Does obesity diminish the positive effect of oral contraceptive treatment on hyperandrogenism in women with polycystic ovarian syndrome?

Polycystic ovarian syndrome (PCOS) is an obvious indication for long-term treatment. Combined oral contraceptives (COC) remain the first choice for the treatment of hyperandrogenism in most patients. However, differences in endocrine and metabolic parameters between obese and lean patients have been postulated. This is the first study evaluating the effect of COC treatment in obese versus non-obese PCOS patients. In total, 28 lean [body mass index (BMI) <25 kg/m(2))] and 15 obese (BMI >30 kg/m(2)) women patients were enrolled in the study. The concentrations of androgens, sex hormone-binding globulin (SHBG) and lipids were measured before and after 6 months of treatment with COC containing low-androgenic progestins. Clinical androgenic symptoms were monitored. There was a lower concentration of SHBG in obese patients, but there were no differences in androgen concentrations between both groups before the study. Highly significant changes in concentrations of testosterone (P < 0.001), androstenedione (P < 0.0001), SHBG (P < 0.001) and LH (P = 0.01) were demonstrated in lean patients, with only less significant changes in SHBG (P < 0.01) and testosterone (P < 0.05) in obese patients during the study. Clinical androgenic symptoms improved significantly (P = 0.05) only in the group of lean women. No reduction in low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol ratio was observed in either group. In conclusion, the positive effect of COC treatment on androgen production, serum androgen binding capacity, and clinical androgenic symptoms was negatively influenced by an increased BMI.     

Should androgen supplementation be used for poor ovarian response in IVF?

Poor ovarian response is reported in 9-24% of IVF cycles. Several interventions have been proposed to improve the outcome, although evidence to support these has been scant. There has been interest in the use of adjuvant androgens in this context and a recent worldwide survey showed that nearly a quarter of IVF clinicians used dehydroepiandrosterone (DHEA) in poor responders. We examine the rationale for the use of adjuvant androgens and suggest that the current clinical uncertainty should be addressed by a randomized controlled trial of DHEA in poor responders.     

Should slow coronary flow be considered as a coronary syndrome?

The concept of slow coronary flow was firstly described in 1972. This phenomenon indicates a coronary slow flow phenomenon in the absence of any known etiology. This phenomenon is not infrequently detected finding during routine coronary angiography, while it is, apparently, quite different from coronary slow flow phenomenon with evident causes. Slow coronary flow, consequently, should be distinguished from occurrence of slow flow in the context of coronary reperfusion therapy such as angioplasty or thrombolysis that is associated with different pathophysiological and clinical implications. Similarly, coronary slow flow associated with coronary spasm, coronary artery ectasia, myocardial dysfunction, valvular heart disease and certain connective tissue disorder involving coronary microvasculature is definitely need to be differentiated in patients with slow coronary flow. In addition, coronary slow flow phenomenon was also found in the situation from inadvertent air-embolism during angioplasty or due to an overlooked ostial lesion. Furthermore, the features of slow coronary flow are not in agreement with cardiac syndrome X. It is not certain, however, whether slow coronary flow phenomenon in the absence of any of known causes represents merely an angiographic curiosity or has special physiologic or therapeutic implications up to now. What kind of factors or etiologic reasons contributes to slow coronary flow? Is slow coronary flow an independent entity of coronary artery disease? All of those answers are still unknown and deserves further investigation. In our opinion, slow coronary flow without evident cause may represent a new entity of coronary heart disease. Therefore, we would like to consider it as a syndrome, and call it as a "slow coronary flow syndrome".     

Should patients with polycystic ovarian syndrome be treated with metformin?: an enthusiastic endorsement

Insulin resistance is a prominent feature of polycystic ovarian syndrome (PCOS), and women with the disorder are at increased risk for the development of other diseases that have been linked to insulin resistance-namely, type 2 diabetes and cardiovascular disease. This association between insulin resistance and PCOS must guide the chronic management of the disorder, and accumulating evidence suggests that administration of insulin-sensitizing drugs to individuals at high risk for type 2 diabetes decreases the rate of conversion to overt disease. In contrast, limited evidence exists to suggest that oral contraceptive pills-the currently standard therapy for PCOS-may actually decrease insulin sensitivity and induce impaired glucose tolerance in women with PCOS. Hence, PCOS should be regarded as a general health issue and the use of insulin-sensitizing drugs such as metformin should be considered for the prevention of type 2 diabetes.     

Should patients with polycystic ovarian syndrome be treated with metformin? A note of cautious optimism

Hyperinsulinaemia has proved to be a key link in the enigmatic generation of the symptoms of polycystic ovarian syndrome (PCOS), i.e. anovulatory infertility and the skin stigmata induced by hyperandrogenism. Regression of these symptoms may be achieved by reducing the hyperinsulinaemia. As obesity exaggerates the expression of the symptoms induced by hyperinsulinaemia, a low calorie diet and lifestyle change resulting in loss of weight for obese women with PCOS is capable of reversing these symptoms. Insulin-sensitizing agents, predominantly metformin, have been examined for their ability, in all patients with PCOS, to achieve similar beneficial changes to those induced by loss of weight in the obese. While the scientific value of many of these studies is questionable and solid evidence of efficiency and safety is not complete, the honourable intent of lowering high insulin levels in this way prompts the bottom line of this debate to strike a note of cautious optimism that insulin-sensitizing agents will be of some clinical usefulness both in the short-term aiding of infertility treatment and, possibly, in the prevention of the long-term sequelae for this troublesome and very prevalent condition.     

Should patients with polycystic ovary syndrome be treated with metformin? Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction

The debate on metformin use in polycystic ovary syndrome (PCOS) has mainly focused on its treatment for infertility in ovulation induction and menstrual cyclicity. Here we will summarize the data supporting the effect of metformin on improving hyperandrogenaemia and hyperinsulinaemia in PCOS patients. We propose that metformin benefits PCOS patients undergoing gonadotrophin therapy and IVF as well as ovulation induction. We also advocate the use of insulin sensitizing drugs to reduce miscarriage rates, and risks associated with coronary artery disease, gestational diabetes and obesity.     

Should patients with benign positional vertigo be imaged?

Unexpected intra-cranial pathology is unusually encountered in patients with BPV in the presence of a classically positive Hallpike's response and in the absence of any other neurological signs or symptoms. We carried out a retrospective review to assess the incidence of unexpected intra-cranial pathology in patients with a clinical diagnosis of benign positional vertigo (BPV) and to review the role of radiological imaging in these patients. 145 consecutive patients seen by the senior author with a diagnosis of posterior semi-circular canal BPV over a five-year period were reviewed. In the series of 63 patients who underwent MRI, two cases (3.2%) had cerebral aneurysms, one patient had an epidermoid cyst (1.58%) and one patient had a large right parietal arterio-venous malformation. We would conclude that possible warning signs exist that may alert the clinician to the possibility of unexpected intracranial pathology including failed response to the initial Epley manoeuvre or any asymmetry in hearing. Thus, we would advocate imaging be performed on this sub-group of patients with BPV.     

What is polycystic ovarian syndrome? A proposal for a consensus on the definition and diagnosis of polycystic ovarian syndrome

The criteria for diagnosis and definition of polycystic ovarian syndrome used by clinicians and investigators are almost as heterogeneous as the syndrome itself. This has confused and seriously hindered the clarification of the genetics, aetiology, clinical associations and assessment of treatment and later sequelae of the syndrome. This article proposes a consensus for a unifying balanced and practical working definition for use as a standard. The proposal incorporates confirmation of the diagnosis suggested by clinical symptoms by ultrasound, and the use of hormonal estimations if typical ultrasound features are not seen and for the purpose of defining subsets of the syndrome. This consensus proposal attempts to bridge the gap between predominately American biochemical marker-based diagnosis and predominately European reliance on ultrasound as a sine qua non for diagnosis. It has been deliberately designed to be simple, practical and cheap, and if universally adopted as a standard could contribute much to all future work involving this most prevalent of syndromes.     

Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study

STUDY QUESTION: Do different dosages of metformin account for different clinical and biochemical outcomes in women with polycystic ovary syndrome (PCOS) and do basal anthropometric and metabolic characteristics of the patients provide any indications regarding the dose required to reach the target effect? SUMMARY ANSWER: Different doses of metformin exerted the same effects on clinical, biochemical and metabolic parameters in patients affected by PCOS. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Since the insulin-sensitizing agents came into use in the management of PCOS, metformin has shown a positive benefits-risks ratio. Nonetheless, therapeutic schedules are not well standardized. This is the first study which systematically analyses the effect of different doses of metformin on clinical, hormonal and metabolic features of PCOS. On the basis of our results, higher doses are no more effective than lower doses. DESIGN: A multicentric cohort prospective study. A total of 250 PCOS women were enrolled, 49 lost to follow-up. Menstrual cyclicity, hormonal assays, oral glucose tolerance test, lipid profile and ultrasonographic pelvic examination were evaluated at the baseline and after 6 months of metformin treatment at different doses (1000, 1500 and 1700 mg). PARTICIPANTS AND SETTING: A total of 201 PCOS patients completed the study without protocol violations in three university hospitals: seventy-three patients from Centre A (treated with metformin 500 mg twice a day), 60 patients from Centre B (treated with metformin 500 mg three times a day) and 68 patients from Centre C (treated with metformin 850 mg twice a day). MAIN RESULTS AND THE ROLE OF CHANCE: Metformin exerted an overall positive effect on the clinical and endocrine-metabolic features of PCOS. The degree of these effects was independent of the administered dosage in every range of basal body mass index (BMI). When patients were stratified according to their insulinaemic status, scattered inter-doses differences were found in some of the outcome measures. Patients who exhibited an increase of >2 menstrual cycles/year were considered as responders to treatment. Responders had a higher basal BMI than non-responders and showed a greater reduction in plasma testosterone levels after metformin treatment, but other outcome measures did not differ significantly. Total insulin secretion in the 180 min following the glucose tolerance test before metformin treatment (basal AUC-I) was significantly correlated with the decrease in insulin secretion induced by metformin in both the whole group and in responders, but only correlated with the variation in the number of cycles in responders. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The different doses were administered in different centres, and between-centre variation is a potential confounding factor. GENERALIZABILITY TO OTHER POPULATIONS: The paradigm of using the minimum effective dose of metformin could be pursued in other pathological conditions characterized by insulin resistance. STUDY FUNDING/COMPETING INTEREST(S): No funding or competing interests to declare.     

Should endometriomas be treated before IVF-ICSI cycles?

The laparoscopic excision of ovarian endometriomas appears to increase the chances of spontaneous conception, but the value of this treatment in women selected for IVF-ICSI cycles is debated. Studies recruiting women with unilateral disease and comparing ovarian responsiveness in the affected and contralateral intact gonads indicate that excision of endometriomas is associated with a quantitative damage to ovarian reserve. There are no randomized trials comparing laparoscopic excision to expectant management before IVF-ICSI cycles. The idea that surgery increases IVF pregnancy rates is not supported by the available evidence. However, the chance of conception is not the only issue that has to be considered. Some potential drawbacks are associated with both therapeutical strategies. Specifically, costs and hazard of surgical complications support expectant management whereas oocyte retrieval risks, the possibility of missing occult malignancy and endometriosis progression due to ovarian stimulation would favour surgical treatment. Alternative therapeutical options include medical treatment and ultrasound-guided aspiration. Whereas prolonged GnRH agonist down-regulation may be beneficial, data on ultrasound aspiration are more controversial.     

Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?

Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and leptin must be elucidated, as well as the mechanisms that account for the ultradian leptin release.     

Should chromosome breakage studies be performed in patients with VACTERL association?

The VACTERL association is characterized as a non-random pattern of defects including at least three of the following cardinal features: vertebral anomalies, anal atresia, cardiovascular malformations, tracheoesophageal fistula, renal and limb anomalies, and is postulated to be a very heterogeneous disorder. These defects can also be seen as part of the Fanconi anemia (FA) spectrum. Although VACTERL with hydrocephaly has clearly been associated with FA, the indication for chromosome breakage studies is not clear in VACTERL without hydrocephaly. We report on three unrelated patients with the VACTERL phenotype and the confirmed diagnosis of FA. Together with the data of 13 similar cases extracted from a European genotype-phenotype correlation study for FA and those from the four reported cases of the literature, we show that (i) in a series of individuals proven to have FA, 5% (13/245) also have the VACTERL phenotype, (ii) all have radial ray anomalies and 12 of these 13 subjects show at least 1 other feature of FA (café au lait spots, growth retardation, microcephaly, dysmorphism), and (iii) the VACTERL phenotype appears to be over represented in the FA complementation groups D1, E, and F. Since the diagnosis of FA is important for genetic counseling and early therapeutic intervention in patients, we conclude that chromosomal breakage studies should be performed, not only in cases of VACTERL with hydrocephaly, but also in cases VACTERL with radial-ray anomalies and especially if the individual has additional FA associated manifestations such as skin pigmentation abnormalities, growth retardation, microcephaly, or microphthalmia.     

Does laparoscopic ovarian diathermy affect the outcome of IVF-embryo transfer in women with polycystic ovarian syndrome? A retrospective comparative study

Controlled ovarian stimulation for IVF and embryo transfer and outcome parameters were compared retrospectively in 31 women with clomiphene-resistant polycystic ovarian syndrome (PCOS). Of these women, 15 had previously undergone laparoscopic ovarian diathermy before IVF (group A, total 22 cycles) and 16 had not had surgical treatment (group B, total 24 cycles). No statistically significant differences were observed in the number of oocytes retrieved, although the number of embryos available for transfer was significantly higher in group B (7.1 +/- 3.8 versus 4.6 +/- 2.7, P < 0.01). The clinical pregnancy rate per embryo transfer appeared to be higher in group B (63.2 versus 41.2%), as did the miscarriage rate (66.7 versus 28.6%), giving an apparent improved ongoing pregnancy rate per embryo transfer in group A (29.4 versus 10.5%), but this was not statistically significantly different. The incidence of severe ovarian hyperstimulation syndrome (OHSS) was apparently higher in group B (4.2 versus 0%), but this difference was not statistically significant. No cases of severe OHSS were seen in group A. Ovarian diathermy does not appear to have a deleterious effect on controlled ovarian stimulation, and the outcome of IVF-embryo transfer may be beneficial in decreasing the risk of severe OHSS and improving the ongoing clinical pregnancy rate.     

Early ovarian ageing: are women with polycystic ovaries protected?

Screening asymptomatic women in the general population for 'early ovarian ageing' will be more effective in high-risk groups. Recent findings support the hypothesis that women with polycystic ovaries (PCO) may have actually been born with a larger pool of resting follicles. The mechanism is almost certainly genetic and occurs in fetal life. If, as is widely accepted, the rate of depletion of the ovarian reserve depends primarily on the size of the remaining pool of small follicles, women with PCO will be unlikely to undergo an accelerated depletion of their follicle pool, normally seen in the late thirties, significantly earlier. In terms of asymptomatic screening for early ovarian ageing in the general population, women with PCO constitute a low-risk group and should therefore be excluded.     

Should multivisceral transplantation be considered in patients colonized with multidrug-resistant Pseudomonas aeruginosa?

This report describes two subsequent liver-small bowel-pancreas-kidney (multivisceral) transplantations in a child colonized with multidrug-resistant Pseudomonas aeruginosa. We discuss the dilemma concerning the transplantation of patients colonized with multidrug-resistant Pseudomonas spp., its potential consequences, and the peri and postoperative management of these patients.     

Obstructive sleep apnea syndrome: who should be treated?

Most, if not all patients referred for assessment require some form of therapeutic intervention. In particular, general lifestyle advice, sleep hygiene, and weight reduction in overweight patients should always be promoted, even where additional specific therapy such as NCPAP is also being considered. Treatment decisions are relatively easy at the extremes of the clinical spectrum, but there is an increasing choice of therapeutic options available for those patients in the mid-range of severity. Criteria based on AHI levels are inappropriate to dictate treatment choice, particularly NCPAP.