Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

Minimising twins in in vitro fertilisation: a modelling study assessing the costs, consequences and cost-utility of elective single versus double embryo transfer over a 20-year time horizon.

OBJECTIVES: To assess the cumulative costs and consequences of double embryo transfer (DET) or elective single embryo transfer (eSET) in women commencing in vitro fertilisation (IVF) treatment aged 32, 36 and 39 years. DESIGN: Microsimulation model. SETTING: Three assisted reproduction centres in Scotland. SAMPLE: A total of 6153 women undergoing treatment at one of three Scottish IVF clinics, between January 1997 and June 2007. METHODS: A microsimulation model, populated using data inputs derived from a large clinical data set and published literature, was developed to compare the costs and consequences of using eSET or DET over multiple treatment cycles. MAIN OUTCOME MEASURES: Disability-free live births; twin pregnancy rate; women's quality-adjusted life-years (QALYs); health service costs. RESULTS: Not only did DET produce a higher cumulative live birth rate compared with eSET for women of all three ages, but also a higher twin pregnancy rate. Compared with eSET, DET ranged from costing an additional £ 27,356 per extra live birth in women commencing treatment aged 32 years, to costing £ 15,539 per extra live birth in 39-year-old women. DET cost ∼ £ 28,300 and ∼ £ 20,300 per additional QALY in women commencing treatment aged 32 and 39 years, respectively. CONCLUSIONS: Considering the high twin pregnancy rate associated with DET, coupled with uncertainty surrounding QALY gains, eSET is likely to be the preferred option for most women aged ≤ 36 years. The cost-effectiveness of DET improves with age, and may be considered cost-effective in some groups of older women. The decision may best be considered on a case-by-case basis for women aged 37-39 years.

Report on the donation of supernumerary embryos from fresh IVF and ICSI treatment cycles for human stem cell research.

BACKGROUND: Research involving human embryos promises exciting therapeutic advances but raises ethical and moral dilemmas for scientists and potential donors. The aim of this study is to report the proportion of couples donating supernumerary fresh embryos for development of stem cell lines from a single centre and the characteristics of those who donate. METHODS: Couples undergoing assisted conception treatment in a teaching hospital received research information between January 2005 and July 2006. Counselling and consenting was performed by a dedicated research nurse. Demographic data was collected for couples who enrolled in the study. MAIN OUTCOME MEASURES: To determine the proportion of couples willing to donate surplus embryos for stem cell derivation and to examine the characteristics of those who consent to donate. RESULTS: Of 508 couples, 353 (69%) expressed an interest in research on their treatment consent forms. Sixty-six percent of those interested in research and 87% of counselled couples consented to donation. The demographic characteristics of those who agreed to donate were similar to those of all couples attending the unit. CONCLUSIONS: Approximately half of couples consented to donate under the described system in our centre. Detailed information provision helps the majority of those counselled to proceed to donation.

Individual ovarian volumes obtained from 2-dimensional and 3-dimensional ultrasound lack precision.

Measuring ovarian volume has been suggested as a possible screening test to assess a woman's ovarian reserve. For such a screening tool to be clinically useful, knowledge of its precision and reproducibility is essential. Recent advances in ultrasound scanning techniques allow the measurement of volumes in three dimensions rather than the traditional estimation from two dimensions. Transvaginal 2-dimensional (2D) and 3-dimensional (3D) ultrasound examinations were performed on 49 women attending a tertiary centre for investigation or treatment for subfertility between January and May 2006. Two observers calculated ovarian volume using both 2D (prolate ellipsoid formula) and 3D techniques [virtual organ computer-aided analysis (VOCAL)] with rotation steps of 30 degrees (3D-30). For the four comparisons (inter- and intra-observer; 2D and 3D-30) intraclass coefficients of 0.97 to 0.98, and standard errors ranging from 17% to 14% (for inter-observer 2D and intra-observer 3D, respectively) were obtained. The corresponding coefficients of repeatability ranged from 33% to 28%. These results suggest that measurement of transvaginal ovarian volumes using both 2D and 3D ultrasound is imprecise for individuals. The imprecision is greater for lower ovarian volumes, which may be important in clinical practice. The average of two or more measurements is likely to be more accurate than a single measurement.

Reasons for discontinuation of IVF treatment: a questionnaire study.

BACKGROUND: IVF and embryo transfer has become an established and increasingly successful form of treatment for infertility, yet significant numbers of couples discontinue treatment without achieving a live birth. This study aims to identify major factors that influence the decision to discontinue IVF treatment. METHODS: Questionnaires were sent to 1510 couples who had undergone IVF treatment at Ninewells Hospital and Medical School, Dundee, Scotland, between January 1995 and December 2001. The main outcome measure was the number of couples who discontinue treatment and the reasons for discontinuation including live birth, lack of success, lack of funding, psychological stress, medical advice, physical discomfort, personal and other reasons. RESULTS: The response rate was 55% (732/1327) with 183 questionnaires returned as address unknown. A total of 515 couples had discontinued treatment at time of response, with 266 (52%) having achieved a live birth. Achieving a live birth was the reason for discontinuation where a single reason was given. Those who did not conceive gave a combination of reasons. Lack of personal and/or National Health Service funding was cited by 23% of couples as a reason. Lack of success and psychological stress were reported as factors by 23 and 36% of couples respectively. These two factors are very strongly associated (P < 0.001), both being reported by 18% of couples with a reciprocal increase in those quoting lack of success and psychological stress as reasons for discontinuation with increasing number of attempts (P < 0.0005). Changes in personal circumstances were reported by 30% and <10% gave general discomfort or advice from medical staff as reasons. CONCLUSIONS: Though funding is an important issue, factors including lack of success and psychological stress play a greater role in influencing the decision to discontinue treatment. Better information and support are needed to improve the continuation rates.

Factors influencing the cumulative conception rate and discontinuation of in vitro fertilization treatment for infertility.

OBJECTIVE: To examine the cumulative conception rate and live birth rate in women undergoing IVF and to assess the influence of prognostic factors on cumulative conception rate and discontinuation of treatment. DESIGN: Retrospective analysis of data from couples undergoing IVF. SETTING: Assisted conception unit of a university hospital. PATIENT(S): Two thousand fifty-six patients undergoing 2708 cycles of IVF from April 1992 to March 1999. MAIN OUTCOME MEASURE(S): Cumulative conception rate by age, number of oocytes retrieved, and embryos transferred, and the influence of these factors on dropout rates. RESULT(S): The cumulative conception rate and cumulative live birth rate after four attempts were 75% and 66%, respectively. The cumulative conception rate differed significantly between women 35 years of age or younger and those older than 35 years who had five or more oocytes retrieved (83% vs. 63%). When fewer than five oocytes were retrieved in women 35 years of age or younger, the cumulative conception rate decreased to 33%. Overall, 36% of patients continued treatment after the first attempt; these patients were more likely to have more than five oocytes retrieved and more than two embryos available for transfer. CONCLUSIONS: The cumulative conception rate was greater when the female partner was 35 years of age or younger and had more than five oocytes retrieved and more than two embryos were available for transfer. These factors influenced dropout rates.

Malaria-attributable morbidity in Assam, north-eastern India.

Malaria is endemic in the Indian state of Assam and transmission of the causative parasites is perennial and persistent. The available data on malaria-related morbidity and mortality in the state for the years 1991-1999 have been reviewed. Over this period, Plasmodium falciparum was the predominant parasite, causing 58%-68% of the malaria cases; all other cases were attributed to P. vivax. All malaria-related deaths were attributed to P. falciparum infection, and the numbers of such deaths were correlated with the numbers of cases of P. falciparum malaria. The deaths occurred mostly in the rainy season (April-September) and among all age-groups of both sexes. The factors responsible for focal outbreaks of malaria across the state are discussed in relation to the existing health infrastructure.

Trends in the incidence of ectopic pregnancy in England and Wales from 1966 to 1996.

OBJECTIVE: To examine the incidence of ectopic pregnancy over the period 1966 to 1996. SETTING: England and Wales. DESIGN: Use of official statistics on hospital discharges, maternities, legal abortions and estimated populations of women aged 15-44 years. MAIN OUTCOME MEASURES: Incidence rates of ectopic pregnancies. RESULTS: Between 1966 to 1970 and 1994 to 1996 the recorded incidence increased 4.5-fold from 3.45 to 15.5 per 1000 maternities, 3.8-fold from 3.25 to 12.4 per 1000 pregnancies and 3.1-fold from 30.2 to 94.8 per 100,000 women aged 15-44. The rate of increase was not uniform. Incidence approximately doubled between 1966 and 1985, when the official data collection system changed. By 1989, when data from the new system became available, there had been a further almost doubling of recorded incidence. Subsequently, the upward trend appears to have continued until 1991 to 1992 and has remained stable in the last four years of the study. The trends were similar in each of three 10-year age groups. CONCLUSIONS: The recorded incidence of ectopic pregnancy has increased markedly over the last three decades. This may be partly due to artefacts of data recording and more sensitive diagnostic tests, but it is likely that the actual incidence has increased, probably due to a sexually transmitted agent.

Altered composition of high density lipoproteins in women with the polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) appear at increased cardiovascular risk due in part to a dyslipidemia characterized by increased plasma triglyceride and reduced high density lipoprotein (HDL) cholesterol levels. This is a detailed exploratory study of HDL composition in 35 obese [body mass index (BMI), > 27] and 22 nonobese subjects with PCOS and in 14 healthy obese and 18 nonobese women. Although we found reduced levels of total and HDL2 cholesterol in obese women with PCOS, HDL composition was modified by depletion of lipid relative to protein, with reduced ratios of HDL total cholesterol and HDL phospholipids to apolipoprotein A-I (apoA-I) compared to those in obese controls (P = 0.008 and P = 0.012, respectively). This was explained by reduced cholesterol (P = 0.004) and phospholipid (although not significant, P = 0.07) in HDL with no change in the content of apoA-I, its major protein. Obesity, insulin resistance, and hyperandrogenemia are features of PCOS and potentially affect lipid metabolism. Insulin sensitivity was assessed by the reduction in endogenous glucose concentration after exogenous insulin; the insulin, glucose, and fatty acid responses to oral glucose; and the fasting insulin concentration. When age, BMI, free androgen index, insulin sensitivity determined by all methods, and the presence of PCOS were subjected to stepwise multivariate regression analysis, the presence of PCOS was the most consistent predictor of lipid-depleted HDL (HDL total cholesterol/apoA-I and HDL phospholipids/apoA-I). We speculate that altered activity of hepatic lipase or lipid transfer protein could explain this aspect of the dyslipidemia. Obesity has an important influence on the lipid profile. Obese PCOS and control subjects had higher levels of cholesterol, triglyceride, apoB, and fatty acids than their lean counterparts, and BMI proved the best predictor of blood levels on multiple regression analysis. In contrast, lean PCOS patients had normal sensitivity to insulin and lipid profiles similar to those of the lean controls and did not manifest the HDL abnormalities. Although in PCOS, correlations were obtained between the free androgen index and cholesterol, triglyceride, and apoB levels and between the integrated glucose and insulin responses after oral glucose and fasting fatty acid and triglyceride levels, when age and adiposity were included as covariates only fatty acids and the integrated glucose response remained significantly correlated. Among the controls, total, low density lipoprotein cholesterol, triglycerides, and apoB were related to aspects of insulin sensitivity independent of age and BMI. Lipid metabolism in PCOS is dependent on several related factors, but subjects with PCOS who are obese show a specific reduction in HDL lipid, suggesting a reduced capacity for cholesterol removal from tissues with diminished antiatherogenic potential. Efforts should be directed toward reducing obesity in PCOS to improve the metabolic disturbance in addition to ameliorating the presenting symptoms.

Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is a common disorder characterized by chronic anovulation and infertility, hyperandrogenaemia, and frequently insulin resistance. This study investigated whether mutations in the insulin receptor gene could explain the insulin resistance in subjects with PCOS. From a total of 108 women with PCOS, a subgroup of 24 were selected on the criteria of being in the upper quartile for insulin resistance as assessed by fasting serum insulin, insulin area under the curve following 75 g oral glucose tolerance test, and endogenous glucose disposal as a measure of insulin sensitivity. An additional five normal women were also investigated. The entire coding region of the insulin receptor gene, comprising of 22 exons, was amplified by the PCR using genomic DNA and then subjected to single-stranded conformation polymorphism (SSCP) analysis to screen for single-base DNA sequence changes. DNA sequencing revealed that SSCP variants were detected in regions encompassing exons 3, 6-8, 11, 13, 15, 17, and 22. SSCP variants in regions of exons 3, 6, 7, 11, 15 and 22 were caused by nucleotide substitutions within intronic regions flanking the exon. The considerable variation seen in the 5' intron of exon 3 was found to be caused by variation in the number of (ATTT, 8-11) and (TC, 10-13) short sequence repeats. SSCP variants in exons 8 (Asp519, Ala523), 13 (Asn 838), and 17 (Tyr984, His1058) were caused by known silent polymorphisms. Southern blotting experiments excluded major gene deletions, insertions, or rearrangements. We conclude that insulin resistance in subjects with PCOS is not commonly a consequence of missense or nonsense mutations in the insulin receptor gene.

Polymorphism of glycogen synthetase gene in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome is a heterogeneous disorder associated with a moderate degree of insulin resistance and a higher risk of developing NIDDM. The exact mechanism of insulin resistance is unclear. This study examines the frequency of an Xbal polymorphism of the glycogen synthetase gene (A2 allele) as a marker of insulin resistance and seeks to relate the presence of the A2 allele to indices of insulin sensitivity in women with polycystic ovary syndrome (PCOS). METHODS: Insulin sensitivity was assessed by fasting insulin measurements, as well as following oral glucose tolerance test. An i.v. insulin tolerance test was performed to measure the rate of endogenous blood glucose disposal following an i.v. bolus of insulin. Restriction fragment length polymorphism was performed with Xbal digestion of PCR amplified product to detect the presence of A1 and A2 allele. PATIENTS: Seventy-one obese (BMI > 25.1) and 19 non-obese (BMI < 25) women with PCOS, and 62 controls (33 obese and 29 non-obese) participated in the study. RESULTS: Obese PCOS had significantly higher fasting insulin (P = 0.002) compared to obese controls. There was no difference between non-obese PCOS and controls. Twenty per cent of obese PCOS had impaired glucose tolerance. The A1A2 genotype was detected in 16 of the 150 (10.7%) subjects examined. Of these, 11/88 (12.5%) were PCOS and 5/62 (8%) were controls. The A2A2 genotype was not present in any of the subjects. The A1A2 genotype was not detected in any of the subjects with impaired glucose tolerance. There was no significant difference in the incidence of the A1A2 genotype between PCOS and controls or between the individual groups. There was no association between the presence of the A1A2 genotype and indices of insulin sensitivity. CONCLUSION: The Xbal polymorphism (A2 allele) of the glycogen synthetase gene was not over represented in the PCOS subject and did not relate to the indices of insulin sensitivity or glucose intolerance.

Prevalence of an immunological LH beta-subunit variant in a UK population of healthy women and women with polycystic ovary syndrome.

OBJECTIVE: An immunological LH beta-subunit variant has been described, which is undetectable using monoclonal antibodies directed to the intact LH molecule alone. Subjects have been found homozygous or heterozygous for nucleotide mutations within codons 8 and 15 in the LH beta-subunit gene. The prevalence of the variant LH beta-subunit has been estimated in a healthy UK population of women of reproductive age and in women with polycystic ovary syndrome (PCOS). The relationship of the variant molecule to the clinical and hormonal parameters of the subjects has been evaluated. DESIGN: The control and PCOS subjects were screened for the presence of the mutation by using a ratio of two immunofluorometric assays using monoclonal antibodies (Mab). One assay, not detecting the LH variant, uses a Mab directed to the intact LH molecule and a beta-specific Mab. The other assay, detecting both the variant and wild-type LH, uses two beta-subunit specific Mabs. The mutations in the LH beta-subunit gene were confirmed by restriction fragment length polymorphism. The relationship of the presence of the variant to the clinical and hormonal parameters was assessed by ANOVA. PATIENTS: Two hundred and twelve normal ovulatory women, of whom 66 (31%) were obese (body mass index > 25) and 146 (69%) non-obese, and 153 women with PCOS, 115 (75%) obese and 38 (25%) non-obese participated in the study. RESULTS: The variant LH was detected in 31 (15%) controls and 32 (21%) PCOS subjects (P = 0.124) using specific Mab. Obese PCOS had a higher incidence of the heterozygous LH variant compared to obese controls (odds ratio 2.5, P = 0.03), and compared to non-obese PCOS (odds ratio 6.3, P = 0.01). The previously described two mutations in codon 8 and codon 15 were present in all subjects detected to be mutant hetero of homo-zygous by RFLP. There was no relationship between the presence of the variant LH and the clinical and hormonal parameter in the PCOS subjects; however, in the controls the presence of the variant LH was associated with a higher serum total testosterone (P = 0.046), oestradiol (P = 0.03) and SHBG (P = 0.002). CONCLUSIONS: The results of this study show that the variant LH beta-subunit is a common polymorphism occurring in 15% of a healthy UK population of women. The prevalence was not higher in women with PCOS, though it was over represented in obese women with PCOS. The presence of the variant did not alter the clinical or hormonal expression of the disorder in women with PCOS. Its presence in the controls was however associated with higher serum oestradiol and probably secondary elevation of SHBG and testosterone, suggesting that the variant form of LH may be associated with subtle changes in the function of the hypothalamic-pituitary-gonadal axis.

Insulin sensitivity in women with polycystic ovary syndrome: relationship to hyperandrogenemia.

OBJECTIVE: To evaluate the extent of decreased insulin sensitivity in relation to body mass index and its relationship to serum androgens in women with polycystic ovarian syndrome (PCOS). DESIGN: Comparative study of endogenous glucose disposal and serum insulin responses to oral glucose load with endocrine parameters in PCOS. SETTING: Fertility and Endocrine Clinics, North Staffordshire Hospital Centre. PATIENTS: Forty-nine obese and 16 nonobese women with PCOS were compared with 18 obese and 16 nonobese control women with regular ovulatory cycles and no features of PCOS. MAIN OUTCOME MEASURES: Basal concentrations of serum LH, FSH, T, androstenedione, sex hormone-binding globulin (SHBG), and free T index. Measurements of insulin sensitivity by rate of endogenous glucose disposal after i.v. bolus injection of insulin and glucose mediated insulin responses. RESULTS: Obese women with PCOS showed decreased insulin sensitivity and hyperinsulinemia to an extent greater than can be explained by obesity alone. Serum insulin showed inverse correlation with SHBG, and therefore hyperinsulinemia increased the bioavailability of androgens in obese PCOS. In nonobese PCOS, this method of assessment failed to reveal insulin resistance. CONCLUSION: Hyperandrogenemia and insulin resistance are independent features of PCOS. Hyperinsulinemia enhances expression of hyperandrogenemia by increasing bioavailability of androgens.