The luteal phase of a menstrual cycle is the time between ovulation and, in case of conception, the establishment of a pregnancy or otherwise the onset of menses. In a natural cycle, under the influence of luteinizing hormone (LH), formation of the corpus luteum will occur after ovulation.
The corpus luteum is characterized by the production of progesterone and also estradiol. Progesterone causes the secretory transformation of the endometrium in the luteal phase and promotes local vasodilation and relaxation of the uterine muscle.
Medication for Luteal Phase Support in ART
Progesterone will be produced by the corpus luteum after LH surge in a normal, un-stimulated cycle. It is shown that the prevalence of the luteal phase defect (LPD) in the natural cycles in patients with an ovulation rate with primary or secondary infertility is about 8.1%. The minimum threshold of progesterone level that is essential for the maintenance of a pregnancy is yet unknown, and successful pregnancies have been reported even when the concentration of progesterone was never above 15 nmol/L for the first 14 days.
After ovarian stimulation for IVF/ICSI treatment, it seems that patients having progesterone levels at the day of implantation of more than 30 ng/mL and estradiol levels of more than 100 ng/mL are more likely to have a viable and ongoing pregnancy compared to patients with hormone levels below those thresholds.
In stimulated cycles for IVF, a defective luteal phase occurs in almost all patients. However, the reason for the luteal phase insufficiency seen after controlled ovarian stimulation seems to be the multi-follicular development achieved during the follicular phase, resulting in supra-physiological luteal levels of P and E2 that inhibit LH secretion by the pituitary via negative feedback actions at the level of the hypothalamic-pituitary axis. Besides the defective luteal phase due to the supra-physiologic levels of estradiol and progesterone, the window of implantation might be shorter in IVF cycles compared to a natural cycle.
To counterbalance the luteal phase insufficiency after ovarian stimulation, different methods of luteal phase support can be applied—either direct substitution of progesterone via different routes of administration or indirect substitution of progesterone by stimulating the remaining corpora lutea to maintain progesterone production.
As a consequence of the increasing knowledge of patient-specific characteristics, the old concept of one type of luteal phase support for all IVF patients has to be abandoned and a personalized approach, depending on the type of final oocyte maturation and the ovarian response, should be implemented into daily clinical routine.
Timing of Luteal Phase Support with Progesterone
The timing of luteal phase support in ART cycles is crucial, as it has to be initiated before endogenous progesterone levels are decreasing or low. Pre-ovulatory exposure of the endometrium to progesterone may have a negative impact on the endometrial receptivity as already described.
When luteal phase support was started before oocyte retrieval, a decreased likelihood of pregnancy was found when compared to starting on the day of oocyte retrieval. When progesterone was started in the evening of oocyte retrieval compared with the start of 1–3 days after oocyte retrieval, there was no difference in clinical PR. However, when progesterone administration was started on day 6, a decreased likelihood of pregnancy was found. Therefore, initiation of progesterone supplementation between the evening of oocyte retrieval and day 3 after retrieval seems to be ideal.
Duration of Luteal Phase Support
In early pregnancy, the embryo is producing a significant and rapidly increasing amount of hCG that will replace a possible lack of endogenous LH after ovarian stimulation. Later in the pregnancy, between seven and nine weeks, progesterone production will shift from the corpora lutea toward the placenta. Studies evaluating the duration of progesterone administration after a positive pregnancy test did not find any influence on the miscarriage rate and the delivery rate when progesterone application was continued or discontinued for three weeks after positive pregnancy test.
Luteal Phase Support After GnRH-Agonist Trigger
The use of GnRH agonist for final oocyte maturation is common in high-responder patients as development of OHSS can almost completely be avoided. After the introduction of the GnRH agonist for the final maturation of oocytes in the protocols of the GnRH antagonist, the first large randomized controlled trials showed a very poor reproductive outcome with this approach. It was assumed that the severity of the induced luteolysis by application of GnRH agonist cannot be counterbalanced using standard luteal phase support with “only” progesterone administration. The administration of hCG or high doses of steroids is considered to be essential to prevent luteolysis. There is an ongoing debate on the adequate luteal phase support in this scenario.
Luteolysis occurs when LH support from the primate corpus luteum is withdrawn for three or more days. Hence, corpus luteum function can be rescued if LH activity is reinitiated within 3 days, suggesting that corpus luteum viability can be preserved without LH support for at least 72 hours. In order to sustain progesterone production from the corpora lutea and therefore rescue the luteal phase, different treatment options have been described.
OHSS can be almost completely avoided by the use of GnRH agonist (200 mg of GnRH-agonist nasal spray twice daily. A total of 400 mg/d) for LPS after GnRH-agonist trigger without exogenous progesterone, and mid-luteal progesterone levels of around 190 nmol/L (approximately 59.7 ng/mL) can be achieved.
As a consequence of these findings, it is now recognized that not all patients after GnRH-agonist trigger are in need of an intensive and aggressive luteal phase support and should not be treated with a “one-size-fits-all” approach. The concept of “luteal coasting” is based on the individual luteolysis pattern by applying hCG based on the progesterone levels measured in the early and mid-luteal phases and can be performed with or even without the additional use of exogenous progesterone. Depending on the progesterone level 48 hours after oocyte retrieval, a single hCG dosage between 375 and 1500 IU, given in early luteal phase, can maintain adequate progesterone levels, and this approach may well optimize the chance of pregnancy while reducing the risk of OHSS associated with higher doses of hCG supplementation in the luteal phase. The necessity for repeat blood tests to measure progesterone levels poses the most important disadvantage of this approach.
Luteal Phase Support in Insemination Cycles
Intrauterine insemination (IUI) is a frequently applied technique to increase the probability of conception in couples with subfertility or unexplained infertility; however, the necessity of luteal support is addressed in only a few studies.
IUI can be performed in either natural cycles or stimulated cycles by using Сlomiphene citrate or gonadotropins for stimulation.
In natural IUI cycles, it can be assumed that no luteal phase insufficiency should be present; therefore, there is no biological or empirical evidence that treatment with hCG or progesterone in the luteal phase is necessary or improves the pregnancy rate. However, the addition of progesterone, hCG and/or other substances has become established clinical practice even in the absence of any conclusive evidence of effectiveness.
In patients who undergo mild ovarian stimulation for IUI, it can be assumed that due to supra-physiologic hormonal levels, endogenous LH will be low, leading possibly to a luteal phase insufficiency.
However, it is crucial to differentiate between the kind of stimulation done. After administration of Сlomiphene citrate, an increase in the frequency of LH pulse will lead to a significant increase in the level of E2 and progesterone in serum with an extension of the luteal phase. A study evaluating a beneficial impact of progesterone application in normo-ovulatory patients stimulated with Сlomiphene citrate for IUI did not find higher ongoing pregnancy rates in patients receiving progesterone after IUI compared to those who had no luteal phase support.
However, after gonadotropin stimulation, comparable to ovarian stimulation for IVF, supra-physiologic hormonal levels will lead to suppression of endogenous LH, and development of luteal phase insufficiency can be expected. It was shown that after IUI in a gonadotropin-stimulated cycle, the chance of pregnancy and live birth is higher, when progesterone application is done after IUI.
Luteal Phase Support in Frozen Embryo Transfer Cycles
Due to the improvement of the cryo-conservation techniques in the IVF laboratory with the introduction of vitrification, more and more frozen embryo transfer (FET)—or warmth oocyte embryo transfer—cycles are performed worldwide. This move toward frozen embryo transfer is the result of an ongoing debate on the impact of supra-physiologic hormonal levels on endometrial receptivity, particularly in the case of progesterone elevation. In addition, frozen embryo transfer facilitates preimplantation genetic testing for aneuploidy (PGT-A) at the blastocyst stage, which prevents a timely transfer on day 5 after oocyte retrieval.
To optimize the pregnancy rates, synchronization of the embryo development and the endometrium is crucial. There are different ways to prepare and synchronize the endometrium:
Natural cycle: A simple way to prepare endometrium is to use the natural cycle with endogenous production of estradiol of the growing follicle. In this scenario, the LH surge has to be detected in order to plan correct timing for embryo thawing and embryo transfer. Another option is to use an injection of hCG to trigger the ovulation (modified natural cycle). A study designed to compare the pregnancy rates between natural cycles and modified natural cycles showed significantly higher pregnancy rates in the natural cycle with the detection of LH surge. The administration of hCG to end the follicular phase resulted in significant lower pregnancy rates compared to natural cycles. It is assumed that hCG may have a negative effect on endometrium receptivity.
Hormonal-replacement cycle: This is a more common approach with the administration of exogenous estradiol and progesterone. The advantages of this approach are that disturbances due to cycle variation can be avoided, and also planning of the embryo transfer is possible, which will smooth the workflow for the IVF laboratory. The hormonal replacement cycle can be performed with or without co-treatment with GnRH agonists.
Until now, the best approach for FET is still under discussion, and there is an urgent need for randomized controlled trials to compare the correctly conducted natural cycle with correct determination of LH surge and the hormonal replacement cycle.
The task of a specialist in reproductive medicine is to individualize the support of the luteal phase in accordance with the specific characteristics, needs and desires of the patient, as well as the type of treatment performed.
After the use of hCG for final oocyte maturation, exogenous progesterone administration in the form of vaginal tablets, creams or suppositories is the gold standard and seems to be sufficient to maintain an adequate luteal phase support. Oral medication might be an alternative, yet more data are required to rely on this approach. Daily application of hCG in low dosages represents a progesterone-free alternative; however, until now, this is not a patient-friendly approach, as the low hCG dosages recommended are not presently commercially available.
The greatest indication for individualizing the luteal phase is following GnRH agonist triggers in high response patients to adapt the luteal phase support to a patient-specific luteolysis regimen and minimize the risk of OHSS with unreasonably high doses of hCG. Case series have demonstrated that reducing the hCG dosage according to a patient’s progesterone level or even foregoing luteal phase support is feasible. Future studies should develop an algorithm that provides the minimal-required hCG dosage, depending on the systemic progesterone levels.