Ovulation Stimulation with Gonadotropins, 1st ed. 2015

7. Supporting the Luteal Phase

Jean-Claude Emperaire1

(1)

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].

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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 [23]. 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.

·                                   Intramuscular depot of smaller progesterone doses (50 mg daily) have much less potential for cycle disruption but this approach requires a series of daily administrations rather than a single large one.

·                                   Subcutaneous self-administration of aqueous progesterone (Prolutex®) has shown similar results to vaginal progesterone, but this product is not yet available in every country [17].

·                                   Oral dydrogesterone (Duphaston®) at a 20 mg daily dose provides a comfortable, effective luteal support, but is curiously seldom used [18].

·                                   None of the various progesterone preparations available in different countries appears to be superior to the others, and none is actually more efficacious than treatment with hCG [19].

·               Estradiol: The exact role of the luteal secretion of estradiol remains hypothetical. During COH, estradiol reaches supra-physiologic levels that peak just before the hCG administration, then it rapidly decreases following oocyte retrieval and rises again during mid-luteal phase, much as in the normal menstrual cycle pattern. Following a report [20] that estradiol levels were higher 9–10 days after the ovulatory gonadotropin surge in conception cycles, interest appeared for supplementation with progesterone and estradiol during the luteal phase following COH. On the other hand, it remains debated whether a systematic 2–8 mg dose of oral micronized estradiol should be administered to patients whose endogenous estradiol levels have already exceeded the normal physiologic range [21]. Nevertheless, continued post-ovulatory monitoring of some patients will determine whether estradiol administration is advantageous. It has been proposed to use estradiol supplementation only in cycles where the plasma level falls below 100 pg/ml within 11 days after the embryo transfer [22].

·               GnRH agonists are paradoxically able to improve the luteal phase in certain situations by provoking additional LH secretion. One approach is to continue with daily intranasal application of buserelin following a classic ovulation triggering with 200 μg of the same agonist. However, dosing must retreat below a level (e.g., 100 μg) that desensitizes the pituitary [23]. Another approach is to administer a single dose of 0.1 mg triptorelin 6 days after oocyte retrieval. This is reported to improve the implantation rate significantly, with effects on pituitary, the endometrium and possibly the embryo itself through their GnRH receptors [24]. This effect remains to be confirmed, and furthermore, one should be cautious when supporting the luteal phase with GnRH agonists following COH because effects of these peptides on the embryo are largely unknown. On the other hand, there are also reassuring reports of spontaneous conceptions during the activity period of long acting agonists [25].

·               Pituitary LH: If a GnRH agonist is used to trigger ovulation during an antagonist COH protocol, progesterone alone will not be able to maintain the luteal phase. However, the addition of 300 IU recombinant LH (Luveris®) every other day is able to restore an adequate luteal phase. This would appear to confirm the belief that luteal abnormalities following COH with GnRH analogues result from an insufficient LH support [26]. Still, the cited report was only a feasibility study; the cost of recombinant hormone treatment in a clinical practice study would be excessively expensive in comparison with the administration of progesterone alone that would be expected to yield the same result [27].

7.2.2 When to Start?

Progesterone administration can be started on the day of triggering ovulation, on the day of oocyte retrieval (Day 0) or on the day of embryo transfer (Day 3) [28]. However, further delay does appear to diminish the pregnancy rate [29].

7.2.3 When to Stop?

Although various approaches coexist in this field, it is now fairly well understood that continuing luteal phase support beyond the first positive pregnancy test has essentially no effect upon the future course. The rates of chemical pregnancy, ectopic pregnancy, or spontaneous abortion are comparable whether progesterone administration is stopped on the first day of a positive pregnancy test, or continued on up through three more weeks, or even longer [30].

7.3 Conclusion

Luteal support is mandatory only following a COH with GnRH analogues. Whatever galenic formulation is chosen, progesterone is capable of restoring both luteal phase quality and normal pregnancy rates, except in the particular case of the agonist-triggered ovulation. Use of hCG is as effective as progesterone but this hormone increases the risk for secondary OHSS.

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