Dimitra Kyrou1 and Human Mousavi Fatemi2
Assisting Nature, Assisted Reproduction Unit, G. Kranidioti 2 & Thessaloniki-Thermi Av., Thessaloniki, 57001, Greece
Department of CRG, University Hospital Brussels, Laarbeek laan, 121, 1090 Brussels, Belgium
Dimitra Kyrou (Corresponding author)
Human Mousavi Fatemi
Stimulated in vitro fertilization (IVF) cycles due to supraphysiological hormonal profiles are associated with a defective luteal phase. The currently available evidence suggests diverse agents in order to support the process of implantation. However, there is a lack of evidence regarding the need of luteal support in natural and minimal stimulated IVF cycles. The aim of this chapter is to provide data and give answers on the benefit of luteal phase support in non-stimulated IVF cycles. There is certainly a need for further prospective randomized trials to bring light to this issue.
Natural cycleIVFMini IVFModified natural cycleLuteal phase defectLuteal phase support
The luteal phase is defined as the period between ovulation and either the occurrence of pregnancy or the onset of menses 2 weeks later (Fatemi et al. 2007). If conception and implantation occur, trophoblast production of human chorionic gonadotropin (hCG) prevents regression of the corpus luteum and amplifies steroid secretion that consequently decidualizes the endometrial stroma and supports early embryonic development (Penzias 2002).
The most reasonable consensus of a luteal phase defect (LPD) is a lag of more than 2 days in endometrial histological development compared to the expected day of the cycle (Jones 1991). Luteal phase defects have been attributed principally to inadequate production of progesterone, the major product of the corpus luteum, which is absolutely essential for the establishment and maintenance of early pregnancy (Csapo et al. 1972). The reported frequency of LPD ranges from 3.7 to 20 % among patients with infertility (Balasch and Vanrell 1986; Olive 1991) and in natural cycles in normo-ovulatory patients with primary or secondary infertility, was demonstrated to be about 8.1 % (Rosenberg et al. 1980). The three main causes of LPD in non-stimulated cycles include poor follicle production, premature demise of the corpus luteum, and failure of the uterine lining to respond to normal levels of progesterone.
Stimulated IVF cycles are associated with a defective luteal phase in almost all patients (Ubaldi et al. 1997; Macklon and Fauser 2000). The objective of superovulation is to achieve the development of multiple follicles. As a result, multiple follicles and corpora lutea secrete supraphysiological concentrations of progesterone and estrogen in the luteal phase. These high concentrations of steroids result in a negative feedback on the pituitary–hypothalamic axis and thus, inhibit the production of luteal luteinizing hormone (LH), mandatory for luteal progesterone production (Fauser and Devroey 2003). Studies in human and primates have demonstrated that the corpus luteum requires a consistent LH stimulus in order to perform its physiological function (Jones 1991). LH support during the luteal phase is entirely responsible for the maintenance and the normal steroidogenic activity of the corpus luteum (Casper and Yen 1979). As a result, withdrawal of LH unnecessarily causes premature luteolysis (Duffy et al. 1999). In the context of assisted reproduction techniques, luteal phase support (LPS) is defined as the administration of medication in order to support the implantation process (Fatemi et al. 2007).
Although the benefit of luteal phase support has been well documented in IVF (Fatemi et al. 2007), the question remains whether it is really necessary in natural or minimal stimulated IVF cycles, in which one to two follicles have developed.
Natural IVF Cycle
There is lack of evidence in the literature that could give us an answer regarding the need for luteal phase support in natural cycles. This patient-friendly, natural IVF treatment is associated with close to zero multiple pregnancy rates, zero risk of ovarian hyperstimulation syndrome (OHSS), and an ongoing pregnancy rate of about 16 % per embryo transfer. However, it is not really clear if luteal phase support is necessary in natural IVF cycles.
Based on a recent review concerning the effectiveness of natural cycle (Pelinck et al. 2002), ten studies reported luteal support in which 535 embryos were transferred and a 14.8 % ongoing pregnancy rate was achieved. In two studies, no luteal support was given and yet a 17.1 % ongoing pregnancy was achieved. Moreover, in eight studies in which there was no information about the administration of luteal support, and among a total of 214 embryo transfers, a 17.8 % ongoing pregnancy was reported. Therefore, ongoing pregnancy rates were comparable in studies with and without luteal support.
In contrast to the above findings, Garcia et al. (1981) supported the surmise that the depletion of granulosa cells by follicular aspiration might cause corpus luteum dysfunction, making luteal support necessary in spontaneous cycles, especially among those in whom repeated flush aspiration was performed.
This hypothesis was disproved by Kerin et al. (1981) who reported a normal luteal phase after follicle aspiration and oocyte recovery in spontaneous cycles. The aspiration of a preovulatory oocyte in a natural cycle neither diminished the luteal phase steroid secretion nor shortened the luteal phase. Nevertheless, it should be noted that the preovulatory follicle grew to a diameter of at least 18 mm (maximum 23 mm) and the preovulatory estradiol concentration was greater than 1.1 nmol/L. These conditions are perhaps optimal for forming an adequate corpus luteum.
This is not the case in all non-stimulated cycles for IVF that human chorionic gonadotropin (hCG) was used for triggering at different stages of follicular growth.
Luteal phase quality was evaluated in 32 patients with non-stimulated cycles after laparoscopic oocyte recovery for in vitro fertilization (Feichtinger et al. 1982). A transitory drop in progesterone on day 7 after oocyte retrieval was reported, and prophylactic luteal support with Dydrogesterone was given.
A retrospective analysis of different luteal phase supplementation in 587 patients undergoing IVF and intracytoplasmic sperm injection (ICSI) in unstimulated cycles was performed. In the group where Dydrogesterone was used, 96 embryos were transferred and the implantation rate was 12.5 %. In the group where the luteal phase was supplemented with hCG, 158 embryos were transferred and the implantation rate was 23.4 % (Vlaisavljević et al. 2001). However, the difference in implantation rate was not significant (95 % CI 5.7–19.3 versus 95 % CI 16.7–30.2).
Are there any differences in the approach when natural cycle IVF is supplemented with or without terminal hCG? The hCG administered for the final oocyte maturation could potentially cause a luteal phase defect by suppressing the LH production via a short-loop feedback mechanism (Miyake et al. 1982). However, the administration of hCG did not downregulate the LH secretion in the luteal phase of normal, unstimulated cycles in normo-ovulatory women. It was demonstrated that in natural cycles with and without hCG injection, serum LH concentrations were similar, indicating that ovulatory hCG does not reduce LH concentrations (Tavaniotou and Devroey 2003).
Minimal Stimulated IVF Cycles
Is there really a need for luteal supplementation in minimal stimulated cycles in which a few follicles have developed? Which approach should be adopted regarding luteal support? The one as for a stimulated cycle or as for a natural cycle? Does it depend on the type of the agent used for stimulation?
It has already been demonstrated (Van Steirteghem et al. 1988) that in IVF or gamete intra-Fallopian transfer, there is absence of a beneficial effect of luteal support in cycles stimulated with Clomiphene citrate.
The only prospective randomized controlled trial that was performed in order to assess the effect of intravaginal micronized progesterone as luteal support on the probability of ongoing pregnancy in patients stimulated with Clomiphene citrate concerned intrauterine insemination (IUI) (Kyrou et al. 2010). Normo-ovulatory women were randomized, either to receive luteal phase support (n = 243) in the form of vaginal micronized progesterone in three separate doses (200 mg, three times a day) or to the control group who did not receive luteal phase support (n = 225). No difference was observed in ongoing pregnancy between patients who did or did not receive vaginal progesterone as luteal support [8.7 % (17/196) versus 9.3 % (19/204), respectively, P = 0.82; difference −0.6 %, 95 % confidence interval (CI): −6.4, 5.2]. Additionally, the early pregnancy loss rate did not differ between groups (1.5 % progesterone group versus 2 % no progesterone group, P = 0.78; difference −0.5 %, 95 % CI: −3.6, 2.7). Despite the fact that the study was not documented in IVF cycles, the principle is the same.
Clomiphene citrate stimulates follicular growth by competing with estrogen for binding to hypothalamic estrogen receptors, leading to an increase in gonadotropin-releasing hormone (GnRH). Additionally, Clomiphene citrate increases the pituitary sensitivity to GnRH in a similar fashion to estradiol (E2). As a result, follicle-stimulating hormone (FSH) and LH secretion are increased during Clomiphene citrate administration (Dickey et al. 1965). High LH level is responsible for maintenance of the corpus luteum during the luteal phase (Casper and Yen 1979).
Additionally, serum progesterone and E2 concentrations are increased during the luteal phase of the cycle in a direct dose–response relationship with Clomiphene citrate (Hammond and Talbert 1982; Fukuma et al. 1983). Dickey (1984) showed that serum progesterone levels during the mid-luteal phase averaged 2700 ng/dL in spontaneous cycles and 3200 ng/dL in Clomiphene citrate cycles of pregnancies, which went to term: the increased progesterone concentration continued until the 11th post-ovulation week before returning to the values found in a spontaneous pregnancy (Dickey and Hower 1995).
Moreover, the fact that Clomiphene citrate occupies hypothalamic estrogen receptors for a longer period than estrogens (Dickey and Holtkamp 1996) might account for the greater luteal LH concentration in the Clomiphene citrate cycles (Tavaniotou et al. 2002). Moreover, the increase in LH pulse frequency subsequent to the Clomiphene citrate administration results in a significant increase in serum E2 and progesterone levels, with a lengthening of the luteal phase. As pulsatile LH secretion in the luteal phase is primarily responsible for maintenance of the corpus luteum, this could explain why the necessity of luteal phase supplementation was not demonstrated in the above study.
The strategy of administering low doses of FSH in the late follicular phase will result in fewer oocytes being available for IVF than in conventional stimulation protocols. It may also be possible to selectively stimulate the growth of large follicles in the late follicular phase by the administration of low doses of LH. Recent observations indicate that once FSH has initiated follicular growth, thereafter, either FSH or LH is capable of sustaining follicular estradiol production by acquired LH responsiveness of the dominant follicle (Sullivan et al. 1999).
The smaller cohort of growing follicles may well be better synchronized, which may improve oocyte quality and the capacity to be fertilized and form good quality embryos. Reduced stimulation may also avoid the adverse effects of hyperstimulation on corpus luteum function and endometrial receptivity (Fauser et al. 1999).
The main cause of LPD, observed in stimulated IVF cycles, is not related to the GnRH analog (agonist or antagonist) but to the multifollicular development achieved during ovarian stimulation, which completely alters the hormonal environment. It can be postulated that one of the main causes of the LPD in stimulated IVF cycles is supraphysiological levels of steroids secreted by a high number of corpora lutea during the early luteal phase, which directly inhibits LH release via negative feedback actions at the level of the hypothalamic–pituitary axis (Fauser and Devroey 2003). A rapid recovery of pituitary LH and FSH release after cessation of GnRH antagonist administration might permit the abandonment of additional luteal support and the further simplification of IVF protocols (Fauser et al. 1999).
In a prospective randomized controlled trial, Erdem et al. (2009) evaluated whether luteal phase support with vaginally administered progesterone in mild ovarian stimulation IUI cycles with gonadotropins would have an impact on pregnancy rates. The authors concluded that vaginal progesterone administration in mild stimulated cycles with gonadotropins for IUI significantly affected the success.
However, as of now, scientifically, there is no evidence base regarding the need for luteal support in modified natural IVF cycles. Randomized controlled trials comparing mini IVF with or without luteal support are warranted.
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