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Biomedical subjects

W L Ledger

Publications and source records attributed to W L Ledger.

At least 19 recordsLinked to original sources

Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population.

BACKGROUND: Unexpectedly poor response leading to IVF cycle cancellation is a distressing treatment outcome. We have prospectively assessed several markers of ovarian reserve in a high risk IVF population to determine their utility in predicting IVF cycle cancellation. METHODS: Eighty-four women at high risk of cycle cancellation due to raised FSH, previous poor response and/or age > or =40 years attending for high-dose short protocol IVF treatment had baseline measures of FSH, inhibin B, anti-Müllerian hormone (AMH), antral follicle count (AFC) and ovarian volume. A GnRH agonist was then administered and, 24 h later, estradiol (E(2)) and inhibin B measures were repeated. RESULTS: Fifty-seven per cent of patients in this study had a poor response to stimulation, and 15% were cancelled. Using multivariate logistic regression, we found that day 3 inhibin B levels were the best predictor of cycle cancellation with an area under the receiver operating curve (ROC AUC) = 0.78 (P = 0.017). When only considering baseline variables, mean ovarian volume was the best predictor of cycle cancellation (ROC AUC = 0.78; P = 0.016). AMH concentrations were the best predictor of a poor response (P = 0.003), and AMH was also predictive of cycle cancellation (P = 0.007) with very little inter-cycle variability. None of the parameters studied were predictive of ongoing pregnancy. CONCLUSIONS: This group of at-risk patients had a high rate of poor response to simulation and cancellation. Although several measures of ovarian reserve were able to predict cycle cancellation, none were able to predict pregnancy. AMH was predictive of both cycle cancellation and poor response with little inter-cycle variability.

Adult↗

Effect of laparoscopic ovarian diathermy on circulating inhibin B in women with anovulatory polycystic ovary syndrome.

BACKGROUND: Laparoscopic ovarian diathermy (LOD) frequently induces ovulation in patients with polycystic ovary syndrome (PCOS). The mechanism by which this effect occurs remains largely unexplained. The aim of this study was to measure changes in inhibin B production in response to LOD to see whether this could explain the mechanism of action of LOD. METHODS: This prospective study included 50 anovulatory women with PCOS. All women underwent LOD. Blood samples were collected before and after LOD to measure plasma concentrations of inhibin B, gonadotrophins and androgens. RESULTS: The pre-operative median plasma concentration of inhibin B was 110.0 pg/ml (range 19.0-567.0 pg/ml). There was a statistically significant inverse correlation (r= -0.286; P < 0.05) between body mass index (BMI) and inhibin B. Non-obese women with PCOS (BMI 30 kg/m2; n=13). Following LOD, 39 women ovulated. No statistically significant change of inhibin B after LOD was observed in the overall group of women with PCOS or in the subgroup of non-obese PCOS women with higher pre-operative inhibin B. CONCLUSIONS: The lack of any change of inhibin B after LOD makes it unlikely that this hormone has any role to play in the mechanism of action of LOD.

Adult↗

Ovulation induction using laparoscopic ovarian drilling in women with polycystic ovarian syndrome: predictors of success.

BACKGROUND: Although laparoscopic ovarian drilling (LOD) has been widely used to induce ovulation in women with polycystic ovarian syndrome (PCOS), predicting the clinical response to this treatment remains to be elucidated further. This study was carried out to identify factors that may help to predict the outcome of LOD. METHODS: This retrospective study included 200 patients with anovulatory infertility due to PCOS who underwent LOD between 1990 and 2002. The influence of the various patients' pre-operative characteristics on the ovulation and pregnancy rates after LOD was evaluated. In addition, women were divided into two or three categories according to the severity of each of the various clinical and biochemical parameters of PCOS. The success rates were compared between the categories of each factor using contingency table analyses. Multiple logistic regression analysis was used to identify independent predictors of success of LOD. RESULTS: Women with body mass index (BMI) > or = 35 kg/m2, serum testosterone concentration > or = 4.5 nmol/l, free androgen index (FAI) > or = 15 and/or with duration of infertility > 3 years seem to be poor responders to LOD. In LOD responders, serum LH levels > 10 IU/l appeared to be associated with higher pregnancy rates. CONCLUSION: Marked obesity, marked hyperandrogenism and/or long duration of infertility in women with PCOS seem to predict resistance to LOD. High LH levels in LOD responders appear to predict higher probability of pregnancy.

Adult↗

Menstrual characteristics and pregnancy in women after renal transplantation.

OBJECTIVES: To evaluate menstrual characteristics and pregnancy complications after renal transplantation in women of childbearing age. METHODS: A 10-year retrospective case-control study was carried out in Esfahan Teaching Hospitals, Esfahan, Iran. The case group consisted of 50 female kidney transplant recipients of childbearing age and the control group of 100 women who were matched for age (+/-2 years) and parity with the study group. Menstrual characteristics and pregnancy data were collected by questionnaire and analyzed by chi(2) and t-tests. RESULTS: Menstrual characteristics were improved in the 50 women who had renal transplantation, 18 of them conceived, and 20 pregnancies were evaluated. The mean interval between transplantation and pregnancy was 35.5 months and the birth weight of 44% of the newborns was less than 2500 g. Pregnancy complications included hypertension (65%), premature labor (35%) and decreased GFR (15%) during pregnancy, with a mean gestational age at delivery of 34.8 weeks. The women who conceived during the first 2 years after renal transplantation had more maternal and neonatal complications. CONCLUSIONS: Pregnancy is possible and can be successful and safe after renal transplantation in recipients with normal kidney function. However, maternal and neonatal complications are common and occur more often in patients who conceive within 2 years of transplantation. Post-transplantation pregnancies are high risk and they should be managed in a tertiary center.

Adult↗

The Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ): a validation.

BACKGROUND: We wished to evaluate the psychometric properties of the Polycystic Ovary Syndrome Questionnaire (PCOSQ), a questionnaire developed to measure the health-related quality of life (HRQoL) of women with polycystic ovary syndrome. METHOD: To assess reliability and validity, women recruited from an outpatient gynaecology clinic at the Jessop Wing, Royal Hallamshire Hospital, Sheffield completed two copies of the PCOSQ and the Short Form-36 (SF-36). Secondary factor analysis was carried out to verify the composition of the dimensions. Semi-structured interviews were conducted to assess face validity. RESULTS: Of the 92 women who consented, 82 women (89%) returned questionnaires at time 1, and 69 women (75%) returned questionnaires at time 2. All five PCOSQ dimensions were internally reliable with Cronbach's alpha scores ranging from 0.70 to 0.97. Intra-class correlation coefficients to evaluate test-retest reliability were high (range 0.89-0.95, P < 0.001). Construct validity was demonstrated by high correlations for all comparisons of similar scales of the SF-36 and PCOSQ (0.49 and 0.54). Acne was identified as an important area of HRQoL missing from the questionnaire. CONCLUSIONS: The PCOSQ is a reliable instrument for measuring the HRQoL in women with PCOS. However, the validity of the questionnaire needs to be improved by incorporating a dimension on acne into the instrument.

Acne Vulgaris↗

Production and localization of activins and activin type IIA and IIB receptors by the human endosalpinx.

Fallopian tubes from ten premenopausal women were collected and examined for the presence of inhibin, activin and its type IIA and IIB receptors (ActRIIA and ActRIIB) in the endosalpinx. Immunocytochemistry demonstrated clear staining for the betaA, betaB subunits and ActRIIA and ActRIIB that increased in intensity from the isthmus to the ampulla. No staining for the alpha subunit was observed. Whilst the staining of the betaA subunit and ActRIIA was seen in almost every epithelial cell, staining for the betaB subunit and ActRIIB was more variable. In situ hybridization and RT-PCR confirmed the presence of mRNA for the betaA, betaB subunits and ActRIIA and ActRIIB. These results indicated that the epithelium of the uterine tube is able to synthesize activin but not inhibin and has receptors for activin. Activins may thus act as paracrine regulators of tubal epithelial cell function, and embryonic activity may also bind to epithelial receptor and initiate intracellular processes that alter epithelial cell secretions.

Activin Receptors, Type II↗

Changes in circulating concentrations of inhibins A and pro-alpha C during first trimester medical termination of pregnancy.

BACKGROUND: Both inhibin A and inhibin pro-alpha C are detectable in the circulation in increasing amounts during establishment of pregnancy. However, their origins and functions remain to be elucidated. We have studied levels of inhibin A and inhibin pro-alpha C in serum samples collected at various stages during medical termination of pregnancy with consecutive use of mifepristone and misoprostol. METHODS: Samples were collected from three groups of patients at different weeks of gestation (group A: 6-7 weeks, n = 6; group B: 7-8 weeks, n = 6; group C: 8-9 weeks, n = 6) at the time of administration of oral mifepristone, 48 h later just before administration of vaginal misoprostol and again soon after expulsion of the products of conception. Plasma concentrations of inhibin A and pro-alpha C were assayed using specific and sensitive enzyme-linked immunosorbent assays. Results were correlated with concentrations of hCG and progesterone. RESULTS: We observed a significant fall in plasma concentration of inhibin pro-alpha C following administration of mifepristone, which continued after administration of misoprostol. In contrast mifepristone had no effect on plasma levels of inhibin A, which fell steeply only after administration of misoprostol. CONCLUSIONS: These results suggest dissociation between major sources of inhibin A and inhibin pro-alpha C in early pregnancy. Treatment with mifepristone, a competitive antagonist of the progesterone receptor, resulted in a significant and rapid fall in concentrations of inhibin pro-alpha C, identifying a link between production of pro-alpha C and luteal steroidogenesis. In contrast, concentrations of inhibin A did not fall after mifepristone, identifying a predominantly feto-placental origin in early human pregnancy.

Abortifacient Agents, Steroidal↗

Does the Arg-Gly-Asp (RGD) adhesion sequence play a role in mediating sperm interaction with the human endosalpinx?

BACKGROUND: Sperm from several species, including the human, make direct contact with the endosalpinx. Although this is known to be beneficial to sperm function, the specific mechanisms mediating the adhesion are poorly understood. METHODS: Short linear oligopeptides containing the amino acid sequence Arg-Gly-Asp (RGD) or a scrambled sequence (GRGES) were incorporated into an established sperm-endosalpingeal binding assay. In addition, the ability of fluorescent latex beads coated with an RGD oligopeptide to bind specifically to sperm and/or epithelium was also determined. RESULTS: Significantly fewer sperm associated per field of isthmic epithelium in the presence of 62.5 micro mol/l GRGDTP (1.18 +/- 0.41; mean +/- SEM, P < 0.05) and 250 micro mol/l RGDV (1.17 +/- 0.29; P < 0.01) compared with the control incubation (3.34 +/- 0.45). There was no difference in sperm binding to ampullary epithelium in the presence of any of the oligopeptides tested. Moreover, no beads were observed bound to sperm whereas significantly more RGD-coupled beads bound to isthmic epithelium compared with ampullary epithelium (1.47 +/- 0.26 versus 0.72 +/- 0.16 P < 0.01) and this increased in a dose-dependent manner. CONCLUSIONS: These findings indicate that the recognition between the RGD sequence and integrin receptors may contribute to the interaction between sperm and the human endosalpinx in the isthmic but not in the ampullary region of the uterine tube.

Binding, Competitive↗

IL-1, IL-6 and TNF-alpha concentrations in the peritoneal fluid of women with pelvic adhesions.

BACKGROUND: Pelvic adhesions are a significant cause of morbidity and are associated with infertility and pain. The three pro-inflammatory cytokines interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha are involved in adhesion formation/reformation. METHODS: The concentration of these three cytokines was examined in the peritoneal fluid of women undergoing laparoscopy, in order to examine the factors affecting their concentrations, with specific reference to the presence or absence of adhesions. RESULTS: We found that the concentration of TNF-alpha in the peritoneal fluid was significantly correlated to the menstrual cycle day (P < 0.01), with increasing concentration as the menstrual cycle progressed from the follicular to the luteal phase. In contrast, IL-1 and IL-6 levels did not show any variation throughout the menstrual cycle. Increased TNF-alpha was found in patients with pelvic adhesions compared with those with normal pelvis; the concentration of TNF-alpha was highest in mild compared with severe adhesions. In contrast, IL-1 concentration was higher in the presence of severe adhesions. IL-6 levels were significantly correlated with the grade of endometriosis (P < 0.05), but there were no significant correlations of either TNF-alpha or IL-1 concentrations with the various grades of endometriosis. CONCLUSION: The exact role of TNF-alpha and IL-1 in adhesion formation is still unknown, but the results from this study suggest that their concentration in the peritoneal fluid is associated with the degree of adhesions present.

Adnexal Diseases↗

The correlation of adhesions and peritoneal fluid cytokine concentrations: a pilot study.

BACKGROUND: Intra-abdominal adhesion formation and reformation after surgery is a significant cause of morbidity. The greatest problem after the surgical removal of adhesions is their reformation. We examined the concentrations of interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha in the peritoneal fluid throughout the 48 h post-operative period following adhesiolysis, and correlated the results to the extent of adhesion reformation. METHODS: Peritoneal fluid, collected from eight patients following laparoscopy and again at 12, 36 and 48 h after surgery, was analysed using enzyme-linked immunosorbent assay (IL-1 and IL-6) and bioassay (TNF-alpha). At 48 h, a second look laparoscopy was performed to inspect the pelvis for adhesion formation/reformation. RESULTS: Three patients had adhesion reformation >10% at 48 h after surgery. The mean adhesion score 48 h after adhesiolysis was 5 (range 0-17). The mean reduction in adhesion score was 88% (range 83-100%). Newly formed adhesions were filmy, relatively soft and avascular in nature. Adhesion reformation of >10% was associated with (i) high concentrations of IL-6 at 12 h (P < 0.01) and (ii) high concentrations of IL-1 at 48 h (P < 0.001). CONCLUSIONS: Results from this preliminary study suggest that future treatment strategies for adhesion prevention could be aimed at the control of cellular mediators in the peritoneal fluid during the initial adhesion formation period.

Adult↗

Long term follow-up of patients with polycystic ovarian syndrome after laparoscopic ovarian drilling: clinical outcome.

BACKGROUND: Currently, there is an uncertainty about the impact of laparoscopic ovarian drilling (LOD) on the natural history of polycystic ovarian syndrome (PCOS). This longitudinal follow-up study was undertaken to investigate the long-term effects of LOD. METHODS: The study included 116 anovulatory PCOS women who underwent LOD between 1991 and 1999 (study group) and 34 anovulatory PCOS women diagnosed during the same period but who had not undergone LOD (comparison group). The hospital records were reviewed and questionnaires were sent to all the women. In addition, most women attended a follow-up interview. Clinical data recorded at different intervals of follow-up (short-term, <1 year; medium-term, 1-3 years; and long-term, 4-9 years) included: the menstrual pattern, symptoms relating to hyperandrogenaemia and reproductive history. RESULTS: The proportion of women with regular menstrual cycles increased significantly [relative risk (RR) = 1.6, 95% confidence interval (CI) = 1.4-1.9, P < 0.05] from 8% before LOD to 67% post-operatively. The proportion dropped to 37% (RR = 2.6, 95% CI = 1.8-3.8, P < 0.01) at medium-term follow-up and then increased again to 55% (RR = 2.2, 95% CI = 1.7-2.8, P < 0.01) at long-term follow-up. After LOD, 54/110 women (49%) conceived spontaneously during the first year and 42 (38%) during medium- and long-term follow-up. Among women with hirsutism (n = 43) and acne (n = 25), 10 (23%) and 10 (40%) respectively experienced long-term improvement after LOD. CONCLUSION: LOD produces long-term improvement in menstrual regularity and reproductive performance in about one-third of cases. A modest and sustained improvement in acne and hirsutism can be expected in approximately 40 and approximately 25% of patients respectively.

Acne Vulgaris↗

Production of activins by the human endosalpinx.

Uterine tubes from 11 premenopausal and 6 postmenopausal women were collected and examined for the presence of inhibin, activin, and follistatin in the endosalpinx. Immunocytochemistry of tissue from both the isthmic and ampullary regions demonstrated clear staining for the beta(A)- and beta(B)-subunits that increased in intensity from the isthmus to the ampulla. Staining for follistatin showed a similar pattern, but no staining for the alpha-subunit was observed. Although staining for the beta(A)-subunit was seen in almost every epithelial cell, staining for the beta(B)-subunit was more variable. Western blotting showed a band with an apparent molecular mass of 28 kDa (corresponding to the activin dimer) and a band of approximately 60 kDa (corresponding to the pro-protein of activin). In situ hybridization confirmed the presence of mRNA for the beta(A)- and beta(B)-subunits in the endosalpinx. These results indicate that the endosalpinx is able to synthesize activin, not inhibin, suggesting that in premenopausal women they may have an important role in the biology of the developing embryo. The role in postmenopausal women is less certain, but could lead to the stimulation of FSH secretion by the pituitary gland or other autocrine/paracrine function within the uterine tube.

Activins↗

Measurement of inhibin A and activin A in pregnancy--possible diagnostic applications.

Knowledge of the roles of inhibins and activins has progressed rapidly since the development of a specific and sensitive assay that can be used for measurements on human serum and amniotic fluid samples. There is a sound theoretical basis for the role of transforming growth factor-beta family members in inflammatory processes, many of which are analogous to implantation, parturition and a variety of pathological conditions in pregnancy. This review explores the potential use of assays for inhibins and activins in clinical practice and suggests further areas for research.

Activins↗

Clomiphene citrate in the twenty-first century.

Clomiphene citrate is the drug most commonly prescribed for ovulation induction. It is the first choice medication in normogonadotrophic oligo/amenorrhoeic infertility (WHO group 2), essentially associated with polycystic ovaries. Anovulatory women who are responsive to clomiphene citrate should be treated for at least six cycles and the treatment should probably be limited to a maximum of 12 cycles. It is necessary to monitor at least the first cycle with ultrasonography because of the risk of multiple pregnancy and the variable response of patients to different doses of clomiphene. In addition, the risk of ovarian hyperstimulation syndrome should not be underestimated. More triplets and higher order pregnancies result from ovulation induction than from in vitro fertilization, and multiple pregnancy has many risks for both mother and babies. The role of empirical clomiphene in the treatment of unexplained infertility is debatable and the present data are inconclusive. Obesity, hyperandrogenaemia and insulin resistance are important factors in clomiphene-resistant patients. Failure to ovulate in response to clomiphene has been approached by either medical or surgical treatment. An effective alternative medical treatment is gonadotrophin injections. Treatment with metformin and the new generation of insulin-sensitizing drugs is under evaluation. The most widely used surgical treatment today is laparoscopic ovarian drilling, which appears to be as effective as gonadotrophin therapy.

Clomiphene↗

Efficacy and safety of long-acting GnRH agonists in in vitro fertilization and embryo transfer.

The introduction of gonadotrophin-releasing hormone (GnRH) agonists combined with gonadotrophins is considered to be one of the most significant events in the development of in vitro fertilization and embryo transfer (IVF-ET) programmes. This article reviews the use of GnRH agonists in IVF-ET programmes and the efficacy and safety of long-acting GnRH agonists. The use of agonists results in higher clinical pregnancy rates, more supernumerary embryos for cryopreservation and allows convenient programming of oocyte recovery. There are different types of agonist and ovarian stimulation protocol available for clinical use. Recent meta-analysis of the Cochrane database has demonstrated the superiority of the long protocols over the short and ultra-short protocols for GnRH agonist use in IVF and GIFT. The depot injection offers increased clinical and patient compliance and improves efficacy of pituitary downregulation. However, compared with short-acting agonists, the depot preparations are associated with a longer period of stimulation and higher doses of gonadotrophins. To date, there is no evidence of an increased risk of pregnancy wastages or teratogenicity in human pregnancies exposed to long-acting agonists.

Animals↗

Serum concentrations of dimeric inhibins, activin A, gonadotrophins and ovarian steroids during the menstrual cycle in older women.

The transition from regular ovarian cyclicity to menopause is associated with a rise in the circulating concentrations of follicle stimulating hormone (FSH), despite the maintenance of serum oestradiol concentrations during the perimenopause. The aim of this study was to compare the pattern of secretion of dimeric inhibins, activin A, gonadotrophins and steroids in regularly cycling women of 40-50 years with normal and raised early follicular phase serum FSH concentrations and young women (25-33 years) during the menstrual cycle. Blood samples were taken prospectively almost daily throughout the menstrual cycle. Women recruited were classified into three groups: (i) older women with normal FSH [(ON-FSH), day 3 FSH <8 mIU/ml, n = 10]; (ii) older women with raised FSH [(R-FSH), day 3 FSH >8 mIU/ml, n = 6] and (iii) young normal FSH (YN-FSH) women, age 25-32 years (n = 6). Cyclic patterns of serum inhibins and activin A were similar in the ON-FSH and YN-FSH groups. The R-FSH group had significantly lower concentrations of inhibin A prior to the luteinizing hormone (LH) surge and in the mid-luteal phase and lower concentrations of inhibin B in the early follicular phase compared with the ON-FSH group. Serum concentrations of activin A, progesterone and oestradiol were similar in all three groups. It is concluded from this study that the rise in early follicular phase serum FSH in older women is associated with a decrease in circulating concentrations of inhibin B in the early follicular phase. However, lower circulating concentrations of inhibin A in the luteal phase of the R-FSH group may also contribute to the rise in early follicular phase FSH concentrations during the menstrual cycle, although further studies with larger numbers are required to confirm this observation.

Activins↗