Biomedical subjects
Publications and source records attributed to D J Cahill.
This article has provided outcome-based evidence using easily understood graphic representation of cumulative pregnancy rates whenever possible for the methods used to investigate and treat female infertility. A scheme of basic routine investigations in specialist practice is developed and clear guidance provided on the choice of treatment for each couple.
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PURPOSE: The impact of endometriosis and unexplained infertility on follicular function and fertilization of oocytes in cycles totally unperturbed by exogenous gonadotrophins, when compared with controls with tubal damage, were examined. METHODS: In natural cycles, without any exogenous gonadotropins, endocrine and ultrasonographic studies of follicular maturation in 18 women with minor endometriosis (41 cycles), 15 women with unexplained infertility (31 cycles), and 34 women with tubal damage (88 cycles) were performed. RESULTS: The endometriosis group had a significantly longer follicular phase (median: 15, 13, and 13 days). Both endometriosis and unexplained infertility had significantly reduced LH concentrations in follicular fluid compared with tubal damage (median: 12.1, 11.5, and 15.9 IU/L, respectively). Endometriosis was associated with a significantly reduced fertilization rate compared with unexplained infertility or tubal damage (46, 65, and 69%, respectively). CONCLUSIONS: These data show continuing evidence of ovulatory dysfunction leading to reduced fertilization rates in women with minor endometriosis.
Tumors of central nervous system elements are uncommon in cystic teratomas and tend to be derived from glial or primitive neuroectodermal cells. We describe the case of a 23-year-old woman with a central neurocytoma arising in an otherwise mature cystic teratoma of the ovary. Histologically, the neurocytoma was composed of collections of oligodendroglioma like cells in a fibrillary matrix. Cytologically the tumor was identical in appearance to central neurocytomas occurring within the adult brain. It expressed synaptophysin and neuron-specific enolase, confirming its neuronal lineage, but not glial fibrillary acidic protein. The site of the tumor recapitulated the typical location of neurocytomas adjacent to the lateral ventricle in that in abutted onto an ependyma-lined cyst within the teratoma. The patient remains well and free of tumor 1 year after cystectomy, in keeping with favorable follow-up data for surgically excised central neurocytomas within the brain.
The GTP cyclohydrolase I (GTP-CH) gene of the cellular slime mould Dictyostelium discoideum has been cloned and sequenced. The 855 bp cDNA of this gene contains the open reading frame (ORF) encoding 232 amino acids with a predicted molecular mass of approx. 26 kDa. Southern blot analysis indicated the presence of a single gene for GTP-CH in Dictyostelium. PCR amplification of the ORF from chromosomal DNA and sequencing showed the existence of a 101 bp intron in the GTP-CH gene of Dictyostelium discoideum. The amino acid sequence has 47% and 49% positional identity to those of the human and yeast enzymes respectively. Most of the sequence variation between species is located in the N-terminal part of the protein. The overall identity with the E. coli protein is markedly lower. The enzyme was expressed in E. coli and purified as a 68 kDa fusion protein with the maltose-binding protein of E. coli. GTP-CH of Dictyostelium is heat-stable and showed maximal activity at 60 degrees C. The Km value for GTP is 50 microM.
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Evidence of pituitary-ovarian dysfunction in unexplained and endometriosis-associated infertility has been reported previously. Hormone-suppressive therapy is often used in an attempt to improve fertility, although benefits have not been proven. Our study examines the effect of progestogen (medroxyprogesterone acetate) treatment on women with endometriosis-associated and unexplained infertility, compared with women with tubal damage as functional controls. Pre-ovulatory follicular size and serum and follicular fluid hormone concentrations were measured, and oocyte collection and in-vitro fertilization were attempted, in natural cycles totally unperturbed by exogenous gonadotrophins, for two cycles before and two cycles following treatment with medroxyprogesterone acetate for 2 months. In the endometriosis and unexplained infertility groups, compared with the tubal group, the treatment led to significant reductions in the integrated luteinizing hormone (LH) values (483 versus 664, 559 versus 762 and 864 versus 820 notional IU/l respectively). There were no changes in serum oestradiol or follicular fluid oestradiol, progesterone, follicle stimulating hormone or LH concentrations after treatment. The results suggest that progestogen therapy has no beneficial effect on the pituitary-ovarian dysfunction which contributes to endometriosis-associated and unexplained infertility.
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To examine the cause of altered follicular fluid steroid levels and lower in vitro fertilization rate observed in infertile women with minor endometriosis, we have compared the production of estradiol (aromatase activity) and progesterone of freshly isolated granulosa cells (3h. incubation) from such women and a control group with tubal or unexplained infertility, having IVF during unstimulated or gonadotropin-stimulated cycles. As previously observed, mature oocytes from women with endometriosis had a reduced fertilization and cleavage rate in vitro in unstimulated cycles (19/37[51%] vs. 69/94[73%], p < 0.05) and stimulated cycles (20/37[57%] vs. 32/39[82%], p < 0.01). Median [95%CI] basal aromatase activity was lower in endometriosis compared with control in unstimulated cycles (2.84[2.03-3.49] pmol E2/10(3) cells/3h, n = 31 vs. 3.63[2.72-3.49], n = 55, p = 0.057) and stimulated cycles (0.31[0.16-0.50], n = 14 vs. 0.99[0.70-1.52], n = 20, p < 0.001). Progesterone production followed a similar pattern in unstimulated (0.56[0.50-0.89] pmol/10(3) cells/3h, n = 29 vs. 1.23[0.69-1.54], n = 52,) and stimulated (0.37[0.20-0.73], n = 16 vs. 0.95[0.72-1.17], n = 21) cycles (p < 0.05). Addition of FSH, LH or hCG (30ng/mL) to the incubation medium enhanced progesterone production 2 to 3-fold, but had no effect on aromatase activity. Our results indicate a defect in granulosa cell steroidogenesis associated with endometriosis, which could affect oocyte function and explain the reduction in fertilizing capacity and subsequent competence of the corpus luteum, and the associated subfertility.
Transforming growth factor alpha (TGF alpha) is implicated as a paracrine growth factor in the regulation of human granulosa cell function. To investigate this further, we have examined the actions of TGF alpha on the basal and follicle-stimulating hormone (FSH)-stimulated aromatase activity of human granulosa cells to determine how this growth factor influences oestrogen biosynthesis in the follicle. Granulosa cells from women having in-vitro fertilization during untreated or gonadotrophin-stimulated cycles were cultured for 1-6 days in the presence or absence of FSH or TGF alpha at a range of doses. Aromatase activity, expressed as oestradiol production, was determined after culture during a 3 h test period. After 2 days, TGF alpha (1-300 ng/ml) decreased basal and FSH-stimulated aromatase activity in a dose-dependent manner (ED50 = 3 ng/ml). In contrast, after 4 days, TGF alpha enhanced both basal and FSH-stimulated aromatase activity. Repeated experiments revealed a consistent pattern of inhibition on day 2, which was more marked in the presence of FSH (reduction by 30.6 +/- 9.1%, mean +/- SEM; n = 14; P < 0.01), and stimulation on day 4 in both the absence (increased by 61.4 +/- 20.6%, mean +/- SEM; n = 6; P < 0.05) and presence of FSH (increased by 36.0 +/- 15.2%, mean +/- SEM; n = 8; P < 0.05). The results provide further evidence that TGF alpha is a paracrine factor in the control of oestrogen biosynthesis, but the actions can be either inhibitory or stimulatory depending on the duration of exposure.
This study examines circulating and follicular hormone concentrations and fertilization of oocytes in cycles totally unperturbed by exogenous gonadotrophins in 10 women (25 cycles) with untreated minimal-mild endometriosis and nine women (23 cycles) with prolonged unexplained infertility compared with 16 women (50 cycles) with tubal damage as functional controls. Endometriosis was associated with a significantly longer follicular phase (median 15, 12, 13 days respectively) and reduced oestrogen secretion (median index area under the curve 3063, 3842, 3805 units respectively) compared with controls. Both endometriosis and unexplained infertility had significantly reduced serum luteinizing hormone (LH) surges [median peak serum (LH) 43, 39, 55 IU/l respectively and median area under the curve 661, 687, 823 units respectively] and reduced LH concentrations in follicular fluid (median 19.6, 10.6, 9.2 IU/l respectively). These findings suggest that infertility associated with minor endometriosis and of apparently unexplained aetiology share a common pathophysiology in impaired LH surge secretion. Whether that represents a primary pituitary disorder or is secondary to a defective ovarian signal is discussed.
Our objective was to assess the efficacy of in-vitro fertilization (IVF) in natural ovarian cycles in couples with tubal and unexplained infertility. A prospective study design was used. A total of 39 fully investigated couples, who were patients at the Reproductive Medicine Unit, St Michael's Hospital, Bristol, UK, took part; they were diagnosed with either tubal disease (n = 26) or unexplained infertility (n = 13). Procedures involved daily capillary blood sampling, daily vaginal ultrasonography and vaginal oocyte recovery under sedation at mid-cycle. The main outcome measures were fertilization, implantation and pregnancy rates. Although more of the women with tubal disease were parous, there were no other significant differences between the two groups. The 39 couples with infertility of tubal or unexplained aetiology had 79 cycles of IVF in otherwise completely natural cycles. The overall fertilization rate was 80% and the implantation rate was 14.0%. A trend was observed for higher success rates in women with tubal disease. We conclude that natural cycle IVF and embryo transfer offers an acceptable chance of pregnancy and an opportunity for the in-depth investigation of follicular and ovarian function in couples with defined causes of infertility. The possibly lower success rate in women with unexplained infertility warrants further study of follicular function and endocrinology.
We have studied the rat ethanol-liquid diet model for chronic ethanol modulation of lipid homeostasis, apolipoprotein (apo) B production and apoB mRNA editing. Male Wistar rats were fed one of three diets: i) regular chow, ii) an isocaloric liquid diet, or iii) isocaloric ethanol-liquid diet where ethanol accounts for 35.5% of the total calories, for up to 40 days. There was no difference in body weight or liver/body weight ratio among the three groups of animals at the end of the feeding period. Hepatic and plasma triglycerides were elevated in the ethanol-treated animals only, correlated with an accumulation of lipid particles in the liver of these animals. By DNA excess hybridization, the steady state mRNA levels of apoB and apoB mRNA-editing protein relative to actin were not significantly altered. The proportion of edited apoB mRNA; i.e., apoB-48 mRNA/(apoB-48 + B-100) mRNA, increased in a time-dependent manner from approximately 50% to 100% in the ethanol-treated group. It remained unchanged in the chow- and liquid diet-fed animals. The proportion of apoB-48/apoB-100 protein synthesis was determined by [35S]methionine labeling followed by specific immunoprecipitation and SDS-polyacrylamide gel electrophoresis. The amount of newly synthesized apoB-48 increased from 30-50% to > 99% of the total apoB (apoB-48 + apoB-100). This increase in apoB-48 biosynthesis is reflected by an increase in circulating plasma apoB-48 from barely detectable to approximately 50% of total plasma apoB. Fractionation of plasma lipoproteins by fast protein liquid chromatography (FPLC) indicates that the ethanol-induced hypertriglyceridemia is completely accounted for by an increase in plasma very low density lipoprotein (VLDL). The proportion of apoB-48 as a percent of total apoB in the VLDL fraction increased from approximately 50% in controls to > 90% in ethanol-treated animals. Furthermore, there is a strong correlation between plasma triglyceride concentration and proportion of edited apoB-mRNA in the liver of ethanol-treated rats, but no direct correlation of the latter with intrahepatic triglyceride content. Ethanol-treated rats represent a new model for studying the regulation of apoB mRNA editing by dietary factors in vivo.
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All women undergoing pituitary down-regulation before planned in-vitro fertilization (IVF) treatment in two IVF units were studied to assess the risks of and to pregnancies occurring inadvertently when gonadotropin-releasing hormone agonists (GnRHa) were used to achieve pituitary desensitization during the luteal phase prior to planned IVF treatment. In 2670 cycles, 25 women conceived (0.9% of cycles). Of these, three resulted in pre-clinical abortions (12%) but there were no clinical abortions, and 22 have ended with live births at term of apparently normal infants. Collation of these and other published data suggest that pregnancy outcome is not adversely affected by GnRHa administration in the luteal phase of the conception cycle.
After three endocrinologically normal cycles while undergoing unstimulated in-vitro fertilization treatment, a woman took a herbal medicine (Vitex agnus castus) at the beginning of a fourth unstimulated IVF treatment cycle. In this fourth cycle, her serum gonadotrophin and ovarian hormone measurements were disordered. One embryo resulted from the three eggs collected but a pregnancy did not ensue. She had symptoms suggestive of mild ovarian hyperstimulation syndrome in the luteal phase. Two subsequent cycles were endocrinologically normal. We do not advocate the use of this herbal medicine to promote normal ovarian function.
OBJECTIVE: To determine the relative value of the woman's age, basal follicle stimulating hormone (FSH), basal luteinising hormone (LH) and menstrual cycle pattern (all defined prior to treatment) in predicting the ovarian response to gonadotrophin stimulation for in vitro fertilisation. DESIGN: Open, descriptive cohort study. PATIENTS: One hundred and seventy-one consecutive ovulatory women undergoing their first cycle of in vitro fertilisation with ovarian stimulation after pituitary desensitisation. INTERVENTIONS: Measurement of basal (early follicular phase) and down-regulated concentrations of serum FSH and LH, and calculation of age at treatment and of median length of menstrual cycles and range of variation prior to treatment. MAIN OUTCOME MEASURES: Duration and amount of gonadotrophin stimulation to achieve follicular maturity, number of mature follicles, peak serum oestradiol concentration and number of mature oocytes, were compared between banded values of variables studied. RESULTS: Increasing basal FSH concentrations were significantly associated with reducing oestradiol levels, numbers of mature follicles and oocyte yield even when the FSH levels were still within the normal range though above average (6 to 8.9 i.u./l). There were similar but weaker associations with FSH levels after down-regulation. There were also significant differences between women over and under 40 years old in their oestradiol levels, numbers of follicles and of oocytes. Analysis of variance showed significant independent association of basal FSH with both oestradiol and numbers of oocytes, but not of age, menstrual pattern, or serum LH concentrations. CONCLUSION: Serum FSH is more sensitive than the woman's age in determining her ovarian responsiveness to stimulation. LH concentrations and menstrual cycle patterns are unhelpful.