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Study Question: Does assisted hatching increase the cumulative live birth rate in subfertile couples with repeated implantation failure?, Summary Answer: This study showed no evidence of effect for assisted hatching as an add-on in subfertile couples with repeated implantation failure., What Is Known Already: The efficacy of assisted hatching, with regard to the live birth rate has not been convincingly demonstrated in randomized trials nor meta-analyses. It is suggested though that especially poor prognosis women, e.g. women with repeated implantation failure, might benefit most from assisted hatching., Study Design, Size, Duration: The study was designed as a double-blinded, multicentre randomized controlled superiority trial. In order to demonstrate a statistically significant absolute increase in live birth rate of 10% after assisted hatching, 294 participants needed to be included per treatment arm, being a total of 588 subfertile couples. Participants were included and randomized from November 2012 until November 2017, 297 were allocated to the assisted hatching arm of the study and 295 to the control arm. Block randomization in blocks of 20 participants was applied and randomization was concealed from participants, treating physicians, and laboratory staff involved in the embryo transfer procedure. Ovarian hyperstimulation, oocyte retrieval, laboratory procedures, embryo selection for transfer and cryopreservation, the transfer itself, and luteal support were performed according to local protocols and were identical in both the intervention and control arm of the study with the exception of the assisted hatching procedure which was only performed in the intervention group. The laboratory staff performing the assisted hatching procedure was not involved in the embryo transfer itself., Participants/materials, Setting, Methods: Participants were eligible for inclusion in the study after having had either at least two consecutive fresh IVF or ICSI embryo transfers, including the transfer of frozen and thawed embryos originating from those fresh cycles, and which did not result in a pregnancy or as having had at least one fresh IVF or ICSI transfer and at least two frozen embryo transfers with embryos originating from that fresh cycle which did not result in a pregnancy. The study was performed at the laboratory sites of three tertiary referral hospitals and two university medical centres in the Netherlands., Main Results and the Role of Chance: The cumulative live birth rate per started cycle, including the transfer of fresh and subsequent frozen/thawed embryos if applicable, resulted in 77 live births in the assisted hatching group (n = 297, 25.9%) and 68 live births in the control group (n = 295, 23.1%). This proved to be statistically not significantly different (relative risk: 1.125, 95% CI: 0.847 to 1.494, P = 0.416)., Limitations, Reasons for Caution: There was a small cohort of subfertile couples that after not achieving an ongoing pregnancy, still had cryopreserved embryos in storage at the endpoint of the trial, i.e. 1 year after the last randomization. It cannot be excluded that the future transfer of these frozen/thawed embryos increases the cumulative live birth rate in either or both study arms. Next, at the start of this study, there was no international consensus on the definition of repeated implantation failure. Therefore, it cannot be excluded that assisted hatching might be effective in higher order repeated implantation failures., Wider Implications of the Findings: This study demonstrated no evidence of a statistically significant effect for assisted hatching by increasing live birth rates in subfertile couples with repeated implantation failure, i.e. the couples which, based on meta-analyses, are suggested to benefit most from assisted hatching. It is therefore suggested that assisted hatching should only be offered if information on the absence of evidence of effect is provided, at no extra costs and preferably only in the setting of a clinical trial taking cost-effectiveness into account., Study Funding/competing Interest(s): None., Trial Registration Number: Netherlands Trial Register (NTR 3387, NL 3235, https://www.clinicaltrialregister.nl/nl/trial/26138)., Trial Registration Date: 6 April 2012., Date of First Patient’s Enrolment: 28 November 2012., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Objectives: To assess risk and predictive factors for depression and well-being, 3 and 12 months after elective hysterectomy. Secondary objectives were to assess the incidence of depression, level of well-being, and feelings of femininity., Study Design: A prospective multicenter cohort study was performed among 419 women, undergoing hysterectomy for benign indication. Data were collected in the week prior to surgery, and in the per- and postoperative period up to the fourth postoperative day and 3 and 12 months after surgery. Sociodemographic variables, baseline health status, psychosocial predictors, and surgery data were assessed. Outcome measures were Center for Epidemiological Studies-Depression scale (CES-D, range 0-60), the 12-item well-being questionnaire energy and positive well-being subscales (range 0-12), and feelings of femininity. Predictor analyses were performed using linear mixed model analyses., Results: Levels of depression, energy, and positive well-being after hysterectomy were predicted by their corresponding baseline levels (estimate 0.62 p<0.001, 0.39 p<0.001, 0.37 p<0.001, respectively) and baseline pain (0.31 p=0.003, -0.09 p=0.026, -0.10 p=0.008). Postoperative infection reported at 12 months affected CES-D and energy level. Several other gynaecological, psychosocial, or perioperative factors were also predictive for one of the outcomes. Prevalence of depression at baseline, 3 and 12 months was 24%, 19%, and 21%, respectively. In general, well-being scores were slightly higher 3 and 12 months after hysterectomy than at baseline. Feelings of femininity were not negatively affected in 92% of the patients., Conclusions: Preoperative psychosocial status, perioperative pain, and postoperative infection were found as predictors of psychological outcome after hysterectomy. In the majority of patients we observed small but significant improvements with regard to postoperative depression and well-being, while feelings of femininity were unaffected., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To compare the endocrine changes in the follicular phase in infertile patients with polycystic ovary syndrome (PCOS) treated with either pulsatile IV GnRH after GnRH-agonist (GnRH-a) down-regulation or clomiphene citrate (CC)., Design: Subgroup analysis within a randomized, controlled, multicenter study., Setting: Women referred to the Infertility Clinic, Catharina Hospital Eindhoven, The Netherlands., Patient(s): Twenty-eight infertile patients with PCOS. INTERVENTIONs): Patients were randomly assigned to pulsatile IV GnRH (10-20 microgram/90 min) after GnRH-a down-regulation or CC (50-150 mg; cycle days 3-7). Patients were monitored on alternate days with ovarian sonography and serum concentrations of E(2), LH, and FSH. Serum P and sonography confirmed ovulation., Main Outcome Measure(s): Serum concentrations of E(2), LH, and FSH were assessed before treatment was started and after each ovarian sonography., Result(s): In ovulatory cycles, no statistically significant differences were observed during the follicular phase comparing serum concentrations of E(2), LH, and FSH between the treatments. However, a significant increase in LH occurred in the GnRH group., Conclusion(s): No significant endocrine differences were observed between GnRH and CC treatment. However, there was a significant increase in the serum LH concentration during the follicular phase in the GnRH group. Increments of LH in the GnRH group may be due to recovery of endogenous LH secretion.

Objective: To study ovarian stimulation and response patterns during a gonadotropin step-down dose regimen for induction of ovulation by applying a decremental dose regimen in polycystic ovary syndrome (PCOS) patients., Design: The present prospective study involves 28 infertile clomiphene citrate-resistant PCOS patients during gonadotropin-induced cycles using a modified step-down dose regimen (and adjuvant GnRH agonist medication). Applied gonadotropin doses included initial daily doses of 150 IU IM followed by two reducing steps (37.5 IU each) based on sonographic criteria to a final daily dose of 75 IU IM., Setting: Anovulatory infertile women in an academic referral center., Intervention: Daily blood withdrawal and transvaginal pelvic ultrasound., Main Outcome Measures: Serum FSH and E2 concentration and follicle growth were investigated daily during gonadotropin administration., Results: An initial 2.1-fold increase in serum FSH levels was observed followed by a subsequent decrease of 10% (median) per day for 4 days. Growth of ovarian follicles was sustained and ovulation achieved (midluteal P, 11.7 +/- 1.3 ng/mL; conversion factor to SI unit, 3.180; mean +/- SD) in 22 patients. Major variability in day 3 E2 increase (range, 67 to 866 pg/mL; conversion factor to SI unit, 3.671)--not related to differences in FSH serum concentrations and without changes in follicle number and size--suggests differences in ovarian sensitivity for FSH stimulation. A strong correlation (r = 0.82) was found between day 3 E2 increase and the chance of ovulation. Moreover, E2 levels on the day of gonadotropin dose reduction predict (r = 0.68) chances of late follicular phase E2 levels exceeding 871 pg/mL (conversion factor to SI value, 3.671)., Conclusions: These findings provide the endocrine basis for the concept of gonadotropin induction of ovulation using a step-down dose regimen. Initial E2 increase (before initiation of follicle growth) represent differences in ovarian sensitivity to gonadotropins and predict treatment outcome.

Seven women suffering from hypogonadism due to previous hypophysectomy, isolated gonadotrophin deficiency, or Kallman's syndrome [median age 39 years (range 24-45)] volunteered to participate in a study to assess ovarian response following multiple-dose administration of recombinant human follicle-stimulating hormone (rhFSH; Org 32489). Baseline serum FSH and luteinizing hormone (LH) concentrations were 0.25 (< 0.05-1.15) IU/l and 0.06 (< 0.05-0.37) IU/l, respectively. Subjects received daily i.m. injections of rhFSH for 3 weeks (week 1: 75 IU/day, week 2: 150 IU/day, week 3: 225 IU/day). Blood sampling and sonographic investigations were performed on alternate days. Steady-state FSH concentrations were reached approximately 3-5 days after alterations of the doses administered. Maximum FSH concentrations were between 7.1 and 11.8 IU/l, whereas serum LH concentrations remained unchanged. Due to absent follicle development and lack of a rise in immunoreactive inhibin (INH) (response failure possibly due to early ovarian failure or resistant ovary syndrome) in two subjects, analysis of ovarian response was restricted to five volunteers. Serum androstenedione levels showed no significant changes during rhFSH administration. Although serum immunoreactive INH concentrations reached normal late follicular values [659 (388-993) IU/l], serum oestradiol revealed only a minor increase [77 (18-210) pmol/l]. Moreover, growth of (multiple) ovarian follicles was observed up to pre-ovulatory sizes (> 15 mm) in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The luteal phase was studied in 12 polycystic ovary syndrome (PCOS) patients following ovulation induction using exogenous gonadotrophins combined with a gonadotrophin-releasing hormone agonist (GnRH-a). Human menopausal gonadotrophin (HMG) was preceded by 3 weeks of treatment with GnRH-a (buserelin; 1200 micrograms/day intra-nasally) and administered in a step-down dose regimen starting with 225 IU/day i.m. GnRH-a was withheld the day before administration of human chorionic gonadotrophin (HCG; 10,000 IU i.m.). Blood sampling and ultrasound monitoring was performed every 2-3 days until menses. The luteal phase was significantly shorter in PCOS patients as compared to eight regularly cycling controls: 8.8 (3.3-11.4) days [median(range)] versus 12.8 (8.9-15.9) days (P = 0.01). Median peak values for progesterone did not show significant differences comparing both groups: 52.3 (17.1-510.3) nmol/l versus 43.0 (31.2-71.1) nmol/l, respectively (P = 0.8). The interval between the day of the progesterone peak and return to baseline was significantly shorter in the PCOS patients than in controls: 2.5 (0.3-4.9) days versus 4.2 (3.9-10.5) days (P < 0.005). Luteinizing hormone (LH) concentrations during the luteal phase as reflected by area under the curve were significantly lower in PCOS as compared to controls: 4.4 (1.6-21.0) IU/l x days and 49.0 (27.8-79.6) IU/l x days, respectively (P < 0.001). In conclusion, patients with PCOS may suffer from insufficient luteal phases after ovulation induction using HMG/HCG in combination with a GnRH-a. The corpus luteum apparently lacks the support of endogenous LH and may be stimulated only by the pre-ovulatory injection of HCG.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to investigate the late follicular phase of seven gonadotrophin-treated patients with polycystic ovary syndrome (PCOS) exhibiting monofollicular growth and to compare developmental characteristics with the dominant follicle in seven regularly cycling control women. Daily serum follicle-stimulating hormone (FSH) levels in patients with PCOS decreased more rapidly compared to controls (-0.3 +/- 0.2 IU/day in controls versus -0.7 +/- 0.4 IU/day in PCOS; p < 0.02). No statistically significant differences were seen in daily increase (30% in controls and PCOS) and mean peak levels (825 +/- 94 pmol/l in controls versus 937 +/- 231 pmol/l in PCOS) of oestradiol (E2) serum levels when comparing both groups. Mean daily growth of the dominant follicle (1.7 +/- 0.4 mm in controls versus 1.9 +/- 0.6 mm in PCOS) was not significantly different. It is concluded from the present study that in patients with PCOS treated with gonadotrophin plus adjuvant gonadotrophin-releasing hormone agonist, development of a single follicle can occur using a decreasing dose regimen resulting in decreasing serum FSH levels. In addition, growth and oestrogen production by the dominant follicle in PCOS is not significantly different from follicle growth under normal conditions.

This chapter has focused on the step-down principle for gonadotrophin induction of ovulation in women suffering from clomiphene-resistant anovulation. The physiological rationale of this approach has been highlighted. Under normal conditions, FHS levels surpassing the FSH threshold initiate gonadotrophin-dependent growth of a cohort of follicles (this process is referred to as 'recruitment'). Due to negative feedback actions, the FSH levels decrease and FSH is above the threshold for only a limited number of days (the 'FSH window'). Around the mid-follicular phase, selection of a dominant follicle takes place; in addition to relatively low serum FSH concentrations, intraovarian regulation appears to be important for this process. In the conventional step-up or low dose step-up protocols for gonadotrophin induction of ovulation, administered doses are kept constant once an 'adequate' ovarian response is observed, resulting in high FSH serum levels in the late follicular phase and a broad FSH window. This contradicts normal circumstances and may give rise to unintended interference with the selection process by continuously stimulating follicles to enter the growing pool. This may result in multiple follicle development which, in turn, may be related to higher rates of multiple pregnancies and ovarian hyperstimulation. Potential mechanisms underlying arrested follicle maturation in PCOS are also discussed since they appear to be of relevance for the induction of ovulation. Disturbed selection can be overcome in the majority of cases by elevating the serum FSH concentrations through the administration of exogenous gonadotrophins to surpass the elevated FSH threshold in these patients. Data obtained by our group so far suggest that in PCOS patients treated with gonadotrophins in a step-down fashion, follicles continue to mature and can be stimulated to ovulation. Moreover, the number of functionally active medium-sized follicles seems to be reduced. If monofollicular development is observed in these patients, growth rates and oestrogen serum levels are indistinguishable from unstimulated normal development of the dominant follicle. In our initial series of over 200 cycles of gonadotrophin treatment according to the step-down principle in clomiphene-resistant anovulatory patients, 84% of cycles were ovulatory and pregnancy was achieved in 18% of the cycles (giving a cumulative pregnancy rate of 51%). Moreover, the overall complication rate appears to be low. The potential advantages and critical points of adjuvant treatment with GnRH analogues is also discussed. It has been clearly demonstrated that premature luteinization can be prevented effectively. Various other potential advantages of cotreatment seems to justify adjuvant medication with GnRH agonists.(ABSTRACT TRUNCATED AT 400 WORDS)

Meta-analysis of all randomised trials published so far, was performed to compare the effect of additional gonadotropin releasing hormone (GnRH)-agonist treatment to exogenous gonadotropins for ovulation induction in clomiphene-resistant polycystic ovary syndrome (PCOS) patients. Five clinical studies were included, of which only one showed significant differences in pregnancy rate. In addition, pretreatment with GnRH-agonist was once reported to lead more often to cancellation of medication. Combining the results of all five trials, a significant difference in favour of additional GnRH-agonist administration could only be observed for pregnancy rate. No significant differences in ovulation rate could be found. Due to the relative small number of patients in each separate group, no conclusions could be drawn concerning the influence of GnRH-agonist treatment on gonadotropin doses necessary to induce ovulation, and the incidence of multiple pregnancy, abortion and ovarian hyperstimulation.

To evaluate the importance of luteinizing hormone (LH) for normal estrogen production and subsequent development of ovarian follicles, a woman with isolated gonadotropin deficiency (LH; 0.37 IU/L, FSH 1.2 IU/L) was monitored during recombinant human follicle-stimulating hormone (hFSHrec) administration with respect to ovarian follicular growth and steroid production. During the first week (75 IU/day hFSHrec im) a significant rise in serum FSH (4.9 IU/L) was observed in the absence of changes in serum estradiol (E2) concentrations (36-76 pmol/L). During the following five days 150 IU/day hFSHrec was administered resulting in a further increase of serum FSH levels (maximum 8.5 IU/L). Development of multiple follicles--maximum diameter 22 mm as observed by transvaginal sonography--emerged together with a minor rise in E2 levels (from 76 to 236 pmol/L) and with a minimal increase in endometrial thickness (below 6 mm). Six days following the last injection of hFSHrec, aspiration of 3 follicles (13, 15 and 18 mm) was performed and low intrafollicular androstenedione (AD) (less than 675 nmol/L) and E2 (less than 9400 pmol/L) concentrations as compared to normal follicles were found. These first data on hFSHrec administration in the human suggest that; a) FSH alone can induce growth of preovulatory follicles, b) follicle growth does occur in the presence of subnormal E2 levels, c) LH is needed for adequate AD biosynthesis as substrate for aromatase activity. This indicates that growth and steroidogenic granulosa cell activity may be differentially regulated.

Data presented in this study indicate that ovulation can be induced in patients with PCOS using a GnRH analogue combined with hMG in a decreasing dose regimen. Based on the observed decline in functional, medium sized follicles in the late follicular phase, it may be speculated that the risk of ovarian hyperstimulation during gonadotropin induction of ovulation in patients with PCOS can be reduced.