçenek olmalıdır. Başlangıç Gonadotropin dozu hastanın prediktif özelliklerine göre ayarlanmalıdır. Düşük doz step-up protokolünün en önemli dezavantajı uzamış tedavi süresidir 50

Sonuç-II Takip eden sikluslarda step-up protokollere başlangıç dozu, cevap alınan dozun 25 veya 37.5 IU altı olmalıdır. Düşük doz step-down protokol dirençli hastalar için uygun yaklaşım olabilir ve cevap alınan dozun 25-37.5 IU üstü doz ile başlanır. 51

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