Biomedical subjects
D T Baird
Publications and source records attributed to D T Baird.
A randomised study of two doses of gemeprost in combination with mifepristone for induction of abortion in the second trimester of pregnancy.
Two regimens of the prostaglandin E1 analogue, gemeprost, in combination with mifepristone were compared in a randomised trial for termination of pregnancy between 12-19 weeks. Thirty-six hours after treatment with 200 mg mifepristone, women were allocated at random to receive either 4 x 1 mg (Group I) or 4 x 0.5 mg (Group II) gemeprost by vaginal pessary every 6 hours (n = 50 in each group). If abortion had not occurred after 24 h, 5 x 1 mg of gemeprost was administered every 3 h to both groups of women. Although the median abortion interval was slightly shorter in the 1 mg group (7.8 h vs. 8.4 h, p = 0.5), the cumulative abortion rates at 24 h were similar (98% vs. 96%). Women in Group I required significantly more gemeprost to induce abortion than Group II (p < 0.0001). Parous women in both groups required significantly less of the prostaglandin to induce abortion. In Group II, the median abortion interval was significantly longer in primigravidae than multigravidae (9.5 h vs. 6.1 h; p < 0.02). There were no significant differences between the groups in the incidence of vomiting, diarrhoea or the request for analgesia. The results suggest that in parous women, the dose of gemeprost can be reduced to 0.5 mg every 6 h within the first 24 h without loss of clinical efficacy.
Prostaglandins and menstruation.
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The effects of post-ovulatory administration of onapristone on the developmnent of a secretory endometrium.
The purpose of this study was to assess the ability of the anti-progestin onapristone administered in the immediate post-ovulatory period to disrupt endometrial differentiation as a potential method of fertility control. In all, 10 healthy female volunteers were given 400 mg onapristone 2 days after the mid-cycle luteinizing hormone (LH) surge in urine (LH+2). An endometrial biopsy was taken 4 or 6 days after the LH surge (i.e. LH+4 or LH+6) in a control cycle and on the corresponding day of the treatment cycle. Biopsies were assessed for histological dating and immunolocalization of oestrogen receptors, progesterone receptors and 15-hydroxyprostaglandin dehydrogenase (PGDH). On day LH+12, blood was taken for the measurement of insulin-like growth factor binding protein-1 (IGFBP-1) and placental protein 14 (PP14). Hormonal measurements in blood and urine were used to monitor the effects on the menstrual cycle. In addition, the concentration of cortisol in plasma was measured to determine if this dose of onapristone exerted significant anti-glucocorticoid activity. Treatment with onapristone retarded the development of secretory changes within the endometrium without affecting the length of the luteal phase. Intense nuclear immunostaining of oestrogen and progesterone receptors was evident in glands and stroma after treatment, suggesting that the progesterone-dependent down-regulation of steroid receptors was inhibited by the anti-progestin. Onapristone also affected the production of luteal phase endometrial proteins, as judged by the pronounced reduction in immunostaining of PGDH within the glands and the significant reduction in plasma concentrations of PP14. However, plasma concentrations of IGFBP-1 did not differ between cycles. Onapristone did not appear to exert significant anti-glucocorticoid activity because concentrations of cortisol were unaffected. These findings suggest that onapristone could potentially be used as a method of postovulatory fertility control.
Sex steroid regulation of leukocyte traffic in human decidua.
Endometrial leukocyte subpopulations vary over the reproductive cycle, but no data exist on the mechanism regulating their recruitment into uterine tissue. This study has evaluated the role of progesterone in the recruitment of selected leukocyte populations in early pregnancy decidua. Decidua was collected from women in early pregnancy at the time of vacuum aspiration of the uterus 6, 12, 24 and 36 h after taking 200 mg mifepristone (RU486). Standard immunohistochemical techniques were employed to demonstrate the selected leukocyte populations in decidual tissue and these were analysed using imaged analysis. Fresh decidua was incubated in medium for 24 h and supernatants assayed for interleukin (IL-8) (neutrophil chemotactic factor) and MCP-1 (monocyte chemoattractant protein-1) content. Analysis of variance demonstrated a significant increase in tissue monocyte number in decidua 12-36 h after mifepristone administration. No significant changes in other leukocyte subpopulations were observed. Decidua IL-8 concentrations were significantly increased (P = 0.019) 6 h after mifepristone and decidual MCP-1 concentration rose (non-significant) and fell significantly (P = 0.029) between 6 and 12 h after mifepristone. Progesterone withdrawal may initiate a local cascade of events involving inflammatory mediators which in turn are responsible for the influx of monocytes. This influx may be essential in the process of shedding of endometrium or decidua since monocytes and neutrophils are important sources of proteases and collagenases. Furthermore, these cells are potential local sources of immunomodulatory cytokines.
Effects of daily low dose mifepristone on endometrial maturation and proliferation.
Following an ovulatory control cycle, six women took 2 mg of mifepristone daily for 30 days. Endometrial biopsies were collected in the control cycle between 7 and 11 days after the plasma luteinizing hormone (LH) surge and on the corresponding day of the treatment cycle (days 19-28). In order to investigate the effects of unopposed oestrogen on the endometrium, persistent proliferative endometrium was obtained from six women with anovulatory infertility due to polycystic ovarian syndrome (PCOS) on a similar cycle day (days 21-23) following a progestogen-induced withdrawal bleed. Endometrium was evaluated for histology and immunolocalization of oestrogen receptors (ER), progesterone receptors (PR) and the cell proliferation markers [proliferating cell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristone inhibited ovulation in four of the six subjects. In the two subjects in whom ovulation did occur, secretory transformation was delayed, suggesting that successful implantation of a blastocyst would be unlikely. In subjects who remained anovulatory during treatment, the histology and pattern of steroid receptor expression was similar to proliferative phase endometrium. In women with PCOS, mitoses and intense immunostaining for ER, PR and cell proliferation markers were observed in both glands and stroma. Although PCNA and Ki67 immunostaining were also present in mifepristone-treated endometrium from subjects who did not ovulate, there were no mitoses and significantly less ER immunostaining in spite of exposure to unopposed oestrogen for a similar duration. Since PCNA and Ki67 detect cells throughout all stages of the cell cycle this would suggest that mifepristone might affect the entry of cells into the mitotic phase of the cell cycle and, therefore, might prevent endometrial hyperplasia. These findings add further evidence to support the contraceptive potential and antiproliferative activity of daily low dose mifepristone.
Impact of the introduction of new medical methods on therapeutic abortions at the Royal Infirmary of Edinburgh.
OBJECTIVE: To assess the impact of the introduction of new medical methods on the provision of therapeutic abortions at the Royal Infirmary Edinburgh. DESIGN: A review of the total number of abortions performed by medical and surgical means between 1989 and 1995 (inclusive); a prospective survey of the terminations of pregnancy (< or = 9 weeks of gestation) performed over the six-month period of January to June 1994; and a questionnaire of the reasons why women chosen a particular method. SETTING: Large teaching hospital in Scotland. SUBJECTS: One thousand and seven women seeking early pregnancy termination between January and June 1994. MAIN OUTCOME MEASURES: Proportion of pregnancies terminated by medical means; comparison of complete abortion rate, incidence of complications and morbidity following both medical and surgical methods (< or = 9 weeks of gestation); reasons for preference of the method of abortion. RESULTS: Since 1991 there has been a progressive increase in the number of medical abortions performed at the Royal Infirmary of Edinburgh, and by 1994 the majority of women (57%) seeking abortion at < or = 9 weeks chose a medical method. Women who chose medical abortion had more years at full-time education and were less likely to smoke (P < 0.04). Both medical and surgical methods were highly effective (> 96% complete abortion) with a low incidence of complications and morbidity. However, women who had chosen the medical method were less likely to receive antibiotics for suspected endometritis than their surgical counterparts (chi 2, P = 0.0001). CONCLUSIONS: If this trend towards medical methods in Edinburgh is repeated elsewhere, it will inevitably have an impact on gynaecological services by releasing staff and operating time for other purposes.
Measurement of circulating inhibin forms during the establishment of pregnancy.
This study investigated the forms of inhibin released into the circulation 1) in very early pregnancy, 2) after stimulation of the corpus luteum by exogenous hCG, and 3) in abnormal and failing human pregnancy. Samples were assayed by enzyme-linked immunosorbent assays for inhibin A, inhibin B, and inhibin pro-alphaC-related immunoreactivity (pro-alphaC-RI). The concentration of inhibin A rose steadily during the conception luteal phase to an initial peak 12 days after ovulation (104 +/- 23 pg/mL), then rose rapidly to a further peak 43 days after ovulation 424 +/- 6 pg/mL). The concentration of pro-alphaC-RI exhibited a much larger peak on day 15 after ovulation (1423 +/- 361 pg/mL), but fell thereafter. The concentration of inhibin B was low after ovulation and subsequently barely detectable in pregnancy. hCG treatment resulted in a significant rise in the concentrations of inhibin A and pro-alphaC-RI, but had no effect on the inhibin B concentration. The pro-alphaC-RI concentration was a better indicator of continuing pregnancy viability than either hCG or inhibin A. Early trophoblast secretes proportionately more bioactive inhibin than the corpus luteum. The corpus luteum and trophoblast do not secrete inhibin B into the circulation. These data support the concept of different physiological roles for different inhibin forms.
Follicular dynamics and ovarian steroid secretion in sheep during anoestrus.
The dynamics of ovarian follicular development and its relationship to ovarian and pituitary hormones during seasonal anoestrus were investigated for 10 days in nine ewes with autotransplanted ovaries in a longitudinal study. The size and position in the ovary of individual follicles over 2.5 mm in diameter were recorded by daily ultrasonography. Samples of ovarian and jugular venous blood were collected at intervals of 12 h, before and after a GnRH challenge (2.50 ng GnRH, i.v.) so that basal and LH-stimulated ovarian steroid secretion could be determined. Throughout the experimental period, all animals developed at least one large antral follicle > 5 mm, which secreted increased (P < 0.05) amounts of oestradiol and androstenedione in response to an LH challenge as the diameter of the follicle increased. However, a decrease (P < 0.05) in ovarian steroid secretion preceded any significant change in follicular diameter, indicating a dissociation between morphological and functional stages of dominance in sheep. We conclude that follicular growth and ovarian steroid secretion in sheep occur in wave-like forms, with the ascending and static part of both waves being synchronous but with a decline in steroid secretion preceding any changes in follicular diameter. Therefore, in sheep, follicular size alone is not an adequate parameter to assign dominance, and the secretory status of the follicle at any given time must be taken into account when studying the dynamics of follicular growth.
Expression of inhibin alpha- and beta A-subunit mRNA and protein in the fetal sheep ovary throughout gestation.
In adult sheep, inhibin expression in developing follicles appears to be associated with antrum formation. Our objective was to investigate using in situ hybridization and immunohistochemistry whether antral follicles present before birth in the sheep expressed mRNA or peptide for inhibin alpha- and beta A-subunits. At days 70 and 100 when only primordial and primary follicles were present, there was no detectable mRNA or peptide for either inhibin subunit. By days 130 and 140 (term = 145 days), many secondary follicles were present, a proportion of which (approximately 50%) expressed detectable levels of alpha-subunit mRNA but not peptide. A number of antral follicles were present by this stage, all of which expressed alpha-subunit mRNA and peptide. Expression of beta A-subunit mRNA and peptide was undetectable at all stages of gestation. Our results indicates that even in non-ovulatory follicles present before birth, expression of inhibin, at least the alpha-subunit, is developmentally linked with antrum formation.
Randomized trial of misoprostol and cervagem in combination with a reduced dose of mifepristone for induction of abortion.
Mifepristone (600 mg) in combination with a prostaglandin has been demonstrated to be a safe, acceptable alternative to vacuum aspiration for induction of abortion in the first 9 weeks of pregnancy. However, the efficacy and side-effects of different prostaglandins used in combination with mifepristone have not been assessed in a randomized trial. In this study, 800 women seeking an abortion at gestational age < or = 63 days amenorrhoea were randomized to receive either 0.5 mg gemeprost by vaginal pessary (group I) or 600 micrograms misoprostol (group II) by mouth approximately 48 h after taking 200 mg mifepristone by mouth. The side-effects and number of complete abortions were used as measures of efficacy. There was no significant difference in the rate of complete abortion between group I [96.7%; 95% confidence interval (CI) 94.9-98.5%, n = 391] and group II (94.6%; 95% CI 92.3-96.9, n = 386). It was not possible to assess the outcome with certainty in the remaining 23 women. However, there were significantly more ongoing pregnancies in the women who received misoprostol than in those who received gemeprost (nine versus one, P < 0.01) and in eight of these 10 women the gestation was > 49 days. Fewer women in group II required analgesia than in group I (48 versus 60%, P < 0.001) although the number requesting opiate was similar in each group (6.9 versus 5.2%, P > 0.4). The incidence of nausea and vomiting after misoprostol (47.8 and 21.9% respectively) was higher (P < 0.001) than after gemeprost (33.9 and 12% respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Donated ovarian tissue in embryo research and assisted conception--the view of women of reproductive age.
In response to widespread interest by the media, the Human Fertilisation and Embryology Authority (HFEA) recently produced a document entitled 'Donated Ovarian Tissue in Embryology Research and Assisted Conception'. Interested organizations and the public were asked for their views on the use of eggs or ovarian tissue obtained from live donors, cadavers or fetuses for both research and the treatment of infertility. For 6 weeks from mid-March 1994, we made the HFEA document available to women attending a Family Planning/Well Woman Clinic (n = 1142), an Infertility Clinic (n = 241) and 200 women about to have a termination of pregnancy, in an attempt to develop an understanding of the attitudes of the general public. We asked them to answer anonymously the questions posed by the HFEA. Over 89% of women thought that ways should be sought to increase the supply of eggs for research and treatment. There were no significant differences in attitudes between the three groups, except that women seeking an abortion were significantly less likely to support the use of cadavers as a source of eggs for either research (48 versus 67%) or treatment (48 versus 59%) (P < 0.05 in both cases). Although all three groups of women found live donors the most acceptable source (90% for research, 88% for treatment), the majority supported the use of fetal eggs/tissue for both research (60%) and treatment (54%) of infertility. This study represents the first systematic attempt to determine the opinion of women who may not otherwise make their views known to the HFEA.
Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days.
It has been demonstrated previously that administration of the antiprogestin mifepristone (RU 486; 1-5 mg daily) inhibits or delays both the pre-ovulatory luteinizing hormone (LH) surge and ovulation. To investigate this mechanism, dynamic tests of pituitary ovarian function were performed in six healthy women before and during the administration of mifepristone (2 mg daily for 30 days). On day 9 of the control and treatment cycles, samples of blood were collected every 15 min over 12 h for measurement of LH concentration. After 10 h, the responsiveness of the pituitary was tested by the i.v. injection of 10 micrograms of gonadotrophin-releasing hormone (GnRH). On day 10 of the control and treatment cycles, two patches releasing 200 micrograms/day of oestradiol were applied to skin on the abdomen for 3 days. Blood was collected at 24, 48, 59, 72, 81 and 96 h after application of the oestrogen patches for the measurement of gonadotrophin and ovarian hormone concentrations. Follicular development continued in all women during their treatment with mifepristone, and ovulation was suppressed (four women) or delayed (two women). There was no significant difference in the basal concentration of LH between the control and treatment cycles (mean +/- SE; 5.5 +/- 0.4 versus 7.7 +/- 0.4 IU/l respectively), or in the frequency (interpulse interval, 101 +/- 12 versus 105 +/- 13 min respectively) and the amplitude (2.1 +/- 0.4 versus 2.6 +/- 0.4 IU/l respectively) of LH pulses. The response to GnRH was similar. On day 10, the basal concentrations of LH, follicle-stimulating hormone (FSH), prolactin, oestradiol and progesterone and the diameter of the dominant follicle (15.7 +/- 1.8 versus 13.3 +/- 1.9 mm) were similar during control and treatment cycles. In control cycles, there were significant increases in the concentrations of LH and FSH within 72 h of application of the oestrogen patches. During treatment cycles, concentrations of FSH and LH remained low, and were significantly lower than the values observed during control cycles (P < 0.006). We conclude that the antiprogestin mifepristone disrupts ovulation by inhibiting the positive feedback effect of oestrogens and, hence, prevents or delays the generation of a pre-ovulatory LH surge.
Effect of daily low dose mifepristone on the ovarian cycle and on dynamics of follicle growth.
BACKGROUND AND OBJECTIVE: The antiprogestin mifepristone has been shown to disrupt folliculogenesis and endometrial maturation and, therefore, has the potential to be used as a novel form of contraception. The purpose of this study was to investigate further the effects of daily administration of a low dose of mifepristone (2mg) on the ovarian cycle and on the dynamics of follicle growth. SUBJECTS: Six healthy female volunteers were given 2mg mifepristone daily for 30 days following an ovulatory control cycle. MEASUREMENTS: Follicle growth was monitored with transvaginal ultrasonography and hormonal measurements in blood and urine were used to monitor effects on the ovarian cycle. In addition, concentrations of cortisol and ACTH in serum were measured to assess the effects of mifepristone on the pituitary-adrenal axis. RESULTS: Treatment with mifepristone retarded the follicular growth rate in all women (P = 0.01). Ovulation was inhibited in 4 of 6 subjects and appeared to be mediated through an effect on the hypothalamo-pituitary axis, as no surge of FSH or LH occurred. In these subjects the dominant follicle continued to grow and developed into a persistent follicle. In two cases the persistent follicle remained functional and ovulation occurred soon after stopping treatment. In the remaining two subjects, the dominant follicle developed into a non-functioning cyst ( > 30 mm) which persisted for one month after the end of the post-treatment cycle. In the two subjects who ovulated, the LH surge was delayed by 6 and 7 days but was followed by a luteal phase of normal length. There was no significant change in the concentration of ACTH or cortisol suggesting that treatment with mifepristone in this dose has little if any effect on the pituitary-adrenal axis. CONCLUSION: These findings add further evidence to support the contraceptive potential of mifepristone through effects on follicular development and on the menstrual cycle.
Uterine rupture during therapeutic abortion in the second trimester using mifepristone and prostaglandin.
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Expression of mRNA and immunocytochemical localization of inhibin alpha- and inhibin beta A-subunits in the fetal sheep testis.
In order to investigate the ontogeny of gonadal inhibin production in the male fetal sheep, testes were collected from male fetuses at days 70, 100, 130 and 140 of gestation (term = 145 days). The expression and localization of inhibin alpha- and inhibin beta A-subunit mRNA and protein were evaluated using in situ hybridization and immunocytochemistry. The expression of inhibin alpha-subunit mRNA was localized within the seminiferous cords of the developing fetal testis and progressively increased with gestational age. Immunostaining corresponding to immunoreactive inhibin alpha-subunit was detected in Sertoli cells within the seminiferous cords at days 100, 130 and 140 of gestation. In addition, immunostaining was detectable in a small proportion of Leydig cells. No expression of inhibin beta A-subunit mRNA or immunoreactivity was detected in any testicular tissue at any stage of gestation. These data show that the Sertoli cells of the developing fetal sheep testis have the capacity to produce inhibin alpha-subunit by day 100 of gestation and that production increases during late gestation.
Donated ovarian tissue: the public's view.
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Prostaglandin inactivation is increased in endometrium after exposure to clomiphene.
Prostaglandin (PG) dehydrogenase inactivates PGs by oxidising the 15-hydroxyl group and thus plays a key role in controlling their effective local concentrations. This enzyme is thought to be under the control of steroid hormones and is found in human endometrium at high levels in the secretory phase of the menstrual cycle but is absent during the proliferative phase. We have examined the PG dehydrogenase activity in human endometrium from women who had been treated with the anti-oestrogen clomiphene at an earlier stage of the cycle and found high levels of the enzyme in the proliferative phase. This data was supported by the culture of endometrium from clomiphene treated women which showed both high PG production and extensive inactivation comparable to that seen in the secretory phase. This effect of clomiphene on the PG inactivating ability of endometrium could be of clinical use in management of disorders where elevated PGs are present.