Decline in semen concentration and morphology in a sample of 26,609 men close to general population between 1989 and 2005 in France.

STUDY QUESTION: Are temporal trends and values of semen quality parameters in France identifiable in partners of totally infertile women? SUMMARY ANSWER: Among a sample of 26 609 partners of totally infertile women undergoing an assisted reproductive technology (ART) procedures in the whole of France over a 17-year period, there was a continuous decrease in semen concentration of about 1.9% per year and a significant decrease in the percentage with morphologically normal forms but no global trend for motility. WHAT IS KNOWN ALREADY: A global decrease in human sperm quality is still debated as geographical differences have been shown, and many criticisms have risen concerning studies with small and biased study populations or inappropriate statistical methodology. However, growing biological, toxicological, experimental and human exposure data support the endocrine disruptors' hypothesis assuming that fetal exposure to endocrine disruptors could impair reproductive outcomes. STUDY DESIGN, SIZE, DURATION: This was a retrospective and descriptive study using data registered by Fivnat, the professional association in charge of statistics for ART in France during the 1989-2005 study period. Data were provided by 126 main ART centres over the whole metropolitan territory. The source population included 154 712 men, aged 18-70, who were partners of couples undergoing their first ART cycle and for whom semen quality indicators (concentration, total motility and percentage of morphologically normal forms), measured on fresh ejaculated semen, were available. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population was 26 609 partners of women who had both tubes either absent or blocked. The temporal trends for each indicator of semen quality were modelled using a generalized additive model that allowed for nonlinear relationships between variables and were adjusted for season and age. In-depth sensitivity analyses included the reiteration of the analysis on data from a second spermiogram available for each man and on another subsample of men diagnosed as fertile. Variables such as centre, technique (standard in vitro fertilization or intra-cytoplasmic sperm injection) and an interaction factor between technique and time were also included in the model. MAIN RESULTS AND THE ROLE OF CHANCE: There was a significant and continuous decrease in sperm concentration of 32.2% [26.3-36.3] during the study period. Projections indicate that concentration for a 35-year-old man went from an average of 73.6 million/ml [69.0-78.4] in 1989 to 49.9 million/ml [43.5-54.7] in 2005. A significant, but not quantifiable, decrease in the percentage of sperm with morphologically normal forms along the 17-year period was also observed. There was no global trend but a slight, significant increase in total motility between 1994 and 1998 was observed. The results were robust after sensitivity analysis. LIMITATIONS, REASONS FOR CAUTION: Socioeconomic status could not be controlled for. Despite universal access to medical services in France, couples undergoing ART are expected to have a higher educational level on average compared with those of the general population. Therefore, the real values in the general population could be slightly lower than those presented and the decrease possibly stronger, as the population study is less likely to smoke or be overweight, two factors known to impair semen quality. WIDER IMPLICATIONS OF THE FINDINGS: As the men were selected without a priori knowledge regarding their semen quality characteristics, the results are expected to be close to the values in the general French population. The very large sample size and the robustness of the results confer great statistical power and credibility to the results. To our knowledge, it is the first study concluding a severe and general decrease in sperm concentration and morphology at the scale of a whole country over a substantial period. This constitutes a serious public health warning. The link with the environment particularly needs to be determined.

Breast-cancer anti-estrogen resistance 4 (BCAR4) encodes a novel maternal-effect protein in bovine and is expressed in the oocyte of humans and other non-rodent mammals.

STUDY QUESTION: Does BCAR4 have a role in mammalian embryo development? SUMMARY ANSWER: Expression, localization and functional data support that BCAR4 is a maternal-effect protein in non-rodent mammals. WHAT IS KNOWN ALREADY: BCAR4 was previously identified as an oocyte-specific gene in cattle, and as a marker of certain breast tumors in humans. STUDY DESIGN, SIZE, DURATION: Human oocytes were obtained from patients undergoing IVF, but had failed to mature after ovarian stimulation. Dog oocytes were obtained from ovariectomized bitches. Pig, horse and bovine ovaries were obtained from commercial slaughterhouses for extraction of immature oocyte-cumulus complexes. In vivo matured bovine matured oocytes were obtained after ovulation induction and ovulation inducing treatment of Montbeliard heifers. MATERIALS, SETTING AND METHODS: Expression at the RNA level was analyzed by reverse transcription coupled to polymerase chain reaction. Western blot and immunolabeling coupled to confocal or electronic microscopy were used to analyze bovine protein expression and intracellular localization. For the functional approach, short-interfering RNA were microinjected into mature bovine oocytes, followed by IVF; cleavage and embryo development were recorded. MAIN RESULTS AND THE ROLE OF CHANCE: The BCAR4 gene is conserved in mammalian species from various orders and has been lost in rodents after divergence with lagomorphs. The transcript is expressed in the oocytes of humans and domestic species. We bring the first experimental evidence of the BCAR4 protein in mammals. In cattle, the protein is not detected in immature oocytes but starts to be synthesized during maturation, increases in the zygote and persists until the morula stage. The protein is detected throughout the cytoplasm in mature oocytes, concentrates in and around the pronuclei in the zygote, and appears to shuttle in and out of the nuclei starting in the 2-cell embryo; BCAR4 is also present at the junctions between blastomeres from 2-cell to morula. In our functional approach, targeting the BCAR4 transcript by small-interfering RNA significantly compromised development to the morula or/and blastocyst stages (P < 0.05, logistic regression). LIMITATIONS, REASONS FOR CAUTION: As indicated above, protein expression and function were investigated in cattle and mostly in vitro matured oocytes were used. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a novel candidate gene whose mutation or deregulation may underlie certain cases of unexplained female infertility.

Clinical outcome after insemination with donor sperm in patients with poor results in ICSI cycles.

The introduction of intracytoplasmic sperm injection (ICSI) provided an effective treatment for infertile couples whose infertility was attributed to male factors. However, some of them face poor results after ICSI and subsequently use artificial insemination with donor sperm (AID). Only a few studies have reported on the clinical outcome of AID cycles after previous failed ICSI cycles, with contrasting results. The results reported here involve a cohort of 47 couples undertaking 175 AID cycles after 120 failed ICSI cycles for various reasons. Couples were allocated to two groups according to the availability of top quality embryos (TQE) in ICSI cycles. In our series, AID was successful for couples with and without TQE previously transferred in ICSI cycles, the live birth rate (LBR) per cycle being 20.0% and 13.3%, respectively. However, couples with TQE tended to succeed more rapidly than couples with poor quality embryos, with a higher cumulative LBR (68.0% versus 54.5%, respectively). These findings demonstrate that even couples with a history of unsuccessful ICSI cycles because of poor embryo quality are able to achieve high LBR after AID cycles. However, such couples have a lower cumulative LBR and are required to be more patient to achieve parenthood.

Semen variation in a population of fertile donors: evaluation in a French centre over a 34-year period.

Although it has been suspected that there is a decrease in semen quality over time, the results reported to date remain debatable because of methodological issues. The aim of the study reported here was to investigate the evolution of semen quality over time in a population of 1114 fertile candidates for sperm donation at CECOS, Tours, between 1976 and 2009. We investigated semen volume, sperm concentration, progressive motility, vitality, percentage of normal forms and multiple abnormalities index of the first ejaculate in this population. We did not find a decline in semen volume, whereas we observed a significant decrease in total sperm count (from 443.2 million in 1976 to 300.2 million in 2009), motility (from 64% in 1976 to 49% in 2009) and vitality (from 88% to 80%). Moreover, a significant decline in the percentage of normal forms was noted between 1976 and 1997 (from 67% to 26%) with a steady rise in the multiple abnormalities index between 1998 and 2009 (from 1.19 to 1.65). This study involving a population of fertile men from a restricted area revealed various degrees of decline in semen parameters over a period of 34 years. These findings will have to be compared with findings in other geographical areas.

Treating women under 36 years old without top-quality embryos on day 2: a prospective study comparing double embryo transfer with single blastocyst transfer.

BACKGROUND Embryologists currently face a challenge when counselling patients regarding the stage and the number of embryos to transfer when no top-quality embryos (TQE) are available. METHODS The aim of this study was to evaluate the efficacy of single blastocyst transfer (SBT) in comparison with the transfer of two cleavage-stage embryos in women under 36 years old. A total of 450 women under 36 years undergoing their first or second IVF treatment who had no TQE on Day 2 were included in this prospective study. Couples were assigned to either a SBT or a double cleavage-stage embryo transfer (DET). The clinical end-points monitored were rates of implantation, delivery and multiple deliveries. RESULTS The rate of transfer was significantly lower for couples assigned to the SBT group compared with the DET group (88 versus 100%, respectively, P < 0.001) while the delivery rate per oocyte retrieval was similar in both groups (26.7%). By contrast, the rate of multiple deliveries was significantly lower in the SBT group compared with the DET group (3.3 versus 23.3%, respectively, P < 0.01). Blastocyst cryopreservation was twice as high in the SBT group compared with the DET group (39 versus 18%, respectively, P < 0.001). CONCLUSIONS These findings show the value of extended embryo culture for couples without TQE. In such situations, delaying embryo transfer in order to select a single blastocyst with the highest potential for implantation can reduce the number of multiple pregnancies. Furthermore, our results demonstrate that extended culture allows blastocyst cryopreservation from embryos not available for Day 2 cryopreservation.

Sperm morphology assessment using David's classification: time to switch to strict criteria? Prospective comparative analysis in a selected IVF population.

The aim of this study was to compare assessment of sperm morphology by using David's classification (DC), a method of manual analysis most common in France, with a computer-assisted method (Integrated Visual Optical System) based on the strict criteria (CASA SC) for their ability to predict fertilization in a selected in vitro fertilization (IVF) population. A total of 120 couples engaged in IVF protocols were prospectively included in the study. To focus mainly on sperm morphology, couples were excluded in cases of abnormalities of sperm concentration and/or motility and immunological factors and when a low number of oocytes were collected. Sperm morphology analysis was performed on the day of oocyte retrieval by the same trained biologist. Our results showed a moderate correlation between the two techniques (r = 0.49). The DC sperm morphology analysis was less indicative of fertilization than CASA SC (r = 0.07, p = 0.47 vs. r = 0.22, p = 0.014). Using receiver-operating characteristics analysis, we showed that DC was not discriminating in the prediction of fertilization (AUC = 0.572). DC seemed less appropriate for the prediction of fertilization success or failure. In contrast, with CASA SC, the previously determined cut-off value of around 14% was confirmed (AUC = 0.735, cut-off = 6%). Our results argue in favour of the replacement of DC by SC to tend towards worldwide standardization.

Does early morphology provide additional selection power to blastocyst selection for transfer?

Routine early developmental parameters are widely used in IVF centres to evaluate embryo development and fresh single-blastocyst transfer currently seems superior to single-embryo transfer. Would early morphological parameters help to choose the single blastocyst to be transferred, thereby improving the chances of implantation and live birth rate? This prospective observational study analysed the individual outcomes of 2617 embryos from 511 IVF couples scheduled for a single-blastocyst transfer. Embryo and blastocyst scores were constructed. There was a clear relationship between the kinetics and morphology of blastocysts and further implantation and live birth rate. There was a limited predictive value of embryo score with regard to blastocyst development and growth kinetics. Implanted and non-implanted blastocysts showed similar embryo scores. Thus usual morphological parameters on days 1 and 2 seem to have no additional value in indicating the right blastocyst to transfer. Non-invasive approaches might be helpful to increase the chances of implantation in the future.

Single Day 2 embryo versus blastocyst-stage transfer: a prospective study integrating fresh and frozen embryo transfers.

BACKGROUND: Whether extended culture allowing selection of embryos with high development potential has any advantage over cleavage-stage embryo transfer remains a matter of debate. Among the currently unsolved questions, the cumulative delivery rate resulting from fresh and frozen embryo transfers needs to be taken into account in both strategies. The aim of our study was, therefore, to compare the efficacy of single embryo transfer either on Day 2 or on Day 5/6 combining fresh and frozen embryo transfers. METHODS: A prospective study including 478 couples assigned on a voluntary basis to undergo elective single embryo transfer (eSET, n = 243) on Day 2 or single blastocyst transfer (SBT, n = 235) on Day 5/6 was performed. The primary outcome measurement was the cumulative delivery rate including fresh and frozen-thawed cycles in both groups. RESULTS: The delivery rate per cycle following fresh embryo transfer was significantly higher in the SBT group compared with the eSET group (P < 0.01). Conversely, frozen embryo and/or blastocyst transfers tended to result in a higher number of deliveries in the eSET compared with the SBT group. Altogether, the cumulative delivery rate per couple, including fresh and frozen embryo transfers, was similar between the two groups (37.9% versus 34.2% in the SBT and eSET groups, respectively). CONCLUSIONS: The observed cumulative delivery rates in this study do not allow us to take a position in favor of SBT or eSET. An improvement in blastocyst cryopreservation may change this attitude.

[Non invasive assessment of embryo quality: proteomics, metabolomics and oocyte-cumulus dialogue]. / Approches non invasives de l'embryon : protéomique, métabolomique, dialogue ovocyte-cumulus.

Preimplantation embryo development is one of the key features with implantation itself to achieve a pregnancy. Assisted Reproductive Technologies both in human and animal have improved our knowledge on these events, although it remains elusive to predict embryo potential to give a baby. Among various ways to define embryo viability, noninvasive approaches get a serious advantage linked to the final transfer of the embryo. Techniques devoted to characterize the embryo secretome using proteomic or metabolomic approaches may be non invasive. Based on a direct identification of products of the embryo metabolism or an assessment of profile(s) related with embryo viability, they have greatly improved their sensitivity to allow their use in clinical embryology, once validated. Oocyte-cumulus dialogue, as a key factor for oocyte competence to meiosis and embryo development, was particularly concerned with both genomic and proteomic assessment of cumulus cells. While it is not possible to designate at the time being which among these approaches will be robust and cost-efficient enough to help routinely the clinical embryologist in assisted reproductive techniques (ART), one can predict that our ability to select the "right" embryo will combine morphological criteria already available with validated biomarkers.

Serum antimüllerian hormone is not predictive of oocyte quality in vitro fertilization.

OBJECTIVES: The assessment of the ovarian reserve is mandatory in women undergoing assisted reproduction. Antimüllerian hormone (AMH) produced by granulosa cells from preantral and early antral follicles, is a promising indicator of ovarian reserve. However, few studies have evaluated the predictive value of AMH on oocyte quality. MATERIAL AND METHODS: A retrospective study was undertaken at the Bretonneau University Hospital of Tours. A total of 559 women undergoing in vitro fertilization treatment between January 2007 and December 2007 were included in the study. Serum AMH levels were determined by using an ultrasensitive ELISA test. Total number of oocytes, rate of mature oocytes, fertilization rate, embryo quality and clinical pregnancy rate were recorded. RESULTS: Serum AMH was significantly lower in groups of patients with few oocytes collected. However, serum AMH was not predictive of nuclear maturity of oocytes, fertilization rate and quality of early embryos. Additionally, low levels of AMH do not preclude clinical pregnancy, in in vitro fertilization. CONCLUSION: At the moment, serum AMH is a relatively predictive indicator of the ovarian reserve, in terms of quantity but not in terms of quality. Moreover, it is still not possible to determine serum AMH cut-off value to predict clinical pregnancy in IVF programmes.

[Preimplantation embryo development: current status and perspectives in clinical embryology]. / Développement de l'embryon préimplantatoire : état actuel et perspectives en embryologie clinique.

Preimplantation embryo development is one of the key features with implantation itself to achieve a pregnancy. Assisted Reproductive Technologies (ART) both in human and animal have improved our knowledge on these events, although predicting embryo potential to give a baby remains elusive. However data from the last 10 years have allowed either to hierarchize the available parameters or to open some new perspectives to predict embryo developmental potential. Both kinetics and morphological parameters belong to noninvasive quality embryo assessment for many years, although recent data on microvideographic analysis and multivariate analysis led to reduce their biological meaning. Moreover, new technical detection of meiotic spindle birefringency or zona pellucida anisotropy has improved the oocyte quality assessment with a deep impact for countries with restrictive legislation. Beyond such morphological criteria, more functional approaches concerned the oocyte (embryo) or its environment. Direct transcriptomic analysis, while invasive and therefore experimental, brought important data on embryo "quality". However, noninvasive metabolomic or proteomic analysis of embryo media gave promising results as well as respirometry. The environment of the oocyte has focused a specific attention, either based on regulatory proteins or cytokines present in follicular fluid, or involving genes or proteins from cumulus cells, as oocyte-cumulus dialog is a key factor in oocyte maturation. Whereas it is not possible for the time being to predict which parameter(s) will be implemented routinely, all data obtained underline that the ability to develop and implant is not based on embryo superlatives (more rapid, expressing more genes or proteins, larger metabolites uptake) but rather on a quiet state, as claimed by Leese some years ago, where a lot of resources would not be mobilized by any stressful situation.

[Semen characteristics and quality of the conceptus in fertilization in vitro]. / Caractéristiques du sperme et qualité du conceptus en fécondation in vitro.

OBJECTIVE: Assisted reproductive technology (ART) is associated with increased risks for the neonate, compared to natural fertility, mainly because of multiple pregnancies and increased maternal age. On the opposite, the impact of paternal factors has been scarcely studied, except for the relationship between surgically retrieved sperms and genetic abnormalities. PATIENTS AND METHODS: This study has been realized using the large French register on in vitro fertilization (FIVNAT) that collects information on 80% of French ART activity. For the study, all the pregnancies obtained from oocyte recoveries between January 1996 and December 2003, for which information on cycles could be linked to the pregnancy were included, i.e. 34223 pregnancies, resulting in 27025 deliveries and 33945 neonates. Sperm quality was defined either according to the semen origin (spouse's ejaculate, epididymis, testis, or donor), or according to the spermiogramme values for concentration, motility and morphology. The statistical analysis included the use of multivariate logistic models, with the main prognostic factors. RESULTS: The delivery, spontaneous abortion and ectopic pregnancy rates were not influenced by semen origin nor by quality, all the 95% confidence intervals including 1. The neonates conceived through surgically retrieved sperms were at a slightly increased risk of hypotrophy (weight under the 10% centile of reference curves) and of malformation (OR=1.18, 95CI: 1.03-1.36 and OR=1.30 [0,95-1,84], respectively). On the opposite, when analysis was restrained to ejaculated semen, no risk was demonstrated. DISCUSSION AND CONCLUSION: The semen quality has little impact on pregnancy issue. Only the semen origin seems to act on hypotrophy and malformation, but these results deserve to be further analyzed for confirmation.

[Analysis of prenatal follow-up strategies for trisomy 21 affected pregnancies in France]. / Analyse du parcours de dépistage prénatal des femmes ayant donné naissance en France à un enfant atteint de trisomie 21.

OBJECTIVE: The main objective of this study was to screen the prenatal follow-up of women with live birth trisomy 21 child in order to evaluate the proportion of prenatal screening failure versus cases where the women refused either the screening or the prenatal diagnosis of Down syndrome. This study covers the period of time from 2009 to 2012 when the national prenatal screening policy changed from second to first trimester and allows for a comparative assessment of the nationwide efficiency of the various maternal serum marker based strategies. METHOD: All authorized cytogenetic laboratories sent required data for all cases of trisomy 21 diagnosed in FRANCE in new-borns (less than 1-year-old) from January 2010 to July 2013. RESULTS: A total of 1253 cases of trisomy 21 were diagnosed before 1 year of age whose mother did not had prenatal diagnosis. For 861 of them, information on the prenatal follow-up was available, with 72% of cases where a prenatal screening was organized either by maternal serum marker or by ultrasound. Results of the screening strategy was positive with maternal serum marker in 28% of cases (calculated risk≥1/250), positive because of abnormal ultrasound in 5% and negative with maternal marker screening (whatever the strategy used) in 67% of cases. Detection rate over the period of the study was 82%, with similar efficiency of first and second trimester strategies (83%) but significantly lower with sequential association of first trimester Nuchal translucency measurement and second trimester serum screening (70%). CONCLUSION: Switching from second trimester to first trimester screening strategy, with as many trisomy 21 foetuses diagnosed with half invasive procedures fulfilled national health policy objectives. Analysis of these data gives useful insights to elaborate a future screening policy involving cell-free foetal DNA sequencing.

[Oocyte-cumulus dialog]. / Le dialogue ovocyte-cumulus.

The dialog between oocyte and cumulus cells brings a major contribution for oocyte meiotic and developmental competence. On the one hand, the oocyte will modulate follicle growth through specific gene expression (Figalpha, GDF-9, BMP15) as well as its meiosis (GPR3 et PDE3A). Beyond its action on proliferation, oocyte will control in part the differentiation of cumulus cells with a particular involvement of GDF-9, BMP15 in this late maturation process. On the other hand, somatic cells are the main targets of gonadotropins and will modulate both oocyte growth and maturation. Gap-junctions between oocyte and cumulus cells have a major role in this interaction, since they allow the action of some oocyte specific genes (GDF9) but also the control of its own metabolism and calcium movements. While ovulation will involve gonadotropins action on somatic cells, EGF-like factors recruited at the cumulus level will participate in this process. Finally we may suspect that improving the knowledge on oocyte-cumulus dialog will contribute to better define oocyte competence, while bringing some clues for in vitro maturation.

[Sequential assessment of individually cultured embryos in IVF]. / Suivi individuel des embryons en FIV.

OBJECTIVE: It is a challenge for IVF centers to propose a method to select the most viable embryo to transfer, thereby minimizing the risk of multiple births. In this study, a prospective investigation was made to determine if non-invasive developmental markers on day 1 combined to conventional evaluation on day 2 can predict in vitro blastocyst development. PATIENTS AND METHODS: A total of 4190 individually cultured embryos from patients undergoing IVF/ICSI treatment at the Tours University Hospital Center from January 2002 to December 2004 were included. Individual embryos were cultured in sequential media in microdrops under mineral oil from j1 to j5/j6 allowing to record their sequential growth until the blastocyst stage. RESULTS: The results showed a significant positive relationship between pattern 0 zygote, early cleavage, 4 cells embryos with < 20% fragmentation on day 2 and the rate of blastocyst development on day 5 (P < 0.05). In our hands, zygote pattern does not bring additional benefit to better select embryo. DISCUSSION AND CONCLUSION: Zygote and early cleavage assessments on day 1, morphological appearance on day 2 are some other parameters related individually to blastocyst development on days 5 and 6. These parameters can be used collectively to establish a predictive in vitro sequential embryo assessment model for routine use in IVF clinics.

[Oocyte maturation: can oocyte competence be defined?]. / Maturation ovocytaire: peut-on définir la compétence d'un ovocyte?

Oocyte competence is acquired throughout oogenesis, via the interaction with somatic cells. The ability to reinitiate the meiotic process and undergo preimplantation development is progressively determined during the antral phase. It is well-known that these changes involve the nuclear and cytoplasmic compartments, respectively, but the underlying cellular and molecular mechanisms are still poorly understood. The oocyte undergoes a progressive series of morphological modifications as it grows and proceeds through the different stages of development. These structural rearrangements facilitate the increasing energy and nucleic acid synthesis requirements of the developing oocyte and are a prerequisite to the oocytes achieving meiotic and embryo developmental competence. The complexity of the orchestration of the events that control oocyte growth and ultimate acquisition of developmental competence is under continuous investigation. The present review describes some of the findings to date.

A randomized prospective study comparing pregnancy rates after clomiphene citrate and human menopausal gonadotropin before intrauterine insemination.

OBJECTIVE: To determine whether hMG offers an advantage over clomiphene citrate (CC) in achieving pregnancy after IUI with husband's sperm. DESIGN: Randomized prospective trial. SETTING: Infertility patients in a university teaching hospital. PATIENT(S): Fifty-eight women under 39 years old undergoing ovulation induction before IUI. INTERVENTION(S): The women were assigned randomly to one of two treatment groups. Patients in group I (CCHH) received CC for the first two cycles and hMG for the last two cycles. Patients in group II (HHCC) received hMG for the first two cycles and CC for the last two cycles. MAIN OUTCOME MEASURE(S): Cycle fecundity rates for the two treatment modalities were compared statistically with use of life-table analysis. RESULT(S): Of the 174 cycles studied, overall cycle fecundity rate was 11.11 (9 of 81 cycles) in the CCHH group and 10.75 (10 of 93 cycles) in the HHCC group. The difference was not statistically significant. The cycle fecundity rate was 14.44% (13 of 90 cycles) for cycles with CC and 7.14% (6 of 84) with hMG. The difference was not statistically significant. CONCLUSION(S): These data suggest that CC is an effective alternative to hMG in the population examined.

[Study of the plethysmographic amplification factor during vasodilator treatment. Healthy subject versus primary Raynaud phenomenon]. / Etude du facteur d'amplification en pléthysmographie sous traitement vasodilatateur. Sujet sain versus phénomène de Raynaud primaire.

Digital arterial circulation before and after administration of a vasodilator orally was explored by mercury gauge pulsed plethysmography and photoplethysmography in 12 patients with primary Raynaud's phenomenon and results compared with those of 10 healthy volunteers. The amplification factor F, ratio of amplitude in reactive hyperemia over amplitude at rest was determined in the index before and after 8 mg daily of dihydroergokryptine over 4 weeks. Before treatment, for each of the two plethysmographic technics, a significant increase in mean factor F values was noted in the patients with Raynaud's phenomenon when compared with healthy controls. This is due to a decline in digital arterial flow at rest. Using the mercury gauge plethysmograph, a significant reduction in factor F was observed after vasodilator treatment corresponding to an increase in digital flow at rest without increase in flow during hyperemia. Using photoplethysmography, no significant variation in factor F was noted after treatment. Mercury gauge plethysmography, which measures global digital blood flow appears to be a more sensitive method than photoplethysmography, which measures dermal and hypodermal blood flow, for follow-up of effects of vasodilator treatment on Raynaud's phenomenon.

[Intrauterine insemination: state-of-the-art in humans]. / Insémination intra-utérine: état des lieux chez l'humain.

Despite its being used for a long time, intrauterine insemination (i.u.i.) remains debated as to its precise place and efficacy among assisted reproductive technologies. Data issued from the French Health Ministry inquiries are strictly limited to the number of cycles and the pregnancies and births including the multiple ones. Concerning 2000, more than 44,000 cycles were registered with 8% deliveries per cycle and 12% multiple pregnancies. Apart from the cervical female infertility which is considered to have the best prognosis with i.u.i., literature data remain controversial with male and unexplained infertility. Prospective randomized studies are rather scarce, particularly when considering the inclusion of untreated control population. Meta-analyses have been published for ten years, which allowed to better define the place of i.u.i. in patient management. However one may notice that the sperm cut-off parameters for male infertility and the respective contribution of i.u.i. and ovulation treatment do not allow develop some evidence-based guidelines for i.u.i. good practice. Quite all meta-analyses modulated their conclusions by addressing the need for large randomized controlled studies. Such a need seems now quite reinforced since results were until now expressed as pregnancy rate per cycle or pregnancy rate per couple, whereas single live birth rate and drop out rate are claimed to be taken into account nowadays. Moreover the level of controlled hyperstimulation is highly questionable with both hyperstimulation ovary syndrome and multiple pregnancy risks. Patients facing with failed i.u.i. cycles may turn to i.v.f. or i.c.s.i.. Interestingly data coming from the French national register (FIVNAT) did not show major differences between couples turning to i.v.f. (i.c.s.i.) after previously failed i.u.i. cycles or using directly i.v.f. (i.c.s.i.). Moreover the prognostic as evaluated on pregnancy rate per cycle was unchanged between such patients, which does not support some selection of patients by i.u.i. failure. Thus, although i.u.i. seems likely a cost-effective treatment in infertile couples, the precise conditions of its management (spontaneous or stimulated cycle, mono-, pauci- or multi-follicular induction) remain to be assessed. Indeed large controlled randomized studies including untreated group are required even if such design might have a non negligible cost. However these rather common treatments do have a high cost and any effort to rationalise them will have some economical impact. Another practical approach, although less ambitious, might consist in developing a per cycle registry which should allow to precise the French practice at a large national level.

[Insulin-resistant diabetes and polycystic ovary]. / Diabète insulino-résistant et ovaire polykystique.

The observation of one patient with insulin resistance (114 unités of soluble insulin in 3 injections per day + 54 units of medium acting insulin at 8 pm) associated with a polycystic ovarian disease prompted us to discuss the relationship between hyperandrogenism, acanthosis nigricans and endogenous hyperinsulinism. An in vitro study of the insulin binding to patient's erythrocytes allowed to diagnose the rare Type A insulin-resistance syndrome proposed by Kahn.