IVF - Luteal support - IVF-Worldwide

In order to achieve pregnancy, a delicate communication between the blastocyst and endometrium is needed over a specific time during the cycle. This period, termed the "Implantation Window" occurs during the luteal phase and is controlled by estrogen (E) and progesterone (P).

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Administration of hormones, usually P, and occasionally also E, human chorionic gonadotropin (hCG), or GnRH-agonist (GnRH-a) are required during the luteal phase, to support the implantation and early development of the embryo.

The success of donor egg programs, in which pregnancy can be achieved by supplementation of only only E and P demonstrates the sufficiency of these hormone only for luteal support and implantation in order to achieve a successful pregnancy.

Normal secretion of E and P during the luteal phase:

Average E production is 0.6 mg/day, and that of P is 25 mg/day (40-fold higher).

In a nonpregnant woman, E and P production peaks about 4 days after ovulation, and continues at this level for approximately a week, until it declines several days before the next menses. During pregnancy, E and P production is restored by hCG stimulation of the corpus luteum. A shift from ovarian to placental production of gonadal steroids occurs approximately 7 weeks’ gestation. This reflects well with the observation that surgical removal of the corpus luteum, if performed before 7 weeks’ gestation, results in miscarriage in all cases, and almost never if performed after that time.

What are the reasons for luteal support in IVF?
After stimulation treatment in IVF, the luteal phase differs from the normal one in two important things:
1. Production of multiple corpora lutea that causes supraphysiological levels of P during the early luteal phase
2. Sharp, and not gradual increase in P
3. Sharp decline in P production
4. Use of GnRH-a causes short luteal phase

On Figure – JG, etc. are these initials of patients – should be deleted??
Normal luteal phase (left panel) compared to ovarian stimulation luteal phase (right panel) clearly shows:
a) sharp increase in P; b) short duration of steroids; c) sharp decline of P

Examination of P levels during pregnancy as projected in the graph indicate that P levels in IVF cycles may be equivalent to those at 26 weeks’ gestation.

What are the detrimental effects of high levels of E and P as reflected in the IVF cycle?
Histological investigation of the endometrium clearly showed that in approximately 50% of females treated for IVF the endometrial development is not entirely normal, and the stroma is more advanced than the glands, leading to a “dyssynchrony” of histological appearance. DeZiegler, in a paper published in 1994, suggested that endometrial glandular development is mainly related to the duration of P exposure, whereas stromal development is mainly related to the P dose.

The above figure describes some of the mechanisms that may lead to corpus luteum dysfunction, luteal phase defect and irregular endometrial development. In summary, the main causes may be the use of GnRH-a untimely supraphysiological steroid production and mechanical intervention in the corpus luteum structure due to multiple punctures.

What is the evidence for luteal support?
Studies by Leeton et al. (1985), Yovich et al. (1985) and Belaisch-Allart et al. (1987) all showed higher pregnancy rates when comparing cycles with P luteal support to no luteal support.
Studies comparing luteal support with hCG to those with no support also showed higher pregnancy rates (Smith et al., 1989, Belaisch-Allart et al., 1990; Herman et al., 1990).
Several meta-analyses that compared support with P/hCG demonstrated significantly higher pregnancy rates in cycles with the support/than those without support (Soliman et al., Fertil Steril 1994:61;1068, Pritts & Atwood, Hum Reprod 2002:9;2287; Daya and Gunby, Cochrane 2006:3).

What element/drug(s) should we use to support the luteal phase?
Based on studies in egg donation programs in women with no ovarian function, it was shown that endometrial supplement with E and P is sufficient.
The highest pregnancy rate with luteal support is achieved by hCG. However, given the increased risk that hCG may cause ovarian hyperstimulation syndrome (OHSS), the use of hCG to provide combined E and P secretion has not been widely adopted. Administration of hCG results in increased serum concentrations of E and P. There is no question regarding the necessity for P but there is still some controversial opinion as to whether E is needed.
Two recent studies support the hypothesis that E is needed. In one study high-responder patients (>2500 pg/ml E at time of hCG) pretreated with a long GnRH-a protocol were randomized to receive either P alone (50mg p.v. b.i.d. and 50mg i.m. q.i.d.) or E (2mg p.o. bid) and P. Patients who received both E and P had higher pregnancy rates (40% vs. 26%), higher implantation rates (15% vs. 10%), and lower miscarriage rates (11% vs. 17%) than those who did not receive E. In the second study more positive pregnancy tests (38.5%) were observed when E2 patches were used than with P alone (13.5%). A Cochrane meta-analysis also suggested the benefit of E supplementation.

New evidence supports the use of midluteal phase with GnRH-a.

Route of support (P)
Progestrone can be delivered in several ways:

 Transdermally (ineffective due to poor skin permeability, large quantity is needed)

 Nasally (ineffective as requires many repeated doses)

 Rectally (inconvenient, associated with unpleasant discharge)

 Sublingually (causes enhanced absorption)

 Intramuscularly (P in oil, very effective, keeps the endometrial architecture "in Phahse" but is painful and is associated with sterile abscess formation)

 Orally (associated with poor bioavailability and rapid clearance rate. Bypasses the liver and therefore the plasma level is about 10% of the original dose administered. Its metabolites cause dizziness, sleepiness and nausea)

 Transvaginally (P administration) - The vaginal route is convenient and acceptable, rarely produces allergic reactions. There is a discrepancy between the low serum P levels and the complete predecidualization. However, comparing concentrations of P in the endometrium the highest level is reached when P is administered vaginally.. This reflects the "first uterine pass effect" described in 1997 by Bulletti and colleagues.

There are several formulae for delivering P vaginally:
Micronized P (Prometrium or Utrogestan) 200 mg administered vaginally t.i.d. produces satisfactory endometrial effects.

Paraffin-based suppositories (Endometrin). Micronized P, 100 mg, given twice daily. produces satisfactory endometrial effects.

Vaginal gel (Crinone 8%). This is a bioadhesive vaginal gel containing 90 mg micronized P in an emulsion system designed to adhere to the vaginal mucosa. It is administered once-daily. The dose administered is approximately 4-fold higher than that required for satisfactory endometrial development.

In general

GnRH-a administration during the mid-luteal phase

This notion is based on the observation of Tesarik et al. regarding the increased pregnancy rates in egg donation as well as conventional IVF groups. Data was published in 2004 and 2006 in the Human Reproduction Journal. This concept may be supported by a previous work of Raga et al. (Endocrinology 1999) showing that adding GnRH-agonist to the culture media of murine embryos enhanced significantly embryonic development.

When should treatment be initiated?

It has been shown that the best pregnancy rate (PR) can be achieved when the endometrium is treated with P 3 to 4 days prior to embryo transfer (ET). In addition to creating an adequate endometrium for implantation, P contributes to the decrease in uterine contractions that also support implantation.

Suggested protocol for luteal support

How long is supplementation needed?

In a conventional IVF treatment cycle, when GnRH-a is administered, the recommendation is that the luteal phase should receive support up to the stage of early pregnancy. Some physicians stop the support when the pregnancy test is positive, others continue until the appearance of a fetal heart rate.

In cases of egg donation cycles, when there is no ovarian function whatsoever,, the period during which the luteoplacental shift occurs and which is the major source of P, appears to be critical. The majority of treating physicians continue support up to the end of 12 weeks’ gestation even though it would be safe to stop treatment by 10 weeks.

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