Cyclic activity of signal transduction pathways in fimbrial epithelium of the human fallopian tube.

INTRODUCTION: The local environment of the fallopian tube represents the optimal conditions for reproductive processes. To maintain tissue homeostasis, signal transduction pathways are thought to play a pivotal role. Enhancing our understanding of functional signal transduction pathway activity is important to be able to clarify the role of aberrant signal transduction pathway activity leading to female subfertility and other tubal diseases. Therefore, in this study we investigate the influence of the hormonal cycle on the activity of key signal transduction pathways in the fimbrial epithelium of morphologically normal fallopian tubes. MATERIAL AND METHODS: We included healthy pre- (n = 17) and postmenopausal (n = 8) patients who had surgical interventions for benign gynecologic conditions. Histologic sections of the fallopian tubes were reviewed by two pathologists and, for the premenopausal patients, hormone serum levels and sections of the endometrium were examined to determine the hormonal phase (early follicular [n = 4], late follicular [n = 3], early luteal [n = 5], late luteal [n = 5]). After laser capture microdissection, total mRNA was extracted from the fimbrial epithelium and real-time quantitative reverse transcription-PCR was performed to determine functional signal transduction pathway activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor-beta (TGF-ß) and canonical wingless-type MMTV integration site (Wnt) pathways. RESULTS: The early luteal phase demonstrated high AR and ER pathway activity in comparison with the late luteal phase (p = 0.016 and p = 0.032, respectively) and low PI3K activity compared with the late follicular phase (p = 0.036), whereas the late luteal phase showed low activity of HH and Wnt compared with the early follicular phase (both p = 0.016). Signal transduction pathway activity in fimbrial epithelium from postmenopausal patients was most similar to the early follicular and/or late luteal phase with regard to the AR, ER and PI3K pathways. Wnt pathway activity in postmenopausal patients was comparable to the late follicular and early luteal phase. We observed no differences in HH and TGF-ß pathway activity between pre- and postmenopausal samples. The cyclic changes in signal transduction pathway activity suggest a stage-specific function which may affect the morphology and physiology of the human fallopian tube. CONCLUSIONS: We demonstrated cyclic changes in activity of the AR, ER, PI3K, HH and Wnt pathways throughout the hormonal cycle.

Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer.

IMPORTANCE: Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up. OBJECTIVE: To assess long-term risk of breast cancer after ovarian stimulation for IVF. DESIGN, SETTING, AND PARTICIPANTS: Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group. EXPOSURES: Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires. MAIN OUTCOMES AND MEASURES: Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]). RESULTS: Among 25,108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes). CONCLUSIONS AND RELEVANCE: Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

IVF with planned single-embryo transfer versus IUI with ovarian stimulation in couples with unexplained subfertility: an economic analysis.

Couples with unexplained subfertility are often treated with intrauterine insemination (IUI) with ovarian stimulation, which carries the risk of multiple pregnancies. An explorative randomized controlled trial was performed comparing one cycle of IVF with elective single-embryo transfer (eSET) versus three cycles of IUI-ovarian stimulation in couples with unexplained subfertility and a poor prognosis for natural conception, to assess the economic burden of the treatment modalities. The main outcome measures were ongoing pregnancy rates and costs. This study randomly assigned 58 couples to IVF-eSET and 58 couples to IUI-ovarian stimulation. The ongoing pregnancy rates were 24% in with IVF-eSET versus 21% with IUI-ovarian stimulation, with two and three multiple pregnancies, respectively. The mean cost per included couple was significantly different: €2781 with IVF-eSET and €1876 with IUI-ovarian stimulation (P<0.01). The additional costs per ongoing pregnancy were €2456 for IVF-eSET. In couples with unexplained subfertility, one cycle of IVF-eSET cost an additional €900 per couple compared with three cycles of IUI-ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. When IVF-eSET results in higher ongoing pregnancy rates, IVF would be the preferred treatment. Couples that have been trying to conceive unsuccessfully are often treated with intrauterine insemination (IUI) and medication to improve egg production (ovarian stimulation). This treatment carries the risk of multiple pregnancies like twins. We performed an explorative study among those couples that had a poor prognosis for natural conception. One cycle of IVF with transfer of one selected embryo (elective single-embryo transfer, eSET) was compared with three cycles of IUI-ovarian stimulation. The aim of this study was to assess the economic burden of both treatments. The Main outcome measures were number of good pregnancies above 12weeks and costs. We randomly assigned 58 couples to IVF-eSET and 58 couples to IUI-ovarian stimulation. The ongoing pregnancy rates were comparable: 24% with IVF-eSET versus 21% with IUI-ovarian stimulation. There were two multiple pregnancies with IVF-eSET and three multiple pregnancies with IUI-ovarian stimulation. The mean cost per included couple was significantly different, €2781 with IVF-eSET and €1876 with IUI-ovarian stimulation. The additional costs per ongoing pregnancy were €2456 for IVF-eSET. In couples with unexplained subfertility, one cycle of IVF-eSET costed an additional €900 per couple compared to three cycles of IUI-ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. We conclude that IUI-ovarian stimulation is the preferred treatment to start with. When IVF-eSET results in a higher ongoing pregnancy rate (>38%), IVF would be the preferred treatment.

Long-term outcome in couples with unexplained subfertility and an intermediate prognosis initially randomized between expectant management and immediate treatment.

BACKGROUND: We recently reported that treatment with intrauterine insemination and controlled ovarian stimulation (IUI-COS) did not increase ongoing pregnancy rates compared with expectant management (EM) in couples with unexplained subfertility and intermediate prognosis of natural conception. Long-term cost-effectiveness of a policy of initial EM is unknown. We investigated whether the recommendation not to treat during the first 6 months is valid, regarding the long-term effectiveness and cumulative costs. METHODS: Couples with unexplained subfertility and intermediate prognosis of natural conception (n=253, at 26 public clinics, the Netherlands) were randomly allocated to 6 months EM or immediate start with IUI-COS. The couples were then treated according to local protocol, usually IUI-COS followed by IVF. We followed couples until 3 years after randomization and registered pregnancies and resources used. Primary outcome was time to ongoing pregnancy. Secondary outcome was treatment costs. Analysis was by intention-to-treat. Economic evaluation was performed from the perspective of the health care institution. RESULTS: Time to ongoing pregnancy did not differ between groups (log-rank test P=0.98). Cumulative ongoing pregnancy rates were 72-73% for EM and IUI-COS groups, respectively [relative risk 0.99 (95% confidence interval (CI) 0.85-1.1)]. Estimated mean costs per couple were € 3424 (95% CI € 880-€ 5968) in the EM group and € 6040 (95% CI € 4055-€ 8125) in the IUI-COS group resulting in an estimated saving of € 2616 per couple (95% CI € 385-€ 4847) in favour of EM. CONCLUSIONS: In couples with unexplained subfertility and an intermediate prognosis of natural conception, initial EM for 6 months results in a considerable cost-saving with no delay in achieving pregnancy or jeopardizing the chance of pregnancy. Further comparisons between aggressive and milder forms of ovarian stimulation should be performed.

Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology.

BACKGROUND: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. METHODS: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. RESULTS: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. CONCLUSIONS: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.

The value of chromosomal analysis in oligozoospermic men.

OBJECTIVE: To determine the prevalence of chromosomal abnormalities in relation to sperm concentration in subfertile oligozoospermic men. DESIGN: Retrospective cohort study. SETTING: Two teaching hospitals. PATIENT(S): We retrospectively studied all men who received chromosomal analysis prior to intracytoplasmic sperm injection (ICSI) treatment from 2000 to 2010 in two teaching hospitals. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The results of chromosomal analysis and semen analysis were recorded. The frequency of abnormal karyotypes was analyzed in relation to the sperm concentration, categorized as extreme oligozoospermia (>0 to ≤1 million/mL), severe oligozoospermia (>1 to ≤5 million/mL), moderate oligozoospermia (>5 to ≤20 million/mL), or normospermia (>20 million/mL). RESULT(S): Among 582 male ICSI candidates, the rates of abnormal karyotypes were 1.2% (2/162), 2.2% (5/227), and 1.5% (2/130) for men with extreme, severe, and moderate oligozoospermia, respectively. No abnormalities were present in normospermic men. CONCLUSION(S): The risk of conceiving a viable child with unbalanced structural chromosomal abnormalities in men with oligozoospermia may not justify karyotyping.

Measuring outcomes in fertility trials: can we rely on clinical pregnancy rates?

OBJECTIVE: To assess whether the estimates of treatment effect in randomized clinical trials (RCTs) in reproductive medicine differ when either clinical pregnancy or live birth is used as the outcome measure. DESIGN: Metaanalysis. SETTING: We analyzed RCTs in reproductive medicine found in systematic reviews published in the Cochrane Library that reported on both clinical pregnancy and live birth. PATIENT(S): Subfertile couples. INTERVENTION(S): For each individual RCT, data on clinical pregnancy and live birth were extracted. MAIN OUTCOME MEASURE(S): We compared the outcome of each study by calculating a kappa-statistic (statistically significant treatment effective or not) and by comparing the odds ratio by calculating the ratio of the odds ratios (ROR). RESULT(S): We found 67 systematic reviews, of which 42 reported on pregnancy and live birth. These 42 reviews included 654 RCTs, of which 143 (22%) reported both on pregnancy and live birth. The pregnancy loss rates in the treatment and control groups were comparable. Of the 143 RCTs, the conclusion based on pregnancy rate and live birth rate was comparable (kappa value of 0.81; 95% confidence interval [CI], 0.68-0.94). The odds ratios estimating treatment effect from pregnancy and live birth were also comparable (ROR, 1.01, 95% CI 0.9 to 1.12). CONCLUSION(S): Only a minority of randomized clinical trials in reproductive medicine report on live birth. Conclusions on the effectiveness of a treatment based on either clinical pregnancy or live birth as endpoints are comparable.

Bipolar radiofrequency endometrial ablation compared with hydrothermablation for dysfunctional uterine bleeding: a randomized controlled trial.

OBJECTIVE: To compare the effectiveness of two second-generation ablation techniques, bipolar radiofrequency impedance-controlled endometrial ablation and hydrothermablation, in the treatment of menorrhagia. METHODS: This study was a double-blind, randomized controlled trial, which took place in a large teaching hospital in The Netherlands with 500 beds. Women with menorrhagia were randomly allocated to bipolar radiofrequency ablation (bipolar group) and hydrothermablation (hydrotherm group). At follow-up, both women and observers remained unaware of the type of treatment that had been performed. The primary outcome was amenorrhea. Secondary outcome measures were patient satisfaction and reintervention. RESULTS: We included 160 women in the study, of which 82 were allocated to the bipolar group and 78 to the hydrotherm group. No complications occurred in either of the treatment groups. After 12 months, 87% (65 of 75) of the patients in the bipolar group were completely satisfied with the result of the treatment compared with 68% (48 of 71) in the hydrotherm group (relative risk 1.3, 95% confidence interval [CI] 1.03-1.6). The amenorrhea rates were 47% (35 of 75) in the bipolar group and 24% (17 of 71) in the hydrotherm group (relative risk 2.0, 95% CI 1.2-3.1). The relative risks for a reintervention in the bipolar group compared with the hydrotherm group was 0.29 (95% CI 0.12-0.67), whereas for hysterectomy, this was 0.49 (95% CI 0.15-1.5). CONCLUSION: In the treatment of menorrhagia, bipolar radiofrequency endometrial ablation system is superior to hydrothermablation. CLINICAL TRIAL REGISTRATION: ISRCTN Register, www.isrctn.org, ISRCTN23845359. LEVEL OF EVIDENCE: I.