İnfertil çifte hangi tedaviyi önerelim? Kime, ne zaman, hangi tedavi ? Doç.Dr.Şahin ZETEROĞLU ACIBADEM BURSA HASTANESİ Üreme Sağlığı ve Tüp Bebek Merkezi

İnfertilite Reproduktif dönemde bir yıllık düzenli cinsel ilişkiye rağmen gebelik elde edememe1 % 15- 202 %50 tedavi almakta Tedavi ile 2/3 ü gebe kalmakta The definition of infertility is the inability of couples of reproductive age to establish a pregnancy within 1 year through unprotected sexual intercourse.1 In the United States, 7.3 million women (12% of women of reproductive age) had difficulty or were unable to get pregnant or carry a baby to term.2 (Based on data from 2002) Only half of those couples will actually seek and receive treatment, but with treatment, 2 of 3 couples will succeed in having a child. 1. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S60. 2. Chandra et al. Vital Health Stat 23. 2005;(25):1. 1. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril. 2008;90(5 suppl):S60. 2. Chandra A, Martinez GM, Mosher WD, Abma JC, Jones J. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat 23. 2005;(25):1-160.

Yaş ile beraber over rezervi ve fertilite azalmakta Aylık Fertilite oranı Relative rate Over the past few decades, postponement of childbearing has led to a decrease in family size and increased rates of age-related female subfertility. Age-related decreases in ovarian follicle numbers and a decay in oocyte quality dictate the occurrence of natural loss of fertility and, ultimately, menopause. While ART may help, it does not modify physiology. Fixed early in life: primordial germ cells arrive in the gonadal ridge by the seventh week of gestation. Total germ cell number peaks at 20 weeks of gestation! From a peak of 6-7 million, oocyte number declines to 350,000 by birth. By puberty, there are 200,000 follicles remaining in the ovary. Menopause sets in at an average age of 51 years, although the rate of the ovarian aging process is highly variable. Female age (y) Broekmans et al. Trends Endocrinol Metab. 2007;18:58. Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab. 2007;18(2):58-65. McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000;21(2):200-214.

ART:Yaş ile beraber Gebelik ve doğum oranı azalmakta 60 50 40 Percent 30 20 This graph presents the pregnancy rates, live birth rates, and singleton live birth rates for ART cycles using fresh nondonor eggs or embryos, by the age of the woman in 2006 (for consistency, all percentages are based on the number of cycles started). As you see, a woman’s ability to become pregnant and carry to term decreases dramatically after age 35. 10 <21 22 24 26 28 30 32 34 36 38 40 42 44 46 48 >48 Age (years) Pregnancy Live birth Singleton live birth *For consistency, all percentages are based on cycles started. Centers for Disease Control and Prevention. 2006 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. 2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009. Centers for Disease Control and Prevention. 2006 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. 2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.

Problem ? 35 yaşın altında bir yıllık düzenli ilişkiye rağmen gebelik yok 35 yaşın üzerinde ve 6 ay düzenli ilişkiye rağmen gebelik yok Adet düzensizliği, Kıllanma, Galaktore vb semptomlardan biri var ise If the woman is under 35 and has tried unsuccessfully to conceive for more than 12 months or if the women is over 35 and has tried for more than 6 months, then the couple may need to be evaluated. Often the Ob/Gyn will do initial evaluations and perform first-line treatments. Depending on the findings, patients may need to be referred to an infertility specialist known as a reproductive endocrinologist. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S264. Taylor. BMJ. 2003;327:494. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril. 2006;86(5 suppl):S264-S267. Taylor A. ABC of subfertility. Making a diagnosis. BMJ. 2003;327(7413):494-497.

Değerlendirme/ Kadın Klinik Rutin testler İlk vizit Hikaye ve FM Ovulasyonun değerlendirilmesi Midluteal serum progesteron Ultrasound takibi Endometrial biopsy ? Bazal vücud ısısı ? Ovarian reserv Basal FSH, E2, inhibin B, anti-Müllerian hormone, Clomiphene citrate, exogenous FSH, or GnRH antagonist testing Antral folikül sayısı Uterin faktör Ultrasonografi Histeroskopi Histerosalpingografi (HSG) Tubal faktör HSG LS ? There are a number of tests that can be performed to help diagnose the cause of a patient’s infertility and help determine the course of treatment. During the first exam, the patient’s medical history will be taken, a full physical will be performed, and hormone levels will be measured. Biochemical markers such as basal LH, FSH, E2, inhibin B, anti-Müllerian hormone (AMH), FSH:LH ratio, and midluteal progesterone concentrations can be used to determine the patient’s ovulatory status and ovarian reserves. Other tests are also used to verify ovulatory status, ovarian reserves, and other factors that may impact the patient’s ability to conceive and carry a pregnancy to full term. The next few slides will show some examples of other tests that may be performed. Bowen et al. Fertil Steril. 2007;88:390. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86 (5 suppl):S264. Taylor. BMJ. 2003;327:494. Bowen S, Norian J, Santoro N, Pal L. Simple tools for assessment of ovarian reserve (OR): individual ovarian dimensions are reliable predictors of OR. Fertil Steril. 2007;88(2):390-395. Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril. 2006;86(5 suppl):S264-S267. Taylor A. ABC of subfertility. Making a diagnosis. BMJ. 2003;327(7413):494-497.

Değerlendirme/ Erkek Klinik Rutin Testler İlk muayene Reproduktif hikaye, FM Semen analysis Volum pH Sperm konsantrasyon Total sperm sayısı Hareket yüzdesi İleri hareket Normal morfoloji Sperm agglutinasyonu Viskozite Ek testler Basal hormon analizi: FSH, LH, testosterone, prolactin Postejaculatory urin analizi Ultrasonography Testis bx ? Genetik tarama Ideally, evaluation of the male partner should be conducted at the same time as the female partner to determine appropriate management of the couple as well as to spare the couple the distress of attempting ineffective therapies. During the first exam, the male partner’s reproductive medical history will be taken and a full physical will be performed with a semen analysis. If possible, 2 semen analyses should be conducted, separated by a period of 1 month. Semen analysis provides information on semen volume and sperm quality and quantity. Analysis of basal hormone concentrations may provide information on abnormal spermatogenesis. Hormonal abnormalities of the hypothalamic-pituitary-testicular axis are rare, but are a possible cause of male infertility. Testicular biopsy or examination and ultrasonography may reveal pathologies or obstructions. In addition, further specialized genetic and sperm analyses may be useful in a small number of patients. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S202. Taylor. BMJ. 2003;327:494. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril. 2006;86(5 suppl):S202-S209. Taylor A. ABC of subfertility. Making a diagnosis. BMJ. 2003;327(7413):494-497.

Cut-off reference values for semen characteristics as published in consecutive WHO manuals 1980 1987 1992 1999 2010 Volume (mL) ND ≥ 2 ≥ 1.5 Sperm count (106/mL) 20-200 ≥ 20 ≥ 15 Total sperm count (106) ≥ 40 ≥ 39 Total motility (%) ≥ 60 ≥ 50 Progressive motility ≥ 25% ≥ 25% (a) ≥ 32% (a+b) Vitality (%) ≥ 75 ≥ 58 Morphology (%) 80.5 ≥ 30 (14)* ≥ 4* Leukocyte count (106/mL) < 4.7 < 1.0 The World Health Organization (WHO) periodically releases manuals for laboratory examination of human semen. The first one was published in 1980, with subsequent updates in 1987, 1992 and 1999. These manuals are used as a source of standard methodology for laboratories performing semen analyses worldwide. In 2010, the World Health Organization (WHO) has established new reference values for human semen characteristics which are markedly lower than those previously reported. At first glance, these new values seem to indicate that semen quality is declining worldwide. However, before making any assumption, it is important to understand how these values were obtained. *Strict (Tygerberg) criterion

Tedavi seçenekleri Klinik Tedavi seçeneği Female Faktör Ovulasyon bozukluğu OI Tubal faktör KOH/ IVF Endometriosis IUI (tüpler patent ise), veya KOH/ IVF Male Faktör Male subfertilite IUI +/- KOH Male faktör Female ve/veya male infertilite Unexplained Bekle, IUI, KOH/ IVF Different treatment options are suitable for women and men with infertility due to different causes. Ovulatory failure or dysfunction can be treated with ovulation induction (OI); tubal factor infertility or endometriosis can be treated with controlled ovarian stimulation (COS) and IVF. Male subfertility can be treated with intrauterine insemination (IUI) with or without OI. Unexplained male or female infertility can be treated with IUI, COS with IVF, or ICSI. All conditions need to be considered on a case-by-case basis (eg, not all patients with endometriosis should be treated with IVF; if analysis indicates the patient has patent tubes, these patients may first try IUI). National Institute for Clinical Excellence. Fertility assessment and treatment for people with fertility problems. 2004. http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf. Accessed April 20, 2009. National Institute for Clinical Excellence. Fertility assessment and treatment for people with fertility problems. 2004. http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf. Accessed April 20, 2009.

Yönetim Değerlendirme ve bekleme. Nedene yönelik tedavi. Ovulasyon indüksiyonu IUI IVF/ICSI

Nedene yönelik tedavi: Male Faktör: (Gerekli ise Androlog ile konsültasyon) Tıbbi tedavi: - Hipogonadotropik hipogonadizm : gonadotropin ile tedavi - İdiopatik sperm anormallikleri olgularına anti- estrojen, gonadotropin, androjen, verilmesi anlamsız !! - Varikosel olgularının cerrahi tedavisi Yeteri kanıt yok Halen tartışmalı

Tubal ve uterin faktör: IVF öncesi hidrosalpinks tedavisi Laparoskopik salpenjektomi veya uterin bağlantının kesilmesi IVF başarısına olumlu etki sağlar Tubal microcerrahi ve laparoskopik tubal cerrahi: Hiç tedavi verilmemesine oranla yararlı olabilir. İntrauterin adhezyon - histeroskopik adezyolizis.

WHO ovulatuar bozukluklar 3 grup

Ovulatuar Bozukluklar Grup I: Hipotalamik pituiter yetmezlik Hipotalamik amenore (hipogonadotropik hipogonadizm). Grup II: Hipotalamik-pituiter-ovarian disfonksiyon (PCO). Grup III: Hipergonadotropik hipogonadizm ( ovarian yetmezlik ).

Grup I: Ovulasyon bozuklukları - BMI 19 dan az ise kilo alımı Grup I: Ovulasyon bozuklukları - BMI 19 dan az ise kilo alımı. - Gonadotropin tedavisi (LH mutlaka olmalı).

WHO Group II Ovulasyon Bozuklukları Kilo ver New 2013

WHO Group II Ovulasyon Bozuklukları Kilo vermek Ovulasyonu düzeltir Ovulasyon induksiyonuna cevabı artırır Gebelik sonuçları üzerine olumlu katkı new 2013

BU ARADA risklerde belli bir limitin üzerine çıkıyor. 18

WHO Group II Ovulasyon Bozuklukları Ovulasyon induksiyonu – ( 6 aydan fazla önerilmemektedir). - Klomifen sitrat - Metformin. İkisinin kombinasyonu - Gonadotropinler Ovulasyonu doğrulamak amacıyla 21. gün progesteron testi önerilir. new 2013

OI: Clomiphene Citrate CC Anti- estrogen Estrojen reseptörlerine bağlanarak estrogen-negative feedback üzerinden etki Sonuçta pulsatil GnRH sekresyonu gonadotropin sekresyonu, folliküler gelişimi sağlar Özellikle PCOS ilk seçenek unexplained infertilite ? tedavi ile 6 ay içinde kadınların %80’inde ovulasyon gebelik %40 - %50’sinde gebeliklerin %75’i tedavinin ilk 3 siklusunda CC is an antiestrogen that binds to estrogen receptors and interferes with estrogen-negative feedback. Results in an alteration in pulsatile GnRH secretion Leads to increases in gonadotropin secretion and follicular development CC is widely used for ovulation induction in women with PCOS and in couples with unexplained infertility. CC treatment successfully induces ovulation in about 80% of properly selected candidates. The key is “properly selected candidates.” Successful ovulation does not necessarily translate into a pregnancy. Pregnancy rates are much lower (30%-40% per cycle). 40%-45% of couples can become pregnant within 6 cycles. Failure to conceive after successfully induced ovulation is indication for further evaluation. Patient characteristics predictive of poor response to CC: Hypothalamic disorder Low estrogen levels Obesity American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Case. Can Fam Physician. 2003;49:1465. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86:S187. American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Case AM. Infertility evaluation and management. Strategies for family physicians. Can Fam Physician. 2003;49:1465-1472. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2006;86(5 suppl):S187-S193.

CC: Riskler CC Tedavi 6 siklus ile sınırlandırılmalı. Genel olarak iyi tolere edilir Kısa dönem yan etkileri: sıcak basmaları Mood değişiklikleri Görme bozuklukları Meme hassasiyeti Bulantı Antiestrojenik etki nedeniyle, endometriuma olumsuz etkisi olabilir. Çoğul gebelik Tedavi 6 siklus ile sınırlandırılmalı. Kişisel özellikler ön plana alınarak daha kısa olabilir Yaş, evlilik süresi, bazal karekteristikler vb CC is generally well tolerated although some side effects limit efficacy and raise safety concerns. Short-term, reversible side effects include: hot flashes, mood swings, visual disturbances, breast tenderness, pelvic discomfort, and nausea. The antiestrogenic effects may negatively impact the uterine lining leading to lower pregnancy rates. Transvaginal ultrasound assessment of endometrial thickness before ovulation can indicate thin endometrium (<6 mm). This is a repetitive effect, so patients with a diagnosis of thin endometrium during their first cycle are not candidates for further CC treatment. Risk of multiple pregnancy is increased with CC. Risk of cancer is increased among women who were treated with CC. Uterine cancer risk increases with more than 6 cycles of CC treatment. Risk of ovarian cancer increases among women treated with CC for more than 12 cycles. Treatment should be limited to no more than 6 cycles. The chance of success declines greatly after multiple cycles. Because of the potential side effects associated with CC, all patients should be monitored to assess response to treatment. Without ultrasound monitoring, the number of CC cycles should be limited to 3 (or fewer), and early referral should be considered. Althuis et al. Am J Epidemiol. 2005;161:607. Case. Can Fam Physician. 2003;49:1465. Althuis MD, Moghissi KS, Westhoff CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol. 2005;161(7):607-615. Case AM. Infertility evaluation and management. Strategies for family physicians. Can Fam Physician. 2003;49:1465-1472.

OI: Gonadotropinler CC ile başarısız olgular Veya beklemek istemeyen hastalar FSH, hMG Başarı oranları WHO grup I: %30 / siklus WHO grup II: %17/ siklus Altı aylık kümülatif gebelik ve canlı doğum oranları %62 ve %54 IUI +/- OI Gonadotropin therapy should only be administered under the direction of REs who have the requisite training and experience in its use. Exogenous gonadotropin therapy is optimal for women who have failed CC or who cannot risk waiting (due to age, known male infertility, etc). Used in women with inadequate pituitary secretion of LH and FSH (hypogonadotropic amenorrhea) or PCOS Other causes for infertility should be excluded before gonadotropins are administered. Agents: FSH, hCG, human menopausal gonadotropin (hMG) Success rates WHO class I: 30% per cycle WHO class II: 17% per cycle May include IUI or natural intercourse This slide depicts a typical gonadotropin (low-dose FSH) ovulation induction protocol, with the aim of producing a single oocyte (multiple follicular growth for ARTs such as IVF and ICSI will be discussed later). hCG American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7. American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Practice Committee of the American Society for Reproductive Medicine. Use of exogenous gonadotropins in anovulatory women: a technical bulletin. Fertil Steril. 2008;90(5 suppl):S7-S12.

İntrauterin İnseminasyon Ovulasyon zamanlaması ile konsantrasyonu ve hareket yeteneği artmış spermlerin yumurta yakınına verilmesi gebelik olasılığını arttırır. The rationale is that increasing the density of both eggs and sperm near the site of fertilization will increase the likelihood of pregnancy

IUI Endikasyonları - oligospermi Vajinal ejakülasyonun mümkün olmadığı durumlar - Psikojenik veya organik impotans - Ağır hipospadias, retrograd ejakülasyon Male faktör - oligospermi - asthenospermi - teratospermi Açıklanamayan infertilite ? Servikal faktör Eşin uzun süre karısından uzak kalması (Yurt dışında çalışma gibi) HIV (+) eşe sahip HIV (-) kadınlar

Kanıta dayalı yaklaşımlar- IUI Grade A öneriler* NICE Guidance Feb. 2004 Hafif – orta derecede erkek faktörü Açıklanamayan infertilite ? Hafif- orta endometriozis Olgularına gebelik şansı nedeniyle 2 kez IUI önerilmelidir KOH+IUI * Grade A : Randomize kontrollü çalışmalar

Endometriozis KOH + IUI Bekle–gör veya tek başına IUI uygulamalarına göre daha başarılı RCOG Guidelines : Grade A Recommendation

Kanıta dayalı yaklaşımlar- IUI Grade A öneriler* Eğer IUI erkek faktörü nedeniyle yapılıyorsa KOS zorunlu değildir Bu durum artmış çoğul gebelik riski ile beraberdir Yıkama sonrası total hareketli sperm 5 mil üstü Cohlen et al., January 1999 (Cochrane Review). In: The Cochrane Library, Issue 2 2002. Oxford: Update Software.

Ağır Erkek İnfertilitesi ICSI, IUI ya göre daha cost efektif Van Voorthis et al, 2001

Açıklanamayan infertilite IUI vs TI veya Beklentisel Yaklaşım Intra-uterine insemination for unexplained subfertility (Review) Veltman-Verhulst SM,Cohlen BJ, Hughes E, Heineman MJ The Cochrane Library, 2012 334 Açıklanamayan infertilite vakasının incelendiği Cohrain derlemesinde SADECE aşılama ve zamanlanmış koit veya beklentisel yaklaşım karşılaştırıldığında aşılama grubunda canlı doğum oranları %23, zamanlanmış koit grubunda ise canlı doğum oranları %16 olarak hesaplanmış. Aradaki fark istatistiksel olarak anlamlı olmadığı görülmüştür. 29

Açıklanamayan infertilite IUI veya KOH+IUI İnsemine edilecek spermlerin daha fazla sayıda matür oositle karşılaşması ve tedavi başarısının artırılması için ovulasyon indüksiyonun protokole eklenmesi tedavi başarısını nasıl etkiliyor? Aynı metaanlizde yapılan bir diğer değerlendirmede ovulasyon indüksiyonu ve aşılama yapılan hastalarda canlı doğum oranlarının sadece aşılama yapılan hastalara göre 2 kat artmış olduğu gösterilmiştir. Intra-uterine insemination for unexplained subfertility (Review). Veltman-Verhulst SM,Cohlen BJ, Hughes E, Heineman MJ The Cochrane Library, 2012 30

Klomifen Sitrat Anti- estrojen Kolay kullanım OHSS riski oldukça düşük D 2-5. (50- 250 mg) olarak başla 5 gün süre ile kullan USG D 10 DHEAS >2µg/mL ise, CC+glukortikoid (5mg/gün dex) uygula - CC ile ovulasyon olmaz ise, metformin ekle. (ACOG Practice Bulletin No.34, 2002) CC acts as an anti est on the CNS and increases the secretion of FSH and LH 31

>40y Kadınlarda CC+IUI Check, JH. Archives of Andrology 44:193. 2000

Gonadotropinler Step-Up +75 IU + 75 IU 75 – 150 IU 1 5-7 10-14 18 mm foll olduğu zaman hCG yapılarak 36 h sonra IUI 1 5-7 10-14 33

Step-Down 150 IU/g 112,5 IU/g 75 IU/g Step-up Step-down p Monofollicular 56 % 88 % 0.04 Foll 10 mm- 12 mm ye ulaştığında doz azaltılır, 2 gün sonra tekrar bakılarak foll 14 ün üzerinde ise ve E2 artışı %50- 100 arasında ise tekrar doz azaltılabilir. Doğal siklusda FSH foliküler faz boyunca düşer Low dose step up *Suprafizyolojik FSH? *Multifoliküler gelişim  Başlangıç dozu : 150 iU, en büyük folikül >10 mm ise 37.5iU ve 3 gün devam et Van Santbrink&Fauser, J Clin Endocrinol Metabol 1997 xxxxxsedcrtfvgb jnkml,

Homologous intrauterine insemination: An evaluation of prognostic factors based on a review of 2473 cycles Khalil, MR. Acta Obstet Gynecol Scand 80: 4, 2001.

Kaç kez IUI ? Gebelikler genellikle ilk uygulanan sikluslarda meydana gelir Gebeliklerin %88’ i ilk 3 siklusta %95.5’i ilk dört siklusta Morshedi M et al, 2003 Üç denemeden sonra IUI uygulamasına devam etmek önerilmemektedir.

In Vitro Fertilizasyon. IVF / ICSI Prosedür İlk olarak tubal faktör nedeniyle yapılmakta idi Günümüzde bir çok nedende IVF önerilmekte (endometriozis, male faktör, açıklanamayan vs) Aşamalar KOH Yumurta toplama ICSI, embriyo kültürü Embriyo transfer Ekstra embriyoların Kriyopreservasyonu Riskleri (OHSS) Genellikle ayaktan tedavi edilebilir Hasta dostu ve dondurma teknolojilerinin gelişmesine paralel neredeyse yok kadar az Anestezi Çoğul gebelik Maliyet Psikolojik stress Initially, IVF was used to treat women with blocked, damaged, or absent fallopian tubes. Today, IVF is used to treat many causes of infertility, such as endometriosis and male factor, or when a couple’s infertility is unexplained. The basic steps in an IVF treatment cycle are COS, egg retrieval, insemination, fertilization, embryo culture, and embryo transfer. The medical risks of ART depend upon each specific step of the procedure and include: ovarian hyperstimulation syndrome (OHSS), complications associated with egg retrieval, ectopic pregnancy, and miscarriage. OHSS is usually not serious and resolves with outpatient management, although 1%-2% of cases are severe and require hospitalization. OHSS is dose-dependent and is avoided by careful titration. Some may view the increased probability of multiple births as a risk associated with IVF. This procedure is also costly and may result in significant psychologic distress for couples. American Society for Reproductive Medicine. Assisted reproduction technologies: a guide for patients. 2008. http://www.asrm.org/Patients/patientbooklets/ART.pdf. Accessed April 20, 2009. American Society for Reproductive Medicine. Assisted reproduction technologies: a guide for patients. 2008. http://www.asrm.org/Patients/patientbooklets/ART.pdf. Accessed April 20, 2009.

KOH: Gonadotropin Tedavisi Amaç, daha fazla sayıda oosit elde etmek olduğundan daha yüksek dozlarda gonadotropin kullanılmakta (KOH: 150-225 IU FSH; OI: 50-75 IU FSH) Endojen hormonlarla etkileşimi önlemek için GnRH analog (agonist/ antagonist) Takiben oosit toplama, ICSI ve ET COS COS is used in protocols involving IVF to create multiple oocytes for eventual insemination and implantation. In order to initiate and sustain the growth and development of multiple follicles (rather than to support a single ovulation), higher doses of gonadotropins are required. COS requires higher doses of gonadotropins than OI (150-225 IU of FSH vs 50-75 IU for OI). COS also requires cotreatment with a GnRH analog to prevent interference of COS by endogenous hormones. hCG Borini and Dal Prato. Reprod Biomed Online. 2005;11:283. Arslan M, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S. Controlled ovarian hyperstimulation protocols for in vitro fertilization: two decades of experience after the birth of Elizabeth Carr. Fertil Steril. 2005;84(3):555-569. Borini A, Dal Prato L. Tailoring FSH and LH administration to individual patients. Reprod Biomed Online. 2005;11(3):283-293.

KOH hCG Embryo Transfer rFSH/hMG IVF or ICSI GnRH agonist rFSH/hMG Day 2 or 3 of menses Embryo Transfer Day 6 of FSH GnRH antagonist Cycle day 21-24 rFSH/hMG IVF or ICSI Luteal phase support There are 2 types of GnRH analog: GnRH agonists bind to GnRH receptors on the anterior pituitary and elicit the release of FSH and LH, which initially cause a flare response then a downregulation of the endogenous GnRH, FSH, and LH. GnRH antagonists bind to GnRH receptors and do not elicit a release of hormones, but instead cause an almost immediate downregulation of endogenous hormones. This diagram illustrates a treatment regimen with GnRH antagonists and a “long protocol” with a GnRH agonist in patients undergoing COS with recombinant FSH. In the antagonist protocol, gonadotropins are started on day 2 or 3 of the cycle, then the antagonist is started on day 6 and continues until the day of hCG administration. In the “long agonist” protocol, the agonist is started on day 21 to 24 of the previous cycle and continues through the day of hCG administration with gonadotropins started on day 2 or 3 of the treatment cycle. After hCG, the oocytes are retrieved, and fertilized in the laboratory using either IVF or ICSI, and then the embryos are transferred back into the patient. In most cases, luteal phase progesterone support is given. GnRH agonist rFSH/hMG Down regulation

38- 42 Y / 6 aylık infertilite öyküsü 2 siklus CC/IUI n: 51 2 siklus FSH/ IUI n: 52 Direkt IVF n: 51 Goldman MB, Fertil Steril. 2014

An RCT to compare treatment initiated with 2 cycles of COH/IUI to immediate IVF in older women with unexplained infertility demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group Objective—To determine optimal infertility therapy in women at the end of their reproductive potential. Design—Randomized clinical trial. Setting—Academic medical centers and private infertility center in a state with mandated insurance coverage. Patients—Couples with ≥ 6 months of unexplained infertility; female partner aged 38–42. Interventions—Randomized to treatment with 2 cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. Main Outcome Measures—Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after 2 treatment cycles and at the end of treatment. Results—154 couples were randomized to receive CC/IUI (N=51), FSH/IUI (N=52), or immediate IVF (N=51); 140 (90.9%) couples initiated treatment. Cumulative clinical pregnancy rates per couple after the first 2 cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatment, 71.4% (110/154) of couples conceived a clinically recognized pregnancy and 46.1% delivered at least one live-born baby. 84.2% of all live born infants resulting from treatment were achieved from IVF. There were 36% fewer treatment cycles in the IVF arm compared to either COH/IUI arm and couples conceived a pregnancy leading to a live birth after fewer treatment cycles. Conclusions—An RCT to compare treatment initiated with 2 cycles of COH/IUI to immediate IVF in older women with unexplained infertility demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group Goldman MB, Fertil Steril. 2014 43

The Cochrane Library, 2012

Açıklanamayan infertilite-IVF Başarı şansı en yüksek Gebeliğe ulaşma süresi en kısa Totalde maliyet düşük OHSS ve çoğul gebelik riskinde artış

Kadın yaşı >40 yaş olmak üzere >35 IUI başarı şansı belirgin derecede IVF önceliğini düşün

Tekrarlayan IUI ile başarıda artış yok, maliyet Belli bir sayıdan sonra IVF düşün

TMSS<5-10x106 TMSS>5x106 ve kadın yaşı > 35 IUI başarı IVF

Özet İnfertilite tedavi protokolleri ve başarı temel olarak over yaşı ile ilişkilidir. Bu her zaman gözönüne alınmalıdır. Ek bir faktör yok ise 35 yaşından önce bir yıllık infertilite öyküsü 35 yaşından sonra ise 6 aylık infertilite öyküsü var ise değerlendirmeye alınmalıdır. Temelde nedene yönelik tedavi planlanmalı WHO grup I de OI ilk seçenek Gonadotropin FSH +LH WHO grup II ilk seçenek CC IUI ın yeri tartışmalı, ancak ilk 2 deneme için geçerliliğini koruyor. Açıklanamayan infertilitede özellikle ileri yaşlarda direkt IVF e geçilmesi daha mantıklı Tedavinin tamamen bireyselleştirilmesi gerekir. Zaman ve yaş kaybına dikkat !!!

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