Middle East Fertility Society Journal Middle East Fertility Society ISSN: 1110-5690 Vol. 12, Num. 3, 2007, pp. 166-167

Middle East Fertility Society Journal, Vol. 12, No. 3, 2007, pp. 166-167

DEBATE

Luteal phase support in assisted reproduction 

Code Number: mf07031

Comment by: Heshan Al Insany, M.D.

Luteal phase supplementation or support is a common practice in IVF treatment. It significantly improves the embryo implantation rate, pregnancy and delivery rates as ovarian superstimulation during IVF is commonly associated with luteal phase deficiency. The aspiration of the granulosa cells that surround the oocyte and the use of gonadotropin releasing hormone agonists (GnRHa) during assisted reproduction technology (ART) treatment can interfere with the production, during the luteal phase, of progesterone, which is necessary for successful implantation of the embryo (1).

The second mechanism of luteal phase deficiency is caused by gonadotropin releasing hormone agonist (GnRH-a) used in the ovarian stimulation regimen to prevent premature LH surge. This results in persistent block of the LH output for at least ten days after discontinuing GnRH-a, which can result in impairment of progesterone secretion by the corpus luteum (2). This increases estrogen/ progesterone ratio, which is associated with an inhibitory effect on embryo implantation.

In an attempt to enhance the probability of pregnancy, different doses, durations and types of treatments for LPS have been evaluated. There is, however, no agreement regarding the optimal supplementation scheme (3). Some authors suggested IM progesterone-in-oil as the best method of luteal phase support (4). Others suggested vaginal progesterone (5) while some claimed that both hCG and intra-vaginal progesterone are equally effective (6).

GnRH agonist was recently suggested as a novel luteal phase support. The mechanism of the presumed beneficial effect of luteal-phase GnRH agonist administration is not clear and may be due to the drug action at multiple levels. It was hypothesized that GnRH agonist may support the corpus luteum by stimulating the secretion of LH by pituitary gonadotrophin cells or by acting directly on the endometrium through the locally expressed GnRH receptors (7). Tesarik et al. (2004) evaluated 138 women who were assigned to receive a single injection of 0.1 triptorelin 6 days after ICSI treatment or to receive placebo. In their series, they reported a significantly higher implantation and pregnancy rates in the GnRH agonist treated group compared with the placebo (8). Moreover, Pirard et al. (2005) investigating whether the intranasal administration of 100 µg of buserelin to 23 patients who underwent IVF treatment, found that E2 and P concentrations were sustained and the implantation and pregnancy rates were significantly improved with increased doses and frequency of GnRH-a administration. These findings may suggest a direct effect of GnRH agonist on the embryo (7). In a prospective randomized study, Tesarik et al. evaluated the effect of GnRH agonist (0.1 mg triptorelin) administration in the luteal phase on outcomes in both GnRH agonist (n = 300) and GnRH antagonist (n = 300) ovarian stimulation protocols (9). They were randomly assigned to receive a single injection of GnRH agonist (study group) or placebo (control group) 6 days after ICSI. The PR were enhanced for both protocols, in long GnRH agonist protocol the clinical implantation rate were 29.8 versus 18.2% respectively (P < 0.05). Ongoing PR were 46.8 versus 38.0% respectively (P = NS). In patients treated with the GnRH antagonist protocol, clinical implantation rates were 27.1 versus 17.4% respectively (P < 0.05) and ongoing PR were 44.8 versus 31.9% respectively (P < 0.05).

Luteal-phase GnRH agonist administration additionally increased the luteal-phase serum hCG, E2 and progesterone concentrations in both ovarian stimulation regimens. It was postulated that the beneficial effect may have resulted from a combination of effects on the embryo and on the corpus luteum (9).

Despite these encouraging results, this way of supplementation was not widely adopted as great concern exists about possible adverse effects on oocytes and, more importantly, on embryos (10). However, the incidence of miscarriage and the long term follow-up of children born after inadvertent administration of GnRH-a in early pregnancy do not appear to be altered (11, 12).  In order to establish a potential positive role of GnRH agonist administration in the luteal phase of stimulated IVF cycles, further large prospective trials are needed.

REFERENCES

1. Daya S, Gunby J.  Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev. 2004;(3):CD004830.
2. Damario MA, GoudasVT, Session DR., Hammitt DG, Dumesic DA. Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization- embryo transfer. Fertil Steril. 1999; 72 (5), 829-836.
3. Fatemi HM, Popovic-Todorovic B, Papanikolaou E, Donoso P, Devroey P. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update. 2007 Nov-Dec;13(6):581-90.
4. Friedler S, Raziel A, Schachter M. 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 (8), 1944-1948.
5. Martinez F, Coroleu B, Parera N. Human chorionic gonadotropin and intra-vaginal natural progesterone are equally effective for luteal phase support in IVF. Gynecol Endorinol. 2000; 14(5): 316-320.
6. Soliman S, Daya S, Collins J. The role of luteal phase support in infertility treatment: a meta analysis of randomized trials. Fertil Steril. 1994; 61, 1068-1076.
7. Pirard C, Donnez J, Loumaye E.  GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study. Hum Reprod. 2006 Jul;21(7):1894-900.
8. Tesarik J, Hazout A, Mendoza C. (2004) Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation. Hum Reprod 19:1176–1180
9. Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C.  Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum Reprod. 2006 Oct;21(10):2572-9
10. Lambalk CB, Homburg R. GnRH agonist for luteal support in IVF? Setting the balance between enthusiasm and caution. Hum Reprod. 2006 Oct;21(10):2580-2
11. Elefant E, Biour B, Blumberg-Tick J, Roux C, Thomas F.  Administration of a gonadotropin-releasing hormone agonist during pregnancy: follow-up of 28 pregnancies exposed to triptorelin. Fertil Steril. 1995 May;63(5):1111-3.
12. Wilshire GB, Emmi AM, Gagliardi CC, Weiss G.  Gonadotropin-releasing hormone agonist administration in early human pregnancy is associated with normal outcomes. Fertil Steril. 1993 Dec;60(6):980-3.

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