Impact of ovarian stimulation on corpus luteum function and embryonic implantation

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Abstract

The luteal phase has been found to be defective in virtually all the stimulation protocols used in in-vitro fertilization (IVF), indicating that common mechanisms might be involved despite the use of different drugs. A normal luteal phase is characterised by a normal hormonal environment, normal progesterone secretion by the corpus luteum and adequate endometrial secretory transformation. Luteinizing hormone supports the corpus luteum and luteal luteinizing hormone (LH) levels have been found to be reduced in human menopausal gonadotrophin (HMG), gonadotrophin-releasing hormone (GnRH)-agonist/HMG and GnRH-antagonist/HMG protocols, probably leading to an insufficient corpus luteum function. Supraphysiological steroid serum concentrations routinely observed in stimulated cycles may adversely affect LH secretion and induce a luteal-phase defect. In turn, these high steroid serum concentrations may advance early luteal-phase endometrial development leading to embryo–endometrial asynchrony and decreased pregnancy rates in IVF cycles.

Introduction

The luteal phase is important as it is during this period that embryonic implantation takes place. Normal corpus luteum function requires optimal follicular development in the follicular phase, especially follicular stimulating hormone (FSH) stimulation, adequate luteinizing hormone (LH) surge during ovulation and continuous tonic LH pulses during the luteal phase (Speroff et al., 1994). In turn, the normal luteal phase is characterised by an optimal hormonal environment and adequate endometrial secretory transformation. As many factors contribute to a normal corpus luteum function, any alteration might exert a deleterious effect on the final target, the endometrium, leading to embryo–endometrial asynchrony (Fig. 1).

Controlled ovarian stimulation may be divided into three phases: the pre-agonist phase, the gonadotrophin-releasing hormone (GnRH)-agonist phase and the GnRH-antagonist phase. A direct drug effect on any factor (hypothalamus, pituitary, ovary, or endometrium) might induce a defective luteal phase (Fig. 1). Although not yet established, GnRH-agonists or antagonists may exert a direct effect on the ovary (Minaretzis et al., 1995) or the endometrium (Dong et al., 1998). However, in current in-vitro fertilization (IVF) practice, corpus luteum deficiency has been described under different stimulation protocols, indicating that other mechanisms are also involved (Edwards et al., 1980, Smitz et al., 1988, Albano et al., 1998).

Section snippets

Assessment of the luteal phase

Luteal-phase length, mid-luteal serum progesterone values and timed endometrial biopsy are the three methods by which to evaluate a luteal phase. A delay of more than 2 days in endometrial histological development is the most frequent definition of a defective luteal phase in the literature. Endometrial dating is usually performed according to the classic criteria by Noyes (Noyes et al., 1950). Except for dating, endometrial specimens may also be analysed for steroid receptors and functional

Corpus luteum function in stimulated cycles

Corpus luteum insufficiency is well established after the use of GnRH-agonists (Smitz et al., 1988). In GnRH-agonist/human menopausal gonadotrophin (HMG) IVF cycles, the capacity of the pituitary for gonadotrophin secretion remained impaired for the whole length of the luteal phase, despite the cessation of the analogue (Smitz et al., 1992). Corpus luteum function is dependent on LH stimulation and LH is dependent on GnRH secretion (Fig. 1). In GnRH-agonist IVF cycles, LH concentrations were at

Endometrial receptivity in stimulated cycles

The ultimate aim of infertility treatments is embryonic implantation. A receptive endometrium facilitates the timed ‘dialogue’ between the embryo and the endometrium. Altered endometrial development has been demonstrated with most of the protocols used in ovarian stimulation (Sterzik et al., 1988). Since the introduction of GnRH-agonists, it has been detected that pregnancy rates increased significantly by luteal-phase supplementation (Smith et al., 1989). This favourable effect of luteal-phase

Conclusion

In conclusion, ovarian stimulation affects luteal-phase function in terms of endocrinology and histology. High steroid serum concentrations may disturb feedback mechanisms and induce premature luteolysis. High steroid concentrations may also alter endometrial development and embryonic implantation. However, further research is needed in order to investigate the effect that different stimulation protocols and GnRH antagonists or a more ‘friendly’ stimulation might exert on endometrial

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