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C Simón

Publications and source records attributed to C Simón.

At least 109 records · Page 6Linked to original sources
PubMed1997

The interleukin-1 system and human implantation.

PROBLEM: Cytokines and growth factors are increasingly implicated in embryonic implantation. In the present study, we focus on the interleukin-1 system as an example of local regulator in human implantation. METHOD: Three different approaches are considered. First, we present evidence demonstrating its presence, regulation, and relevance on the human endometrium. Second, we demonstrate the presence of IL-1 system in the human embryo and the selective IL-1 release only when embryos were co-cultured with human endometrial epithelial cells (EEC) or EEC-conditioned media, indicating an obligate role of the endometrium in the regulation of the embryonic IL-1 system. Finally, we show data regarding the presence, hormonal regulation, and endometrial origin of IL-1 alpha, IL-beta, and IL-1ra levels in the endometrial fluid inside the endometrial cavity. Specifically, we present the IL-1 intracavitary microenvironment surrounding the human embryo at the apposition phase. RESULTS: This work suggests that the IL-1 system seems to be relevant for human endometrial and embryonic physiology. Furthermore, this family of molecules must be considered as a relevant paracrine language displayed by both partners that may be important to endometrial and embryonic crosstalk during embryonic implantation.

Embryo Implantation↗
PubMed1997

Embryonic regulation of integrins beta 3, alpha 4, and alpha 1 in human endometrial epithelial cells in vitro.

In the present study, we examined the embryonic regulation of beta 3 integrin in human endometrial epithelial cells (EEC) at the protein level and analyzed putative embryonic factors responsible for this regulation. The model employed is based on a clinical in vitro fertilization program in which single human embryos were cocultured with EEC until blastocyst stage and then transferred back to the uterus. After embryo transfer, EEC wells were divided according to the embryonic status reached: EEC with embryos that achieved the blastocyst stage, EEC with arrested embryos, and EEC without embryos. Immunostaining for beta 3 was positive in plasma membrane of EEC. Flow cytometry showed a mean percentage of beta 3-stained cells of 24.1 +/- 5.7 in EEC cocultured with embryos that achieved the blastocyst stage (n = 13) vs. 9.5 +/- 1.6 (P < 0.05) in those EEC cultured with arrested embryos (n = 12). Immunostaining for alpha 1 and alpha 4 integrins was negative in EEC monolayers studied, regardless of the presence or absence of embryos, and these findings were confirmed by flow cytometry. The possibility that the embryonic IL-1 system and leukemia inhibitory factor were involved in the endometrial beta 3 up-regulation was investigated by neutralizing experiments demonstrating a significant inhibition of beta 3-stained cells when EEC monolayers were cultured in the presence of EEC/blastocyst-conditioned media with (n = 4) vs. without (n = 8) antihuman interleukin (IL)-1 alpha + IL-1 beta (1.65% vs. 14.6%; P < 0.05). Dose-response experiments further demonstrated an up-regulation of beta 3 positive cells when IL-1 alpha + IL-1 beta were added to the medium at a concentration of 10 pg/mL compared with control medium without added cytokines (40% vs. 20%, n = 4). The functional relevance of the EEC beta 3 up-regulation was tested using a mouse blastocyst adhesion assay. More mouse blastocysts attached to EEC previously in contact with human blastocyst (72.7%) compared with those EEC previously in contact with arrested embryos (40%). Our results demonstrate the selective effect of a developing human embryo on EEC expression of beta 3, which is maximal when a human blastocyst instead of an arrested embryo is considered. Furthermore, the embryonic IL-1 system seems to be involved in the EEC beta 3 up-regulation, reinforcing the concept of precise paracrine cross-talk between blastocyst and endometrial epithelium during embryonic implantation.

Adult↗
PubMed1996

Factors responsible for multiple pregnancies after ovarian stimulation and intrauterine insemination with gonadotropins.

PURPOSE: The present study was undertaken in order to analyze possible factors that could be responsible for multiple pregnancies in normoovulatory women undergoing superovulation with gonadotropins and intrauterine artificial insemination. METHODS: We retrospectively analyzed several clinical parameters in patients that achieved gestation with this treatment. Patients were divided into two groups depending on sperm origin (husband and donor sperm). Furthermore, they were subclassified as follows: (a) cycles resulting in single pregnancies (n = 366), (b) cycles ending in multiple pregnancies (n = 126), and (c) a control group composed of unsuccessful cycles (n = 366). RESULTS: In cycles employing husband's sperm, the age, number of cycles necessary to reach pregnancy, serum estradiol (E2) levels, and number of follicles were significantly (P < 0.05) different in multiple pregnancies compared to single or nonpregnant cycles. In donor insemination, women with multiple pregnancies were significantly younger than nonpregnant patients. There was a significant increase in the number of follicles developed (P < 0.00001) and serum E2 levels on the day of hCG (P < 0.05) in multiple compared to single pregnancies and unsuccessful cycles. The number of motile sperm in the insemination specimen was not different among the established groups. When both types of treatments were grouped, pregnant patients were significantly (P < 0.00001) younger than women with failed cycles. In addition, multifetal pregnancies were significantly (P < 0.05) more frequent in women < 30 years old. E2 production was significantly (P < 0.00008) higher in twin and multifetal pregnancies than in single or nonpregnant cycles. Follicular development was also significantly (P < 0.00001) higher in twin and multifetal pregnancies compared to failed cycles. CONCLUSIONS: The results suggest that young women (< 30 years) who develop more than six follicles with E2 > 1000 pg/ml when stimulated with gonadotropins are at higher risk of multiple gestation. These data may be helpful in preventing this undesired complication of assisted reproduction techniques.

Adult↗
PubMed1996

Hormonal regulation of serum and endometrial IL-1 alpha, IL-1 beta and IL-1ra: IL-1 endometrial microenvironment of the human embryo at the apposition phase under physiological and supraphysiological steroid level conditions.

We have investigated serum and intracavitary levels of IL-1 alpha, IL-1 beta and IL-1ra from agonadal women undergoing mock cycles (n = 20) of oocyte donation as a clinical model of controlled hormonal stimulation. Further, we compared the intracavitary IL-1 alpha, IL-1 beta and IL-1ra levels in the microenvironment of the human embryo at the apposition phase, day 5 after progesterone (P) administration using two different clinical models: oocyte donation (n = 20) which provides physiological steroid levels and a higher implantation rate per embryo, and in vitro fertilization (n = 6) with supraphysiological hormonal levels and a lower implantation rate.

Embryonic and Fetal Development↗
PubMed1996

Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period.

OBJECTIVE: To determine serum E2 and P levels around the time of implantation in normal and high IVF responders. SETTING: In Vitro Fertilization program at the Instituto Valenciano de Infertilidad. PATIENTS: Twenty-nine women undergoing IVF, who accepted to be studied daily, were classified according to the number of oocytes retrieved in normal (n = 16) and high responders (n = 13). DESIGN: Prospective study in which blood was drawn daily from the day of hCG administration (day 0) up to 7 days later (day 6). MAIN OUTCOME MEASUREMENTS: In vitro fertilization parameters (number of ampules, FSH-hMG, number of oocytes, fertilization rates, number of transferred embryos, implantation rates, and pregnancy rates); serum E2 and P levels during the 7 days of the study. RESULTS: Implantation rate was significantly higher in normal (18.5%) as compared with high (0%) responders. Estradiol and P levels were elevated significantly in high responders. The E2:P ratio was significantly different between normal and high responders during the preimplantation period. Pregnancy and implantation rates decreased as serum E2 levels increased on days 4 to 6 of the study. CONCLUSIONS: A different endocrine milieu between normal and high responders is detected by daily steroid measurements up to the preimplantation period, suggesting that this difference could be responsible for an impaired implantation in high responder patients undergoing IVF. An increase in serum E2 levels seems to be the cause of this difference.

Chorionic Gonadotropin↗
PubMed1996

Effect of age on sperm fertility potential: oocyte donation as a model.

OBJECTIVE: To determine the effect of age on sperm fecundability using oocyte donation as an in vivo model. SETTING: Oocyte donation and IVF programs at the Instituto Valenciano de Infertilidad. DESIGN: Retrospective study in which four groups of oocyte donation cycles were established according to age of the male providing the semen sample: group 1 (n = 31) < 30 years; group 2 (n = 195) 31 to 40 years; group 3 (n = 98) 41 to 50 years; group 4 (n = 21) > 51 years, the oldest being 64 years. All donated oocytes were obtained from patients < 35 years old. MAIN OUTCOME MEASUREMENTS: Male age, sperm characteristics (volume, concentration, motility, morphology), fertilization, embryo quality, pregnancy, implantation, and abortion rates among recipients. RESULTS: Similar sperm characteristics in fresh as well as after preparation for IVF were observed among males of different ages. Fertilization, embryo quality, pregnancy, and implantation were similar among the established groups. The mean age of the females included in each group significantly increased from group 1 to group 4. CONCLUSIONS: Age (up to 64 years) does not affect sperm characteristics or its ability to fertilize human eggs. Similarly, embryo development in vitro as well as implantation in recipient uteri are not affected by age of the male providing the semen sample.

Abortion, Spontaneous↗
PubMed1996

Age does not affect uterine resistance to vascular flow in patients undergoing oocyte donation.

OBJECTIVE: To determine whether uterine vasculature is affected by age using oocyte donation as an in vivo model. DESIGN: Prospective longitudinal study in which recipients were grouped according to age. They underwent a successful oocyte donation cycle, and single pregnancies were followed during the first trimester by color Doppler ultrasound in uterine arteries. SETTING: Oocyte donation and IVF program at the Instituto Valenciano de Infertilidad. INTERVENTIONS: Serum E2, P, and hCG levels in single ovum donation pregnancies; pulsatility and resistance indexes in uterine arteries during initial pregnancy. RESULTS: Similar serum levels of E2, P, and hCG in both groups of patients were observed. There was no difference between groups regarding the flow indexes analyzed. CONCLUSIONS: The increased incidence of early pregnancy losses observed in patients > 40 years cannot be attributed to defective response of uterine vasculature to exogenous hormone replacement. Thus, uterine aging does not appear to be a factor influencing the poor reproductive performance of women with advancing age.

Adult↗
PubMed1996

Cytokines-adhesion molecules-invasive proteinases. The missing paracrine/autocrine link in embryonic implantation?

How implantation is regulated and brought about remains an enigma. The objective of the present review is to propose a hypothetical model based on our actual knowledge of the role of cytokines, adhesion molecules and invasive proteinases in the adhesion and invasion phases of embryonic implantation. For the purpose of clarity we will describe first what is known about the presence of these molecules in the endometrium and embryo in animal models and their relevance in embryonic implantation. Secondly, since human implantation is unique the presence of these factors in the human endometrium and embryo and their possible clinical relevance is considered separately. Finally, the link between cytokines, adhesion molecules and invasive proteinases as well as their endocrine/paracrine/autocrine regulation is put forward as a possible model that could lead us to a better understanding of the implantation process in humans.

Animals↗
PubMed1996

Oocyte donation in women with recurrent pregnancy loss.

The prognosis of couples with recurrent miscarriage is controversial despite efforts made during this century to learn about the physiopathology and treatment of this troublesome condition. Here we present our experiences of employing oocyte donation in eight couples in whom the woman was a low responder to gonadotrophin stimulation and had a previous history of recurrent abortion with negative routine infertility work-up for repeated pregnancy loss. Patients were desensitized with gonadotrophin-releasing hormone analogues and supplemented with oestradiol valerate for a minimum of 15 days until oocytes were donated from in-vitro fertilization and fertile donors. Then, progesterone was added until day 100 of pregnancy. A total of 12 oocyte donation cycles were performed in these patients. Clinical pregnancy and delivery rates per cycle were 75.0 and 66.6% respectively. The delivery rate per patient was 85.7% in this series, and the miscarriage rate per cycle was 11.1%. The results of ovum donation compared favourably with low responders without a history of recurrent abortion undergoing this treatment during the study period. These results strongly suggest that the oocyte may be the origin of infertility in women with idiopathic recurrent miscarriages. In addition, the results question the role of maternal local and systemic factors in early recurrent pregnancy loss, as well as the paternal contribution to its aetiology.

Abortion, Habitual↗
PubMed1996

Role of endometrial factors in regulating secretion of components of the immunoreactive human embryonic interleukin-1 system during embryonic development.

In the study reported here, we localized at the protein level the major components of the interleukin (IL)-1 system in the human embryo, and we investigated the endometrial factors influencing their secretion during embryonic development. To localize these components, we performed immunohistochemical experiments in 44 oocytes and 78 embryos. The following primary antibodies were used: monoclonal mouse anti-human IL-1 receptor type I (IL-1R tl), monoclonal mouse anti-human IL-1 beta, and polyclonal rabbit anti-human IL-1 receptor antagonist (IL-1ra). For embryo culture, human embryos at different developmental stages were cultured in 100-microliters drops of Ham's F-10 medium + 4 mg/ml BSA (n = 33), in 100-microliters drops of Menezo B2 culture medium (n = 18), or in wells with 1 ml of Menezo B2 culture medium (n = 8). For embryo coculture, endometrial stromal cells (ESC) and endometrial epithelial cells (EEC) were isolated from human secretory endometrium and cultured until confluence in 75% Dulbecco's Modified Eagle's Medium and 25% MCDB-105 containing antibiotics and supplemented with 10% charcoal-Dextran-treated fetal bovine serum. Individual human embryos were cocultured with experimental EEC and ESC (n = 23 and n = 4, respectively) for 5 days in 600-microliters drops of Menezo B2 medium, and conditioned medium was removed every 24 h. Human embryos were also cultured with EEC-conditioned medium (n = 9). IL-1 alpha, IL-1 beta, and IL-1ra levels were determined by ELISA in the 24-h culture- or coculture-conditioned media. Immunostaining confirmed the presence of IL-1 beta, IL-1ra, and IL-1R tl in oocytes and embryos in all stages analyzed, with no statistical differences. IL-1 alpha, IL-1 beta, and IL-1ra were absent in conditioned media of cultured embryos and embryos cocultured with ESC. However, when human embryos were cocultured with EEC or with EEC-conditioned medium alone, two different populations of embryos were observed: IL-1 producers (57% and 56%) and IL-1 nonproducers (43% and 44%, respectively). Finally, the IL-1 profile of a single human embryo cocultured with maternal EEC which successfully implanted and developed is presented, this pattern being similar to that described in the IL-1 producer population. These results demonstrate the presence of the IL-1 system in the human embryo. However, the selective release of IL-1 only when embryos were cocultured with EEC or EEC-conditioned medium indicates an obligatory role of the endometrium in the regulation of the embryonic IL-1 system. Furthermore, the differential embryonic production of IL-1 may be related to the implantation capability of the embryos.

Adult↗
PubMed1995

Effect of aging on the female reproductive system: evidence for a role of uterine senescence in the decline in female fecundity.

OBJECTIVE: To determine the effects of age on reproductive performance of women using oocyte donation as an in vivo model. SETTING: Oocyte donation and IVF programs at the Instituto Valenciano de Infertilidad. PATIENTS: Seventy-six women undergoing 90 cycles of ovum donation, who were recipients of 36 donors undergoing IVF, and 9 fertile women. DESIGN: Prospective longitudinal study: [1] recipients underwent an artificial cycle to demonstrate adequate response of the endometrium to exogenous steroids; [2] oocytes from the same cohort of follicles were distributed randomly into recipients younger and older than 40 years; and [3] pregnancies were followed during the first trimester. MAIN OUTCOME MEASURES: Endometrial histology, fertilization, embryo quality, pregnancy, implantation, and abortion rates in both groups of recipients. Serum E2, P and beta-hCG levels during initial pregnancy. RESULTS: Similar implantation rates but significantly higher abortion rates were detected in women > 40 years despite an appropriate action of P on the endometrium and the transfer of embryos in similar number and quality. The secretion of E2 and P by the placenta started earlier in pregnancies included in the group < 40 years. CONCLUSIONS: Age increases pregnancy losses in ovum donation patients after implantation is completed. This is accompanied by a retardation of steroid synthesis and suggests that the mechanism(s) responsible for placenta formation and functioning in the uterus is affected by age. Thus, uterine aging also is a factor influencing the poor reproductive performance of women with advancing age.

Adult↗
PubMed1995

Long oestradiol replacement in an oocyte donation programme.

The objective of this study was to optimize, in terms of endometrial receptivity (embryo implantation), the limits of unopposed administration of oestrogens beyond 35 days in an in-vitro fertilization (IVF) and ovum donation programme. Oocytes donated by 182 women undergoing IVF were distributed among 186 women treated by ovum donation. Five groups of recipients were established according to the duration of oestradiol valerate administration, in a 'prolonged follicular phase' protocol, before embryo replacement, employing oestradiol valerate at increasing doses up to 6 mg/day. Gonadotrophin-releasing hormone analogues (GnRHa) were simultaneously administered in ovulatory patients. The dosage of oestradiol valerate was maintained until oocytes were available for insemination and subsequent transfer. Donors and recipients were equally distributed among groups in terms of age and cause of infertility. There was no difference among groups in serum oestradiol concentration the day in which progesterone was added to obtain a secretory transformation of the endometrium. An analysis of the ovum donation cycles showed no difference among groups in pregnancy and implantation rates after the replacement of a similar number of embryos. Successful implantation was observed even after 100 days of unopposed oestradiol valerate administration. Break-through bleeding increasingly appeared according to the duration of oestrogen replacement. These clinical observations provide evidence that the concept of 'prolonged follicular phase' oestrogen replacement for ovum donation can be maintained, at least as long as 15 weeks. However, because of the high (> 44%) incidence of break-through bleeding after 9 weeks, it is advisable to stop oestrogen treatment at this point.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Role of embryonic factors in human implantation.

Implantation biology is now at a stage where experimental science will be very productive in answering basic questions about the ability of an embryo to implant. The advancement of our knowledge of cytokines and growth factors has been critically important in fuelling the recent new understanding of embryo implantation. Specifically, our increased knowledge of the interleukin (IL)-1 system, as well as leukaemia-inhibiting factor (LIF), epidermal growth factor and colony-stimulating factor-1, and the availability of recombinant protein, specific antibodies and knockout mice, have led to a more detailed outline of implantation events. LIF and IL-1 are the two systems where recent advances have suggested their importance in implantation events. Recently, LIF has been shown in mice to be an endometrial requirement for implantation and embryo development. Although LIF is a pleiotropic molecule, with many interactions in multiple body tissues, in the uterus, concentrations are elevated on day 4 of pregnancy. Experiments with knockout mice have shown the requirement for endometrial LIF for successful implantation. The IL-1 system, consisting of two agonists (IL-1 alpha and IL-1 beta), two receptors (IL-1R types I and II) and the homologous IL-1 receptor antagonist (ra), has also been studied. Knowledge that the embryo secretes IL-1 suggested the interaction between embryonic IL-1 and endometrial receptor, which has been shown to occur. IL-1R type I is plentiful on endometrial epithelial cells and appears to interact with embryonically secreted IL-1 beta to favour implantation. Such implantation events in vivo in mice are blocked by the introduction of large quantities of IL-1ra, consistent with the hypothesis that appropriate interactions between agonist and receptor at the level of the endometrial surface are a requisite for successful implantation. As more specific information on each cytokine or growth factor system comes to light, more complete information on the multiple molecular steps of implantation will become apparent. However, it is clear that no single cytokine or growth factor will be able to explain the complicated events of embryo implantation. Such an important necessary phenomenon has multiple redundancies. The interactions between cytokines and growth factors are becoming increasingly apparent and will need more experimental evidence before a full understanding of implantation is available.

Embryo Implantation↗
PubMed1995

Interleukin-1 system crosstalk between embryo and endometrium in implantation.

Nowadays, cytokines and growth factors have become increasingly implicated in embryo implantation. Endometrial function, embryo secretions and embryo-endometrial interactions require a continuous dialogue and synchronism between both partners (endometrium and embryo), not only at the endocrine level but also at the local (paracrine/autocrine) level. This review focuses on the interleukin-1 system as an example of a local regulator in embryo implantation. Evidence demonstrating its presence and relevance to human endometrial physiology and human embryo development is presented. Finally, we show data which suggest the possible role of this cytokine in implantation.

Cell Communication↗
PubMed1995

Effects of aging on the female reproductive system.

There is an evident decline in human fertility with age. The fundamental physiological question is whether the ovary, the uterus, or both are affected by the changes induced within the body by senescence. Based on clinical studies performed in in-vitro fertilization (IVF) laboratories, there is no doubt that age affects the oocyte. However, the effect of age on the remaining cellular components of the preovulatory follicle have yet not been fully elucidated. In addition, whether the ability of the uterus to have normal implantation of human embryos is age-related is also a matter of controversy. In this review, we analyse the results of our studies that were conducted in order to answer these relevant questions. In the first series of experiments we tested the hypothesis that the function of granulosa cells is affected in older patients (> or = 40 years). In these experiments, we cultured in vitro granulosa-luteal cells from 15 women aged < 40 years and 18 patients aged > or = 40 years undergoing IVF. Immunoreactive alpha-inhibin and progesterone were measured after 48 and 96 h in culture. The measurements showed a significantly higher secretion of inhibin (P < 0.01) after 48 h, and progesterone (P < 0.05) after 48 and 96 h, in the younger as compared to the older group. In addition, we tested the ability of the uterus to sustain normal implantation by an analysis of our oocyte donation programme. In the first approach, we divided all the transfer cycles according to the age of the recipient. We found no differences among groups with regard to pregnancy, implantation or abortion rates. We explored this fundamental question further by performing oocyte donation cycles in which oocytes from the same donor were distributed into a recipient aged < 40 years and another recipient of > or = 40 years. An analysis of 45 cycles in each group of recipients showed a significant (P < 0.05) increase in abortion rates in older as compared to younger patients. When the serum oestradiol concentrations were followed in those women who carried normal single ongoing pregnancies, we found that a significant increase in blood oestradiol concentrations (which probably represents the luteo-placental shift) was detected 2 weeks earlier in younger than in older patients, suggesting a defective vasculature of the uterus that could ultimately be the cause of an increased abortion rate in patients aged > or = 40 years. In conclusion, we firmly believe that senescence affects both the ovary (oocyte and granulosa cells) and the uterus, and these observations should be taken into account in order to advise our patients.

Aging↗
PubMed1995

Donor-recipient synchronization and the use of gonadotrophin-releasing hormone agonists to avoid the premature luteinizing hormone surge in oocyte donation.

Since the introduction of the oocyte donation technique in humans, a number of reports have been published reflecting the success and improvement of this technique. Initially, the most important problems were donor-recipient synchronization at the moment of donation and the premature secretory changes in the endometrium consequent to the spontaneous luteinizing hormone (LH) rise in patients that still showed ovarian function. Today, with the new substitutive hormonal protocols, these two major problems have been solved. The endogenous LH rise can be avoided by administering gonadotrophin-releasing hormone agonists, without any deleterious effects on implantation when they are used in patients with ovarian function. Donor-recipient synchronization is possible because the recipients can remain indefinitely with substitutive therapy until the donation becomes feasible. Here, our experiences with both new strategies are presented.

Adult↗