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Bordeaux, France
The luteal phase extends from the moment of ovulation triggering until the beginning of menses, or of pregnancy. The corpus luteum is generated from luteinized granulosa and theca interna cells that remained in the follicle after oocyte extrusion. It secretes both estrogens and progesterone under the effect of a pulsatile LH stimulation that is slower (3–5 pulses/24 h) than during the follicular phase (one pulse every 90 min). If conception and nidation follow ovulation, hCG secreted by the embryonic pouch maintains the luteal gland trophicity for secretion of both steroid classes (Fig. 7.1). Between the fifth and the seventh weeks of pregnancy the placenta also begins to assume autonomous synthesis and secretion of these hormones. Csapo showed in 1973 that the pregnancy was interrupted if the corpus luteum was removed earlier than the seventh week, but progesterone administration could rescue the pregnancy by this time [1].
Fig. 7.1
Steroidogenesis in the corpus luteum, illustrating the contributions of separate compartments of theca and granulosa cells
In a natural menstrual cycle, a corpus luteum will typically produce 25–50 mg of progesterone daily, to maintain plasma levels at a mid-phase range of 10–20 ng/ml [2, 3]. Luteal phase defects may compromise the chances for pregnancy during the cycle leading to fertilization. Whereas there is little consensus regarding precise definitions (examples: short luteal phase of <10 days, plasma progesterone of <10 ng/ml, discrepancies between chronologic and endometrial dating in relation to the LH surge or to the previous menses), defects of the luteal phase are believed to be responsible for infertility in some 8 % of normally cycling patients. This type of dysfunction may be obviated by progesterone administration to induce a secretory transformation of the endometrium, thereby enhancing uterine mucosa receptivity to implantation, and by inhibiting uterine contractions [4].
Luteal phase defects are often secondary to an abnormal follicular development during the first part of the cycle, or to an inadequate pre-ovulatory surge of gonadotropins. This may explain how the process of directed ovarian stimulation can become involved in the quality of the resulting corpus luteum, and it also raises the question of efficacy of luteal supplementation. Luteal gland abnormalities appear to vary according to the type of ovarian stimulation. Whereas luteal insufficiencies are often documented following a COH with GnRH analogues, their appearance following other stimulation conditions remains controversial and relies more on beliefs, habits, or some contradictory uncontrolled studies. The whole issue of maintaining luteal function also remains important on numerous fronts, as evidenced by a recent report that appears to link the occurrence of certain cancers in childhood with the administration of progesterone to the mother [5].
7.1 Luteal Phase Defects Following a Classic (Mono-to Paucifollicular) Stimulation
There are two types of scenario, depending upon the presence or the absence of an endogenous pulsatile LH secretion.
7.1.1 Normal Gonadotropins in Ovulation and Anovulation
An inadequate luteal phase can develop in a patient having a normal hypothalamic-pituitary-ovarian axis in two basic ways:
A suboptimal follicular stimulation process leading to a granulosa cell population that remains insufficient for transformation to an adequate luteal gland. In this case, the luteal insufficiency could have been prevented with a more robust follicular stimulation.
When hCG is used to trigger ovulation, there can be a temporary depression of LH pulsatility and secretion due to a short loop feedback. This has been identified under experimental conditions following hCG administration, and it can deprive the corpus luteum of sufficient LH stimulation [6]. However, this scenario has not been definitively identified in normally ovulating women [7]. Moreover, the action of a single hCG injection on the luteal gland typically persists for several days and should compensate for any temporary shortfall of LH secretion.
In fact, the standard practice of progesterone administration following a simple ovarian stimulation is not supported by study data. Reports are unable to establish its validity even after COH without analogues [8]. Luteal support also seems unnecessary following a single antagonist administration for insemination purposes [9]. On the other hand, progesterone administration may be mandatory in certain other situations, such as treating a short luteal phase (<10 days) or a when a post-ovulatory progesterone level remains under 10 ng/ml.
Two other points that are worthy of attention:
Progesterone administration should not be started within 2 days of an hCG injection so that the integrity of the thinner pre-ovulatory cervical mucus will not be disturbed.
Triggering ovulation with a GnRH agonist instead of hCG produces a short or inadequate luteal phase in about a third of the cycles, in certain patients. In those instances luteal support with progesterone is mandatory, or even better when combined with a single low dose of hCG (750 IU) 2–3 days after ovulation [10].
7.1.2 Hypogonadotropic Anovulation
In cases of primary or secondary pituitary insufficiency, supporting corpus luteum steroidogenesis becomes mandatory because LH secretion is definitely inadequate or possibly absent. When stimulation is conducted with a GnRH pump, the pulsatile gonadorelin administration should be continued for 7–10 days following ovulation. When stimulation is conducted with a gonadotropin preparation containing FSH and LH, luteal support should be provided either as progesterone or by injections of 1,500 IU hCG given three times at 3-day intervals [11]. In our experience, absence of luteal support does not reduce the pregnancy rate, probably because of LH-like properties of the hCG used for triggering ovulation that remain active until the time for implantation.
7.2 Multifollicular (COH) Stimulation
Typically, luteal support with progesterone or hCG has been prescribed following COH since the early days of IVF, in order to increase the pregnancy rate by preventing a possible luteal insufficiency. This situation often occurs when large numbers of granulosa cells become aspirated together with the oocyte, and/or when supra-physiologic levels of secreted estrogens have suppressed LH secretion. Nevertheless it was extensively documented that additional luteal support was not necessary in stimulation protocols using clomiphene + HMG or HMG alone. The activity of a typical 10,000 IU hCG triggering dose on the corpora lutea usually persists through the implantation period [12].
This situation changed dramatically with the arrival of GnRH agonists, because their use in COH protocols was usually followed by luteal phase perturbations that decreased pregnancy rates [13]. This premature luteolysis is due mainly to the prolonged suppression of pulsatile LH secretion that is necessary to maintain corpus luteum activity and steroid hormone production. Administration of a long acting GnRH agonist can permanently suppress pituitary LH secretion, and even a short-acting agonist can suppress LH for 10–20 days following the final application.
7.2.1 Types of Luteal Support
Five substances are available for corpus luteum support, or as a substitute in case of its failure.
Chorionic gonadotropin, which binds to the LH/hCG receptors of luteal cells and stimulates secretion of estradiol and progesterone. Continuing hCG administration during the post-ovulatory period provides a very effective support of luteal function, but it also carries a real risk for late ovarian hyperstimulation (OHSS). Repeated injections of hCG lead to an accumulation in plasma because of the hormone’s prolonged prolonged half-life [14]. For this reason, this potentially hazardous yet effective method of support is not usually prescribed following COH with GnRH analogues. Progesterone administration provides the same quality of result without any risk for OHSS.
On the other hand, when ovulation is triggered with a short acting GnRH agonist in an antagonist protocol, administration of a small dose of hCG (750–1,500 IU) is mandatory in order to regain a normal luteal phase and pregnancy rates; indeed, administration of progesterone alone or with estradiol, may not be sufficient [15].
Progesterone administration is adequate for luteal support of COH stimulation cycles. Several routes of administration are possible, but each has certain drawbacks [16]:
Vaginal suppositories of micronized progesterone are widely used at a 200–600 mg daily dose, but this may result in vaginal discharges with occasional local irritation.
Vaginal 8 % progesterone gel (Crinone®), 90 mg daily, has the same efficacy and drawbacks as the suppositories.
Intramuscular depot of 500 g progesterone in oil on the evening following oocyte retrieval, plus a second injection 7 days later, is effective. However, prolonged absorption of hormone from the injection site may result in menstrual cycle disorders for several months if a pregnancy is not achieved.
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