Ovariel stimulering og IVF princip. P Humaidan Fertilitetsklinikken, Skive og Faculty of Health Aarhus Universitet Odense Januar 2014

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1 Ovariel stimulering og IVF princip P Humaidan Fertilitetsklinikken, Skive og Faculty of Health Aarhus Universitet Odense Januar 2014

2 The hypothalamus pituitary ovarian axis

3 Natural menstrual cycle Speroff et al. 5th Edition

4 Folliculogenesis 400 follicles mature sequentially and ovulate during the reproductive lifetime of a woman The other 99.98% of her follicles initiate development, but never complete it These follicles go into atresia due to inadequate stimulation by gonadotrophins Baker and Sum, 1976 Hillier, 1994

5 Folliculogenesis The life-cycle of a follicle lasts at least 85 days (3 cycles) and has 4 phases with different requirements for stimulation by FSH and LH Initiation from birth to senescense - independent of gonadotropic support (appx. 60 days, mm) Progression requires tonic stimulation by FSH (< 2 weeks, 1 5mm; luteal phase) FSH and LH responsive growth and preovulatory maturation (follicular phase) Ovulation induced by the mid-cycle LH/FSH surge

6 Selection - follicular recruitment during natural cycle Hillier et al., 1985

7 FSH is not just FSH FSH released in pulses 1-2 per hour FSH exists in a number of iso-forms Negatively charged sialic acid residues, having a different isoelectric point (pi) Less acidic more acidic FSH iso-forms

8 FSH is not just FSH More acidic isoforms: High number of sialic acid residues clearance lower longer half-life Lower bio-activity Prevailing in the early follicular phase Less acidic isoforms: Fewer number of sialic acid residues shorter half-life Higher bio-activity Estradiol promotes the release of less acidic FSH isoforms from the pituitary Prevailing in the mid-follicular phase and

9 FSH is not just FSH During the follicular phase, the follicle is exposed to an almost constantly changing composition of FSH iso-forms

10 FSH isoform distribution of commercially available FSH preparations Name of prep. pi < 4 (%) pi 4 (%) Acidic isoforms Less acidic isoforms Metrodin Metrodin-HP Puregon 9 91 Gonal-F Horsman et al., Hum. Reprod., , 2000

11 Meta-analysis of studies specifically comparing the clinical efficacy of Metrodin-HP and Gonal-F Parameters relating to the ovarian stimulation Yding Andersen et al., RBMOnline 2004,9,231

12 Meta-analysis of studies specifically comparing the clinical efficacy of Metrodin-HP and Gonal-F Parameters relating to the pregnancy outcome Yding Andersen et al., RBMOnline 2004,9,231

13 Hormones for IUI/IVF/ICSI

14 Follicular stimulation Hillier et al., 1985

15 Follicular stimulation FSH to overcome the threshold level of a follicle derives from either: Endogenous sources Exogenous sources

16 Endogenous stores Clomiphene citrate and aromatase inhibitors (anti-estrogens) CC and aromatase inhibitors increase the endogenous release of FSH

17 Follicular stimulation - exogenous stores Recombinant FSH Gonal F; Puregon, Elonva Urinary FSH Menopur; Bravelle; Fostimon Recombinant FSH/LH Pergoveris

18 GnRH receptorblokering GnRH agonist GnRH agonist (GnRHa) blokerer i løbet af 7-10 dage GnRH receptorer i hypofyse, hvorved LH og FSH frigørelse hæmmes (desensitivering) Præparater: Suprefact (buserelin) s.c. 1mg/ml, 5.5ml Synarela (nafarelin) spray 0.2 mg/pust

19 GnRH receptorblokering GnRH antagonist GnRH antagonist: blokerer i løbet af få timer GnRH receptorer i hypofyse, hvorved LH og FSH frigørelse hæmmes (desensitivisering) Præparater: Cetrotide (0.25 mg/3 mg) Orgalutran 0.25 mg/3 mg)

20 Ovulationsinduktion (ægmodning) Oocyten afslutter første meiotiske deling, hvorved pollegeme (1.) udskydes, og 2. meiotiske deling påbegyndes, men stopper i metafasen; ægget er nu modent Præparater: Urinderiveret hcg (Pregnyl, 5000IU) Rekombinant hcg (Ovitrelle IU) GnRHa (Suprefact 0.5mg) Ovulation indtræffer timer senere

21 Lutealfase støtte Progesteron Præparat: Crinone (gel, 90 mg) Cyklogest (vagitorium, 400 mg) Progestan Estradiol (kapsel, 200 mg) Estrofem (tablet, 2 mg)

22 Ovarian stimulation for IVF/ICSI IN ART : There is no standard patient

23 Ovarian stimulation for IVF/ICSI Standard patients treated with standard doses - frequently do not exhibit standard responses

24 Ovarian stimulation for IVF/ICSI AIM: Accurate assessment of ovarian response potential, before entering the ART programme Individually tailored protocols

25 Can we increase the number of cycles with an adequate response? FSH exposure: the dose and duration Key word: personalized treatment

26 Anti-Mullerian hormone (AMH) AMH produced by granulosa cells barely detectable at birth - reaches the highest value after puberty Mainly expressed on preantral and early antral follicles Most probably reflects the activity of preantral and early antral follicles Reflects the number of selectable follicles during the early follicular phase Seifer et al., 2002 De Vet et al., 2002 Fanchin et al., 2003

27 Anti-Mullerian hormone (AMH) Cut off level of 1.26 ng/ml predicts normal response to stimulation (> 4 oocytes) with success rate of 98% (Hehenkamp et al., 2006) Cut off level of 3.36 ng/ml --- sensitivity of 90.5% and specificity of 80% in predicting OHSS (Lee et al., 2008) Assessable on any day of cycle (La Marca et al., 2007) Systematic review indicates AMH may be a better marker predicting ovarian response than age, FSH, E2 and inhibin B (Reviewed in La Marca et al., 2010)

28 Sonographic parameters Antral follicle count (AFC)

29 Antral follicle count (AFC)

30 Antral follicle count (AFC) 2-10 mm Low Normal PCO like < 5 follicles 5-15follices > 15 follicles (Tomas et al., 1997) <= 3 follicles 4-10 follicles > 11 follicles (Chang et al., 1998) Rotterdam criteria (PCOS): 12 follicles measuring 2-9 mm in diameter in one ovary (Balen et al. 2003)

31 Cheap easy Antral follicle count AFC > 14 may predict hyperresponse One of the best currently available markers of ovarian reserve in predicting poor response (Laszlo et al., 2002) Interobserver variability- endometriosis/cysts inferior compared to AMH Recommended standardization (Broekmans et al. 2010) Additional predictive information provided with the combination of AFC and AMH

32 Other markers BMI Cycle length ( follicles - cycles)

33 Lifestyle Some cornerstones Obesity Smoking Caffeine Psychology (stress, anxiety etc)

34 IVF/ICSI

35 IVF/ICSI Tubal factor Endometriosis Unexplained infertility after IUI x 3 PCOS after IUI x 3 Male factor Combinations

36

37 Henvisning Praktiserende læge Speciallæge Gynækologisk afdeling. Ingen eller kort ventetid

38 Fortid/nutid Lang ventetid Mange forgæves operative indgreb Lav cost/benefit IVF tilbud fra 1984 i DK Donorbehandling eneste tilbud ved mandlig faktor til ca Hurtig diagnostik/behandling Behandling lokaliseret til få specialiserede centre. Tilbud i ekspansion IVF/ICSI : kumulativ PR : 75 % efter 3 forsøg

39 Behandlingskriterier Medicinsk indikation for behandling Behandling afsluttes når kvinden fylder 40 år (45 år) Ingen fælles børn i hjemmet Enlige Lesbiske 3 inseminationsforsøg 3 gennemførte IVF/ICSI behandlinger, dog maximalt 5 påbegyndte behandlingscycli

40 Behandlingstilbud IVF (almindelig reagensglasbehandling) IVF med microinsemination (ICSI) Operativ udhenting af sædceller (PESA/TESA/TESE) kombineret med ICSI Frys/tø behandling Ægdonation - sæddonation Kryopræservation af ovarievæv Sæddeponering

41 Hvad indebærer et IVF/ICSI behandlingsforløb for patienten? Behandling Gener spray og dagl. sprøjte Lettere klimakterielle symptomer første uge af beh (GnRHa). 2-3 scanninger Ægudhentning (5-10 min.) Gener Ubehag og smerter, som kan afhjælpes ved akupunktur eller medicin Træthed, hvis medicinering samme dag Oppustethed 2-4 dage

42 Stimuleringsprincipper IVF/ICSI behandling Traditionel protokol (28 dage) Kort protokol (14 dage) 14 dages forbehandling spray/s.c. 12 dages stimulering (FSH) Ægmodnende sprøjte Ægudhentning Ingen forbehandling dages stimulering (FSH) Sidste 4 dage ægløsningshæmmende sprøjte daglig Ægmodnende sprøjte Ægudhentning

43 Stimuleringsprincipper IVF/ICSI behandling Mål: 8-10 oocyter E2 stimulation dag nmol/l nmol/l 150 FSH < 35 år 225 FSH > 35 år < 0.30 nmol/l : øge dosis - scan stimulation dag > 1.0 nmol/l : reducere scan stimulation dag 8

44 Methods I (FSH <12 IU/I) Gold standard stimulation Protocol (long): GnRHa (Buserelin s.c.) 0.8 mg s.c. daily from the mid-luteal phase, min. 12 days, hereafter 0.4 mg s.c.daily. FSH in individualized dose of IU s.c. according to basal FSH, LH, antral follicle count, AMH and BMI +/- r-hlh from S8 > 35 years, 1LH:2 FSH

45 Methods II (FSH <12 IU/I) 2 generation stimulation Protocol Antagonist (flexible) FSH in individualized dose of IU s.c. according to basal FSH, LH, antral follicle count, age, AMH and BMI from cd 2 GnRH antagonist, 0.25mg at follicle size 12mm +/-r-hlh from S8 > 35 years, 1LH:2 FSH

46 Indvirkning på resultatet Patientens alder Indikation (endometriose, kroniske tarmlidelser, bindevævssygdomme) Adipositas Rygning Psykologiske faktorer Klinikkens håndtering

47 Fortsættelse følger.