Luteal Phase in Assisted Reproductive Technology

Abstract

Luteal phase (LP) is the period of time beginning shortly after ovulation and ending either with luteolysis, shortly before menstrual bleeding, or with the establishment of pregnancy. During the LP, the corpus luteum (CL) secretes progesterone and some other hormones that are essential to prepare the uterus for implantation and further development of the embryo, the function known as uterine receptivity. LP deficiency (LPD) can occur when the secretory activity of the CL is deficient, but also in cases of normal CL function, where it is caused by a defective endometrial response to normal levels of progesterone. LPD is particularly frequent in treatments using assisted reproductive technology (ART). Controlled ovarian stimulation usually aims to obtain the highest number possible of good-quality oocytes and requires the use of gonadotropin-releasing hormone (GnRH) analogs, to prevent premature ovulation, as well as an ovulation trigger to achieve timed final oocyte maturation. Altogether, these treatments suppress pituitary secretion of luteinizing hormone (LH), required for the formation and early activity of the CL. In addition to problems of endometrial receptivity for embryos, LPD also leads to dysfunction of the local uterine immune system, with an increased risk of embryo rejection, abnormally high uterine contractility, and restriction of uterine blood flow. There are two alternatives of LPD prevention: a direct administration of exogenous progesterone to restore the physiological progesterone serum concentration independently of the CL function, on the one hand, and treatments aimed to stimulate the CL activity so as to increase endogenous progesterone production, on the other hand. In case of pregnancy, some kind of LP support is often needed until the luteal–placental shift occurs. If LPD is caused by defective response of the endometrium and uterine immune cells to normal concentrations of progesterone, a still poorly defined condition, symptomatic treatments are the only available solution currently available.

Double HCG trigger improves recovery of oocytes in women with a paucifollicular response to ovarian stimulation: A pilot study

“…In fact, the natural luteinizing hormone trigger consists of a primary peak followed by secondary peaks, maintaining the medium levels of luteinizing hormone, between the first peak and ovulation, well above that produced by a single bolus of recombinant HCG, which is cleared rapidly from the circulation 17 . This rapid decrease in luteinizing hormone activity is suspected to be responsible for the failure of granulosa cell transformation into granulosa‐lutein cells, impeding the formation of a fully functional corpus luteum 17 . Consequently, it was hypothesized that, despite the capacity of a single bolus of HCG to induce the final maturation of oocytes, it might be insufficient, in some cases, to loosen the attachment of the cumulus granulosa cells to the parietal granulosa cells lining the follicular cavity, so that the negative pressure during follicular aspiration may not be sufficient to separate the two entities.…”

“…17 This rapid decrease in luteinizing hormone activity is suspected to be responsible for the failure of granulosa cell transformation into granulosa-lutein cells, impeding the formation of a fully functional corpus luteum. 17…”

“…This appears not to be so much a question of the rapidity of recombinant HCG degradation, which might even take a longer time as compared to luteinizing hormone, owing to its higher degree of glycosylation 9 . In fact, the natural luteinizing hormone trigger consists of a primary peak followed by secondary peaks, maintaining the medium levels of luteinizing hormone, between the first peak and ovulation, well above that produced by a single bolus of recombinant HCG, which is cleared rapidly from the circulation 17 . This rapid decrease in luteinizing hormone activity is suspected to be responsible for the failure of granulosa cell transformation into granulosa‐lutein cells, impeding the formation of a fully functional corpus luteum 17 .…”

Patient-tailored reproductive health care

“…The follow-up of women after the ART attempt is another issue which is still underestimated nowadays. Contrary to earlier opinions suggesting that luteal phase deficiency is a relatively marginal issue, more recent data suggest that this is not the case, even in natural conception cycles (36), and the problem is even more important after ART attempts using different ovarian stimulation protocols (37,38). Moreover, in addition to the luteal phase itself, the luteoplacental shift (the relief of the role of the corpus luteum by the placenta as the main source of progesterone) also appears to be disturbed in some women after ART treatments (39), and prolonged administration of progesterone during pregnancy may be useful when serum progesterone levels after the supposedly completed luteoplacental shift begin to fall (40).…”

The Freeze-All Strategy Revisited: New Pieces to the Old Puzzle

“…In fact, ovarian stimulation enables excess number of oocytes to be obtained, but at the same time it impairs endometrium receptivity owing to supraphysiologically high hormone levels during the follicular phase [6]. Moreover, all of the currently used ovarian stimulation protocols also disturb the implantation process after fresh embryo transfer through altering the secretion of progesterone by the corpus luteum, even though this drawback can be partially overcome by an adequate luteal phase support, adapted to the ovarian stimulation protocol used and to the individual characteristics of each patient [7]. In fact, several studies [8][9][10] reported an improvement of live birth rate (LBR) after frozen embryo transfer (FET) as compared with fresh embryo transfer.…”