Ovarian pregnancy following in-vitro fertilization and embryo transfer.
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Biomedical subjects
Publications and source records attributed to R G Edwards.
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Over a period of 4 months, 262 infertile couples participated in a prospective pseudorandom trial of a novel short-term luteinizing hormone-releasing hormone/human menopausal gonadotropin (LH-RH/hMG) treatment; the short-Buserelin-gonadotropin (Hoechst, Hounslow, United Kingdom) regimen. Patients treated with the short-Buserelin-gonadotropin regimen had a significantly higher likelihood of achieving pregnancy than patients treated with the standard clomiphene citrate (CC)/hMG regimen (respectively, 35.5% and 18% per treatment cycle). A significantly higher number of eggs were collected after short-Buserelin-gonadotropin treatment than CC/hMG, but the proportion of patients having a given number of embryos replaced was similar in the two groups. The short-Buserelin-gonadotropin-treated patients were distinguished from the CC/hMG-treated group by significantly lower levels of LH in the late follicular phase and a lower plasma level of estradiol. A detrimental relationship between elevated endogenous LH secretion and failure of implantation has been established. The nature of the short-Buserelin-gonadotropin regimen provokes high levels of endogenous gonadotropin secretion in the early follicular phase and induces a suppression of gonadotropin secretion in the late follicular phase. This may be the physiologic basis of the greater implantation rate after short-Buserelin-gonadotropin treatment than is seen with conventional CC/hMG treatment.
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Human serum and Albuminar 5 (A5) were compared as medium supplements to Earle's solution containing pyruvate in clinical IVF. One-hundred patients in each group showed a fertilization rate of 60% with serum and of 62% with A5. The overall pregnancy rates in the serum and A5 groups were 20 and 24%, respectively. The incidence of failed fertilization (6-7%) and of multipronucleate oocytes (4-5%) was similar in both groups. At 37 degrees C, sperm survived less well in A5 although the rate of fertilization was not reduced. Blastocyst formation was not seen in 'spare' embryos grown in vitro in medium containing 15% v/v A5.
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Paroxetine is a novel and selective neuronal 5-hydroxy-tryptamine uptake inhibitor with anti-depressant activity. Paroxetine was examined for its ability to induce adverse immunological reactions, either as a consequence of a specific immune response or by a direct or indirect effect on the immune system. Paroxetine did not react in vitro with protein amino or thiol groups, suggesting that it lacks the capacity to form potentially immunogenic hapten protein conjugates. No anti-paroxetine antibody was detected in plasma or serum samples from patients and rats following oral administration over prolonged periods, or from epicutaneously exposed guinea pigs, or from rabbits given paroxetine in Freund's adjuvant, suggesting that paroxetine does not have the capacity to elicit humoral immune responses. Guinea pigs epicutaneously exposed to paroxetine did not develop contact sensitivity, suggesting that it does not have the capacity to elicit cell-mediated immune responses. These results suggest that paroxetine lacks intrinsic immunogenicity. Anti-SRBC antibody plaque-forming cell responses in mice were unaffected by oral administration of paroxetine, and paroxetine had no significant effect on ex vivo and in vitro murine macrophage phagocytosis of opsonized SRBC or on ex vivo murine splenocyte mitogen responses, suggesting that paroxetine does not exert modulatory effects on the immune system or on macrophage function. These findings, together with the results of pre-clinical safety evaluation studies, suggest that paroxetine is unlikely to have immunotoxic effects.
Successful in-vitro fertilization (IVF) requires the generation of a number of healthy embryos and adequate priming and maintenance of a receptive endometrium. Both of these factors are influenced by ovarian stimulation regimes and are responsive to endocrine manipulation. Detailed analysis of follicular phase patterns of hormone secretion have established an inverse relationship between luteinizing hormone (LH) and egg/embryo quality which is not discernible on microscopic examination. The advent and extensive use of LHRH agonists in ovarian stimulation has gone some way towards optimizing embryo fitness by suppressing LH secretion and this has exposed the endometrial contribution to a failure of implantation to closer examination. The supraphysiological production of oestradiol and progesterone from the large numbers of follicles developed during ovarian stimulation cannot be without effect on the endometrium. Data presented in this brief review show how our understanding of ovarian stimulation and its influence on the outcomes of IVF has advanced and highlights the opportunities for manipulation of the endometrium to encourage implantation.
The roles of various organizations in ethical decision making are considered. Such organizations include local and national ethical committees, professional organizations, religious organizations and governments, and their respective strengths and limitations are discussed in turn. The practising individual scientist or doctor must decide where he or she stands on specific issues, and how he or she will work within the framework established by such organizations. The role of the individual in introducing new concepts or studies under these circumstances is discussed.
Twenty-eight patients superovulated with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) were given a single injection of 25 mg progesterone (P group) 4 h prior to the ovulation-inducing injection of human chorionic gonadotrophin (HCG). Plasma and urinary LH levels were significantly higher (P less than 0.05) in the P group immediately prior to HCG compared to controls. Plasma progesterone concentrations were also elevated (P less than 0.01) in the P group from the time of injection to oocyte recovery. The number of mature oocytes recovered was also higher (P less than 0.001; 59% versus 40% in controls) and the time interval between oocyte recovery and insemination was also shorter (P less than 0.01) in the P group. The pregnancy rate/replacement 15 days after oocyte recovery was 39% versus 23% in the P and control groups respectively. It was concluded that as more mature oocytes were recovered in the P group, progesterone supplementation in the late follicular phase may be beneficial for patients undergoing GIFT. This was borne out when the first two GIFT patients pretreated in this way became pregnant.
The diagnosis of genetic disease in preimplantation embryos is discussed. The typing of spermatozoa may be feasible for factors such as the presence of an X and Y chromosome. Embryos might be typed by non-invasive methods, by assessing their uptake of metabolites although the widest opportunities may arise by the use of invasive methods which involve the removal of one or a small number of cells. The methods of diagnosis are discussed, including enzyme assays and the use of DNA probes, preliminary results with human embryos are presented and the difficulties related to these techniques are debated. The low rate of implantation of replaced embryos will mean that many embryos will have to be diagnosed, and certain embryological factors such as the high incidence of chromosomal imbalance and the problems of 'imprinting' might obscure certain diagnoses. The advantages and disadvantages of the method are discussed.
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Two newer beta-lactam-containing structures, a clavam, clavulanic acid, and a carbapenem, MM22383, have been studied for their intrinsic immunogenicity and allergenicity. Clavulanic acid has a very low immunogenic and allergenic potential, in contrast to MM22383 which is a contact sensitiser in guinea pigs and an immunogen in rabbits. Evidence for the allergenic potential of MM22383 in man through occupational exposure is also presented. Consideration of the chemistry of these two compounds with respect to their reactivity with protein provides a rationale for the marked difference in their behaviour. The importance of stable hapten-protein conjugates and epitope density is discussed in relation to immunogenicity.
Human IgG antibody subclasses have been measured in the sera of workers exposed to rats, using a crude extract of rat urinary protein antigens, in an ELISA system. The antibody titres in individuals either with or without specific IgE were similar, with the exception of IgG4 where the mean level of this subclass was lower in those individuals with measurable titres of IgE (p less than 0.01). Symptomatic individuals, with specific IgE, also had lower titres of IgG4 than the corresponding asymptomatic, IgE-positive subjects (p less than 0.05). The frequency of positives in each subclass assay was similar in both groups. These findings suggest that higher levels of IgG4 may have a protective rôle.
Two-hundred patients, half of whom had on-going pregnancies, were examined in terms of follicular growth, urinary oestrogen and LH output, oocytes recovered and embryos replaced. The two groups were identical in all parameters measured except that urinary LH output was significantly higher (P less than 0.01) in non-pregnant patients on the two days prior to HCG administration. During the early to mid-luteal phase, plasma progesterone concentrations were related to the number of follicles aspirated at oocyte recovery, but the overall pattern of secretion was similar in both groups. It is concluded that monitoring urinary LH output, a non-invasive technique, may be of great value for assessing oocyte quality and predicting the outcome of in-vitro fertilization and embryo replacement.
Thirty-one patients superovulated with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) were given a single injection of 25 mg progesterone (P group) 6 h prior to injection of human chorionic gonadotrophin (HCG). Levels of urinary and plasma luteinizing hormone (LH) were significantly higher (P less than 0.001) immediately prior to HCG in the P group compared with thirty-one control patients who had HCG on the same night. Plasma levels of progesterone remained significantly elevated (P less than 0.02) for 80 h after injection in the P group, thereafter the level was similar to controls. The number of oocytes recovered, fertilized and replaced per patient was identical in both groups. However, four control patients had no embryos replaced due to failed fertilization. It is concluded that in the majority of P patients the timing of ovulation induction by HCG injection was appropriate as an LH surge was elicited thus reflecting a physiological stage of readiness, and elevated plasma progesterone levels around the time of oocyte recovery and in the early luteal phase do not increase the likelihood of the establishment of pregnancy in patients stimulated for in-vitro fertilization and embryo replacement (IVF/ER) with CC and HMG.
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