A novel application of cell-free seminal mRNA: non-invasive identification of the presence of germ cells or complete obstruction in men with azoospermia.
Hum Reprod. 2012 Jan 26;
Authors: Li H, Wu C, Gu X, Xiong C
Abstract
BACKGROUNDCell-free seminal mRNA (cfs-mRNA) exists in human ejaculate at high concentrations and with high stability, and contains many tissue-specific transcripts secreted from the male reproductive system. Owing to the sensitivity of RNA technology, cfs-mRNAs are ideal candidates for non-invasive biomarkers of physiopathological conditions. This study applied cfs-mRNA in identifying the presence of either germ cells or complete obstruction in men with azoospermia.METHODSRT-PCR was performed to amplify the germ cell-specific (DDX4), seminal vesicle-specific (SEMG1) and prostate-specific (TGM4) mRNAs from cfs-mRNAs, which were isolated from the seminal plasma of men with non-obstructive azoospermia (NOA) or obstructive azoospermia (OA). The 39 patients with NOA, diagnosed by testicular biopsy, included 8 men with maturation arrest (MA), 3 men with incomplete sertoli cell only (iSCO) syndrome and 28 men with complete SCO (cSCO). The 29 patients with OA, confirmed by the presence of sperm in the testis or epididymis, included 8 men with congenital bilateral absence of the vas deferens (CBAVD) and 21 men with non-CBAVD. Healthy individuals and vasectomized men were enrolled as controls.RESULTSTGM4 was detected in all participants. Consistent with their diagnosis, DDX4 was detected in all patients with MA or iSCO but was absent in most cases of cSCO (n = 21, 75.0%) or non-CBAVD (n = 18, 85.7%), and in all men with vasectomy or CBAVD. The presence of DDX4 in the other seven men with cSCO and three patients with non-CBAVD suggests the presence of germ cells in the testis, and incomplete obstruction, respectively. SEMG1 was undetectable in three patients with CBAVD with bilateral absence of the seminal vesicles, and in two non-CBAVD cases with low ejaculate volume.CONCLUSIONSThese results suggest that, with high sensitivity and representativity, cfs-mRNA could be non-invasive biomarkers for identifying the presence of germ cells or complete obstruction in azoospermia.
PMID: 22286264 [PubMed - as supplied by publisher]
Premature birth and low birthweight are associated with a lower rate of reproduction in adulthood: a Swedish population-based registry study.
Hum Reprod. 2012 Jan 26;
Authors: Dekeyser N, Josefsson A, Bladh M, Carstensen J, Finnström O, Sydsjö G
Abstract
BACKGROUNDThe aim of this study was to investigate if individuals born with sub-optimal birth characteristics have reduced probability of reproducing in adulthood.METHODSUsing population-based registries, the authors included 522 216 males and 494 692 females born between 1973 and 1983 and examined their reproductive status as of 2006. Outcome measure was the hazard ratio (HR) of reproducing. Adjustments were made for socio-economic factors.RESULTSMales and females born very premature displayed a reduced probability of reproducing [HR = 0.78, 95% confidence interval (CI): 0.70-0.86 for males; HR = 0.81, CI: 0.75-0.88 for females]. Likewise for very low birthweight (HR = 0.83, CI: 0.71-0.95 for males; HR = 0.80, 95% CI: 0.72-0.89 for females). Individuals born large for gestational age (LGA) displayed no significant changes. Males born small for gestational age (SGA) had a 9% lower reproductive rate (CI: 0.89-0.94) and that reduction increased as the individuals aged. Women born SGA tended to start reproducing at an earlier age.CONCLUSIONThe results suggest that being born with low birthweight, premature or SGA (for males) is associated with a reduced probability of reproducing as an adult. LGA shows no statistically significant relationship with future reproduction.
PMID: 22286265 [PubMed - as supplied by publisher]
Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome.
Hum Reprod. 2012 Jan 24;
Authors: Gallot V, Berwanger da Silva AL, Genro V, Grynberg M, Frydman N, Fanchin R
Abstract
BACKGROUNDLooking for a qualitative marker of ovarian function, we aimed to verify whether responsiveness of antral follicles to FSH administration, as reflected by the Follicular Output RaTe (FORT), is related to their reproductive competence.METHODSWe studied 322 IVF-ET candidates aged 25-43 years who underwent controlled ovarian hyperstimulation with similar initial FSH doses. Antral follicle (3-8 mm) count (AFC) and pre-ovulatory follicle (16-22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (<42%; n= 102), average (42-58%; n= 123) and high (>58%; n= 97).RESULTSThe average FORT was 50.6% (range, 16.7-100.0%). Clinical pregnancy rates per oocyte retrieval increased progressively from the low to the high FORT groups (33.3, 51.2 and 55.7%, respectively, P< 0.003) and such a relationship assessed by logistic regression was independent of the confounding covariates, women’s ages, AFC and PFC.CONCLUSIONSThe observed relationship between IVF-ET outcome and the percentage of antral follicles that effectively respond to FSH administration reaching pre-ovulatory maturation suggests that FORT may be a qualitative reflector of ovarian follicular competence. Further studies with broader inclusion criteria and more personalized protocols are needed to validate these results.
PMID: 22279090 [PubMed - as supplied by publisher]
Unconjugated bisphenol A cord blood levels in boys with descended or undescended testes.
Hum Reprod. 2012 Jan 20;
Authors: Fénichel P, Déchaux H, Harthe C, Gal J, Ferrari P, Pacini P, Wagner-Mahler K, Pugeat M, Brucker-Davis F
Abstract
BACKGROUNDHuman toxicity of bisphenol A (BPA), a weak estrogenic environmental endocrine disrupting compound, widely used in plastics, baby bottles, cans and dental sealants, is under investigation. Fetal or perinatal exposure in rodents is associated with programmed adult reproductive diseases. Human epidemiological studies remain scarce, especially concerning testicular development. We have investigated the relationship between fetal exposure to BPA and cryptorchidism.METHODSUsing a radioimmunoassay performed after extraction, validated by high-performance liquid chromatography and mass spectrometry, active levels of unconjugated BPA (uBPA) in cord blood (CB) were measured in 152 boys born after 34 weeks gestation, with cryptorchid or descended testes.RESULTSActive uBPA was detectable in all CB samples, with values in the control group (n = 106) of 0.14-4.76 ng/ml, median: 0.9 ng/ml; mean ± SD: 1.12 ng/ml ± 0.86 ng/ml, which did not differ from cryptorchid boys (n = 46, 1.26 ± 1.13 ng/ml, P = 0.38). uBPA in controls correlated with CB inhibin B (P < 0.01) and total testosterone (P < 0.05), and with maternal milk polychlorinated bisphenyl 138 (P < 0.03). uBPA did not correlate with clinical maternal or fetal parameters or with other steroid or polypeptide CB hormones assessed.CONCLUSIONSThe presence of uBPA in all CB samples suggests placental transfer and fetal exposure. Similar uBPA levels in the control and cryptorchid groups make the participation of fetal exposure to uBPA in the physiopathology of undescended testes unlikely. However, the observed nanomolar uBPA concentrations support assessment of epidemiological relationships between CB uBPA and other human diseases.
PMID: 22267833 [PubMed - as supplied by publisher]
Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence.
Hum Reprod. 2012 Jan 20;
Authors: Petro EM, Leroy JL, Covaci A, Fransen E, De Neubourg D, Dirtu AC, De Pauw I, Bols PE
Abstract
BACKGROUNDIncreased global industrial activity has exposed humans to a wide variety of chemical substances some of which, called ‘endocrine-disrupting chemicals’ (EDCs) or ‘endocrine disruptors’, can disrupt the endocrine system in the body. The ovarian follicle is a very fragile micro-environment where interactions between hormones, growth factors, the oocyte and its surrounding somatic cells are essential to generate a fully competent oocyte. In vitro experiments suggest that EDCs can disturb this finely tuned balance, but very scarse in vivo data are available to confirm this assumption. Therefore, we have investigated if the presence of EDCs in human follicular fluid is a risk factor for the developmental competence of an in vivo exposed oocyte. Furthermore, because of the limited access to human follicular fluid, we verified if follicular fluid contamination can be predicted based on EDC levels in serum.METHODSFollicular fluid (n = 40) and serum (n = 20) samples from women undergoing assisted reproductive technology (ART) were analyzed by means of gas chromatography combined with mass spectrometry to examine the presence of different EDCs, such as polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides. Statistical models were used to investigate the relation between the characteristics and ART results of the patients and the contamination status of their follicular fluid and to assess the capacity of serum samples to predict follicular fluid contamination.RESULTSChlorinated biphenyl 153 (72 ± 44 and 201 ± 106 pg/ml) and p,p’-DDE (392 ± 348 and 622 ± 406 pg/ml) were the compounds found in the highest concentrations in follicular fluid and serum samples, respectively. A new variable principal component 1, representing the overall contamination status of the follicular fluid samples, is strongly associated with fertilization rate (P < 0.00001) and the proportion of high-quality embryos relative to the amount of retrieved oocytes (P < 0.05), even when the analysis is adjusted for age, estradiol concentration, BMI, fertilization procedure and male subfertility as explanatory variables. The strong correlations between the EDC concentrations in serum and follicular fluid (r ≥ 0.93) allowed us to build regression models, which accurately predict EDC concentrations in the follicular fluid based on serum samples.CONCLUSIONSAn overall higher EDC contamination in the follicular micro-environment was associated with a decreased fertilization rate and consequently with a lower chance of an oocyte to develop into a high-quality embryo. In addition, EDC concentrations in serum were reliable predictors of the contamination status of the follicular micro-environment.
PMID: 22267834 [PubMed - as supplied by publisher]
Cumulative parenthood rates in 1735 couples: impact of male factor infertility.
Hum Reprod. 2012 Jan 23;
Authors: Walschaerts M, Bujan L, Isus F, Parinaud J, Mieusset R, Thonneau P
Abstract
BACKGROUNDMost studies assessing the outcome of assisted reproductive technologies (ARTs) have reported live birth rates in couples by taking mainly the female factor into account. However, infertility is a couple’s concern, and the majority of publications do not take into consideration the true impact of male infertility on having the desired number of children.METHODSWe carried out a follow-up study to evaluate the probability of having a child during treatments at the Toulouse Male Sterility Centre and after discontinuation from 2000 through 2008. Couples were followed for at least 4 years until discontinuation of treatment or delivery of a live infant.RESULTSWe were able to contact 65% of the 1735 male partners by telephone. Of the 1131 respondents, 56% had become parents (60% if adoption is included), 28% after ART, 16% by natural pregnancy, 8% after non-ART treatment and 4% after ART in another centre. The cumulative rates of success reached 64% [95% confidence interval (CI), 60-67] for men ≤35 years and women ≤35 years after 9 years, and 31% (95% CI, 24-39) in older patients. With optimistic analysis, which assumes that patients for whom no information was available have the same chance of success in having a child as those whose reproductive outcome was known, the cumulative rate of success was 48% (95% CI, 45-50) in the 1735 couples.CONCLUSIONSMore than half of couples consulting for male infertility succeeded in having a child. Male age over 35 years old appears as a key risk factor as well as the woman’s age, and these findings should encourage couples to attempt parenthood earlier.
PMID: 22271929 [PubMed - as supplied by publisher]
Treatment should be considered a competing risk when predicting natural conception in subfertile women.
Hum Reprod. 2012 Jan 13;
Authors: Van Geloven N, Broeze KA, Bossuyt PM, Zwinderman AH, Mol BW
Abstract
BACKGROUNDPrediction of natural conception in subfertile couples can help to differentiate between couples who should have immediate treatment and couples who can aim for natural conception for some time. Natural conception rates are often estimated using standard techniques such as Kaplan-Meier or Cox proportional hazard models. These estimates can be biased by incorrect handling of data from women who start assisted reproductive technology therapy before the end of the follow-up period. This paper discusses the validity and the impact of the assumption of non-informative censoring as used in the Kaplan-Meier and Cox models.METHODSIn a cohort of 5360 subfertile couples with suspected tubal pathology, the probability of natural conception and the prognostic value of additional tests for tubal pathology were estimated using traditional methods and with a competing risks analysis.RESULTSThe estimated probability of natural conception within 3 years was almost 2-fold higher when assuming non-informative censoring compared with the competing risks model, 41 versus 22%. The prognostic value of tests was more conservative using the competing risks model than with the traditional methods, the fecundity rate ratio for Chlamydia antibody testing was 0.72 versus 0.67, for hysterosalpingography, 0.83 versus 0.71 and for diagnostic laparoscopy, 0.89 versus 0.74.CONCLUSIONSGiven the improbable validity of the non-informative censoring assumption, the predictions of natural conception and of the prognostic value of tests are likely to be overestimated by the traditional analytic methods. We suggest the use of competing risks models as an alternative, more conservative, form of analysis when predicting natural conception and evaluating prognostic fertility tests.
PMID: 22246447 [PubMed - as supplied by publisher]
BACKGROUNDPerfluorinated chemicals (PFCs) have been widely used and have emerged as important food contaminants. A recent study on pregnant women suggested that PFC exposure was associated with a longer time to pregnancy (TTP). We examined the association between serum concentrations of PFCs in females and TTP in 222 Danish first-time pregnancy planners during the years 1992-1995.METHODSThe couples were enrolled in the study when discontinuing birth control and followed for six menstrual cycles or until a clinically recognized pregnancy occurred. Fecundability ratio (FR) was calculated using discrete-time survival models. In addition, odds ratio (OR) for TTP >6 cycles was calculated.RESULTSOR for TTP >6 cycles for those with PFC concentrations above the median were 0.96 [95% confidence interval (CI): 0.54-1.64] for perfluorooctane sulfonic acid (PFOS), the major PFC, compared with those below the median. FRs for those with PFOS concentrations above the median were 1.05 (95% CI: 0.74-1.48) compared with those below the median. Other PFCs showed the same lack of association with TTP. The results were not affected by adjustment for covariates. PFOS and perfluorooctanoic acid concentrations were similar to those observed in a previous Danish study.CONCLUSIONSThese findings suggest that exposure to PFCs affects TTP only to a small extent, if at all.
PMID: 22246448 [PubMed - as supplied by publisher]
Endometrial receptivity defects during IVF cycles with and without letrozole.
Hum Reprod. 2012 Jan 13;
Authors: Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, Higdon HL, Kitawaki J, Lessey BA
Abstract
BACKGROUNDOur aim was to study ways to improve IVF success rates in women with suspected endometrial receptivity defects.METHODSWe conducted a retrospective cohort study examining the effect of letrozole (aromatase inhibitor) on integrin expression as a marker of endometrial receptivity. We compared IVF outcomes in 97 infertile women who had undergone ανβ3 integrin assessment by immunohistochemistry in mid-luteal endometrial biopsies. Of 79 women undergoing standard IVF, 29 (36.7%) lacked normal integrin expression. Eighteen other women with low integrin were studied after receiving letrozole during early IVF stimulation. An independent set of ανβ3 integrin-negative patients (n = 15) who had undergone repeat endometrial biopsy for integrin testing while taking letrozole were re-evaluated.RESULTSClinical pregnancy and delivery rates were higher in women with normal ανβ3 integrin expression compared with those who were integrin negative [20/50 (40%) versus 4/29 (13.8%); P = 0.02 and 19/50 (38%) versus 2/29 (7%); P < 0.01, respectively]. In 18 women who received letrozole early in IVF, 11 conceived (61.1%; P < 0.001) compared with integrin-negative patients who did not receive letrozole. In integrin-negative women who were rebiopsied on letrozole, 66.7% reverted to normal integrin expression. Positive endometrial aromatase immunostaining using a polyclonal antibody was a common finding in infertile patients compared with controls.CONCLUSIONSLack of endometrial ανβ3 integrin expression is associated with a poor prognosis for IVF that might be improved with letrozole co-treatment. Prospective studies are needed to confirm and extend these findings but the data suggest that aromatase expression may contribute to implantation failure in some women.
PMID: 22246449 [PubMed - as supplied by publisher]
Molecular characterization of corona radiata cells from patients with diminished ovarian reserve using microarray and microfluidic-based gene expression profiling.
Hum Reprod. 2012 Jan 13;
Authors: May-Panloup P, Ferré-L’hôtellier V, Morinière C, Marcaillou C, Lemerle S, Malinge MC, Coutolleau A, Lucas N, Reynier P, Descamps P, Guardiola P
Abstract
BACKGROUNDDiminished ovarian reserve (DOR) is one of the causes of infertility in young women. In this prospective study, gene expression profiling (GEP) of corona radiata cells (CRC) was performed to identify genes deregulated in DOR patients.METHODSMicroarray-based GEP of CRC isolated from eight women undergoing IVF was performed to identify genes differentially expressed between patients with normal ovarian reserve and DOR patients. Microfluidic-based quantitative RT-PCR assays were used to validate selected transcripts on 40 independent patients. A principal component analysis was used to identify more homogeneous subgroups of DOR patients. In silico analyses focusing on cis-regulation were performed to refine the interactions between patient’s biological characteristics and their GEP.RESULTSForty-eight transcripts were differentially expressed, including CXXC finger protein 5 (CXXC5), forkhead box C1 (FOXC1) (down-regulated in DOR) as well as connective tissue growth factor (CTGF), follistatin-like 3 (FSTL3), prostaglandin-endoperoxide synthase 2 (PTGS2) and suppressor of cytokine signaling 2 (SOCS2) (up-regulated in DOR). According to these transcripts, two DOR patients’ subgroups (DOR Gr1 and Gr2) were identified. In DOR Gr2 patients, C-terminal domain 2 (CITED2), CTGF, growth arrest-specific 1 (GAS1), insulin receptor substrate 2 (IRS2), PTGS2, SOCS2 and Versican (VCAN) were expressed at significantly higher levels and CXXC5, FOXC1, guanylate-binding protein 2 (GBP2) and zinc finger MIZ-domain containing 1 (ZMIZ1) at significantly lower levels. Higher baseline estradiol (E(2)) levels were observed in DOR Gr2 patients (P < 0.006). The in silico analyses suggested that all 11 genes differentially expressed between DOR Gr1 and DOR Gr2 subgroups could be transcriptional targets of estrogen.CONCLUSIONSDespite small sample size limitations, 12 genes deregulated in the CRC of DOR patients were identified, which could be involved in DOR pathogenesis. A DOR patient’s subgroup with high baseline E(2) levels and deregulated estrogen-responsive genes was also identified.
PMID: 22246450 [PubMed - as supplied by publisher]
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