Die vaginale Anwendung von natürlichem Progesteron als Lutealphasenunterstützung nach IVF und Embryotransfer

Zusammenfassung

Die Notwendigkeit einer Lutealphasenunterstützung nach Embryotransfer im Rahmen der ovariellen Überstimulation und IVF gilt als gesichert. Zur Lutealphasenunterstützung können Progesteron (P) und humanes Choriongonadotropin (hCG) allein, in Kombination, oder in Kombinationen mit Östradiol (E2) auf verschiedenen Verabreichungswegen verwendet werden. Die gegenständliche systematische Übersichtsarbeit widmet sich der Frage, wie die Effizienz, im Sinne der klinischen Schwangerschaftsrate pro Embryotransfer, der vaginalen Verabreichung von natürlichem Progesteron in Form von Kapseln, Suppositorien und Vaginalcremes im Vergleich zu anderen Formen der Lutealphasenunterstützung, inklusive dem Crinone® 8 % Vaginalgel, ist. Zur Beantwortung dieser Frage wurde die vorliegende Literatur systematisch gesichtet und die relevanten Daten aus randomisierten Vergleichsstudien zur Lutealphasenunterstützung nach IVF‐ET einer quantitativen Datensynthese unterworfen. 24 Studien mit insgesamt 5334 Patientinnen in 33 Vergleichsgruppen konnten eingeschlossen werden. Die häufigsten Vergleichsgruppen waren: vaginales P als Kapsel/Suppositorium vs. 1) intra-muskuläres P (Odds Ratio [OR] 0,99 [95%-Konfidenzintervall {CI} 0,58 - 1,72]); 2) hCG (1,13 [0,84 - 1,52]); 3) vaginales P + hCG (1,02 [0,76 - 1,36]); 4) Crinone® 8 % (0,96 [0,76 - 1,22]); 5) vaginales P + orales E2 (1,03 [0,68 - 1,56]); und 6) oral verabreichtes P oder Gestagen (1,11 [0,69 - 1,76]). Die Studienergebnisse in den einzelnen Vergleichsgruppen waren homogen, mit Ausnahme des Vergleiches von vaginalem P vs. IM P. Die vorliegenden Literaturdaten indizieren keinen signifikanten Unterschied der Vergleichsgruppen hinsichtlich der Wahrscheinlichkeit einer klinischen Schwangerschaft nach IVF‐ET.

Abstract

The beneficial effect of luteal phase support after embryo transfer in IVF treatment (IVF-ET) has unequivocally been accepted. Various substances (human chorionic gonadotropin (hCG), progesterone (P), estradiol [E2]) and regimens of administration are employed. The present systematic review aims at determining the efficacy of administration of vaginal P as capsules, suppositories or vaginal cream versus other forms of luteal phase support (including Crinone® 8 % vaginal gel) after ovarian hyperstimulation and IVF‐ET. The available literature was reviewed and data on clinical pregnancy rates per embryo transfer was retrieved from randomised controlled trials. 24 studies with a total of 5334 randomized patients in 33 group comparisons were included in this review. In these studies, various doses of vaginal P as capsules/suppositories/vaginal cream in various administration regimens were evaluated. The following subgroups were identified: vaginal P vs. 1) intra-muscular P (odds ratio [OR] 0.99 [95 % confidence interval {CI} 0.58 - 1.72]); 2) hCG (1.13 [0.84 - 1.52]); 3) vaginal P + hCG (1.02 [0.76 - 1.36]); 4) Crinone® 8 % (0.96 [0.76 - 1.22]); 5) vaginal P + oral E2 (1.03 [0.68 - 1.56]); and 6) orally administered P or gestagen (1.11 [0.69 - 1.76]). Results of individual studies were homogenous in subgroup comparisons except for vaginal P vs. intra-muscular P. Current data from the literature indicate no significant difference between vaginal P as capsules/suppositories/cream as compared to a wide range of other forms of luteal phase support after IVF.

Schlüsselwörter

Progesteron - IVF - Lutealphase - Utrogest - Crinone

Key words

Progesterone - IVF - luteal phase - Crinone - Utrogest

Literatur

• 1 Abate A, Perino M, Abate F G, Brigandi A, Costabile L, Manti F. Intramuscular versus vaginal administration of progesterone for luteal phase support after in vitro fertilization and embryo transfer. A comparative randomized study.  Clin Exp Obstet Gynecol. 1999;  26 203-206
• 2 Abate A, Brigandi A, Abate F G, Manti F, Unfer V, Perino M. Luteal phase support with 17alpha-hydroxyprogesterone versus unsupported cycles in in vitro fertilization: a comparative randomized study.  Gynecol Obst Invest. 1999;  48 78-80
• 3 Albano C, Grimbizis G, Smitz J, Riethmuller-Winzen H, Reissmann T, Van Steirteghem A, Devroey P. The luteal phase of nonsupplemented cycles after ovarian superovulation with human menopausal gonadotropin and the gonadotropin-releasing hormone antagonist Cetrorelix.  Fertil Steril. 1998;  70 357-359
• 4 Allen C, Harrison R F. Luteal support progesterone vaginal vs. pessary clinical/endocrine outcome. [abstract] ESHRE 27 - 30 June 2004 Hum Rep 19 (Suppl. 1): i125 (abstr. # P‐363). Oxford, UK; Oxford University Press
• 5 Andersen A N, Popovic-Todorovic B, Schmidt K T, Loft A, Lindhard A, Hojgaard A, Ziebe S, Hald F, Hauge B, Toft B. Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial.  Hum Reprod. 2002;  17 357-361
• 6 Artini P G, Volpe A, Angioni S, Galassi M C, Battaglia C, Genazzani A R. A comparative, randomized study of three different progesterone support of the luteal phase following IVF/ET program.  J of Endocrinol Invest. 1995;  18 51-56
• 7 Balasch J. Dydrogesterone treatment of endometrial luteal phase deficiency after ovulation induced by clomiphene citrate and human chorionic gonadotropin.  Fertil Steril. 1983;  40 469-471
• 8 Bellaisch-Allart J, De Mouzon J, Lapousterle C, Mayer M. The effect of hCG supplementation after combined GnRH agonist/HMG treatment in an IVF programme.  Human Reproduction. 1990;  5 163-166
• 9 Bouckaert Y, Robert F, Englert Y. et al . Acute eosinophilic pneumonia associated with intramuscular administration of progesterone as luteal phase support after IVF: case report.  Hum Reprod. 2004;  19 1806-1810
• 10 Chakravarty B N, Shirazee H H, Dam P, Goswami S K, Chatterjee R, Ghosh S. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: Results of a randomised study.  J Steroid Biochem Mol Biol. 2005;  97 416-420
• 11 Beckers N GM, Macklon N S, Eijkemans M J, Ludwig M, Felberbaum R, Diedrich K, Bustion S, Loumaye E, Fauser B CJM. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.  JCEM. 2003;  88 4186-4192
• 12 Daya S, Gunby J. Luteal phase support in assisted reproduction cycles.  The Cochrane Database of Systematic Reviews. 2004;  3 CD004830 DOI: 10.1002/14651858.CD004830
• 13 Devroey P, Palermo G, Bourgain C. Progesterone administration in patients with absent ovaries.  Int J Fertil. 1989;  34 188-193
• 14 De Ziegler D. Hormonal control of endometrial receptivity.  Hum Reprod. 1995;  10 4-7
• 15 Dunstone T, Zosmer A, Hussain S, Tozer A, Paney N, Wilson C. et al .A comparison between Cyclogest pessaries and Crinone gel as luteal support in IVF‐ET cycles [abstract]. British Fertility Society Annual Meeting Abstract Book. 1999 62: (abstr. # FC21)
• 16 Feige A, Rempen A, Würfel W, Jawny J, Caffier H. Frauenheilkunde. 2nd Edition. München, Jena; Urban und Fischer 2001: 191
• 17 Critchley H, Buckley C H, Andersen D. Experience with a “physiological” steroid replacement regimen for the establishment of a receptive endometrium in women with premature ovarian failure.  Br J Obstet Gynecol. 1990;  97 804-810
• 18 De Ziegler D, Bergeron C, Cornel C. et al . Effects of luteal estradiol on the secretory transformation of human endometrium and plasma gonadotropins.  JCEM. 1992;  74 322-331
• 19 Ficicioglu C, Gurbuz B, Tasdemir S, Yalti S, Canova H. High local endometrial effect of vaginal progesterone gel.  Gynecol Endocrinol. 2004;  18 240-243
• 20 Friedler S, Raziel A, Schachter M, Strassburger D, Bukovsky I, Ron-El R. Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophinreleasing hormone agonist: a comparative study between vaginal and oral administration.  Hum Reprod. 1999;  14 1944-1948
• 21 Geber S, Moreira A CF, de Paula S, Veado B, Sampaio M AC. Comparison of different preparations of vaginal progesterone for luteal phase support in assisted reproduction treatment [abstract] ESHRE 2004, 27 - 30 June, 19 (Suppl. 1): i111(abstr. # P‐318). Oxford, UK; Oxford University Press
• 22 Gorkemli H, Ak D, Akyurek C, Aktan M, Duman S. Comparison of pregnancy outcomes of progesterone or progesterone + estradiol for luteal phase support in ICSI‐ET cycles.  Gynecol Obstet Invest. 2004;  58 140-144
• 23 Kleinstein J, Schlegelmilch R, Mazur D, Vens-Cappell B. Pharmacokinetic comparison of progesterone capsules with a progesterone gel after vaginal administration.  Arzneimittelforschung. 2002;  52 615-621
• 24 Kleinstein J. (The luteal phase study group) . Efficacy and tolerability of vaginal progesterone capsules (Utrogest™ 200) compared with progesterone gel (Crinone™ 8 %) for luteal phase support during assisted reproduction.  Fertil Steril. 2005;  83 1641-1649
• 25 Ludwig M. Kinderwunschsprechstunde. Heidelberg; Springer Medizin Verlag 2005: 133
• 26 Ludwig M, Finas A, Katalinic A, Strik D, Kowalcek I, Schwartz P. et al . Prospective, randomized study to evaluate the success rates using hCG, vaginal progesterone or a combination of both for luteal phase support.  Acta Obstetrica et Gyanecologica Scandinavica. 2001;  80 574-582
• 27 Ludwig M, Diedrich K. Evaluation of an optimal luteal phase support protocol.  Acta Obstet Gynecol Scand. 2001;  80 452-466
• 28 Ludwig M, Schwartz P, Babahan B, Katalinic A, Weiss J M, Felberbaum R. et al . Luteal phase support using either Crinone 8 % or Utrogest: results of a prospective, randomized study.  European Journal of Obstetrics and Gynaecology. 2002;  103 4852
• 29 Marcolin G, Buvat J, Guittard C, Herbaut J C, Louvet A L, Dehaene J L. In vitro fertilization after LHRH agonist: randomized comparison of luteal phase support by vaginal progesterone alone or associated with human chorionic gonadotropin [abstract].  Contraception, Fertilité, Sexualité. 1993;  21 434-(abstr. #52C)
• 30 Martinez F, Coroleu B, Parera N, Alvarez M, Traver J M, Boada M. et al . Human chorionic gonadotropin and intravaginal natural progesterone are equally effective for luteal phase support in IVF.  Gynaecological Endocrinology. 2000;  14 316-320
• 31 Miles R A, Paulson R J, Lobo R A. et al . Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal route: a comparative study.  Fertil Steril. 1994;  63 485-490
• 32 Mochtar M H, Hogerzeil H V, Mol B WJ. Progesterone alone versus progesterone combined with hCG in GnRHa/hMG induced IVF cycles: a randomised controlled trial.  Hum Rep. 1996;  11 1602-1605
• 33 Ng E HY, Miao B, Cheung W, Ho P C. A randomised comparison of side effects and patient inconvenience of two vaginal progesterone formulations used for luteal support in in vitro fertilisation cycles.  European Journal of Obstetrics Gynecology and Reproductive Biology. 2003;  111 50-54
• 34 Nosarka S, Kruger T, Siebert I, Grove D. Luteal Phase Support in in vitro fertilization: meta-analysis of randomized trials.  Gynecol Obstet Invest. 2005;  60 67-74
• 35 Perino M, Brigandi A, Abate F G, Costabile L, Balzano E, Abate A. Intramuscular versus vaginal progesterone in assisted reproduction: a comparative study.  Clin Exp Obstet Gynecol. 1997;  24 228-231
• 36 Porcu E. Intramuscular versus vaginal progesterone in assisted reproduction [abstract].  Fertil Steril. 2003;  80 S131-(Abs # P32)
• 37 Pritts E A, Atwood A K. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.  Hum Reprod. 2002;  17 2287-2299
• 38 Procter A, Matthews M, Hurst B, Marshburn P. Effect of early pregnancy progesterone supplementation on IVF pregnancy outcome [abstract].  Fertil Steril. 2004;  82 S201-(abstr. # P189)
• 39 Rabe T (Hrsg). Manual on Assisted Reproduction. 2nd updated edition. Berlin, Heidelberg; Springer Verlag 2000: 143
• 40 Rodriguez-Pezino J, Saucedo-de la Llata E, Batiza-Resendiz V, Galache-Vega P, Santos-Haliscak R, Hernandez-Ayup S, Patrizio P. Vaginal progesterone in assisted reproduction [abstract] ESHRE 2004, 27 - 30 June, 19 (Suppl. 1): i51 (abstr. # O‐144). 
• 41 Schindler A E, Campagnoli C, Druckmann R, Huber J, Pasqualini J R, Schweppe K W, Thijssen J H. Classification and pharmacological properties of progestins.  Maturitas. 2003;  46 7-16
• 42 Schmidt K LT, Ziebe S, Popovic B, Lindhard A, Loft A, Andersen A N. Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery rate.  Fertil Steril. 2001;  75 337-341
• 43 Smitz J, Devroey P, Faguer B, Bourgain C, Camus M, Van Steirteghem A C. A prospective randomized comparison of intramuscular or intravaginal natural progesterone as a luteal phase and early pregnancy supplement.  Hum Reprod. 1992;  7 168-175
• 44 Smitz J, Bourgain C, Van Waesgerghe L, Camus M, Devroey P, Van Steirteghem A C. A prospective randomized study on oestradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation.  Hum Reprod. 1993;  8 40-45
• 45 Steck T. Praxis der Fortpflanzungsmedizin. Stuttgart; Schattauer Verlag GmbH 2001: 134
• 46 Stelling J R, Barrett C B, Penzias A S, Alper M M, Berger M J, Oskowitz S P, Karnis M F, Gray M R, Reindollar R H. Progesterone support in early IVF/GIFT pregnancies may not be necessary [abstract].  Fertil Steril. 1999;  S37-(abstr. # O‐095)
• 47 Strehler E, Abt M, El-Danasouri I, Sterzik K. Transvaginal administration of micronized progesterone does not differ to progesterone gel application in the efficacy of luteal phase support in IVF cycles (abstract). 11th World Congress of In Vitro Fertilization and Human Reproductive Genetics Abstract Book. 1999: 287-(abstr. # P‐243)
• 48 Sumita S, Sofat Sr S. Intra muscular versus intra vaginal progesterone as luteal phase and early pregnancy support in patients undergoing IVF‐ET [abstract].  Fertil Steril. 2003;  80 S134-S135 (abstr. # P‐44)
• 49 Tavaniotou A, Smitz J, Bourgain C, Devroey P. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments.  Hum Reprod Update. 2000;  6 139-148
• 50 Tay P Y, Lenton E A. Inhibition of progesterone secretion by oestradiol administered in the luteal phase of assisted conception cycles.  Medical Journal of Malaysia. 2003;  58 187-195
• 51 Tay P J, Lenton E A. The impact of luteal supplement on pregnancy outcome following stimulated IVF cycles.  Med J Malaysia. 2005;  60 151-157
• 52 Ugur M, Yenicesu O, Ozcan S, Keles G, Gokmen O. A prospective randomized study comparing hCG, vaginal micronized progesterone and a combination regimen for luteal phase support in an in-vitro fertilization programme [abstract].  Fertil Steril. 2001;  76 S118-(abstr. # P‐19)
• 53 Vimpeli T, Tinkanen H, Huhtala H, Ronnberg L, Kujansuu E. Salivary and serum progesterone concentrations during two luteal support regimens used in in vitro fertilization treatment.  Fertil Steril. 2001;  76 847-848
• 54 Williams S C, Oehninger S, Gibbons W E, Van Cleave W C, Muasher S J. Delaying the initiation of progesterone supplementation results in decreased pregnancy rates after in-vitro fertilization: a randomised, prospective study.  Fertil Steril. 2001;  76 1140-1143