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Implantation is a complicated process that involves adequate preparation of the endometrium.
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Implantation is a complicated process that involves adequate preparation of the endometrium. An important contributor to this preparatory process is the corpus luteum, the primary function of which is to secrete progesterone to induce secretory transformation of the endometrium so that implantation can occur and the necessary support can be provided for the pregnancy during the early stages of its development (1). The corpus luteum requires continual stimulation by luteinizing hormone (LH) to maintain adequate production of progesterone which, in pregnancy, is produced by the action of human chorionic gonadotropin (hCG) on the LH receptor.
Aspiration of granulosa cells during oocyte retrieval results in luteal phase disruption, the extent of which varies with the vigour of the aspiration. Additionally, the current practice of using a gonadotropin releasing hormone agonist (GnRHa) in the ovarian stimulation regimen to prevent a premature surge of LH, is associated with persistent blockage of LH output for at least 10 days after discontinuing GnRHa administration (2,3). The prolonged administration of GnRHa may also affect ovarian steroidogenesis directly. Consequently, the ability of the corpus luteum to produce progesterone is impaired.
This effect also increases the estrogen/progesterone ratio in the luteal phase particularly in treatment cycles with assisted reproductive technology in which estradiol levels are usually high. The importance of alterations in this ratio can be inferred from the observations that high levels of estrogen are associated with an inhibitory effect on embryo implantation in animals and humans (4,5).
Collectively, these observations indicate that luteal phase support, either with progesterone or with hCG to stimulate progesterone production by the corpus luteum, should be beneficial
Evidence for Beneficial Effect of Luteal Phase Support
A systematic review of randomized trials of luteal phase support in infertile women undergoing treatment with assisted reproductive technology (ART) was undertaken (6). For trials to be included in the meta-analysis, luteal phase support had to have been administered at least twice in the luteal phase in the case of hCG, and daily for the majority of the luteal phase for progesterone. The ovarian stimulation protocols included clomiphene citrate alone, human gonadotropins with clomiphene citrate (both protocols were without GnRHa), and human gonadotropins, with or without GnRHa.
The primary outcome was clinical pregnancy rate per embryo or gamete transfer. Secondary outcomes were miscarriage rate per clinical pregnancy and rate of ovarian hyperstimulation syndrome (OHSS) per transfer. There were four main groups of comparison, HCG versus placebo or no treatment, progesterone versus placebo or no treatment, progesterone versus hCG, and progesterone and hCG versus progesterone alone.
The summary results (with and without GnRHa and overall) are shown in the table allowing several inferences to be made. First, luteal phase support with hCG is associated with a significantly higher clinical pregnancy rate and lower rate of miscarriage compared to placebo or no treatment. However, this effect was observed only in cycles in which GnRHa was used. It is worrisome to note that the odds of developing OHSS was eight times higher. Second, progesterone administration also resulted in a significant increase in the rate of clinical pregnancy, but the analysis was limited to cycles without GnRHa, because to date, there have been no published randomized trials of progesterone support in cycles with GnRHa. The miscarriage and OHSS rates were unaffected by progesterone support. Third, no significant difference as found between progesterone and hCG or between progesterone and progesterone plus hCG with respect to rates of pregnancy or miscarriage, but the odds of OHSS with progesterone alone was half that of treatments involving hCG.
Conclusions and Implications for Practice
The use of GnRHa for pituitary down regulation in ART is now widespread and the resulting LH suppression persists well into the luteal phase. Consequently, without luteal phase support in such cycles, a sub-optimal hormonal environment is created. Both hCG and progesterone administration in the luteal phase are effective and significantly improve the clinical pregnancy rate. However, hCG use is associated with a marked increase in the risk of OHSS. Therefore, it is prudent to avoid hCG altogether, and particularly in patients at risk of developing OHSS.
1. Daya S. Ovulation induction for corpus luteum deficiency. Semin Reprod Endocrinol 1990; 8:156-65.
2. Smitz J, Devroey P, Camus M, Deschacht J, Khan I, Staessen C, Van Waesberghe L, Wisanto A, Van Steirteghem AC. The luteal phase and early pregnancy after combined GnRH-agonist/HMG treatment for superovulation in IVF or GIFT. Hum Reprod 1988; 5:585-90.
3. Broekmans F, Bernardus R, Berhout G, Schoenmaker J. Pituitary and ovarian suppression after early follicular and mid-luteal administration of LHRH agonist in a depot formulation: decapeptyl CR. Gynecol Endocrinol 1992; 6:153-61.
4. Forman R, Belaisch-Allart J, Fries M, Hazout A, Testart J, Frydman R. Evidence for an adverse effect of elevated serum estradiol concentrations on embryo implantation. Fertil Steril 1988; 49:118-22.
5. Gidley-Baird A, O’Neill C, Sinosich MJ, Porter RN, Pike IL, Saunders DM. Failure of implantation in human in vitro fertilisation and embryo transfer patients: the effect of altered progesterone/estrogen ratios in human and in mice. Fertil Steril 1986; 45:69-74.
6. Daya S, Gunby J. Luteal phase support in treatment cycles with assisted reproduction. Cochrane Reviews, 1999 (in press).