Application of specific ELISAs for BMP15 and GDF9 to cumulus cell extracts from infertile women.

Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) are oocyte-specific paracrine factors which regulate ovarian cumulus cell (CC) functions. This study aimed to investigate if BMP15 and GDF9 bound to CCs can be characterized, quantified, and show an association with IVF outcomes in infertile women. BMP15 and GDF9 ELISAs were validated and applied to discarded CC extracts. Pooled CCs from individual patients were collected from 120 (cohort 1; BMP15 only) and 81 infertility patients (cohort 2; BMP15 and GDF9) undergoing superovulation. BMP15 and GDF9 levels expressed per CC DNA were correlated with maternal age, clinical and embryology data. Total BMP15 and GDF9 were highly correlated with each other (r = 0.9, p < 0.001). The GDF9:BMP15 ratio was unrelated to oocyte number or age. BMP15/CC DNA and GDF9/CC DNA were unaffected by the type of superovulation and were not related to oocyte/embryo outcomes.

In vitro fertilisation/intracytoplasmic sperm injection beyond 2020.

Over 8 million babies have been born following IVF (in vitro fertilisation) and other artificial reproductive technology (ART) procedures since Louise Brown's birth 40 years ago. New innovations have added much complexity to both clinical and laboratory procedures over the last four decades. Translation of novel approaches from basic science into clinical practice continues unabated, widening the applicability of ART to new groups of people and helping improve both chances of healthy live birth and patient acceptability. However, the impact of ART on the health of both patients and their offspring continues to cause concern, and many ethical challenges created by new scientific developments in this field attract widely differing opinions. What is undeniable is that there will be a sustained global growth in utilisation of ART and that reproductive tourism will allow many people to access the treatment they desire notwithstanding national regulations that may forbid some approaches. The greatest challenge is to expand access to ART to those living in the less wealthy nations who are equally deserving of its benefits.

The relationship between serum prolactin concentration and pregnancy outcome in women with unexplained recurrent miscarriage.

The role of prolactin in early pregnancy is controversial. The aim of this study was to evaluate the relationship between serum prolactin concentration and the risk of miscarriage in women with unexplained recurrent miscarriage (RM). A series of 174 women with unexplained RM, who had serum prolactin concentrations measured from January 2000 to September 2009 at the Recurrent Miscarriage Clinic in Royal Hallamshire Hospital in Sheffield, were included in this study. Among the 174 patients with unexplained RM, 40 patients did not conceive during the study period, 9 were lost to follow-up and 125 patients conceived again. Patients who did not conceive were significantly older than those who conceived (p < 0.05, OR: 1.08, 95% CI: 1.03-1.13). Among those who conceived again, the pregnancy outcome data were available for analysis in 109 patients. Those who miscarried were older (p < 0.05, OR: 1.1, 95% CI: 1.01-1.22) and had significantly lower serum prolactin concentrations (p < 0.05, adjusted OR: 0.99, 95% CI: 0.97-0.99) after adjustment has been made for age, than those who had a live birth. Lower basal serum prolactin concentrations were associated with an increased risk of miscarriage in a subsequent pregnancy in women with unexplained RM.

Relationship between psychological stress and recurrent miscarriage.

Stress arousal may compromise the feedback regulation of the hypothalamo-pituitary-adrenal axis, releasing stress-related biomarkers and thereby affecting establishment of pregnancy. This study examined the relationship between stress and recurrent miscarriage (RM) and the impact of stress on establishment of pregnancy. The stress status of 45 patients with unexplained RM and 40 fertile women was investigated with the Fertility Problem Inventory (FPI), Perceived Stress Scale (PSS), Positive and Negative Affect Schedule, peripheral natural killer (NK) cells and cortisol. Patients with unexplained RM had significantly higher scores on the FPI (P<0.05, adjusted OR 1.02), PSS (P<0.05, adjusted OR 1.13) and Negative Affect scale (P<0.05, adjusted OR 1.12) and lower scores on the Positive Affect scale (P<0.05, adjusted OR 0.89) than fertile controls. Patients who had live births (n=20) during the study period had significantly lower scores in the Positive Affect scale (P<0.05, adjusted OR 1.17) than those who miscarried (n=10). There was a little association between psychological stress measurements and biochemical stress measurements. These results suggest that stress is a risk factor of RM. Within women with RM, moderate stress appears to be associated with improved pregnancy outcome.

Effect of cigarette smoking upon reproductive hormones in women of reproductive age: a retrospective analysis.

There is continuing debate concerning the relationship between cigarette smoking and premature ovarian failure. The aim of this retrospective data analysis was to investigate whether smoking has a measurable effect on early follicular serum concentrations of inhibin B hormone, FSH and anti-Müllerian hormone (AMH) in women of reproductive age. A database containing data on age, smoking status and serum concentrations of inhibin B, FSH and AMH was analysed. Pearson's correlation coefficient was calculated to determine the correlation between hormone concentrations and age. One-way analysis of variance was used to determine any significant difference in age between smoking categories and a univariate general linear model was used to compare geometric means and geometric mean ratios of hormone concentrations in relation to smoking status. Serum concentrations of inhibin B were significantly lower in women who had ever smoked cigarettes: F(2,332) = 3.371, P = 0.036. There was no statistically significant difference in FSH or AMH concentrations although a trend towards lower AMH concentrations in smokers was observed. This analysis provides evidence of an advancement of ovarian ageing in women who smoke cigarettes and is relevant to women of childbearing age who wish to avoid premature decline in fertility.

The value of measuring anti-Mullerian hormone in women with anovulatory polycystic ovary syndrome undergoing laparoscopic ovarian diathermy.

BACKGROUND: Anti-Müllerian hormone (AMH) has been implicated in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to measure circulating AMH before laparoscopic ovarian diathermy (LOD) to evaluate its prognostic value for an ovulatory response and to investigate AMH changes after LOD to further explore the effects of LOD. METHODS: This prospective study included anovulatory women with PCOS undergoing LOD (n = 29) or receiving clomiphene citrate (n = 18). Plasma AMH concentrations were measured before and 1 week after treatment. Further measurements of AMH were made at 3- and 6-month follow-up. RESULTS: The pretreatment median (range) plasma AMH concentrations were 6.1 (1.0-21.0) and 5.7 (1.3-9.5) ng/ml in women having LOD and clomiphene citrate treatment, respectively. Women who ovulated after LOD (n = 24) had a significantly (P = 0.032) lower pre-operative AMH [5.6 (1.0-21.0) ng/ml] compared with the non-responders [9.0 (6.1-17.1) ng/ml]. Using receiver-operating characteristic curve analysis, AMH was found to be a useful predictor of no ovulation after LOD with area under the curve of 0.804 (P = 0.025). Using a cut-off of 7.7 ng/ml, AMH had a sensitivity of 78% and a specificity of 76% in the prediction of no ovulation after LOD. For all patients (n = 47, clomiphene citrate or LOD), plasma AMH >or=7.7 ng/ml was associated with a reduced chance of ovulation after treatment (P = 0.004). Following LOD, the median AMH concentration significantly (P = 0.003) decreased to 4.7 (0.3-15.1) ng/ml and remained low at 3- and 6-month follow-up. CONCLUSIONS: Pretreatment circulating AMH level seems to be a good predictor of the ovarian response to LOD.

An RCT of metformin versus orlistat for the management of obese anovulatory women.

BACKGROUND: Treatment of obesity-related anovulation poses a significant clinical challenge. Occasionally, the use of antiobesity medications such as orlistat or insulin sensitizing agents such as metformin is sometimes indicated in these patients. This study aimed to compare the effects of metformin and orlistat for improving ovulation in obese anovulatory women. METHODS: This was an open-label RCT. A total of 40 women were randomized to receive either metformin (n = 20) or orlistat (n = 20). BMI as well as the androgen profile and the ovulatory status were assessed at baseline and at four weekly intervals for 3 months. Different anthropometric and endocrine parameters were also assessed as possible predictors of ovulation. RESULTS: There was no significant difference between the two study arms regarding the ovulation rate for metformin and orlistat [40% (n = 8/20) and 25% (n = 5/20), respectively, P = 0.31]. Both arms showed a significant drop in the BMI, testosterone and androstendione concentrations (P < 0.05), but there was no difference between the two arms. Patients who ovulated had significantly lower concentrations of baseline LH, androstendione, dehydroepiandrosterone and free androgen index (P < 0.05). Among these factors, a low baseline LH was found to be the only independent predictor of ovulation (area under curve, 0.85). CONCLUSIONS: Both metformin and orlistat show a similar effect on weight loss, ovulation rates and androgen concentrations. However, the effects on ovulation rates need to be confirmed in larger studies. The presence of a low baseline serum LH was found to be the most important predictor of ovulation. The study was registered at clinicaltrials.gov. NCT00292799.

Effects of cigarette smoking upon clinical outcomes of assisted reproduction: a meta-analysis.

BACKGROUND: The aim of this meta-analysis was to investigate whether any difference exists in success rate of clinical outcomes of assisted reproductive technologies (ART) between women who actively smoke cigarettes at the time of treatment and those who do not. METHODS: An intensive computerized search was conducted on published literature from eight databases, using search terms related to smoking, assisted reproduction and outcome measures. Eligible studies compared outcomes of ART between cigarette smoking patients and a control group of non-smoking patients and reported on live birth rate per cycle, clinical pregnancy rate per cycle, ectopic pregnancy rate per pregnancy or spontaneous miscarriage rate per pregnancy, and 21 studies were included in the meta-analyses. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated for the data, and statistical heterogeneity was tested for using chi(2) and I(2) values. A systematic review examined the effect of smoking upon fertilization rates across 17 studies. RESULTS: Smoking patients demonstrated significantly lower odds of live birth per cycle (OR 0.54, 95% CI 0.30-0.99), significantly lower odds of clinical pregnancy per cycle (OR 0.56, 95% CI 0.43-0.73), significantly higher odds of spontaneous miscarriage (OR 2.65, 95% CI 1.33-5.30) and significantly higher odds of ectopic pregnancy (OR 15.69, 95% CI 2.87-85.76). A systematic literature review revealed that fertilization rates were not significantly different between smoking and non-smoking groups in most studies. CONCLUSIONS: This meta-analysis provides compelling evidence for a significant negative effect of cigarette smoking upon clinical outcomes of ART and should be presented to infertility patients who smoke cigarettes in order to optimize success rates.

Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome.

BACKGROUND: Laparoscopic ovarian diathermy (LOD) is currently accepted as a successful second-line treatment for ovulation induction (OI) in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS). The aim of this study was to test the hypothesis that LOD may be superior to CC as a first-line treatment. METHODS: The study included 72 anovulatory women with PCOS who were randomized to LOD (n = 36) or CC (n = 36). Women who remained anovulatory after LOD were offered CC. Similarly, women receiving CC who failed to ovulate or conceive were offered LOD. Pregnancy rates were compared between the two groups using chi(2) and odds ratio with 95% confidence interval (OR, 95% CI). RESULTS: After randomization, six women conceived before starting treatment and another patient postponed treatment. The remaining 65 women received the treatment (33 underwent LOD and 32 received CC). After the primary treatment, more pregnancies (44%) occurred in women receiving CC than in those undergoing LOD (27%), although the difference did not reach statistical significance [P = 0.13, OR 2.1 (0.7 - 5.8)]. After adding the second treatment, the pregnancy rate was still higher, but to a less extent, in the CC group [63% versus 52%, P = 0.2, OR 1.6 (0.6 - 4.2)]. CONCLUSIONS: LOD is not superior to CC as a first-line method of OI in women with PCOS. The trial is registered with ClinicalTrials.gov with an identifier number NCT00220545.

Health-related quality of life in PCOS and related infertility: how can we assess this?

In recent years there has been an increasing demand for the design, development and use of questionnaires that can assess patients' experiences of health and illness or their health-related quality of life (HRQoL). The application of these questionnaires in research and clinical practice provides information from the patient's perspective on the ways in which symptoms and treatments can affect their daily well-being and functioning. The aim of this paper is to report on the ways in which information on the HRQoL of women with polycystic ovary syndrome (PCOS) can be collected. With particular reference to PCOS-associated infertility, this paper will discuss the types of questionnaires that are currently available. It will discuss the benefits and limitations of the disease-specific PCOS questionnaire, and the other generic and condition-specific tools that have been used in the existing PCOS literature. Recommendations for future researchers interested in measuring HRQoL outcomes in women with PCOS-associated infertility are also made.

Cost-effectiveness analysis of different embryo transfer strategies in England.

OBJECTIVE: The objective of this study was to assess the cost-effectiveness of different embryo transfer strategies for a single cycle when two embryos are available, and taking the NHS cost perspective. DESIGN: Cost-effectiveness model. SETTING: Five in vitro fertilisation (IVF) centres in England between 2003/04 and 2004/05. POPULATION: Women with two embryos available for transfer in three age groups (<30, 30-35 and 36-39 years). METHODS: A decision analytic model was constructed using observational data collected from a sample of fertility centres in England. Costs and adverse outcomes are estimated up to 5 years after the birth. Incremental cost per live birth was calculated for different embryo transfer strategies and for three separate age groups: less than 30, 30-35 and 36-39 years. MAIN OUTCOME MEASURES: Premature birth, neonatal intensive care unit admissions and days, cerebral palsy and incremental cost-effectiveness ratios. RESULTS: Single fresh embryo transfer (SET) plus frozen single embryo transfer (fzSET) is the more costly in terms of IVF costs, but the lower rates of multiple births mean that in terms of total costs, it is less costly than double embryo transfer (DET). Adverse events increase when moving from SET to SET+fzSET to DET. The probability of SET+fzSET being cost-effective decreases with age. When SET is included in the analysis, SET+fzSET no longer becomes a cost-effective option at any threshold value for all age groups studied. CONCLUSIONS: The analyses show that the choice of embryo transfer strategy is a function of four factors: the age of the mother, the relevance of the SET option, the value placed on a live birth and the relative importance placed on adverse outcomes. For each patient group, the choice of strategy is a trade-off between the value placed on a live birth and cost.

A preliminary study comparing the endometrial expression of inhibin, activin and follistatin in women with a history of implantation failure after IVF treatment and a control group.

The aim of this study was to evaluate the expression of activin: beta A and beta B subunit and follistatin in endometrium of women with implantation failure (n = 10) and compare it with a fertile control group (n = 7). Immunohistochemical staining intensity for follistatin in the endometrial glandular epithelium from women with implantation failure were significantly lower than that in control women (P = 0.03). The decreased expression of follistatin in epithelial cells in the endometrium of women with implantation failure after in vitro fertilisation (IVF) may suggest that follistatin may play a role in the implantation process.

Health-related quality of life measurement in women with polycystic ovary syndrome: a systematic review.

The symptoms typically associated with polycystic ovary syndrome (PCOS) such as acne, hirsutism, irregular menses, amenorrhoea, obesity and subfertility are a major source of psychological morbidity and can negatively affect quality of life (QoL). We systematically searched the literature to identify the impact of symptoms and treatments for PCOS on health-related QoL (HRQoL) and to report on the types and psychometric properties of the instruments used. Papers were retrieved by systematically searching four electronic databases and hand searching relevant reference lists and bibliographies. Nineteen papers used a standardized questionnaire to measure health status; of these 12 (63.2%) used generic tools and 8 (42%) used the disease-specific PCOS questionnaire. Although a meta-analysis was not possible, it appears that weight concerns have a particular negative impact upon HRQoL, although the role of body mass index in affecting HRQoL scores is inconclusive from the available evidence. Acne is the area least reported upon in terms of its impact upon HRQoL. With the exception of three studies, most of the research has focused upon adult women with PCOS. Despite the benefits of HRQoL measures in research, few are being used to evaluate the outcomes of treatment for PCOS upon the subjective health status of women with the condition.

Effect of increased body mass index on oocyte and embryo quality in IVF patients.

Obesity may have an adverse effect on the outcome of IVF/intracytoplasmic sperm injection (ICSI) treatment. In this study, the effects of increased body mass index (BMI) on oocyte and embryo quality during IVF cycles were studied. A retrospective analysis of 426 IVF/ICSI cycles was performed. Cycles were classified according to the BMI: normal BMI (19-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)) and obese (> or = 30 kg/m(2)). Cycles were further stratified based on age (group 1, < 35 years; group 2, > or = 35 years). Markers of oocyte quality (number of oocytes inseminated and fertilization rate) and embryo quality (utilization rate, number of embryos discarded and cryopreserved, and mean embryo grade) were examined. In group 1, obesity had a significant adverse effect on the mean embryo grade (P = 0.02), the embryo utilization rate (P = 0.01), number of embryos discarded (P = 0.007) and cryopreserved (P < 0.05). In group 2, there was no difference in markers of embryo quality between the three BMI ranks. Obesity did not have any significant effect on markers of oocyte quality or clinical pregnancy rates. In conclusion, obesity may adversely affect embryo quality in young women (<35 years) undergoing IVF/ICSI, while the oocyte quality is not affected.

The impact of obesity on female reproductive function.

Obesity may be described as the new worldwide epidemic, and its serious impact on morbidity and mortality are well known. As more and more women become obese, the reproductive problems associated with obesity present an ever-growing challenge to physicians involved in their fertility care. The spectrum of reproductive problems associated with obesity encompasses a wide range of disorders including infertility problems, miscarriage and pregnancy complications. In this review, we aim to discuss the impact of obesity on the various aspects of female reproductive function with focus on the clinical aspects of fertility problems in obese women. We finally comment on the available therapeutic options available to this group of women.

Impact of high body mass index on endometrial morphology and function in the peri-implantation period in women with recurrent miscarriage.

There is evidence that women with a high body mass index may have a higher risk of miscarriage. It is not known if this is due to an endometrial or embryo defect. The aim of this retrospective study was to examine markers of endometrial function in overweight and obese women with recurrent unexplained miscarriage. A total of 136 women were included in the study and classified according to their body mass index (BMI) into two groups, normal BMI (< 25 kg/m(2), n = 70) and high BMI (> or = 25 kg/m(2), n = 66). Endometrial morphology was examined in all patients. A subgroup of 28 patients was examined for endometrial oestrogen and progesterone receptors in different components of the endometrium, and in a further subgroup of 28 patients, endometrial glandular leukaemia inhibitory factor and leukocyte populations were examined. A modest increase in the BMI (30.4 +/- 0.71 kg/m(2)) does not have a significant impact on endometrial steroid receptors, leukocyte populations or endometrial morphology. However, there was a significant negative correlation between endometrial glandular leukaemia inhibitory factor concentrations and the BMI (r = -0.4, P = 0.02), warranting further investigation in prospective studies that include patients with higher BMI levels.

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.