estrogen supplementation for luteal phase support.

Transcription

1 Rationale and regimens of progesterone and estrogen supplementation for luteal phase support. Cicinelli E. IV Dept. Ob/Gyn, University of Bari, Italy

2 Luteal phase defect (LPD) The prevalence of LPD in natural cycles in normoovulatory patients with primary or secondary infertility is about 8.1% (Rosenberg et al.,1980). In IVF cycles LPD in about 100% of cases (Ubaldi et al., 1997; Macklon and Fauser, 2000; Kolibianakis et al., 2003).

3 LPD Etiology of LPD in IVF cycles 1. Removal of large quantities of granulosa cells during the oocyte retrieval (OR). 1. However, the aspiration of a preovulatory oocyte in a natural cycle neither diminished the luteal phase steroid secretion nor shortened the luteal phase (Kerin et al., 1981). 2. Prolonged pituitary recovery following the GnRH-a co-treatment may result in lack of support of the CL (Smitz et al., 1992). 3. hcg for the final oocyte maturation in stimulated IVF cycles could potentially suppress the LH production via a short-loop feedback mechanism (Miyake et al., 1979). 1. However, the administration of hcg did not down-regulate the LH secretion in the luteal phase of normal, unstimulated cycles in normo-ovulatory women (Tavaniotou and Devroey, 2003).

4 LPD Etiology of LPD in IVF cycles 4. Supraphysiological levels of steroids secreted by a high number of corpora lutea during the early luteal phase directly inhibit the LH release via negative feedback actions at the hypothalamic-pituary axis level (Fauser and Devroey, 2003). 1. Studies in human and primates have demonstrated that the CL requires a consistent LH stimulus in order to perform its physiological function (Jones, 1991). 2. LH support during the luteal phase is entirely responsible for the maintenance and the normal steroidogenic activity of the CL (Casper and Yen, 1979). 3. However, withdrawal of LH, unnecessary causes premature luteolysis (Duffy et al., 1999).

5 GnRH antagonists: LPD Preliminary studies (IUI cycles) no deleterious effects on luteal P levels and LP duration (Ragni et al., 2001) Subsequent studies in IVF: Premature luteolysis (Albano et al., 1998; Beckers et al., 2003). Reduced chances for pregnancy: in non-supplemented LP of patients stimulated with rfsh + GnRH antagonist (antide; 1 mg/day) the overall pregnancy rates (PR) was very poor (7.5%) and the study stopped (Beckers et al., 2003). Despite the rapid recovery of the pituitary function in GnRH-ant. p p y p y protocols (Dal Prato and Borini, 2005), LPS remains mandatory (Tarlatzis et al., 2006).

6 Luteal phase support in infertility treatments COH hcg Gonadotropins hcg P4 P4 In COH with GnRH-a or GnRH-antagonist, luteal support is necessary because the pituitary drive to the CL is deficient. Triggering ovulation with hcg alters LH production in the luteal Luteal phase phase P4 Pregnancy test

7 Luteal phase support in infertility treatments COH hcg Gonadotropins hcg P4 P4 E2 P4 E2 By extension: E2 E2 1 2 Donor egg IVF Frozen embryo Luteal transfer phase (FET) Pregnancy test

8 Rationale and regimens of progesterone and estrogen supplementation for luteal phase support. Rationale for LPS with progesterone Regimens for progesterone supplementation Rationale for LPS with estrogens Regimens for estrogenic supplementation ti When to start with LPS When to stop LPS

9 Rationale for LPS with progesterone Progesterone induces: a secretory transformation of the endometrium in the luteal phase (Bourgain et al., 1990). after adequate estrogen priming, progesterone improves endometrial receptivity (Kolibianakis and Devroey, 2002). local vasodilatation. uterine musculature quiescence

10 Pinopodes expression correlates with P levels Temporal and morphologic characteristics of pinopod expression across the secretory yphase of the endometrial cycle in normally cycling women with proven fertility Usadi RS et al., Fertil Steril 2003 LD 2 LD 5 LD 8 LD 10 LD 11 LD 14

11 Ayoubi J-M et al. Ferti Steril 2001;76:

12 Uterine contractility and IVF Uterine contract tion (min) Effects of P 3D derived method Fast play Cycle day Ayoubi et al. Fertil Steril Oct 2001 /min UC 7 UC in menstrual cycle and IVF 5 3 * 1 LH/hCG LH+2/Retrieval LH+4/ET LH+6/ET+2 Ayoubi et al. Fertil Steril 2003 In IVF, starting of Crinone 8% on the day of retrieval decreases UC frequency on < >5 the day of ET (Fanchin et al., 2001)

13 Rationale for LPS with progesterone Morphology Ultrastructure UTZ Uterine receptivity i Ed Endometrium ti +Myometrium ti + P Doppler Contractility

14 Meta-analyses Rationale for LPS with progesterone S Daya and J Gunby The Cochrane Database of Systematic Reviews 2004 Issue 4 Copyright 2004 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: / CD This version first published online: 19 July 2004 in Issue 3, 2004 Nosarka S et al. Luteal phase support in in vitro fertilization: meta-analysis of randomized trials. Gynecol Obstet Invest. 2005;60: Department of Obstetrics and Gynaecology, Stellenbosch Univ., Tygerberg, SA. Reviewers' conclusions Luteal phase support with hcg or progesterone after assisted reproduction results in an increased pregnancy rate. hcg does not provide better results than progesterone and is associated with greater risks of OHSS when used with GnRHa. The optimal route of progesterone administration i i has not been established yet.

15 Regimens for progesterone supplementation Alternative to IM P4 in oil How to administer P4? The options Currently available formulations of progesterone include oral, vaginal, rectal and intramuscular (IM) (Chakmakjian, 1987; Fatemi et al. Penzias, 2002).

16 IM progesterone Doses for LPS in IVF cycles: mg/day without any significant difference concerning the outcome (Pritts & Atwood, 2002). Side effects: painful injections and a rash (Lightman et al., 1999) inflammatory reactions and abscesses (Propst et al., 2001) acute eosinophilic pneumonia (Boukaert et al., 2004; Veysman et al., 2006). possible severe morbidity in otherwise healthy young patients (Boukaert et al., 2004). Lack of enthusiasm for this treatment modality (Costabile et al., 2001).

17 Oral progesterone Oral micronized progesterone: not effective for inducing secretory transformation in patients with POF (Devroey et al., 1989; Bourgain et al. 1990). Dydrogesterone (DG) Good oral bioavailability and capacity to achieve secretory transformation (Whitehead, 1980; Chakravarty et al., 2005). LPS: uncertain efficacy LPS after IVF: PRT (n = 430), DG and vaginal P had similar rates of successful pregnancies (24.1 versus 22.8%, respectively; P = NS) (Chakravarty et al. 2005). In POF: PRT, vaginal micronized P more effective than oral DG in creating an in phase secretory endometrium (Day 21) (P = 0.021) (Fatemi et al., 2007). In 1989 Pellicer et al. found similar results.

18 Side-Effects of oral Progesterone Progesterone can modulate CNS GABA A receptor activity through its reduced metabolite, allopregnanolone Sleepiness, moodiness, depression O CH 3 CH 3 CH 3 O CH 3 CH 3 H CH 3 H H H H H O HO Progesterone Allopregnanolone

19 Nahoul K. et al. Maturitas 1993:16;

20 Endometrial Morphology for Women Who Received Crinone 8% (progesterone gel) or IM Progesterone In-P Phase En ndometria (%) Crinone 8% (progesterone gel) (n=55) IM Progesterone (n=24) From: Gibbons WE et al. Fertil Steril. 1998;69:

21 Vaginal Progesterone: Privileged transport to the uterus Uterine effects exceed expectations drawn from circulating i levels The first uterine pass effect

22 Crinone 8% (progesterone gel) Serum and uterine tissue concentration Serum P4 Endometrial tissue P4 P4 levels (ng/ml) 30 1, ,8 15 0,6 10 0,4 5 0,2 0 0 IM progesterone From: Cicinelli E et al. Obstet Gynecol. 2000;95: Crinone 8% Endometrial samples obtained from hysterectomies

23 Vaginal vs IM progesterone in estrogenized postmenopausal women Endometrium/serum progesterone levels l x * IM P Vaginal P 10 Median 1,15 14,08 Min 0,51 8,46 5 Max 13,07 59,43 0 IM P Vaginal P ~ 1 : 14 (Cicinelli et al., Obstet Gynecol, 2000)

24 First Uterine Pass Effect Functional portal system through counter-current exchanges From: Cicinelli and de Ziegler Human Reprod Update 2000

25 E2/P Continental divide Ovarian artery Uterine artery E2/P Ov. art. Ov. art. Ut. art. Ut. art. Follicular phase Luteal phase (Cicinelli et al., Hum Reprod 2004)

26 1 st uterine pass effect Discovered for P4 but physiological role for PGs From: Cicinelli and de Ziegler Human Reprod 2000 P P P P First uterine pass effect

27 1 st uterine pass effect Discovered for P4 but physiological role for PGs From: Cicinelli and de Ziegler Human Reprod 2000 P P PGs PGs P P PGs PGs First uterine pass effect First uterine pass effect

28 Variation in blood flow in the uterine artery and in the arteries of urethravaginal septum depending on the level of vaginal administration % * * * Omolateral l uterine artery 0 Contralateral t l uterine artery Upper 1/3 Lower 1/3 Site of vaginal administration Vessels of urethrovaginal septum (Cicinelli et al., Am J Obstet Gynecol 2003)

29 Importance of the level of vaginal administration U B Uterus Steroid Local (preferential) transfer of vaginal steroids is influenced by the level of vaginal administration: Upper third: to the uterus Lower third: to the urethra (Cicinelli et al., Am J Obstet Gynecol 2003)

30 Regimens for progesterone supplementation

31 .Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. E.A. Pritts and A.K. Atwood. Human Reprod 2002;17: P4 vs. no treatment Questions Outcome measure Author No. of studies No. of patients RR 95% CI Metaanalysis Power #2 Power #1 P4 (vaginal) vs. no TT CPR Artini et al., 1995; Abate yes et al., 1999b P4 (vaginal) vs. no TT DR Abate et al., 1999b no P4 (vaginal) vs. no OPR Artini et al., 1995; Abate yes treatment et al., 1999b P4 (vaginal) vs. no TT SAB Artini et al., no hcg vs. no TT CPR Smith et al., 1989; * yes Herman et al., 1990; Ati Artini iet al., 1995; Beckers et al., 2000 hcg vs. no TT OPR Herman et al., 1990; yes Artini et al., 1995; Beckers et al., 2000 hcg vs. no TT SAB Herman et al., 1990; yes Artini et al., 1995 P4 (i.m.) versus placebo/no CPR Artini et al., 1995; Abate * yes TT et al., 1999a,b P4 (i.m.) versus placebo/no OPR Artini et al., 1995; Abate * yes TT et al., 1999b P4 (i.m.) vs. placebo/no TT DR Abate et al., 1999b * no P4 (i.m.) vs. placebo/no TT SAB Artini et al., no

32 .Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. P4 E.A. Pritts and A.K. Atwood. Human Reprod 2002;17: Questions Outcome measure Author No. of studies No. of patients P4 vs. no treatment >1 Consensus RR 95% CI Metaanalysis Power #2 Power #1 P4 (vaginal) vs. no TT CPR Artini et al., 1995; Abate yes et al., 1999b P4 (vaginal) vs. no TT DR Abate et al., 1999b no P4 (vaginal) vs. no OPR Artini et al., 1995; Abate yes treatment et al., 1999b P4 (vaginal) vs. no TT SAB Artini et al., no hcg vs. no TT CPR Smith et al., 1989; * yes Herman et al., 1990; Ati Artini iet al., 1995; Beckers et al., 2000 hcg vs. no TT OPR Herman et al., 1990; yes Artini et al., 1995; Beckers et al., 2000 hcg vs. no TT SAB Herman et al., 1990; yes Artini et al., 1995 P4 (i.m.) versus placebo/no CPR Artini et al., 1995; Abate * yes TT et al., 1999a,b P4 (i.m.) versus placebo/no OPR Artini et al., 1995; Abate * yes TT et al., 1999b P4 (i.m.) vs. placebo/no TT DR Abate et al., 1999b * no P4 (i.m.) vs. placebo/no TT SAB Artini et al., no

33 .Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. E.A. Pritts and A.K. Atwood. Human Reprod 2002;17: Vaginal vs. oral P4 >1 Consensus Questions Outcome measure Author(S) No. of studies No. of patients RR 95% CI Metaanalysis Power #2 Power #1 P4 (vaginal) vs. P4 IR Pouly et al., 1996; yes (oral) Friedler et al., 1999 * P4 (vaginal) vs. P4 CPR Pouly et al., 1996; yes (oral) Friedler et al., 1999 P4 (vaginal) vs. P4 DR Pouly et al., no (oral) P4 (vaginal) vs. P4 SAB Pouly et al., 1996; yes (oral) Friedler et al., P4 (i.m.) vs. P4 (oral) CPR Licciardi i et al., no hcg vs. P4 (oral) IR Buvat et al., no (short protocol) 45* hcg vs. P4 (oral) IR Buvat et al., no (long protocol) hcg vs. P4 (oral) CPR Buvat et al., no (short protocol) 74* hcg vs. P4 (oral) CPR Buvat et al., no (long protocol) hcg vs. P4 (oral) OPR Buvat et al., no (short protocol) 64* hcg vs. P4 (oral) (long protocol) OPR Buvat et al., no

34 .Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. E.A. Pritts and A.K. Atwood. Human Reprod 2002;17: i.m. vs. vaginal P4 Equivalent Questions Outcome Author(s) No. of No. of RR 95% CI Meta- Power #2 Power #1 measure studies patients analysis P4 (i.m.) vs. CPR Abate et al., 1999b; * 1 yes P4 (vaginal) Anserini et al., 2001 Artini et al. 1995; Guesa et al., 2001; Perino et al., 1997 P4 (i.m.) vs. OPR Artini et al., 1995; yes P4 (vaginal) Abate et al., 1999b P4 (i.m.) vs. DR Perino et al., 1997; * yes P4 (vaginal) Abate et al., 1999b P4 (i.m.) vs. SAB Artini et al., 1995; yes P4 (vaginal) Perino et al., 1997 NS NS

35 .Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. E.A. Pritts and A.K. Atwood. Human Reprod 2002;17: P4 dose Questions Outcome Author No. of No. of RR 95% CI Meta- measure studies patients analysis Power #2 Power #1 P4 dose (vaginal) 400 mg vs. CPR Chanson et al., no mg each day) P4 dose(i.m.)(25 (25 mg vs. CPR Check et al., no mg each day) P4 dose (i.m.) (25 mg vs. OPR Check et al., no mg each day) P4 dose (i.m.) (25 mg vs. SAB Check et al., no mg each day) P4 dose (vaginal) (90 mg vs. CPR Strehler et al., no mg each day) P4 dose (vaginal) (90 mg vs. SAB Strehler et al., no mg each day) 9 P4 dose (i.m.) (341 mg t.i.d. CPR Costabile et al., no vs. 50 mg each day) P4 dose (i.m.) (341 mg t.i.d. OPR Costabile et al., no vs. 50 mg each day) P4 dose (i.m.) (341 mg t.i.d. SAB Costabile et al., no vs. 50 mg each day)

36 .Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. E.A. Pritts and A.K. Atwood. Human Reprod 2002;17: P4 dose Questions Outcome Author No. of No. of RR 95% CI Meta- Vag: 400 vs. 600mg/day measure studies patients analysis NS Power #2 Power #1 P4 dose (vaginal) 400 mg vs. CPR Chanson et al., no mg each day) P4 dose(i.m.)(25 (25 mg vs. CPR Check et al., no mg each day) P4 dose (i.m.) (25 mg vs. OPR Check et al., no mg each day) P4 Vag: dose (i.m.) 90 (25 vs. mg vs. 600mg/day SAB Check et al., NS no mg each day) P4 dose (vaginal) (90 mg vs. CPR Strehler et al., no mg each day) P4 dose (vaginal) (90 mg vs. SAB Strehler et al., no mg each day) 9 P4 dose (i.m.) (341 mg t.i.d. CPR Costabile et al., no vs. 50 mg each day) P4 dose (i.m.) (341 mg t.i.d. OPR Costabile et al., no vs. 50 mg each day) P4 dose (i.m.) (341 mg t.i.d. SAB Costabile et al., no vs. 50 mg each day)

37 IR Vag P IM P Crinone 8% Alan Penzias, Boston IVF IVF cases, in relation to the type of P4 preparation used for luteal support Penzias AS. Luteal phase support. Fertil Steril. 2002;77: Penzias AS, Alper MM. Luteal support with vaginal micronized progesterone gel in assisted reproduction. Reprod Biomed Online. 2003;6: PR NON Crinone Crinone 8%

38 S Daya and J Gunby The Cochrane Database of Systematic Reviews 2004 Issue 4 Copyright 2004 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: / CD / This version first published online: 19 July 2004 in Issue 3, 2004 Progesterone vaginal vs. IM administration Clinical pregnancy per embryo (gamete) transfer with GnRHa NS

39 Vaginal natural micronized progesterone Wide application as a first choice LPS regimen, mainly due to patient comfort and effectiveness (Levin et al., 2001). At least as effective as IM progesterone at providing LPS in induced cycles (Simunic et al., 2007). In Europe, two different forms: Capsules mg (Utrogestan, Prometrium, Progeffiik) Crinone 8%, controlled sustained-release vaginal gel, 90 mg. Ring in U.S. Dosage: Capsules: 200 mg 2-3 times a day ( mg/day) Crinone 8% once a day (Ludwig et al., 2002; Simunic et al., 2007) At the moment no dose finding studies performed Further PRT essential to define the necessary dose for LPS in IVF.

40 Crinone vs Vaginal capsules RCT (n = 126) (Ludwig et al., 2002): Clinical PR 28.8 vs 18.9% NS Clinical abortion rates 14.3 vs 10.0% NS Ongoing PR 24.7 vs 17.0% NS Side-effects: Crinone 8% gel 38/125 Utrogestan vaginal capsules 68/132 Compliance with capsules better than with gel (P < 0.05) (Simunic et al., 2007; Ludwig et al., 2002).

41 Supplementing Luteal E2 luteal E2? Not supported by donor-egg IVF data (mock cycles). de Ziegler D. J Clin Endocrinol Metab, 1992:74: Younis J.S. Fertil Steril 1994;62: Lewin A. Fertil Steril 1994;62: Not supported by early IVF data Smitz J. Human Reprod 1988;3: Motivated by fear of mid-luteal drop in E2 levels Hung E. Human Reprod 2000;15: Sahara F.I. Human Reprod 1999;14: Smitz J. Human Reprod 1992;7: Smitz J. Human Reprod 1993;8:40-5 Are IVF results better when hcg is used for luteal support? Yes : Hutchinson-W KA Fertil Steril 1990;53: No : Martinez F. Gynecol Endocrinol 2000;14:316-20

42 Effect of the additon of E2 to P on LPS in different stimulation schemes COH GnRH agonist GnRH antagonist Smitz et al. (1993) Fahri et al. (2000) Lukaszuk et al. (2005) Lewin et al (1994) Fatemi et al.. (2006) Patients E2 (mg) 6 2 6,2 and IR (%) (P+E 32.8 vs * vs * vs vs vs. P alone) and 9.8 Clinical 29.2 vs * vs * vs vs vs PR/ET (P+E vs. P alone) and 23.1 * P < 0.05 From Fatemi et al., Hum Reprod 2007

43 Supplementing luteal E2? Lukaszuk K et al. Fertil Steril 2005;83: n=80 n=73 n=78 Ctr 2mg 6mg

44 Supplementing luteal E2? Lukaszuk K et al. Fertil Steril 2005;83: PR and IR / E2 supplement 60 placebo E2 2mg/d E2 6mg/d PR/IR PR/IR PR/IR

45 E2 2mg BID orally or vaginally Vag E2 Vag E2 Tourgman DE et al. Fertil Steril 2001;75:

46 Supplementing luteal E2? Critical points: Starting time: at least 3 days after ET Dosage GnRHa vs. GnRH antagonist: The difference in results with the GnRH ant. cannot be explained by the different forms of stimulation protocols used, since the luteal phase characteristics and dynamics of IVF cycles using GnRH agonist or antagonists have been shown to be similar (Friedler et al., 2006) Vaginal route Need of further RCTs

47 When to start LPS Starting time debated No difference on ongoing PR when LPS started on: the day of hcg administration the day of OR the day of embryo transfer (occurring on day 3) (Baruffi et al., 2003) and administered until 18 days following OR (20.8%, 22.7 and 23.6%) (Mochtar et al., 2006) Delaying LPS until 6 days after OR decreases PR of 24% vs. 3 days after OR (Williams et al., 2001). Fanchin R et al. Uterine contractility decreases at the time of blastocyst transfers. Hum Reprod. 2001;16: UC frequency decreases at the time of blastocyst transfers (day 5). Fanchin R, Righini C, de Ziegler D et al. Effects of vaginal progesterone administration on uterine contractility at the time of embryo transfer. Fertil Steril. 2001;75: Early P4 supplementation decreases UC frequency at the time of ET. Mochtar MH, Van Wely M, Van der Veen F. Timing luteal phase support in GnRH agonist downregulated IVF/embryo transfer cycles. Hum Reprod. 2006;21: No apparent differences between day hcg, retrieval and ET.

48 When to stop LPS Luteal phase support in infertility treatments COH hcg Gonadotropins hcg P4 E2 P4 E2 P4 E2 B Early pregnancy Pregnancy test

49 Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery rate. Schmidt KL et al. Fertil Steril 2001;75: Objective: To compare the delivery rate with IVF or ICSI in women who did and did not receive progesterone supplementation in the first 3 weeks after a positive hcg test result. Design: Retrospective study. Method: Patient(s): 200 pregnant women who did not receive progesterone (intervention ti group) and 200 pregnant women who received progesterone for 3 weeks after a positive hcg result. P4 n=200 Vaginal P4 600 mg/day Vaginal P4 600 mg/day Controls n=200 Pregnancy 3 weeks test

50 Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery rate. Schmidt KL et al. Fertil Steril 2001;75: Result(s): The number of deliveries i was 126 in the study group and 128 in the control group. Conclusion(s): The delivery rate was the same in pregnant women who received and those who did not receive P4 for 3 weeks after a positive hcg result. P4 supplementation for more than 2 weeks after embryo transfer may therefore yield no benefit in terms of pregnancy. P4 n=200 Vaginal P4 600 mg/day Vaginal P4 600 mg/day Pregnancy 3 weeks test 126/200 Controls 128/200 n=200 No difference

51 Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery rate. Schmidt KL et al. Fertil Steril 2001;75: Result(s): The number of deliveries i was 126 in the study group and 128 in the control group. Conclusion(s): The delivery rate was the same in pregnant women who received and those who did not receive P4 for 3 weeks after a positive hcg result. P4 supplementation for more than 2 weeks after embryo transfer may therefore yield no benefit in terms of pregnancy. P4 n=200 Vaginal P4 600 mg/day Vaginal P4 600 mg/day No rationale for continuing luteal support beyond the pregnancy test Pregnancy 3 weeks test 126/200 Controls 128/200 n=200 But like us, most do! No difference

52 The duration of LPS First trimester t progesterone supplementation in IVF may support early pregnancy through h 7 weeks by delaying a miscarriage but it does not improve live birth rates (Proctor et al., 2006).

53 Conclusions LPS with HCG or P after assisted reproduction increases PR. HCG increases risk of OHSS. LPS with hcg should be avoided if E2 > 2700 pg/ml and if follicles l > 10. Natural micronized progesterone is not efficient if taken orally. Vaginal and IM progesterone have comparable implantation i and clinical PR and delivery rates. Vaginal P should be delivered d in the upper third of the vagina. The addition of E2 to the progestin support in long GnRH-a protocol regimen may have a beneficial effect on PR and IR. However, no positive effects in short GnRH agonist and GnRHant protocols. LPS should begin no later than 5 days after HCG to trigger ovulation. The length of LPS not > 14 days: from ET (day 3 post OR) until the day of a positive HCG test.