"Follicular HCG endometrium priming for IVF patients experiencing resisting thin endometrium. A proof of concept study".

PURPOSE: A thin endometrium is one of the most difficult problems encountered in assisted reproduction every day practice. Whether a daily dose of 150 IU HCG for 7 days concomitant with estrogen administration in estrogen replacement cycles can increase the endometrial thickness and improve pregnancy outcome, was the objective of the current study. METHODS: Seventeen infertile patients with successive implantation failures and resisting thin endometrium, being recipients of fresh donor or frozen embryos were recruited. This was a prospective cohort, proof of concept study, NCT01768247. On day-8 or 9 of the estrogen administration, and continuing 8 mg estrogen per day, subcutaneous injections of 150 IU HCG were initiated daily for 7 days. After a week on HCG priming, (day-14 or 15) endometrial thickness was controlled with ultrasound, and progesterone was initiated. RESULTS: Mean endometrial thickness was increased from 5.2 mm to 6 mm (p = 0.008). 35.3 % of the patients had more than 20 % improvement of their endometrial thickness after HCG priming. 17 % achieved an endometrial thickness more than 7 mm, and 29.4 % did not improve their thickness at all. Interestingly, from the later two became pregnant. Overall, 41 % of them (7/17) finally delivered. CONCLUSIONS: One hundred fifty IU HCG endometrial priming for 7 days in the proliferative phase of estrogen substituted cycles for frozen embryos is highly promising, as not only the thickness of the endometrium improves but also eventually the receptivity appears normalized.

The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives.

In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates.

Elevated progesterone during ovarian stimulation for IVF.

There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also explores the origin of the progesterone rise, potential modifying factors and possible methods to prevent its rise during ovarian stimulation. This review draws on information already published from monitoring progesterone concentrations at the end of follicular phase in ovarian stimulation. The databases of Medline and PubMed were searched to identify relevant publications. Good-quality evidence supports the negative impact on endometrial receptivity of elevated progesterone concentrations at the end of the follicular phase in ovarian stimulation. Future trials should document the cause and origin of premature progesterone in stimulated IVF cycles. There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also explores the origin of the progesterone rise, potential modifying factors and possible methods to prevent its rise during ovarian stimulation. This review draws on information already published from monitoring progesterone concentrations at the end of follicular phase in ovarian stimulation. The databases of Medline and PubMed were searched to identify relevant publications. Good-quality evidence supports the negative impact on endometrial receptivity of elevated progesterone concentrations at the end of follicular phase in ovarian stimulation. Future trials should document the cause and origin of premature progesterone in stimulated IVF cycles.

Does cessation of progesterone supplementation during early pregnancy in patients treated with recFSH/GnRH antagonist affect ongoing pregnancy rates? A randomized controlled trial.

BACKGROUND: The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation METHODS: There were 200 patients, with a positive ß-hCG test (followed by a doubling in ß-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second ß-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET RESULTS: The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: -2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446). CONCLUSIONS: After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing ß-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks.

Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit?

BACKGROUND: Limited data exist concerning the need for luteal support in clomiphene citrate-stimulated intrauterine insemination (IUI) cycles. The addition of progesterone became an established clinical practice, despite the absence of evidence of effectiveness. METHODS: A prospective randomized controlled trial was performed in a tertiary referral centre to assess the effect of intravaginal micronized progesterone as luteal support on the probability of ongoing pregnancy in patients stimulated with clomiphene citrate for IUI. Normo-ovulatory women, ≤ 36 years of age, undergoing ovarian stimulation with clomiphene citrate (50 mg) for IUI (n = 468) were randomized during the period from September 2008 to December 2009. Patients were randomized, either to receive luteal phase support (n = 243) in the form of vaginal micronized progesterone in three separate doses (200 mg, 3 times a day), or to the control group who did not receive luteal phase support (n = 225). RESULTS: Data from 400 women were analysed. Following the first interim analysis, the study was prematurely cancelled as an extremely low total pregnancy rate was found. No difference was observed in ongoing pregnancy between patients who did, or did not, receive vaginal progesterone as luteal support [8.7% (17/196) versus 9.3% (19/204), respectively, P = 0.82; difference -0.6%, 95% confidence interval (CI): -6.4, 5.2]. Additionally, the early pregnancy loss rate did not differ between groups (1.5% progesterone group versus 2% no progesterone group, P = 0.78; difference -0.5%, 95% CI: -3.6, 2.7). CONCLUSIONS: Routine supplementation of the luteal phase with vaginal progesterone does not seem to improve pregnancy rates in normo-ovulatory women stimulated with clomiphene citrate for IUI. Clinical trials.gov:NCT01046708.

Steroid receptor expression in human endometrium during the follicular phase of stimulated cycles.

BACKGROUND: No data are currently available regarding kinetics of human endometrial steroid receptors in stimulated cycles. METHODS: In 31 patients (age <39 years) stimulated with gonadotrophins and GnRH antagonists for intrauterine insemination (IUI) an endometrial biopsy was performed on the first day after the end of menstruation and a second biopsy was performed two (Group 0 + 2, n = 10) or four (Group 0 + 4, n = 11) days after the first biopsy, or on the day of hCG administration (Group 0 + hCG, n = 10). Expression of progesterone (PR) and estrogen (ER) receptor was investigated by immunohistochemistry using monoclonal antibodies. RESULTS: PR and ER levels were significantly increased in the second versus the first biopsy, in all groups analyzed (P = 0.01), in both stromal and glandular cells. Between the three groups compared, a significant increase in PR expression was observed for glandular cells (P = 0.03), with the highest value observed in Group 0 + 4. Moreover, the increase in PR expression in stromal cells differed between groups (P = 0.01), with the highest value observed in the Group 0 + hCG. CONCLUSIONS: In stimulated cycles for IUI, ER expression in both glandular and stromal endometrial cells, after an initial increase, does not appear to change significantly during the follicular phase. On the contrary, during the same period of time, following an initial rise, PR expression in glandular and stromal cells continues to increase.

Does the estradiol level on the day of human chorionic gonadotrophin administration have an impact on pregnancy rates in patients treated with rec-FSH/GnRH antagonist?

BACKGROUND: The purpose of this prospective observational study was to evaluate the association between estradiol (E(2)) levels on the day of human chorionic gonadotrophin (hCG) administration and pregnancy rates in a recombinant FSH (rec-FSH) antagonist fixed protocol. METHODS: A group of 207 patients (or=3 follicles of >or=17 mm diameter. One to two embryos were transferred on Day 3 after oocyte retrieval. RESULTS: The area under the curve (AUC) for E(2) on the day of hCG could not distinguish between pregnant and non-pregnant women (AUC:0.5; 95% confidence interval (CI): 0.42-0.59). No significant difference was observed between the three percentile groups of E(2) values on the day of hCG administration [group 1, lower 25th percentile (<1142 pg/ml); group 2, medium 50th percentile (1142-2446 pg/ml) and group 3, higher 75th percentile (>2446 pg/ml)] for the ongoing pregnancy rates (P = 0.52). On the contrary, the linear regression model showed that higher E(2) values on the day of hCG administration significantly improved the scores of transferred embryos (P = 0.01) as well as the total embryo score (P = 0.02). Yet subgroup analysis only in this high responders group revealed lower E(2) and progesterone levels on the day of hCG in pregnant women compared with the non-pregnant (P = 0.01). CONCLUSIONS: E(2) concentrations on the day of hCG administration in GnRH antagonist cycles are not associated with pregnancy rates. A potential deleterious impact of estradiol on endometrial receptivity is shown for the high responders who have high E(2) levels and improved embryo quality without a concomitant rise in pregnancy rate.

The relationship of premature progesterone rise with serum estradiol levels and number of follicles in GnRH antagonist/recombinant FSH-stimulated cycles.

OBJECTIVE(S): To investigate the relationship between premature progesterone (P) rise and serum estradiol (E(2)) levels and the number of follicles in GnRH antagonist/rec-FSH stimulated cycles. STUDY DESIGN: Two hundred and seven patients treated by IVF/ICSI at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University were included in this observational study. They received 200 IU/day rec-FSH from day 2 of the cycle and daily GnRH antagonist starting on day 6 of stimulation. The criteria for hCG administration included the presence of ≥3 follicles of ≥17 mm diameter. Serum P, E(2) and LH were determined on the day of hCG administration. The outcome measure was to identify a threshold of E(2) and number of follicles on the day of hCG administration which would define a progesterone rise on the day of hCG administration (cut-off value of 1.5 ng/ml). RESULT(S): Patients with a P >1.5 ng/ml had significantly higher concentrations of E(2) and increased number of follicles on the day of hCG administration compared to those with P ≤1.5 ng/ml. However, patients with a P >1.5 ng/ml the day of hCG showed lower pregnancy rates than those with P <1.5 ng/ml (17.8 vs. 32.7%, respectively; p<0.05). A ROC curve was employed in order to estimate a cut-off for E(2) on day of hCG >1790.5 pg/ml and more than 9.5 follicles of ≥11 mm in diameter for progesterone rise over 1.5 ng/ml. CONCLUSION(S): A significant impact is shown on progesterone rise by E(2) and number of follicles on the day of hCG administration in GnRH antagonist/rec-FSH-stimulated cycles. With this knowledge, an upcoming progesterone rise during follicular phase can be anticipated and prevented.

Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate whether the addition of GnRH agonist for luteal support in ICSI/IVF cycles enhances the probability of live birth. METHODS: Systematic literature search (MEDLINE, EMBASE, CENTRAL and RCT registries) was conducted to identify relevant randomized controlled trials published as full manuscripts. Meta-analysis of data yielded pooled risk differences (RDs) and 95% confidence intervals (CIs). A random effects model was applied for pooling the studies. RESULTS: Six relevant RCTs were identified including a total of 2012 patients. The probability of live birth rate (RD: +16%, 95% CI: +10 to +22%) was significantly higher in patients who received GnRH agonist support compared with those who did not. The subgroup analysis according to the type of GnRH analogue used for LH suppression did not change the effect observed (studies in which GnRH agonist was used during ovarian stimulation, RD: +15%, 95% CI: +5 to +23%); (studies in which GnRH antagonist was used during ovarian stimulation, RD: +19%, 95% CI: +11 to +27%). CONCLUSIONS: The best available evidence suggests that GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.