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.
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).
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.
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.
Route of support (P)
Progestrone can be delivered in several ways:
There are several formulae for delivering P vaginally:
Micronized P (Prometrium or Utrogestan) 200 mg administered vaginally t.i.d. produces satisfactory endometrial effects.
GnRH-a administration during the mid-luteal phase
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?