The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF.

STUDY QUESTION: Is the total number of oocytes retrieved with dual ovarian stimulation in the same cycle (duostim) higher than with two consecutive antagonist cycles in poor responders? SUMMARY ANSWER: Based on the number of total and mature oocytes retrieved in women with poor ovarian response (POR), there is no benefit of duostim versus two consecutive antagonist cycles. WHAT IS KNOWN ALREADY: Recent studies have shown the ability to obtain oocytes with equivalent quality from the follicular and the luteal phase, and a higher number of oocytes within one cycle when using duostim. If during follicular stimulation smaller follicles are sensitized and recruited, this may increase the number of follicles selected in the consecutive luteal phase stimulation, as shown in non-randomized controlled trials (RCT). This could be particularly relevant for women with POR. STUDY DESIGN, SIZE, DURATION: This is a multicentre, open-labelled RCT, performed in four IVF centres from September 2018 to March 2021. The primary outcome was the number of oocytes retrieved over the two cycles. The primary objective was to demonstrate in women with POR that two ovarian stimulations within the same cycle (first in the follicular phase, followed by a second in the luteal phase) led to the retrieval of 1.5 (2) more oocytes than the cumulative number of oocytes from two consecutive conventional stimulations with an antagonist protocol. In a superiority hypothesis, with power 0.8 alpha-risk 0.05 and a 35% cancellation rate, 44 patients were needed in each group. Patients were randomized by computer allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with POR, defined using adjusted Bologna criteria (antral follicle count ≤5 and/or anti-Müllerian hormone ≤1.2 ng/ml) were randomized, 44 in the duostim group and 44 in the conventional (control) group. HMG 300 IU/day with flexible antagonist protocol was used for ovarian stimulation, except in luteal phase stimulation of the duostim group. In the duostim group, oocytes were pooled and inseminated after the second retrieval, with a freeze-all protocol. Fresh transfers were performed in the control group, frozen embryo transfers were performed in both control and duostim groups in natural cycles. Data underwent intention-to-treat and per-protocol analyses. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference between the groups regarding demographics, ovarian reserve markers, and stimulation parameters. The mean (SD) cumulative number of oocytes retrieved from two ovarian stimulations was not statistically different between the control and duostim groups, respectively, 4.6 (3.4) and 5.0 (3.4) [mean difference (MD) [95% CI] +0.4 [-1.1; 1.9], P = 0.56]. The mean cumulative numbersof mature oocytes and total embryos obtained were not significantly different between groups. The total number of embryos transferred by patient was significantly higher in the control group 1.5 (1.1) versus the duostim group 0.9 (1.1) (P = 0.03). After two cumulative cycles, 78% of women in the control group and 53.8% in the duostim group had at least one embryo transfer (P = 0.02). There was no statistical difference in the mean number of total and mature oocytes retrieved per cycle comparing Cycle 1 versus Cycle 2, both in control and duostim groups. The time to the second oocyte retrieval was significantly longer in controls, at 2.8 (1.3) months compared to 0.3 (0.5) months in the duostim group (P < 0.001). The implantation rate was similar between groups. The cumulative live birth rate was not statistically different, comparing controls versus the duostim group, 34.1% versus 17.9%, respectively (P = 0.08). The time to transfer resulting in an ongoing pregnancy did not differ in controls 1.7 (1.5) months versus the duostim group, 3.0 (1.6) (P = 0.08). No serious adverse events were reported. LIMITATIONS, REASONS FOR CAUTION: The RCT was impacted by the coronavirus disease 2019 pandemic and the halt in IVF activities for 10 weeks. Delays were recalculated to exclude this period; however, one woman in the duostim group could not have the luteal stimulation. We also faced unexpected good ovarian responses and pregnancies after the first oocyte retrieval in both groups, with a higher incidence in the control group. However, our hypothesis was based on 1.5 more oocytes in the luteal than the follicular phase in the duostim group, and the number of patients to treat was reached in this group (N = 28). This study was only powered for cumulative number of oocytes retrieved. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT comparing the outcome of two consecutive cycles, either in the same menstrual cycle or in two consecutive menstrual cycles. In routine practice, the benefit of duostim in patients with POR regarding fresh embryo transfer is not confirmed in this RCT: first, because this study demonstrates no improvement in the number of oocytes retrieved in the luteal phase after follicular phase stimulation, in contrast to previous non-randomized studies, and second, because the freeze-all strategy avoids a pregnancy with fresh embryo transfer after the first cycle. However, duostim appears to be safe for women. In duostim, the two consecutive processes of freezing/thawing are mandatory and increase the risk of wastage of oocytes/embryos. The only benefit of duostim is to shorten the time to a second retrieval by 2 weeks if accumulation of oocytes/embryos is needed. STUDY FUNDING/COMPETING INTERESTS: This is an investigator-initiated study supported by a research Grant from IBSA Pharma. N.M. declares grants paid to their institution from MSD (Organon France); consulting fees from MSD (Organon France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. I.A. declares honoraria from GISKIT and support for travel and meetings from GISKIT. G.P.-B. declares Consulting fees from Ferring and Merck KGaA; honoraria from Theramex, Gedeon Richter, and Ferring; payment for expert testimony from Ferring, Merck KGaA, and Gedeon Richter; and support for travel and meetings from Ferring, Theramex, and Gedeon Richter. N.C. declares grants from IBSA pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. E.D. declares support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Ferring, Gedeon Richter, Theramex, and General Electrics. C.P.-V. declares support for travel and meetings from IBSA Pharma, Merck KGaA, Ferring, Gedeon Richter, and Theramex. M.Pi. declares support for travel and meetings from Ferring, Gedeon Richetr, and Merck KGaA. M.Pa. declares honoraria from Merck KGaA, Theramex, and Gedeon Richter; support for travel and meetings from Merck KGaA, IBSA Pharma, Theramex, Ferring, Gedeon Richter, and MSD (Organon France). H.B.-G. declares honoraria from Merck KGaA, and Gedeon Richter and support for travel and meetings from Ferring, Merck KGaA, IBSA Pharma, MSD (Organon France), Theramex, and Gedeon Richter. S.G. and M.B. have nothing to declare. TRIAL REGISTRATION NUMBER: Registration number EudraCT: 2017-003223-30. ClinicalTrials.gov identifier: NCT03803228. TRIAL REGISTRATION DATE: EudraCT: 28 July 2017. ClinicalTrials.gov: 14 January 2019. DATE OF FIRST PATIENT'S ENROLMENT: 3 September 2018.

Impact of endometrial preparation on early pregnancy loss and live birth rate after frozen embryo transfer: a large multicenter cohort study (14 421 frozen cycles).

STUDY QUESTION: Does the endometrial preparation protocol (artificial cycle (AC) vs natural cycle (NC) vs stimulated cycle (SC)) impact the risk of early pregnancy loss and live birth rate after frozen/thawed embryo transfer (FET)? SUMMARY ANSWER: In FET, ACs were significantly associated with a higher pregnancy loss rate and a lower live birth rate compared with SC or NC. WHAT IS KNOWN ALREADY: To date, there is no consensus on the optimal endometrial preparation in terms of outcomes. Although some studies have reported a higher pregnancy loss rate using AC compared with NC or SC, no significant difference was found concerning the pregnancy rate or live birth rate. Furthermore, no study has compared the three protocols in a large population. STUDY DESIGN SIZE DURATION: A multicenter retrospective cohort study was conducted in nine reproductive health units in France using the same software to record medical files between 1 January 2012 and 31 December 2016. FET using endometrial preparation by AC, modified NC or SC were included. The primary outcome was the pregnancy loss rate at 10 weeks of gestation. The sample size required was calculated to detect an increase of 5% in the pregnancy loss rate (21-26%), with an alpha risk of 0.5 and a power of 0.8. We calculated that 1126 pregnancies were needed in each group, i.e. 3378 in total. PARTICIPANTS/MATERIALS SETTING METHODS: Data were collected by automatic extraction using the same protocol. All consecutive autologous FET cycles were included: 14 421 cycles (AC: n = 8139; NC: n = 3126; SC: n = 3156) corresponding to 3844 pregnancies (hCG > 100 IU/l) (AC: n = 2214; NC: n = 812; SC: n = 818). Each center completed an online questionnaire describing its routine practice for FET, particularly the reason for choosing one protocol over another. MAIN RESULTS AND THE ROLE OF CHANCE: AC represented 56.5% of FET cycles. Mean age of women was 33.5 (SD ± 4.3) years. The mean number of embryos transferred was 1.5 (±0.5). Groups were comparable, except for history of ovulation disorders (P = 0.01) and prior delivery (P = 0.03), which were significantly higher with AC. Overall, the early pregnancy loss rate was 31.5% (AC: 36.5%; NC: 25.6%; SC: 23.6%). Univariable analysis showed a significant association between early pregnancy loss rate and age >38 years, history of early pregnancy loss, ovulation disorders and duration of cryopreservation >6 months. After adjustment (multivariable regression), the early pregnancy loss rate remained significantly higher in AC vs NC (odds ratio (OR) 1.63 (95% CI) [1.35-1.97]; P < 0.0001) and in AC vs SC (OR 1.87 [1.55-2.26]; P < 0.0001). The biochemical pregnancy rate (hCG > 10 and lower than 100 IU/l) was comparable between the three protocols: 10.7% per transfer. LIMITATIONS REASONS FOR CAUTION: This study is limited by its retrospective design that generates missing data. Routine practice within centers was heterogeneous. However, luteal phase support and timing of embryo transfer were similar in AC. Univariable analysis showed no difference between centers. Moreover, a large number of parameters were included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Our study shows a significant increase in early pregnancy loss when using AC for endometrial preparation before FET. These results suggest either a larger use of NC or SC, or an improvement of AC by individualizing hormone replacement therapy for patients in order to avoid an excess of pregnancy losses. STUDY FUNDING/COMPETING INTERESTS: The authors declare no conflicts of interest in relation to this work. G.P.-B. declares consulting fees from Ferring, Gedeon-Richter, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter, Theramex, Teva. N.C. declares consulting fees from Ferring, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring. C.R. declares a research grant from Ferring, Gedeon-Richter; consulting fees from Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter; E.M.d'A. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Theramex, Teva. I.C-D. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, IBSA. N.M. declares a research grant from Merck KGaA, MSD, IBSA; consulting fees from MSD, Ferring, Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Teva, Goodlife, General Electrics. TRIAL REGISTRATION NUMBER: N/A.

[Dydrogesterone versus micronized vaginal progesterone as luteal phase support after fresh embryo transfer in IVF]. / Dydrogestérone vs progestérone vaginale micronisée dans le soutien de la phase lutéale après transfert frais d'embryons.

OBJECTIVES: The objective of the study was to compare the live birth rate and miscarriage rate after fresh embryo transfer (Fresh ET) when patients are treated either with oral dydrogesterone or micronized vaginal progesterone (MVP) as luteal phase support (LPS). The vaginal route is still preferred, despite the discomfort for the patients and recent RCTs showing similar results for dydrogesterone and MVP. METHODS: All 556 consecutive Fresh ET after autologous IVF procedure, from December 2011 to March 2013 in one centre in France were included. Patients were treated either with dydrogesterone 10mg every 12hours (n=267) or MVP 200mg every 12hours (n=289), the physician's arbitrary choice on the day of the oocyte aspiration procedure. RESULTS: The groups were comparable regarding the demographic data and stimulation protocols, except for the rank of the oocyte pickup procedure [1.54±0.80 vs. 1.74±0.96, (P=0.01)], with no significant difference in live birth rates (22.4% vs. 23.8%, P=0.77) and miscarriage rates (4.1% vs. 5.5%, P=0.55) for dydrogesterone vs. MVP respectively. The results were similar in a good prognosis patients' subgroup. CONCLUSIONS: LPS with either dydrogesterone or MVP after Fresh ET showed similar live birth rates and miscarriage rates. The benefits of the oral over vaginal route might be higher tolerance and possibly better compliance. Dydrogesterone seems to be a safe treatment, but its long-term innocuity needs to be further proven.

Random antral follicle count performed on any day of the menstrual cycle has the same predictive value as AMH for good ovarian response in IVF cycles.

OBJECTIVE: To determine whether the predictive value of AFC for ovarian response to stimulation for IVF depends on the day of the menstrual cycle when ultrasound is performed. METHODS: 410 women undergoing their first IVF cycle were included. All the women had AFC performed twice. The first measurement, random AFC (r-AFC), was performed during the fertility workup whatever the day of their menstrual cycle. Three groups were constituted according to the period of ultrasound performance: at early follicular phase i.e., day 1 to day 6 (eFP-AFC); at mid follicular phase i.e., day 7 to 12 (mFP-AFC) and at luteal phase i.e., day 13 or after (LP-AFC). A second AFC measurement was performed before the start of the ovarian stimulation (SD1-AFC). AMH dosing was done in the early follicular phase. RESULTS: Random AFC (r-AFC) was correlated to AMH (r = 0.69; p<0.001), SD1-AFC (r = 0.75; p<0.001) and number of oocytes retrieved (r = 0.49; p<0.001). When regarding AFC depending on the cycle day group, the correlation with AMH was 0.65, 0.66 and 0.85 for the eFP-AFC, the mFP-AFC and the LP-AFC respectively (all p were <0.001). The ROC analysis showed the same predictive value for good ovarian response (more than 6 oocytes retrieved) for the eFP-AFC, mFP-AFC and LP-AFC (AUC 0.73, 0.75 and 0.84 respectively; p = 0.28). The AUC of r-AFC (0.76) were similar to those of AMH (0.74) and SD1-AFC (0.74) (p = 0.21 and 0.92 respectively). CONCLUSION: AFC is strongly correlated with AMH and highly predictive of good ovarian response during the whole menstrual cycle.

A large observational data study supporting the PROsPeR score classification in poor ovarian responders according to live birth outcome.

STUDY QUESTION: Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa? SUMMARY ANSWER: The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data. WHAT IS KNOWN ALREADY: Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO). STUDY DESIGN, SIZE, DURATION: The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer-Lemeshow test) were the two conditions required for evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS: The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR. MAIN RESULTS AND THE ROLE OF CHANCE: The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was -0.0074 (95% CI: -0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer-Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer-Lemeshow test = 1.266688; P = 0.260). LIMITATIONS, REASONS FOR CAUTION: The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies. WIDER IMPLICATIONS OF THE FINDINGS: This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres. STUDY FUNDING/COMPETING INTEREST(S): This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Under-estimation of self-reported occupational exposure by questionnaire in hospital workers.

OBJECTIVES: The aim of the study was to determine whether self-reported occupational exposure to cleaning/disinfecting agents in hospital workers is accurate, in comparison to expert assessment, taken to be the gold standard. METHODS: In the Epidemiological Study of the Genetics and Environment of Asthma (EGEA), participants were interviewed on occupation with a specific questionnaire for hospital workers regarding tasks and cleaning/disinfecting agents. Two estimates of exposure were available: self-report and expert assessment. The expert assessment involved a standardised procedure to estimate intensity, frequency and probability of exposure for each job. The present analysis focused on eight exposures: formaldehyde, glutaraldehyde, bleach/chlorine, alcohol, quaternary ammonium components, ammonia, sprays and latex gloves. Agreement and differences between self-reported and expert estimates were studied by kappa and phi coefficients and McNemar tests, respectively. RESULTS: In the survey of 1571 adults, 176 ever hospital workers (327 occupations) with both self-reported and expert exposure assessments were studied. An underestimation of self-reported exposure was observed especially for formaldehyde (26.5% vs 32.7%, p=0.01), ammonia (7.4% vs 18.8%, p<0.0001), alcohol (64.9% vs 93.0%, p<0.0001) and quaternary ammonium components (16.6% vs 70.9%, p<0.0001), compared to expert assessment. CONCLUSION: Occupational exposure to disinfecting/cleaning agents is common and high in hospitals. A large underestimation of self-reported exposure and a lack of knowledge of product components was observed. Our results show the relevance of expert assessment in epidemiological studies to limit measurement bias. This work underlines the need for health education programmes on the occupational risks induced by these types of products.

Evaluation of different markers of the ovarian reserve in patients presenting with premature ovarian failure.

Premature ovarian failure (POF) is a heterogeneous syndrome, possibly due to mutations of genes involved in the normal development of the ovary and/or the follicles. Based essentially on animal models, these mutations are associated with various ovarian histological phenotypes, from a complete absence of to a partial follicular maturation. The aims of our work were in one hand to determine if ovarian histology, compared to pelvic ultrasonography, would be helpful either in identifying which patients display an impaired follicular growth or in the orientation of the POF etiology; on the other hand, since developing follicles up to the antral stage are reported in POF and that Anti-Müllerian hormone (AMH) might be a good indicator of follicular presence, we decided to determine whether AMH should be a better marker to determine the presence of an ovarian reserve in POF patients. To try to answer to the first question, we studied first 166 patients suffering from POF with a normal karyotype. Vaginal ultrasonography (US) was performed in 134 patients and an ovarian biopsy was obtained in 67 women. The presence of follicles suggested at US was confirmed at histology in only 56% of the patients. Ovarian histology led to the distinction of two phenotypes (a) small-sized ovaries, deprived of follicles, and (b) normal-sized ovaries with partial follicular maturation. To confirm the value of ovarian biopsies, samples from 20 normal women have been studied, confirming that ovarian biopsy at random allow reliable assessment of follicular activity. To try to answer to the second question of our work, a cross sectional study analyzing serum AMH, ovarian histology and AMH immunoexpression in 48 POF patients, was performed. Serum AMH was significantly higher in women with more than 5 follicles at ovarian histology. Ovarian AMH immunostaining revealed a normal AMH expression in POF preantral follicles but a decrease expression at the early antral stages. In conclusion, ovarian histology appears to be a reliable tool to appreciate the follicular reserve, and helpful and complementary to clinical and hormonal phenotyping in order to orient the search for various genetic causes of POF syndrome. Finally, AMH levels in POF patients could identify women with persistent follicles.

Serum anti-Müllerian hormone expression in women with premature ovarian failure.

BACKGROUND: Premature ovarian failure (POF) is generally irreversible. However, developing follicles up to the antral stage are reported in POF and anti-Müllerian hormone (AMH) might be a good indicator of follicular presence. This study analysed serum AMH, ovarian histology and AMH immunoexpression in POF patients. METHODS: A cross-sectional study of 48 POF patients in an Endocrinology Department setting. Patients had an ovarian biopsy simultaneously with serum AMH sampling and/or ovarian AMH immunostaining. RESULTS: Mean serum AMH was 1.04 +/- 1.66 ng/ml. Serum AMH was significantly higher in women with 15 or more follicles at ovarian histology (P = 0.001). Comparison of ovarian AMH immunostaining from POF patients and 10 normal controls revealed a normal AMH expression in POF pre-antral follicles, but a decreased expression at the early antral stages. Serum AMH was undetectable in 77% of the patients with 0-5 AMH immunopositive follicles and detectable in 100% of the patients with more than 15 AMH immunopositive follicles. CONCLUSIONS: AMH levels in POF patients could identify women with persistent follicles. The decrease of AMH immunoexpression in POF antral follicles could suggest a defect of antral development.

Respiratory symptoms and bronchial responsiveness among cleaning and disinfecting workers in the food industry.

OBJECTIVES: To measure the levels of exposure to nitrogen trichloride (NCl3) and aldehydes among cleaning and disinfecting workers in the atmosphere of food industry plants during cleaning and disinfecting operations, and to examine how they relate to irritant and chronic respiratory symptoms-which are indices of pulmonary function-and bronchial hyperresponsiveness (BHR) to methacholine. METHODS: 175 exposed workers (M = 149; F = 26) recruited from 17 enterprises of the food industry (8 cattle, pig, and ovine slaughterhouses, 8 fowl slaughterhouses, and 1 catering firm) and 70 non-exposed workers (M = 52; F = 18) were examined. Concentration levels of NCl3 and aldhehydes were measured by personal sampling. Symptoms were assessed by means of a questionnaire and the methacholine bronchial challenge (MBC) test using an abbreviated method. Subjects were labelled MBC+ if forced expiratory volume in one second (FEV1) fell by 20% or more. The linear dose-response slope (DRS) was calculated as the percentage fall in FEV1 at last dose divided by the total dose administered. RESULTS: 277 air samples were taken in the 17 food industry plants. For a given plant and in a given workshop, the actual concentrations of chloramines, aldehydes, and quaternary ammonium compounds were measured with personal samplers during the different steps of the procedures. For each cleaner, a total exposure index Sigma was calculated. A statistically significant concentration-response relationship was found between eye, nasal, and throat symptoms of irritation--but not chronic respiratory symptoms--and exposure levels or exposure duration. No relation was found between BHR and exposure. CONCLUSIONS: These data show that cleaning and disinfecting workers in the food industry are at risk of developing eye, nasal, and throat irritation symptoms. Although NCl3 exposure does not seem to carry a risk of developing permanent BHR, the possibility of transient BHR cannot be ruled out entirely.

Timing of FSH administration for ovarian stimulation in normo-ovulatory women: comparison of an early or a mid follicular phase initiation of a short-term treatment.

BACKGROUND: In normo-ovulatory infertile women undergoing mild ovarian stimulation out of IVF, FSH stimulation regimen must be carefully adjusted to control the number of recruited follicles and to prevent multiple pregnancies. The aim of this prospective study was to assess the effect of the timing of FSH administration (fixed dose and duration) on the number of large follicles. METHODS: Women were prospectively randomized by means of sealed envelopes to receive daily 112.5 IU recombinant FSH (rFSH), either from cycle day (CD) 2-6 (Group A) or from CD 7-11 (Group B). Hormonal measurements and follicular ultrasound assessments were performed on CD 2, 7 and 12. RESULTS: On CD 12, the development rate of exactly two follicles >or=14 mm in diameter was significantly lower in Group A than in Group B (4% of women versus 42%, P = 0.002). Although the pattern of serum estradiol (E(2)) concentrations in Group A displayed a plateau from CD 7, the cancellation rate for overstimulation (more than three follicles >or=14 mm in diameter) was significantly increased (P = 0.009). CONCLUSIONS: Preventing the closure of the FSH window by mid to late follicular phase FSH administration better fulfils the objective of obtaining a limited number of large follicles than surpassing the FSH threshold by an early administration.

Mortality among Paris sewage workers.

OBJECTIVES: To describe the mortality of Paris sewage workers. METHODS: A cohort of all Paris sewage workers since 1970 was established and followed up in mortality until 1999. The causes of death were determined by matching with a national database. The mortality rates were compared to the rates of a local reference population. RESULTS: A large excess in mortality (standardised mortality ratio (SMR) = 1.25; 530 cases, 95% CI 1.15 to 1.36) and in particular mortality from cancer (SMR = 1.37, 235 cases) was detected which was particularly important in the subgroup of subjects who had left employment because they resigned or were laid off (SMR = 1.77; 50 cases). The excess mortality is to a large extent due to alcohol related diseases (SMR = 1.65, 122 cases) especially malignant (SMR = 1.85, 16 cases) and non-malignant (SMR = 1.68, 38 cases) liver diseases, lung cancer (SMR = 1.47, 68 cases), and infectious diseases (SMR = 1.86, 25 cases). The SMRs for some diseases (all cancers, cancers of the oesophagus and lung, all alcohol related diseases) seem to increase with duration of employment as a sewage worker. Other than lung cancer, smoking related diseases were not in excess. CONCLUSION: The increased mortality by both malignant and non-malignant liver diseases is probably due to excessive alcohol consumption, but could be partially the result of occupational exposure to chemical and infectious agents and interactions of these factors. The excess lung cancer is unlikely to be due to an increased smoking prevalence.

Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study.

BACKGROUND: In primates, androgens can play a synergistic role with FSH in promoting the early follicular recruitment, which is critical in assisted reproduction technique programmes. OBJECTIVE: To assess whether poor responders can benefit from androgen application. METHODS: Inclusion criteria were a previous poor ovarian response to controlled ovarian stimulation and a decreased hormonal ovarian reserve. Selected women were randomized to receive either transdermal application of testosterone (n = 24) or placebo (n = 25) gel for 15 days before FSH treatment for a second IVF cycle. Similar GnRH analogue and equivalent FSH daily doses were used in both cycles. The primary outcome was the total number of oocytes retrieved. RESULTS: Testosterone gel application resulted in a significant increase in plasma testosterone levels but did not significantly improve the antral follicle count. Furthermore, after gel application, the main parameters of the ovarian response (numbers of pre-ovulatory follicles, total and mature oocytes and embryos) did not significantly differ between testosterone and placebo-treated patients. CONCLUSION: No significant beneficial effects of androgen administration on the ovarian response to FSH could be demonstrated. However, subsequent clinical trials are needed to determine whether an optimal dose and/or a longer duration of testosterone administration may be helpful.

Idiopathic premature ovarian failure in 63 young women.

BACKGROUND: Premature ovarian failure (POF) in adolescents is defined as primary or secondary amenorrhea associated with high follicle-stimulating hormone (FSH) levels. In normal 46,XX patients, its etiology is most often unknown. We have evaluated the clinical, hormonal and ovarian phenotypes in patients with a normal karyotype who were diagnosed with POF before the age of 18. METHODS: Sixty-three patients were included in this retrospective study. RESULTS: The mean patient age was 20.4 years. The patients presented with three clinical patterns: lack of pubertal development (n = 23), primary amenorrhea with interrupted puberty (n = 18), and secondary amenorrhea with normal puberty (n = 22). Ten patients had a familial history of POF and 6 presented with hypothyroidism. The FSH, estradiol and inhibin B levels were not statistically different in the three clinical groups. Fifty percent of the patients presented small ovaries (length <2 cm) at ultrasonography. The presence of follicles was found at histology in only 7 of the 27 patients who underwent an ovarian biopsy. CONCLUSION: 46,XX patients presenting with early POF rarely presented a specific, identifiable disorder. We discuss the clinical management and different diagnosis strategies to improve our current knowledge of this syndrome.

[Intrauterine insemination: spontaneous or medically-assisted ovulation?]. / Insémination intra-utérine: ovulation spontanée ou médicalisée?

Intrauterine insemination (i.u.i.) is usually proposed as the first-line therapy for infertility related to cervical factor, male and unexplained infertility. The overall success rate of i.u.i. is about 10-20% clinical pregnancies per cycle. i.u.i. may be performed in patients with or without prior controlled ovarian hyperstimulation (COH). The aim of COH is to closely monitor follicular growth in order to achieve a timely triggering of ovulation and i.u.i. Additionally, ovarian stimulation allows to increase the number of developing follicles. According to the review of previous prospective randomized studies and meta-analyses, it seems that: (i) when a cervical factor is involved, the advantage of COH in conjunction with i.u.i. is likely but has to be confirmed; (ii) in male infertility, COH with gonadotropins in conjunction with i.u.i. increases the clinical pregnancy rate by two. In this situation, the better the sperm parameters are, the more advantageous COH is; (iii) in unexplained infertility, COH in addition to i.u.i. improves the pregnancy rate but stimulation with clomifene citrate appears to be less effective than gonadotropins administration. Beside the sperm parameters, the success rate depends on both woman's age and degree of ovarian stimulation. Meanwhile, ovarian hyperstimulation exposes to the risk of multiple pregnancy and hyperstimulation syndrome. Increasing the number of preovulatory follicles from one to two allows to approximately double the pregnancy rate. However, there is clear evidence that getting three or more than three follicles exposes to a worrying risk of multiple pregnancy. At the present time, the successful outcome of i.u.i. should not be assessed by the clinical pregnancy rate any longer but by the singleton birth rate. Our therapeutic strategy for COH prior to i.u.i. should take into account woman's age, infertility duration and associated infertility factors. The objective in terms of preovulatory follicle number must be determined prior to the stimulation in order to optimise the cycle outcome with a singleton birth.

Significance of ovarian histology in the management of patients presenting a premature ovarian failure.

BACKGROUND: Premature ovarian failure (POF) is a heterogeneous syndrome, possibly due to mutations of genes involved in the normal development of the ovary and/or follicles. Based essentially on animal models, these mutations are associated with various ovarian phenotypes, from a complete absence of follicles to a partial follicular maturation. The aim of the present study was to determine whether ovarian histology, compared to pelvic ultrasonography, would be helpful in identifying which patients display an impaired follicular reserve and/or growth, and in orientating the search for POF aetiology. METHODS AND RESULTS: We studied a cohort of 61 patients suffering from POF with a normal karyotype. Their median age (range) at diagnosis was 26 years (15-39). The FSH plasma level was high, 67.0 IU/l (13-155). Estradiol and inhibin B plasma levels were low: 18.5 pmol/l (18.5-555) and 5 pg/ml (5-105) respectively. Both pelvic ultrasonography and ovarian biopsies were performed in each patient. The presence of follicles suggested at ultrasonography was confirmed at histology in 56% of the patients. Ovarian histology led to the distinction of two phenotypes: (i) small-sized ovaries, deprived of follicles; and (ii) normal-sized ovaries with partial follicular maturation. To confirm the value of ovarian biopsies, samples from 20 normal women were studied. These demonstrated that ovarian biopsy at random enables reliable assessment of follicular presence, especially when their size is <2 mm. CONCLUSION: Ovarian histology appears to be a reliable tool in evaluating the follicular reserve, and helpful and complementary to clinical and hormonal phenotyping in orienting the search for the various genetic causes of POF syndrome.

Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study.

BACKGROUND: When administered in the late follicular phase to prevent an LH surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be detrimental for assisted reproductive technology cycle outcome. Therefore, a prospective study was designed to assess the effects of recombinant human (r)LH supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The protocol consisted of cycle programming with oral contraceptive pill, ovarian stimulation with rFSH and flexible administration of a single dose of cetrorelix (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed envelopes or according to woman's birth date) to receive (n = 114) or not (n = 104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG injection. RESULTS: The only significant difference was a higher serum peak E2 level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P < 0.001) whereas the numbers of oocytes and embryos as well as the delivery rate (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were similar in both groups. CONCLUSIONS: These results show that in an unselected group of patients, there is no evident benefit to supplement GnRH antagonist-treated cycles with rLH.

Beneficial effects of GnRH agonist administration prior to ovarian stimulation for patients with a short follicular phase.

A short follicular phase is an early clinical feature of declining reproductive competence. The shortening of the follicular phase length is related to both advanced recruitment and selection of the dominant follicle secondary to an earlier and higher FSH rise during the luteal-follicular transition, while the late follicular growth is normal. As a short follicular phase may be detrimental for reproduction, it was postulated that increasing the duration of follicular phase could improve conception rate. For that purpose, gonadotrophin-releasing hormone agonist minidoses were administered in the mid-luteal phase to prevent the intercycle FSH rise before tailoring follicular growth by controlled exogenous FSH administration. This regimen, applied to 69 infertile ovulatory women with a short follicular phase (9.6 +/- 1.2 days) actually lengthened the follicular phase by about 3 days. It proved to be effective in 179 cycles to induce paucifollicular development (1.8 +/- 0.9 follicles) with a low cancellation rate (4%) and a moderate requirement for gonadotrophins [13.3 +/- 6.3 ampoules (75 IU)]. In those women with a high frequency (80%) of elevated basal FSH or oestradiol concentrations, the pregnancy rate reached 15.1%/cycle but the miscarriage rate remained high (44%). Thus, increasing the follicular phase length in patients with a short follicular phase may partially restore fecundity.

[Should infertile women with polycystic ovarian syndrome be treated with metformine?]. / Faut-il traiter par metformine les femmes infertiles présentant un syndrome des ovaires polykystiques ?

Polycystic ovary syndrome is a frequent endocrine disorder often associated with insulin resistance and hyperinsulinaemia which may play a role in hyperandrogenism and anovulation. The use of "insulin sensitizing" agents has been suggested to reduce insulin resistance and hyperandrogenism. In that respect, the use of metformin in polycystic ovary syndrome is reviewed. Although its mechanism of action is still unclear, metformin proved to be effective to restore cyclicity and spontaneous ovulation. The synergistic effect of clomiphene citrate and metformin was demonstrated in some studies, suggesting that metformin could be helpful for women with clomiphene citrate resistance. However, the potential effect of metformin administration for reducing hyperstimulation in women treated with exogenous FSH, or for preventing early miscarriages has to be confirmed. Here, we propose a guideline for the use of metformin, as an adjuvant therapy, to restore cyclicity and ovulation in women with polycystic ovary syndrome.

An epidemiological study of the respiratory health of workers in the European refractory ceramic fibre industry.

OBJECTIVES: To investigate possible relations between respiratory health and past airborne exposure to refractory ceramic fibres (RCFs) and respirable dust in workers at six European factories, studied previously in 1987. METHODS: The target population comprised all current workers associated with RCF production, plus others who had participated in 1987 "leavers". Information was collected on personal characteristics, chest radiographs, lung function, respiratory symptoms, smoking, and full occupational history. Regression analysis was used to study relations between indices of health of individual workers and of cumulative exposure to airborne dust and fibres, and likely past exposure to asbestos. RESULTS AND DISCUSSION: 774 workers participated (90% of current workers, 37% of leavers). Profusion of small opacities in exposed workers (51% 0/1+; 8% 1/0+) was similar to that among an unexposed control group but higher than in new readings of the 1987 study films (11% 0/1+, 2% 1/0+). The large difference between 1987 and recent films may be, at least in part, a reading artefact associated with film appearance. Small opacities of International Labour Organisation (ILO) category 1/0+ were not associated with exposure. An association of borderline significance overall between 0/1+ opacities and exposure to respirable fibres was found for some exposure periods only, the time related pattern being biologically implausible. Pleural changes were related to age and exposure to asbestos, and findings were consistent with an effect of time since first exposure to RCFs. Among men, forced expired volume in 1 second (FEV(1)) and forced vital capacity (FVC) were inversely related to exposure to fibres, in current smokers only. FEV(1)/ FVC ratio and transfer factor (TL(CO)) were not related to exposures. The estimated restrictive effect was on average mild. Prevalence of respiratory symptoms was low. Chronic bronchitis and its associated symptoms (cough, phlegm) showed some association with recent exposure to respirable fibres. This could be due to an irritant effect of RCFs.