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Middle East Fertility Society Journal
Middle East Fertility Society
ISSN: 1110-5690
Vol. 12, Num. 3, 2007, pp. 158-160

Middle East Fertility Society Journal, Vol. 12, No. 3, 2007, pp. 158-160

DEBATE

Luteal phase support in assisted reproduction 

Code Number: mf07029

Commented by: Mohamed Yehia, MD

Professor of Obstetrics & Gynecology, Faculty of Medicine, Ain Shams University Cairo, Egypt

1- Is luteal support needed?

The first report of the combined use of pituitary suppression and ovarian hyperstimulation in in-vitro fertilization (IVF) and embryo transfer programmes was published in 1984 (1). Since then, the advantages of gonadotrophin hormone-releasing hormone analogues (GnRHa) have been well documented; the cancellation rate has been decreased through the prevention of premature luteinizing hormone (LH) surge, follicular recruitment has improved, and the ovarian response to hyperstimulation has been better synchronized, thus facilitating the scheduling of oocyte retrieval (OR). This pituitary suppression however, results in an impaired gonadotrophin production later on, and the output of LH remains blocked for at least 10 days after cessation of GnRHa administration (2, 3). As gonadotrophins are necessary to maintain progesterone output by the corpus luteum, exogenous luteal support is mandatory. However several reports have shown that corpus luteum function and luteal phase duration are shortened in IVF cycles regardless of the protocol used for multifollicular induction. In comparing HMG either alone or with the addition of GnRH antagonist cetorolix, Tavaniotuo et al. 2001, have shown that LH concentration declines at the mid luteal phase  and without luteal supplementation the corpus luteum function will be disturbed which results in a very low implantation rate (4). The induction of multiple follicle development per se could either directly or indirectly influence the duration of the luteal phase (5); the removal of large quantities of granulosa cells at oocyte retrieval may diminish the most important source of progesterone synthesis by the corpus luteum, thus disrupting the luteal phase (6).  supraphysiological levels of steroids [related to the larger number of corpora lutea] during the early luteal phase could directly inhibit LH release via negative feedback actions at the hypothalamic-pituitary axis (7). A meta-analysis comparing placebo with any form of luteal support favored the addition of luteal support (8). Vlaisavljevic (2007) compared natural IVF cycles with and without luteal support and concluded that even in a natural cycle IVF a higher pregnancy rate was observed if HCG was administered after embryo transfer (9).

2- What is the best regimen for luteal support?

Human chorionic gonadotropin (HCG), progesterone, with or without estrogen have been used to support the luteal phase.

A- Is HCG superior to progesterone?

In comparing HCG and progesterone –both intramuscular (I.M.) and vaginal- a meta-analysis preformed by Pritts and Atwood (2002) found no differences (10). However, in a recent meta-analysis comparing progesterone versus human chorionic gonadotropin (hCG) alone or in combination with progesterone, it was concluded that hCG was superior to progesterone as luteal phase support with respect to pregnancy rates (8). The drawbacks of using hCG are the increased risk of ovarian hyperstimulation and, in my opinion, the other drawback stems from the long half life of hCG in the circulation (about 8 days) which can occasionally lead to erroneous diagnosis of pregnancy with its distressing  psychological impact on the patient.

B-Which route of progesterone administration confers more reproductive benefit: oral, I.M. or vaginal?

While the oral route is the patients’ preference, the very high dose needed to be administered to reach a sufficient progesterone concentration in the serum will lead to several problems. The breakdown products from the metabolism of oral progesterone have been associated with sedation, drowsiness, and other hypnotic effects, as well as flushing, nausea, and fluid retention. In addition, several studies have shown the superiority of vaginal progesterone (11, 12).  In comparing vaginal and I.M  routes, both  have side effects. Intramuscular injections are not only painful, but can also lead to inflammation and even sterile abscess formation at the injection site (13). Severe allergic reactions to the oil used as a vehicle for progesterone injections have also been reported. Acute eosinophilic pneumonia was reported (14) and can induce severe morbidity in otherwise healthy young women.

Vaginal application of progesterone has also led to some minor side-effects such as vaginal discharge and irritation.  Although I.M. injections have lead to higher serum levels of progesterone, the vaginal formulations have been shown to have better synchronization effects upon the endometrium (15). This is theorized to be due to a first pass uterine effect leading to higher uterine tissue levels and lower systemic serum levels (16). In meta-analysis by Pritts and Atwood 2002, however, the I.M. route conferred higher clinical pregnancy rate (CPR) and delivery rate (DR) than the vaginal route. Unfer et al. (2004) used 17 alpha-hydroxyprogesterone caproate every 3 days (instead of the routine daily dose) versus intravaginal progesterone in IVF-embryo transfer cycles in a prospective randomized study and found the former superior (17). A drawback in I.M. progesterone is the prolongation of luteal phase despite the absence of pregnancy. Bleeding eventually occurs, but patients often feel something is wrong when no menstruation occurs and she is not pregnant. Vaginal progesterone is available in micronized form, cream and tablets. At the present no definite significant difference between the 3 forms was found , however vaginal cream is used once daily while micronized progesterone requires multiple applications (2-3 times/day).

C-When to start luteal support?

Mochtar et al. (2006) compared the effect of the onset of luteal support on pregnancy rate, and found no significant difference whether progesterone support started at hCG injection, at oocyte retrieval or at ET (18). 

D-How long should luteal support be administrated?

There is no consensus regarding the duration of luteal support. Traditionally, progesterone is administrated for 8-10 weeks after positive pregnancy test, however no difference was found if progesterone was withdrawn immediately after positive pregnancy test or continued for 8 weeks. (19, 20).

E-Adding estrogen

Several investigators have noticed that the level of estrogen is low during the luteal phase in IVF cycles. The results of adding estrogen to progesterone produced conflicting data; while Gorkemli et al. (2004) found an increased pregnancy rate (21), Fatemi et al. (2006) found no differences in pregnancy rate or implantation rate (22).

Conclusion

At the present evidence points out the necessity of adding luteal support to any protocol of controlled hyperstimulation; even if no agonist or antagonist is used. HCG is equivalent to progesterone in efficiency but is associated with a higher incidence of hyperstimulation syndrome. Progesterone intramuscularly seems to yield a better pregnancy rate;  however the side effects of intramuscular progesterone make local vaginal progesterone cream or suppository the most common form utilized by patients.  Estrogen addition does not seem to offer an advantage over progesterone alone in spite of sporadic reports of the contrary.

References

  1. Porter, R , Smith, W and Craft, I :Induction of ovulation for in vitro  fertilization using buserelin and gonadotropins Lancet, U.1984,1284-1285.
  2. Smitz J, Devroey P, Van Steirteghem AC  Endocrinology in luteal phase and implantation. Br Med Bull 1990,46:709–19
  3. Broekmans FJ, Bernardus RE, Berkhout G, Schoemaker J. Pituitary and ovarian suppression after early follicular and mid-luteal administration of a LHRH agonist in a depot formulation: decapeptyl CR. Gynecol Endocrinol. 1992 Sep;6(3):153-61.
  4. Tavaniotou A, Albano C, Smitz J, Devroey P. Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix.. Hum Reprod. 2001;16(4):663-7.
  5. Messinis IE, Templeton AA  Disparate effects of endogenous and exogenous estradiol on luteal phase function in women. J Reprod Fertil 1987, 79:549–54
  6. Garcia J, Jones GS, Acosta AA, Wright Jr GL :Corpus luteum function after follicle aspiration for oocyte retrieval. Fertil Steril , 1981 36:565–72
  7. Fauser BC, Devroey P. Reproductive biology and IVF: ovarian stimulation and luteal phase consequences. Trends Endocrinol Metab 2003,14:236–242
  8. Nosarka S, Kruger T, Siebert I, Grové D.Luteal phase support in in vitro fertilization: meta-analysis of randomized trials. Gynecol Obstet Invest. 2005;60(2):67-74.
  9. Vlaisavljevic V, Embryo transfer and luteal support in natural cycles. Reprod Biomed Online.  2007; 14(6):686-92 
  10. Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.  Hum Reprod. 2002;17(9):2287-99..
  11. Pouly, J.L., Bassil, S., Frydman, R., Hedon, B., Nicollet, B., Prada, Y., Antoine, J.M., Zambrano, R. and Donnez, J.  Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone. Hum. Reprod., .1996 ,11, 2085–9.
  12. Friedler, S., Raziel, A., Schachter, M., Strassburger, D., Bukovsky, I. and Ron-El, R. Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotropin-releasing hormone agonist: a comparative study between vaginal and oral administration. Hum. Reprod., 1999, 14:1944–8.
  13. Tavaniotou, A., Smitz, J., Bourgain, C. and Devroey, P. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum. Reprod. Update, 2000,6:139–48.
  14. Bouckaert Y, Robert F, Englert Y, De Backer D, De Vuyst P, Delbaere A. Acute eosinophilic pneumonia associated with intramuscular administration of progesterone as luteal phase support after IVF: case report.Hum Reprod. 2004;  19(8):1806-10.
  15. Bourgain , C., Smitz, J., Camus,M., Erard, P., DeVroey, P., Van Steirteghem, A.C. and Klopppel, G. Human endometrial maturation is markedly improved after luteal supplementation of gonadotrophin-releasing hormone analogue/human menopausal gonadotrophin stimulated cycles. Hum. Reprod. 1994, 9:32–40.
  16. Ludwig, M. and Diedrich, K. Evaluation of an optimal luteal phase support protocol in IVF. Acta Obstet. Gynecol. Scand 2001., 80:452–66.
  17. Unfer V; Casini ML; Costabile L; Gerli S; Baldini D; Di Renzo GC. 17 alpha-hydroxyprogesterone caproate versus intravaginal progesterone in IVF-embryo transfer cycles: a prospective randomized study. Reprod Biomed Online.  2004; 9(1):17-21 
  18. Mochtar MH; Van Wely M; Van der Veen F:Timing luteal phase support in GnRH agonist down-regulated IVF/embryo transfer cycles.  Hum Reprod.  2006; 21(4):905-8
  19. Schmidt, K.L.T., Ziebe, S., Popovic, B., Lindhard, A., Loft, A. and Andersen, A.N. Progesterone supplementation during early gestation after IVF has no effect on the delivery rates. Fertil. Steril.,2001, 75:337–41.
  20. Nyboe Andersen A; Popovic-Todorovic B; Schmidt KT; Loft A; Lindhard A; Højgaard 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(2):357-61.
  21. 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(3):140-4 .
  22. Fatemi HM; Kolibianakis EM; Camus M; Tournaye H; Donoso P; Papanikolaou E; Devroey P: Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial. Hum Reprod.  2006; 21(10):2628-32 

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