Cytokine pleiotropy and redundancy--gp130 cytokines in human implantation.
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Animals↗
Biomedical subjects
C Simón
Publications and source records attributed to C Simón.
Implications of sperm chromosome abnormalities in recurrent miscarriage.
PURPOSE: Our purpose was to assess the existence of sperm chromosome abnormalities in recurrent pregnancy loss in an assisted reproduction program. METHODS: In this prospective study, 12 sperm samples from couples undergoing in vitro fertilization with two or more first-trimester spontaneous abortions were analyzed. Diploidy and disomy in decondensed sperm nuclei were assessed for chromosomes 13, 18, 21, X, and Y using two- and three-color fluorescence in situ hybridization. RESULTS: Sex chromosome disomy in sperm samples from recurrent abortion couples was significantly increased compared to that from internal controls (0.84% vs 0.37%). In a subpopulation of seven couples who underwent oocyte donation, mean frequencies for sex chromosome disomy (1%) were even higher and diploidy (0.43%) was also significantly increased. CONCLUSIONS: These results suggest an implication of sperm chromosome abnormalities in some cases of recurrent pregnancy loss.
Abortion, Habitual↗
Cytokines in older patients undergoing in vitro fertilization: the relationship to the response to controlled ovarian hyperstimulation.
PURPOSE: Our purpose was to assess the endocrine, autocrine, and paracrine milieu in follicles of older women undergoing stimulated cycles, comparing normal (NR) and low (LR) responses, based on the measurement of interleukin (IL)-1 beta, IL-6, and vascular endothelial growth factor (VEGF) in serum and follicular fluid (FF). METHODS: A total of 40 women entered the study, divided into three groups: (1) older patients (> 37 years) with NR (age-NR; n = 18); (2) older women with LR (age-LR; n = 11); and (3) normal controls, aged < 35 years (control; n = 11). IL-1 beta, IL-6, and VEGF measured in serum (day of ovum pickup) and FF, employing ELISAs. RESULTS: Follicular fluid IL-6 was significantly (P < 0.05) higher in age-LR compared to the other two groups. IL-6 and VEGF showed a 4- to 20-fold increase in FF compared to blood, suggesting the ovary as an additional source of both cytokines. IL-1 beta levels remained unchanged in FF compared to blood and, also, among groups. CONCLUSIONS: These data provide further evidence that the endocrine, paracrine, and/or autocrine status in vivo of older patients is different from that of younger women and suggest that cytokines, specifically IL-6, may be involved in the changes observed during senescence within the ovary.
Adult↗
Embryonic regulation in implantation.
Maternal steroid hormones play a critical role in establishing the receptive phase of implantation. In addition to that, the embryo is able to modulate endometrial molecules during the apposition phase (chemokines) and the adhesion phase (adhesion and anti-adhesion molecules). Moreover, the human embryo also exerts a coordinated regulation of endometrial epithelial apoptosis during these implantation phases. In this work, we analyze the embryonic regulation of implantation in humans using an in vitro model.
Apoptosis↗
Maturation in vitro of human oocytes from unstimulated cycles: selection of the optimal day for ovum retrieval based on follicular size.
The potential use of immature oocytes for in-vitro fertilization (IVF) requires the conditions for successful maturation to be defined. This study focused on the day of oocyte retrieval. The selection of a dominant follicle may induce endocrine changes in the remaining cohort that may be detrimental to their subsequent fertilization and embryonic development. Natural cycles in volunteer donors were followed by measurement of serum oestradiol and by vaginal ultrasound, starting on day 3 of the cycle. Cycles were randomly allocated to one of two groups: group 1 (n = 10), in which follicles were aspirated before the leading follicle was 10 mm in diameter; and group 2 (n = 9), in which follicles were aspirated when a dominant follicle was clearly visible with diameter >10 mm. Oocytes were cultured in vitro to metaphase II (MII) stage, donated, and inseminated by intracytoplasmic sperm injection (ICSI) with husband's spermatozoa. Those that became fertilized within 24 h were further co-cultured in autologous endometrial epithelial cells up to the blastocyst stage, and cryopreserved. There was a significantly (P < 0.05) increased rate of oocyte retrieval in group 1 (70.8% of aspirated follicles) compared with group 2 (50.5%). Maturation to MII and fertilization were similar between the groups. However, development to blastocyst stage was significantly (P < 0.05) higher in group 1 embryos (56.5%) compared with group 2 (35.7%). There was a positive correlation (r2 = 0.1978) between the appearance of the cumulus cells and the ability to develop to blastocyst stage when both parameters were analysed in group 1, whereas no such correlation was found in group 2. In conclusion, our data suggest the importance of retrieving immature oocytes before follicular selection, and define the conditions for the first stage in the use of immature oocytes. Further stages must be defined before this technique can be used clinically.
Adult↗
Ovarian stimulation and endometrial receptivity.
Endometrial receptivity is a limiting step in the success of in-vitro fertilization (IVF). To investigate this issue, we selected a specific population of high responder patients in whom implantation was impaired, even when good quality embryos were transferred. We present a series of studies showing that high oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration are detrimental to uterine receptivity. In addition, we suggest clinical strategies to improve endometrial receptivity in high responder patients using a step-down regimen.
Chorionic Gonadotropin↗
Interleukin-1beta (IL-1beta) is a modulator of human luteal cell steroidogenesis: localization of the IL type I system in the corpus luteum.
The present investigation examined the effect of interleukin-1beta (IL-1beta) on progesterone production by human luteal cells and the expression and localization of the IL-1 system in the human corpus luteum (CL). Luteal cells were isolated from corpora lutea collected throughout the luteal phase. After dispersion, luteal cells were treated with a panel of monoclonal antibodies directed to leukocyte-specific molecules. The leukocytes were isolated with immunomagnetic beads. Leukocyte-free luteal cells exhibited greater steroidogenic responsiveness to hCG toward the end of the luteal phase. The treatment of mixed luteal cells (total luteal cells) with IL-1beta inhibited by 60% hCG-stimulated progesterone production. Interestingly, the treatment of leukocyte-free luteal cells with IL-1beta did not affect progesterone production. In addition, the treatment of mixed luteal cells with monoclonal antibodies against IL-1 receptor type I (IL-1RtI) resulted in a 2.5-fold increase in the hCG-supported progesterone production. IL-1RtI and IL-1 receptor antagonist were localized by immunohistochemistry in both somatic and immune cells of the CL. Flow cytometric analysis indicated that both nonleukocyte luteal cells and leukocyte-luteal cells exhibited IL-1Rt-I positive cells, representing 56% and 31% of the total luteal cells, respectively. However, 13% of nonleukocyte luteal cells did not express IL-1Rt-I. Northern analysis demonstrated the presence of the 5.1-kb IL-1RtI messenger ribonucleic acid transcript in CL of different ages. RT-PCR indicated that both leukocyte-free luteal cells and luteal leukocytes express IL-1RtI messenger ribonucleic acid. We conclude that 1) luteal leukocytes have an inhibitory effect on hCG-stimulated progesterone production; 2) IL-1beta inhibits hCG-stimulated progesterone production only in mixed luteal cell cultures, indicating that leukocytes mediate the effect; 3) the somatic and immune cells of the CL are sites of action and expression of the IL-1 system; and 4) interaction between the steroidogenic and immune cells of the CL suggests a functional intraovarian role for IL-1beta in CL physiology.
Adult↗
Coculture of human embryos with autologous human endometrial epithelial cells in patients with implantation failure.
We have developed a coculture system with autologous human endometrial epithelial cells (AEEC) that retained many features of human endometrial epithelium. Implantation failure (IF; >3 previous cycles failed with 3-4 good quality embryos transferred) is a distressing condition in which 2-day embryo transfer repetition is the routine option. The objective of this study was to investigate the basics and to evaluate prospectively the clinical value of embryo coculture on AEEC and blastocyst transfer with their own oocytes [in vitro fertilization (IVF) patients] or with donated oocytes (oocyte donation patients) compared to a routine day 2 embryo transfer for patients with IF. Scanning electron microscopy and mouse embryo assays demonstrate that EEC from fertile and IF patients were morphologically and functionally similar; similar findings were observed in EEC obtained from fresh or frozen endometria. Clinically, 168 IVF cycles were performed in 127 patients with 3.8+/-0.2 previously failed cycles, and 80 cycles were performed in 57 patients undergoing oocyte donation with 3.0+/-0.2 previously failed cycles. Twenty IVF patients and 15 ovum donation patients with 3 previously failed cycles in whom a 2-day embryo transfer was performed were used as controls. In 88% of ovum donation cycles, at least 2 blastocysts were available for transfer, with 60.1% blastocyst formation; 2.2+/-0.1 blastocysts were transferred/cycle, and 36 pregnancies (determined by fetal cardiac activity) were obtained (32.7% implantation and 54.5% pregnancy rates). In 168 IVF cycles, 8.1+/-0.2 embryos/cycle started coculture, resulting in 49.2% blastocyst formation; 2.3+/-0.2 blastocysts were transferred/cycle, and 29 clinical pregnancies were obtained (11.8% implantation and 20.2% pregnancy rates). Fifteen cycles were canceled (9%). In oocyte donation patients with IF undergoing 2-day embryo transfer, implantation and pregnancy rates were significantly lower (4.5% and 13.3%; P < 0.01) than with coculture; however, in IVF patients with IF, results with day 2 transfer (10.7% and 35%) were similar to those with coculture. The present study demonstrates that coculture of human embryos with AEEC and blastocyst transfer is safe, ethical, and effective and constitutes a new approach to improve implantation in patients with IF undergoing ovum donation, but not in IVF patients.
Animals↗
Relationships in medicine--causal vs. casual.
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Chorionic Gonadotropin↗
Embryonic implantation.
Embryo implantation is a progressive process which requires a communication between two different organisms, and consists of three consecutive phases: apposition, adhesion and invasion. It must be realized throughout the period called "window of implantation", which is characterized by morphological and biochemical changes in the endometrium, as the plasma membrane transformation and the presence of some specific adhesion molecules, chemokines, cytokines, growth factors, and invasive proteinases. All of then acting in a paracrine/autocrine manner, and drive by endocrine hormones.
Cell Adhesion Molecules↗
The follicular endocrine environment in stimulated cycles of women with endometriosis: steroid levels and embryo quality.
OBJECTIVE: To assess the endocrine milieu in follicles of stimulated cycles comparing women with and without endometriosis. Steroids were measured in follicular fluid (FF) and in in vitro culture of granulosa-luteal cells, and this status was related to the quality of the embryos obtained after IVF. DESIGN: Case-control study. SETTING: IVF program at the Instituto Valenciano de Infertilidad. PATIENT(S): Twenty-four women with laparoscopically documented endometriosis and 26 controls undergoing IVF. INTERVENTION(S): Individual follicular aspiration, oocyte isolation, FF storage, and preparation of luteinized granulosa cells for culture; oocyte insemination and embryo cleavage in standard IVF. MAIN OUTCOME MEASURE(S): Serum (day of ovum pickup) and FF measurements of estradiol, progesterone, testosterone, and androstenedione. Secretion of progesterone was measured in the cell-conditioned medium. Results were compared between patients with endometriosis and controls, as well as between oocytes that yielded embryos of different quality. RESULT(S): Levels of progesterone in the FF increased with the severity of the disease, whereas testosterone accumulation in the FF decreased with the severity of the disease. An increase in progesterone accumulation in vitro was observed in basal and hCG-induced granulosa cell cultures. No difference was observed in terms of embryo quality, and no steroid marker was able to identify follicles with oocytes that displayed embryos of good or bad quality under the inverted microscope. CONCLUSION(S): The data show differences in the steroidogenesis of follicles from stimulated women with and without endometriosis. These changes indicate good endocrine health but are not predictive of embryo quality.
Adult↗
Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen.
OBJECTIVE: To analyze the effect on uterine receptivity of a decrease in E2 levels during the preimplantation period with the use of a step-down regimen in high responders undergoing IVF. DESIGN: Prospective controlled clinical study. SETTING: The Instituto Valenciano de Infertilidad. PATIENT(S): High responders in whom at least one previous IVF attempt failed in which 3-4 good-quality embryos were transferred and E2 levels were >3,000 pg/mL on the day of hCG administration. INTERVENTION(S): Gonadotropins were administered according to two different protocols. Blood samples were collected and IVF was performed. MAIN OUTCOME MEASURE(S): Serum E2 levels and reproductive outcome of IVF. RESULT(S): Estradiol levels on the day of hCG administration and throughout the preimplantation period and the number of oocytes collected were significantly lower with the use of the step-down regimen than during the previous failed cycle in which the standard protocol was used. The fertilization rate was similar and the number of good-quality embryos transferred was comparable. However, the implantation and pregnancy rates were significantly improved in patients who underwent the step-down regimen compared with those who received the standard protocol. CONCLUSION(S): With the use of a step-down regimen with FSH in high responders, our clinical results demonstrate that uterine receptivity can be improved when E2 levels are decreased during the preimplantation period.
Adult↗
The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production.
OBJECTIVE: To assess the endocrine, paracrine, and autocrine milieu in patients with endometriosis on the basis of the measurement of several cytokines in serum and follicular fluid (FF) and in vitro culture of granulosa luteal cells. DESIGN: Case-control study. SETTING: In vitro fertilization program at the Instituto Valenciano de Infertilidad. PATIENT(S): Twenty patients with laparoscopically documented endometriosis and 18 controls. Fifteen subjects were studied in a natural cycle and 23 were investigated in a stimulated cycle while undergoing IVF. INTERVENTION(S): Individual follicle aspiration, oocyte isolation, FF storage, and preparation of luteinized granulosa cell cultures. Diagnostic laparoscopy in natural cycles. MAIN OUTCOME MEASURE(S): Serum (day of ovum pick-up or laparoscopy) and FF measurement of interleukin (IL)-1beta, IL-6, and vascular endothelial growth factor (VEGF). Secretion of IL-1beta, IL-6, and VEGF in the cell-conditioned medium. Results were compared between patients with endometriosis and controls. RESULT(S): Interleukin-6 levels in serum were increased in the natural cycles of patients with endometriosis and modulated by ovarian stimulation, showing a significant decrease in hMG- and FSH-stimulated cycles and a significant increase after hCG administration. In addition, IL-6 levels were increased in the FF of patients with endometriosis and released in higher amounts by their granulosa luteal cells. Vascular endothelial growth factor was accumulated in lesser concentrations in the FF of patients with endometriosis. Interleukin-1beta levels did not show significant changes. Implantation rates were decreased significantly in patients with endometriosis who were undergoing IVF. CONCLUSION(S): The data demonstrate that cytokines are regulated differently in patients with endometriosis, who have increased IL-6 production, and suggest that fine hormonal modulation of this cytokine occurs at the systemic and local (ovarian) levels. These changes show that the endocrine, paracrine, and autocrine milieu is different in patients with endometriosis and may be related to their lower implantation rates.
Adult↗
Evaluation of the ovarian reserve in young low responders with normal basal levels of follicle-stimulating hormone using three-dimensional ultrasonography.
OBJECTIVE: To assess the ovarian content of selectable (2-5 mm) follicles using three-dimensional ultrasonography in low responders to ovarian stimulation for IVF. DESIGN: Prospective case-control study. SETTING: IVF program at the Instituto Valenciano de Infertilidad. PATIENT(S): Ten low responders < or =35 years of age with normal basal serum FSH and eight control patients with normal response in a previous cycle. INTERVENTION(S): Blood was drawn under basal (day 3) conditions. Three-dimensional ultrasound was performed in both ovaries using a vaginal probe. MAIN OUTCOME MEASURE(S): Basal serum E2 and FSH measurements. The ovarian volume and the number of follicles > or =2 mm in each ovary were recorded and compared between the groups. RESULT(S): Low-responder women had significantly higher serum FSH levels than controls despite having FSH values within the normal range. The number of selectable follicles and the total number of follicles with an antrum were significantly decreased in low responders as compared with normal responders. Ovarian volume did not differ between the groups. CONCLUSION(S): This study introduces three-dimensional ultrasound as a novel method for the evaluation of low responders. The results show that the most plausible explanation for low response in young women with normal serum FSH is diminished ovarian reserve.
Basal Metabolism↗
Interleukin-1 receptor antagonist prevents embryonic implantation by a direct effect on the endometrial epithelium.
OBJECTIVE: To investigate the embryonic and/or endometrial molecular mechanisms underlying the antiimplantation effect of interleukin-1 receptor antagonist (IL-1ra). DESIGN: Controlled experiment. SETTING: Animal facilities at Stanford University and laboratories of the Instituto Valenciano de Infertilidad and the University of Sydney. ANIMAL(S): Twelve-week-old B6C3F-1 female mice. INTERVENTION(S): Intraperitoneal injections of recombinant human IL-1ra during the periimplantation period. MAIN OUTCOME MEASURE(S): Implantation sites, embryonic morphology, and viability. Polymerase chain reaction and immunohistochemistry for integrins and extracellular matrices and transmission electron microscopy of endometrium in IL-1ra-treated versus control animals. RESULT(S): Pregnancy rates in control and IL-1ra-injected animals were 60% and 13%, respectively. At day 8 of pregnancy, flushing of uteri obtained from the treated group resulted in 32 blastocysts. Six pseudopregnant animals received IL-1ra-treated blastocysts (left horn) and control blastocysts (right horn), resulting in one pregnancy, with two embryos and one embryo in the left and right horns, respectively. At day 4 of pregnancy, IL- 1ra down-regulated alpha4 mRNA with use of the polymerase chain reaction. Immunohistochemistry showed a decrease of alpha4, alpha v, and beta3, and transmission electron microscopy revealed inhibition of transformation of the plasma membrane. CONCLUSION(S): Impairment of embryonic adhesion with IL-1ra is mediated through a direct effect on transformation of the epithelial plasma membrane at the time of implantation as a result of down-regulation of alpha4, alpha v, and beta3.
Animals↗
Ovarian follicular dynamics: from basic science to clinical practice.
The management of low responders (LR) to ovarian stimulation in cycles of assisted reproduction (AR) is a difficult challenge. Aging of the ovary and LR are coincidental in many situations, but LR is also present in young patients undergoing AR. In fact, today it is a recognized cause of infertility. When the aged ovary is considered, there is evidence that the functioning of the granulosa cells as well as the quality of the oocytes and resulting embryos are affected. Similarly, in young LR, the production of inhibin is affected. However, there is no evidence that the quality of the oocyte and/or the resulting embryo is affected. In this study, we have retrospectively analyzed our files and observed that the quality of the oocytes and embryos was similar between younger and older LR and normal responders (NR). Studies using color Doppler vaginal ultrasound have shown that the pulsatility index (PI) and the resistance index (RI) were increased in LR as compared with NR, suggesting that there was some degree of vascular resistance to flow. Treatment of LR is also a difficult challenge. Ovum donation is a successful treatment for LR, since cumulative birth rates are > 85% with four attempts of embryo transfer. The future may be promising for LR once new technologies are introduced into clinical practice. The use of recombinant gonadotropins and genetically engineered human gonadotropin derivatives may be of considerable help for LR. Similarly, non-gonadotropin hormones, such as cytokines or growth factors, may be shown to play a role in the stimulation of the ovary in the near future, and may therefore open new frontiers for treatment of LR.
Aging↗
Cytokines and embryo implantation.
The implantation process is currently considered the most relevant limiting factor for successful pregnancy. It is evident that molecular interactions at the embryo-maternal interface at the time of implantation are crucial in order to understand the mechanisms of embryonic implantation. The principal aim of this study is to demonstrate the existence of specific communication pathways between the human embryo and endometrium. The molecular interactions appears to be initiated by the endometrium in the presence of an implanting blastocyst and is mediated through embryonic cytokines (specifically the IL-1 system) and the target is the endometrial epithelial beta3 integrin subunit. If the role of beta3 is accepted as a marker of uterine receptivity these results may indicate that the normal hormonally regulated human endometrium could be the trigger for molecular events preparing the blastocyst to communicate effectively and regulate endometrial adhesion molecules in order to implant.
Animals↗
Potential implications of chemokines in reproductive function: an attractive idea.
Chemokines are a new family of cytokines specialised in attracting leukocytes, acting in physiological conditions and in pathological processes. A wide variety of cell types in response to exogenous irritants or endogenous mediators of the inflammatory reaction produce them. Pivotal parts of reproductive function are based on inflammatory like processes wherein different leukocytes subsets are recruited and activated to produce paracrine autocrine effects in which cytokines and growth factors are implicated. Since chemokines control leukocyte trafficking and belong to the cytokine superfamily, in this review we analyze the implications of these molecules and related cells in ovulation, embryonic implantation, menstruation, parturition and their role in pathological process such as preterm delivery, endometriosis, ovarian hyperstimulation syndrome and HIV infection.
Animals↗