Interindividual variation of progesterone elevation post LH rise: implications for natural cycle frozen embryo transfers in the individualized medicine era.

BACKGROUND: The key to optimal timing of frozen embryo transfer (FET ) is to synchronize the embryo with the receptive phase of the endometrium. Secretory transformation of the endometrium is induced by progesterone. In contrast, detection of the luteinizing hormone (LH) surge is the most common surrogate used to determine the start of secretory transformation and to schedule FET in a natural cycle. The accuracy of LH monitoring to schedule FET in a natural cycle relies heavily on the assumption that the period between the LH surge and ovulation is acceptably constant. This study will determine the period between LH rise and progesterone rise in ovulatory natural menstrual cycles. METHODS: Retrospective observational study including 102 women who underwent ultrasound and endocrine monitoring for a frozen embryo transfer in a natural cycle. All women had serum LH, estradiol and progesterone levels measured on three consecutive days until (including) the day of ovulation defined with serum progesterone level exceeding 1ng/ml. RESULTS: Twenty-one (20.6%) women had the LH rise 2 days prior to progesterone rise, 71 (69.6%) had on the day immediately preceding progesterone rise and 10 (9.8%) on the same day of progesterone rise. Women who had LH rise 2 days prior to progesterone rise had significantly higher body mass index and significantly lower serum AMH levels than women who had LH rise on the same day with progesterone rise. CONCLUSION: This study provides an unbiased account of the temporal relationship between LH and progesterone increase in a natural menstrual cycle. Variation in the period between LH rise and progesterone rise in ovulatory cycles likely has implications for the choice of marker for the start of secretory transformation in frozen embryo transfer cycles. The study participants are representative of the relevant population of women undergoing frozen embryo transfer in a natural cycle.

Prospective observational comparison of arteria uterina blood flow between two frozen embryo transfer cycle regimens: natural cycle versus hormonal replacement cycle.

PURPOSE: Is there a difference in the blood flow of the Arteria uterina in frozen embryo transfer (FET) cycles between a Natural Cycle (NC) and a Hormonal Replacement Therapy (HRT) cycle? METHODS: Prospective observational study with measurement of the pulsatility index (PI) and resistance index (RI) throughout the ovarian stimulation cycle for IVF/ICSI, the FET cycle and at 12 weeks of gestation. RESULTS: A total of 124 ovarian stimulation cycles with preimplantation genetic testing for aneuploidy (PGT-A) and "freeze-all" strategy due to PGT-A were included. Mean patient's age was 31.4 years, mean BMI 26.47 kg/m2, mean AMH 3.62 ng/ml and a mean AFC of 13. FET cycles were performed in 77 patients (NC protocol: 37.7%, HRT protocol: 62.2%). The overall pregnancy rate was 75%, (NC group: 79%, HRT-group 73%; not significant). No significant change of PI and RI was seen during hormonal stimulation. In FET cycles, there was a significant increase between cycle day 2/3 and ovulation/P4-start in the HRT-cycle, followed by a significant decrease until 12 weeks of gestation. The slope of the decrease in patients with a pregnancy in an HRT-approach was a bit steeper than in the NC-approach for both PI and RI, however, without a significant difference. CONCLUSIONS: Early measurements of the blood flow parameters during the FET cycle do not reveal a difference between the NC- and the HRT-approach for FET, which could be predictive for development of pre-eclampsia.

Does blastocyst mitochondrial DNA content affect miscarriage rate in patients undergoing single euploid frozen embryo transfer?

PURPOSE: To determine whether the blastocyst mitochondrial DNA (mtDNA) content is related to the miscarriage rate in patients undergoing single euploid frozen embryo transfer (SEFET). METHODS: A total of 355 single euploid frozen embryo transfer cycles were studied retrospectively between April 2017 and December 2018. A trophectoderm biopsy was performed on day 5/6 blastocysts. Post next-generation sequencing (NGS), the mtDNA content was calculated as the ratio of mitochondrial DNA over nuclear DNA, and the association between blastocyst mtDNA content and miscarriage rate was evaluated. RESULT(S): Three hundred fifty-five euploid blastocysts were selected for SEFET in 314 patients with an average age of 33.7 ± 5.6 years; 255 were biopsied on day 5 (71.8%) and 100 on day 6 (28.2%). Frozen embryo transfer (FET) was performed either in a hormone replacement therapy (HRT) cycle (71.8%; n = 255) or in a natural cycle (NC) (28.2%; n = 100). A pregnancy rate of 66.2% (235/355) was obtained with clinical pregnancy and miscarriage rates of 52.4% (n = 186) and 5.6% (n = 20), respectively. There was no significant difference neither between the blastocyst mtDNA content of pregnant and nonpregnant patients (27.7 ± 9.2 vs. 29.4 ± 8.6, P = 0.095) nor between patients with a clinical pregnancy and miscarriage (30.5 ± 9.3 vs. 27.3 ± 9.2, P = 0.136). Multivariate logistic regression analysis showed the same nonsignificant relationship, except for the miscarriage rate and BMI (OR 1.149, 95% CI 1.03-1.28; P = 0.012). CONCLUSION(S): Mitochondrial DNA content is unable to predict the miscarriage of implanted human euploid blastocysts.

Luteal Coasting and Individualization of Human Chorionic Gonadotropin Dose after Gonadotropin-Releasing Hormone Agonist Triggering for Final Oocyte Maturation-A Retrospective Proof-of-Concept Study.

Ovarian stimulation in a gonadotropin-releasing hormone (GnRH) antagonist protocol with the use of GnRH agonist for final oocyte maturation is the state-of-the-art treatment in patients with an expected or known high response to avoid or at least reduce significantly the risk for development of ovarian hyperstimulation syndrome (OHSS). Due to a shortened LH surge after administration of GnRH agonist in most patients, the luteal phase will be characterized by luteolysis and luteal phase insufficiency. Maintaining a sufficient luteal phase is crucial for achievement of a pregnancy; however, the optimal approach is still under debate. Administration of human chorionic gonadotropin (hCG) within 72 h rescues the corpora lutea function; however, the so far often used 1,500 IU still bear the risk for development of OHSS. The recently introduced concept of "luteal coasting" individualizes the luteal phase support by monitoring the progesterone concentrations and administering a rescue dosage of hCG when progesterone concentrations drop significantly. This retrospective proof-of-concept study explored the correlation between hCG dosages ranging from 375 up to 1,500 IU and the progesterone levels in the early and mid-luteal phases as well as the likelihood of pregnancy, both early and ongoing. The chance of pregnancy is highest with progesterone level ≥13 ng/ml at 48 h postoocyte retrieval. Among the small sample size of 52 women studied, it appears that appropriate progesterone levels can be achieved with hCG dosages as low as 375 IU. This may well optimize the chance of pregnancy while reducing the risk of OHSS associated with higher doses of hCG supplementation in the luteal phase.

Individual luteolysis pattern after GnRH-agonist trigger for final oocyte maturation.

Final oocyte maturation using GnRH-agonist trigger in a GnRH-antagonist protocol is increasingly common, as ovarian hyperstimulation syndrome is almost completely avoided. However, this approach might lead to reduced pregnancy rates due to severe luteolysis. This proof of concept study evaluated the extend of luteolysis by measuring progesterone levels 48 hours after oocyte retrieval in 51 patients, who received GnRH-agonist trigger for final oocyte maturation in a GnRH-antagonist protocol due to the risk of ovarian hyperstimulation syndrome. It was shown, that luteolysis after GnRHa-trigger differs greatly among patients, with progesterone levels ranging from 13.0 ng/ml to ≥ 60.0 ng/ml, 48 hours after oocyte retrieval. Significant positive correlations could be demonstrated between progesterone levels and the number of ovarian stimulation and suppression days (p = 0.006 and p = 0.002 respectively), the total amount of medication used for ovarian suppression (p = 0.015), the level of progesterone on the day of final oocyte maturation (p = 0.008) and the number of retrieved oocytes (p = 0.019). Therefore it was concluded, that luteolysis after GnRH-agonist trigger is patient-specific and also luteal phase support requires individualization. Longer stimulation duration as well as a higher level of progesterone on the day of final oocyte maturation and more retrieved oocytes will result in higher levels of progesterone 48 hours after oocyte retrieval.