Validation of proteomic biomarkers previously found to be differentially expressed in women with polycystic ovary syndrome: a cross-sectional study.

OBJECTIVES: The aim of this study was to independently validate proteomic biomarkers previously reported to be differentially expressed in women with Polycystic Ovary Syndrome (PCOS) compared with controls. This study focused on plasma proteomic biomarkers. METHODS: This was a cross-sectional study at the University of Nottingham, in which samples from 30 PCOS and 30 control women were analysed by Western blotting. RESULTS: Mean abundance ratios from Western blots of plasma total haptoglobin and haptoglobin beta proteins were 1.25 (CI 1.11-1.4) and 1.24 (CI 1.04-1.44). The mean abundance ratio from the blots of alpha-2 macroglobulin was however 1.05 (CI, 1-1.1). The mean PCOS/control BMI ratio was 1.18 (CI 1.17-1.20). There was no correlation between PCOS/control BMI ratio and alpha-2 macroglobulin, total haptoglobin and haptoglobin beta abundance ratios. There was also no correlation between PCOS/control insulin ratio and alpha-2 macroglobulin, total haptoglobin and haptoglobin beta abundance ratios. CONCLUSIONS: Total haptoglobin and haptoglobin beta chain protein abundance was found to be elevated in women with PCOS compared with controls. We were unable to confirm decreased alpha-2 macroglobulin levels as reported in a previous study. Independent validation studies are required to validate early promising proteomic biomarkers in PCOS.

Proteomic biomarkers of endometrial cancer risk in women with polycystic ovary syndrome: a systematic review and biomarker database integration.

There is a need for research studies into the molecular mechanisms underpinning the link between polycystic ovary syndrome (PCOS) and endometrial cancer (EC) to facilitate screening and to encourage the development of novel strategies to prevent disease progression. The objective of this review was to identify proteomic biomarkers of EC risk in women with PCOS. All eligible published studies on proteomic biomarkers for EC identified through the literature were evaluated. Proteomic biomarkers for EC were then integrated with an updated previously published database of all proteomic biomarkers identified so far in PCOS women. Nine protein biomarkers were similarly either under or over expressed in women with EC and PCOS in various tissues. These include transgelin, pyruvate kinase M1/M2, gelsolin-like capping protein (macrophage capping protein), glutathione S-transferase P, leucine aminopeptidase (cytosol aminopeptidase), peptidyl-prolyl cis-transisomerase, cyclophilin A, complement component C4A and manganese-superoxide dismutase. If validated, these biomarkers may provide a useful framework on which the knowledge base in this area could be developed and will facilitate future mathematical modelling to enhance screening and prevention of EC in women with PCOS who have been shown to be at increased risk.

Evaluating the association between endometrial cancer and polycystic ovary syndrome.

BACKGROUND: Given the current lack of clarity in the published literature, we performed a systematic review of the literature to determine the exact strength of the association between polycystic ovary syndrome (PCOS) and endometrial cancer (EC). METHODS: All published studies on the association between PCOS and EC identified through MEDLINE (1966-April 2011), EMBASE (1980-April 2011) and Cochrane (1998-April 2011). Original data were abstracted where available and summarized on a separate Microsoft Excel (2007) database for analysis. A total of 14 studies comparative and non-comparative were identified and included. RESULTS: The non-comparative and comparative data suggested that women with PCOS were more likely to develop EC. A meta-analyses of five comparative studies showed an increased risk of EC in women with an odds ratio of 2.89 with a 95% confidence interval of 1.52-5.48. CONCLUSIONS: Women with PCOS are about three times more likely to develop EC compared with women without it. This translates into a 9% lifetime risk of EC in Caucasian women with PCOS compared with 3% in women without it. Although most women (91%) with PCOS will not develop endometrial cancer, our study has shown that they are more likely at increased risk. More studies are required to clarify the exact molecular mechanisms, determine the best way of screening and preventing disease progression.

Lipidomic analysis of plasma samples from women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common disorder affecting between 5 and 18 % of females of reproductive age and can be diagnosed based on a combination of clinical, ultrasound and biochemical features, none of which on its own is diagnostic. A lipidomic approach using liquid chromatography coupled with accurate mass high-resolution mass-spectrometry (LC-HRMS) was used to investigate if there were any differences in plasma lipidomic profiles in women with PCOS compared with control women at different stages of menstrual cycle. Plasma samples from 40 women with PCOS and 40 controls aged between 18 and 40 years were analysed in combination with multivariate statistical analyses. Multivariate data analysis (LASSO regression and OPLS-DA) of the sample lipidomics datasets showed a weak prediction model for PCOS versus control samples from the follicular and mid-cycle phases of the menstrual cycle, but a stronger model (specificity 85 % and sensitivity 95 %) for PCOS versus the luteal phase menstrual cycle controls. The PCOS vs luteal phase model showed increased levels of plasma triglycerides and sphingomyelins and decreased levels of lysophosphatidylcholines and phosphatidylethanolamines in PCOS women compared with controls. Lipid biomarkers of PCOS were tentatively identified which may be useful in distinguishing PCOS from controls especially when performed during the menstrual cycle luteal phase.

Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: a systematic review and biomarker database integration.

OBJECTIVE: To review and identify possible biomarkers for ovarian cancer (OC) in women with polycystic ovary syndrome (PCOS). DESIGN: Systematic literature searches of MEDLINE, EMBASE, and Cochrane using the search terms "proteomics," "proteomic," and "ovarian cancer" or "ovarian carcinoma." Proteomic biomarkers for OC were then integrated with an updated previously published database of all proteomic biomarkers identified to date in patients with PCOS. SETTING: Academic department of obstetrics and gynecology in the United Kingdom. PATIENT(S): A total of 180 women identified in the six studies. INTERVENTION(S): Tissue samples from women with OC vs. tissue samples from women without OC. MAIN OUTCOME MEASURE(S): Proteomic biomarkers, proteomic technique used, and methodologic quality score. RESULT(S): A panel of six biomarkers was overexpressed both in women with OC and in women with PCOS. These biomarkers include calreticulin, fibrinogen-γ, superoxide dismutase, vimentin, malate dehydrogenase, and lamin B2. CONCLUSION(S): These biomarkers could help improve our understanding of the links between PCOS and OC and could potentially be used to identify subgroups of women with PCOS at increased risk of OC. More studies are required to further evaluate the role these biomarkers play in women with PCOS and OC.

Doppler imaging in the diagnosis of ovarian disease.

INTRODUCTION: Pelvic ultrasonography remains the non-invasive imaging modality of choice for detecting and characterising adnexal masses. The use of Doppler ultrasound has improved the differential diagnosis of ovarian disease and helped to widen the understanding of the aetiology and possible pathophysiology of the various underlying conditions with an aim of improved diagnosis and management. AREAS COVERED: This review describes the basis of different Doppler techniques and their application in ovarian disease. The present evidence is critically analysed in an attempt to define the current role of Doppler ultrasound of the ovaries. The technique holds promise in certain ovarian diseases but remains controversial in others. EXPERT OPINION: Doppler ultrasound has a role in both the clinical and research settings. Clinically, it can be used to differentiate benign and malignant disease and help confirm diagnoses suggested on grey-scale imaging giving the user more confidence. Its use here, however, is generally restricted to a subjective impression of colour flow rather than a quantitative analysis of vascularity or blood flow velocity. These measures are more relevant in the research setting where quantitative Doppler is being used to clarify the possible underlying aetiology of various ovarian diseases such as polycystic ovarian syndrome and benign cysts. Doppler ultrasound has also been used in various models to evaluate the response to ovarian stimulation and the effect of surgery on the ovary.

Metabolomic biomarkers of impaired glucose tolerance and type 2 diabetes mellitus with a potential for risk stratification in women with polycystic ovary syndrome.

There is a need to identify biomarkers of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) risk in women with PCOS to facilitate screening and the development of novel strategies to prevent disease progression. Metabolomic technologies may address this need. All published studies on metabolomic biomarkers of IGT and/or T2DM identified through MEDLINE (1966-December 2010), EMBASE (1980-December 2010) and Cochrane (1993-December 2010) were retrieved. Eligible studies were screened and specific study characteristics recorded including study design, number of participants, selection criteria, type of metabolomic technique used, site of sample collection, and a list of metabolites identified to have been altered in IGT and/or T2DM versus healthy controls was created. Nine metabolomic biomarkers that could potentially be used to identify women with PCOS at risk of developing IGT and/or T2DM were identified including leucine, isoleucine, citrate, glucose, creatinine, valine, glutamine, alanine and HDL. Of these biomarkers, a panel of four biomarkers were consistently either elevated or reduced including glucose (elevated), valine (reduced), HDL (reduced) and alanine (reduced) in IGT/T2DM compared with controls. These biomarkers may predict the development of IGT/T2DM in young women with PCOS. More studies are required to test this hypothesis and translate the findings into patient benefit by reducing the morbidity/mortality associated with IGT/T2DM in PCOS.

A study of the effect of the FertilMate™ Scrotum Cooling Patch on male fertility. SCOP trial (scrotal cooling patch) - study protocol for a randomised controlled trial.

BACKGROUND: Male infertility is a significant contributor to the need for fertility treatment. Treatment currently involves correcting any identifiable adverse lifestyle factors in men with suboptimal sperm parameters, and if these measures are unsuccessful, assisted conception is offered, which can be quite expensive. Raised scrotal temperature is one of the least studied but easily corrected risk factors for male infertility. In a recent review of the literature, sperm count, motility and morphology improved with scrotal cooling devices. The devices used to achieve testicular cooling were, however, not practical for day-to-day use. A potentially more practical device for scrotal cooling has recently been developed. The Babystart® FertilMate™ Scrotum Cooling Patch is a hydrogel pad which allows for comfortable application. The aims of this study were to investigate whether exposing the scrotum to lower temperatures by means of these new patches could improve semen parameters, thereby improving fertility, and to assess the feasibility of a clinical trial. METHODS/DESIGN: This is a randomised controlled trial set in a university teaching hospital in the United Kingdom. The proposed sample size was 40 men with mild, moderate or severe oligoasthenospermia, of whom 20 would be randomised to wearing the scrotum cooling patch for 90 days and 20 men would be acting as controls and not wearing the patches. The primary outcome measure was the change in sperm concentration. Secondary outcome measures included the change in sperm volume, motility and morphology; endocrine parameters; metabolomic biomarkers; testicular volume and blood flow. Reasons for dropping out and non-compliance were also going to be noted and reported. DISCUSSION: The study started recruiting in October 2011 and as of November 2011 four men had been consented and were participating in the study. No operational challenges had been encountered at the time of the submission of this manuscript. Although the study also aimed to evaluate the feasibility of a definitive study, the change in sperm count after 90 days of wearing the scrotal cooling patches was made the primary outcome measure because a statistically significant improvement in sperm parameters with the scrotal patches would in itself be a definitive finding. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94041896.

Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women.

OBJECTIVE: To estimate the probability of live birth, adverse treatment outcome, and extremes of ovarian response at different antral follicle count (AFC) cutoff levels in a large prospective cohort of women undergoing IVF treatment. DESIGN: Prospective study. SETTING: University-based assisted conception unit. PATIENT(S): A total of 1,012 consecutive subjects of all ages undergoing their first cycle of assisted reproductive techniques. INTERVENTION(S): Transvaginal three-dimensional ultrasound assessment and venipuncture in the early follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): Live birth rate, poor ovarian response, and ovarian hyperstimulation syndrome (OHSS). RESULT(S): Analysis was performed in 1,012 subjects. Both age (r = 0.88) and AFC (r = 0.92) thresholds show significant linear relationship with the probability of live birth, but AFC demonstrates a stronger correlation. At AFC quartiles of 3-10, 11-15, 16-22, and ≥23, the mean live birth rates were 23%, 34%, 39%, and 44%, respectively. No live birth was observed in women with AFC <4. Antral follicle count was predictive of ovarian response, with a 67% likelihood of poor ovarian response for AFC ≤4. Although the risk of moderate or severe OHSS is 2.2% with AFC of ≤24, the risk increases to 8.6% at AFC of ≥24. The risk of OHSS increases further to 11% if there are signs and symptoms of polycystic ovary syndrome. CONCLUSION(S): Although age and AFC are significantly correlated with live birth, AFC demonstrates a stronger correlation. Antral follicle count thresholds are useful to predict live birth rates and risks of poor ovarian response and OHSS during IVF treatment.

Levonorgestrel intra-uterine system as a treatment option for complex endometrial hyperplasia.

OBJECTIVE: The objective of this study was to evaluate the potential treatment of atypical and non-atypical endometrial hyperplasia with the levonorgestrel intrauterine system (LNG-IUS). STUDY DESIGN: A prospective observational study was undertaken at Queen's Medical Centre's menstrual disorder clinic between 2001 and 2008. Women presenting with abnormal perimenopausal and postmenopausal bleeding, underwent an endometrial biopsy followed by the insertion of a levonorgestrel intrauterine system (LNG-IUS). The study population comprised of 51 patients. The histology of 32 patients (Group A) showed complex hyperplasia without atypia, and in 19 patients (Group B), biopsy revealed atypical endometrial hyperplasia. These patients chose to be managed conservatively with repeat sampling of the endometrium. RESULTS: Group A: 28 (87.5%) patients out of 32 had regression of their endometrial hyperplasia within the first 12 months of follow-up. Three of the patients achieved regression by 24 months increasing regression rate to 96.8% and the remaining one had a hysterectomy due to a rare side effect. Group B: 16 (84.2%) of 19 patients had regression of the atypical hyperplasia after treatment with the intrauterine system within 12 months of treatment. One patient achieved regression of the hyperplasia by 24 months and two patients went on to have surgical management due to persistent atypia and severe atypia respectively. CONCLUSION: This study contribute further evidence that illustrates that levonorgestrel intrauterine systems have a potential role in patients requiring non-operative management although close follow-up is essential.