The Role of Antiobesity Agents in the Management of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age. Obesity is frequently present in these patients and plays a key role in the pathogenesis of both the endocrine and metabolic abnormalities of the syndrome, particularly infertility, hyperandrogenism and insulin resistance (IR). Diet and exercise is the mainstay of management of obesity in patients with PCOS. In contrast, the eff ects of antiobesity agents on weight and on the obesityrelated characteristics of the syndrome remain unclear. The aim of the present review is to summarize the current data on the eff ects of antiobesity drugs approved in Europe (orlistat, liraglutide 3 mg od and naltrexone/bupropion) on weight loss in patients with PCOS and to discuss their impact on the endocrine, reproductive and metabolic abnormalities of this population. Several studies reported that orlistat induces weight loss, improves IR and reduces androgen levels in PCOS. In contrast, data regarding the eff ects of the dose of liraglutide that is approved for the treatment of obesity (3 mg od) are very limited. Liraglutide 1.2-1.8 mg od results in weight loss in these patients but does not aff ect IR or androgen levels. Finally, there are no studies that evaluated naltrexone/bupropion in patients with PCOS and early studies reported conflicting results regarding the eff ects of naltrexone monotherapy on weight, IR and androgen levels. In conclusion, orlistat appears to have a role in the management of overweight and obese patients with PCOS whereas more studies are needed to clarify the role of liraglutide and naltrexone/bupropion.

Concealed heterotopic pregnancy at 12 weeks, with no coexisting risk factors: Lessons to be learned.

A woman presented at the gynecological emergency clinic with severe lower abdominal pain. Even though she reported normal menses and had no risk factors for ectopic pregnancy, pregnancy test was positive and vaginal sonogram indicated heterotopic pregnancy at 12 weeks of gestation, with rupture of the ectopic pregnancy. Laboratory results indicated significant blood loss, and emergency laparotomy with salpingo-ophorectomy was performed. The intrauterine pregnancy continued uneventfully. Interestingly, the previous month the patient had also undergone investigation for vague abdominal pain and anemia. This case, apart from being very interesting because of the rarity of naturally occurring heterotopic pregnancy, shows how a number of factors in patient management and investigation, when combined with rare and uncommon conditions, can lead to incorrect diagnosis with the associated implications for patient safety. This case therefore demonstrates the need for improved patient care and outcome.

Prenatal diagnosis of 1p34.3 interstitial microdeletion by aCGH in a fetus with jaw bone abnormalities.

BACKGROUND: Interstitial microdeletions in 1p are extremely rare, as very few cases have been reported postnatally and only one prenatally, yet. There is a variability of phenotypic findings such as hypotonia, facial dysmorphisms, mild microcephaly, with being most common developmental delay. CASE PRESENTATION: The present case involved a female fetus with an interstitial deletion on 1p, presenting with micrognathia in the 2nd trimester routine ultrasound examination. Array-based comparative genomic hybridization (a-CGH) revealed a 2,7 Mb deletion located on 1p34.3 which could not be detected by standard karyotyping. CONCLUSIONS: This is the first prenatal case of an interstitial deletion in 1p34.3 with facial dysmorphism detected by a-CGH. Due to the use of a-CGH techniques submicroscopic imbalances could be detected, and a refined genotype-phenotype correlation could be achieved.

Associations of menstrual cycle irregularities with age, obesity and phenotype in patients with polycystic ovary syndrome.

OBJECTIVE: Limited data suggest that menstrual cycle abnormalities are more pronounced in younger and more obese patients with polycystic ovary syndrome (PCOS). We aimed to evaluate the association between menstrual cycle pattern and age, obesity and PCOS phenotype in a large population of women with PCOS. DESIGN: We studied 1,297 women with PCOS and divided them according to: a) age in ≤ 20, 21-30 and > 30 years old, b) body mass index in normal weight, overweight and obese and c) PCOS phenotype in phenotype 1 (anovulation, hyperandrogenemia and polycystic ovaries), 2 (anovulation and hyperandrogenemia without polycystic ovaries), 3 (hyperandrogenemia and polycystic ovaries without anovulation) and 4 (anovulation and polycystic ovaries without hyperandrogenemia). RESULTS: The proportion of women with regular menstrual cycles progressively increased in the older age groups, being 8.1, 10.5 and 12.7% in women ≤ 20, 21-30 and > 30 years old, respectively (p = 0.037). The proportion of women with regular menstrual cycles did not differ between normal weight and obese women but was higher in overweight women (9.3, 9.4 and 13%, respectively; p = 0.020). The proportion of women with regular cycles alternating with irregular cycles was highest in women with phenotype 4, intermediate in women with phenotype 2 and lowest in women with phenotype 1 (74.3, 69.4 and 61.7%, respectively; p = 0.027). CONCLUSIONS: Menstrual cycle pattern is more irregular in women with the "classic" PCOS phenotypes than in phenotype 4 but appears to normalize with ageing. On the other hand, obesity does not appear to have an important effect on menstrual cycle pattern in PCOS.

Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: assessment of non-invasive indices predicting hepatic steatosis and fibrosis.

OBJECTIVE: Insulin resistance contributes to the pathogenesis of both polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). The main aim of the present study was the evaluation of non-invasive indices of hepatic steatosis and fibrosis in PCOS women with or without metabolic syndrome (MetS). DESIGN: In this cross-sectional study, three non-invasive indices for hepatic steatosis [NAFLD liver fat score, lipid accumulation product (LAP) and hepatic steatosis index (HIS)] and four for fibrosis [FIB-4, aspartate aminotransferase (AST)-to-Platelet Ratio Index (APRI), body mass index (BMI)-Age-Alanine aminotransferase (ALT)-Triglycerides (BAAT) and BMI AST/ALT Ratio Diabetes (BARD)] were calculated in 314 PCOS women (77 with, 237 without MetS) and 78 controls. RESULTS: All steatosis indices were significantly higher in the PCOS than the control group (NAFLD liver fat score: -0.139 ± 0.117 vs. -0.976 ± 0.159, p<0.001; LAP: 43.3 ± 1.9 vs. 34.7 ± 3.1, p=0.036; HIS: 44.6 ± 0.5 vs. 42.1 ± 0.8, p=0.016). FIB-4 and BAAT [fibrosis stage (F)2-4] were higher in the PCOS group (0.480 ± 0.020 vs. 0.400 ± 0.013, p<0.001; and 15.6% vs. 5.1%, respectively), whereas APRI and BARD were not. All steatosis indices were significantly higher in PCOS women with than without MetS (NAFLD liver fat score: 1.874 ± 0.258 vs. -0.793 ± 0.099, p<0.001; LAP: 76.8 ± 4.9 vs. 33.4 ± 1.4, p<0.001; and HIS: 49.8 ± 1 vs. 43 ± 0.5, p<0.001). Of the fibrosis indices, only BAAT (F2-4: 50.6% vs. 4.2%) was higher in PCOS women with MetS. CONCLUSIONS: Non-invasive indices of hepatic steatosis were significantly higher in PCOS, especially in the presence of MetS, whereas indices of hepatic fibrosis yielded controversial results. Further studies are warranted to evaluate the long-term outcomes of hepatic steatosis and fibrosis indices in PCOS women.

The role of orlistat combined with lifestyle changes in the management of overweight and obese patients with polycystic ovary syndrome.

OBJECTIVE: Obesity is frequently present in women with the polycystic ovary syndrome (PCOS) and aggravates insulin resistance (IR) and hyperandrogenemia. We aimed to assess the effects of orlistat combined with lifestyle changes in overweight and obese women with PCOS and body mass index (BMI)-matched controls. DESIGN: Prospective study. PATIENTS: We studied 101 women with PCOS (age 26·1 ± 6·4 years, BMI 34·5 ± 5·9 kg/m(2) ) and 29 BMI-matched women with normal ovulating cycles. All women were instructed to follow a low-calorie diet to exercise and were treated with orlistat 120 mg tid for 6 months. MEASUREMENTS: Metabolic and endocrine characteristics of PCOS, blood pressure (BP) and lipid profile. RESULTS: A significant and comparable reduction in BMI was observed in women with PCOS and controls. Systolic and diastolic BP decreased only in women with PCOS. Serum low-density lipoprotein cholesterol levels decreased in both women with PCOS and controls; however, this reduction was greater in controls. In contrast, serum high-density lipoprotein cholesterol levels did not change in women with PCOS and decreased in controls. Serum triglyceride levels decreased significantly and to a comparable degree in the two groups. Similarly, markers of IR improved significantly and to a comparable degree in women with PCOS and controls. Serum testosterone levels and the free androgen index decreased significantly in women with PCOS and did not change in controls. CONCLUSIONS: Orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR, hyperandrogenemia and cardiovascular risk factors.

Minimally invasive techniques for female stress urinary incontinence, how, why, when.

AIM: The main purpose of this paper is to summarize the recent experience that has been obtained till now in the surgical treatment of urinary stress incontinence with less invasive techniques. MATERIALS AND METHODS: We used current literature and papers published in MEDLINE and Cochrane library. The keywords used for this review were Stress urinary incontinence, Tension-free vaginal tape (TVT), Transobturator tape (TOT, TVT-O), and Single-incision mini-slings (SIMS). RESULTS: Tension-free vaginal tape and the transobturator urethral suspension are the most commonly used surgical approach for women who suffer from stress urinary incontinence, with long-term success rates ranging from 84 to 95 %. TVT is shown to be as effective as the older colposuspension, associated with less post-operative complications, shorter hospital stay and shorter recovery period. Bladder perforations that have been mentioned with the TVT inserter apparently do not result in any clinically significant morbidity. Major vascular and bowel injuries have been reported at rates of 0.07 and 0.04 %, respectively. Studies between TVT-O and TOT show equal effectiveness with slightly lower cure rates than TVT group, but TOT had a significant lower risk of bladder and vaginal perforations. There were no significant differences in objective cure rates between 'inside-out' and 'outside-in' transobturator tapes. Very recently a meta-analysis does not support routine use of SIMS in clinical practice, moreover suggested the retropubic TVT as the preferred choice for the management of stress urinary incontinence due to familiarity, its effectiveness, minimal invasiveness and low complication and morbidity rates as a primary procedure. Similar results have been announced in a randomized control trial in USA. CONCLUSIONS: Certainly, larger randomized clinical trials with longer follow-up about the mentioned techniques are needed to accurately determine the efficacy and safety of the mentioned minimally invasive techniques.

The clinical significance and primary determinants of hirsutism in patients with polycystic ovary syndrome.

OBJECTIVE: Hirsutism is frequently present in patients with polycystic ovary syndrome (PCOS) and is a major sign of hyperandrogenism. However, other disorders frequently present in PCOS, particularly abdominal obesity and insulin resistance (IR), have also been implicated in the development of hirsutism in this population but relevant data are limited. We aimed to define the determinants of the presence of hirsutism in PCOS. DESIGN: Observational study. METHODS: We studied 1297 patients with PCOS (age 24.3±5.8 years, BMI 26.8±6.9 kg/m(2)). Hirsutism was defined as a modified Ferriman-Gallwey score ≥8. RESULTS: Women with hirsutism were younger, had greater BMI, and had higher levels of circulating androgens than women without hirsutism; markers of IR did not differ between the two groups after adjustment for age and BMI. The prevalence of hirsutism progressively declined with age, was lower in normal-weight women than in overweight and obese women, and was comparably prevalent in the hyperandrogenemic phenotypes of PCOS. In binary logistic regression analysis, independent predictors of the presence of hirsutism were younger age, larger waist circumference (W), and higher serum testosterone levels. In stepwise linear regression analysis, the Ferriman-Gallwey score independently correlated with age, W, free androgen index, and serum Δ4-androstenedione and DHEAS levels. CONCLUSIONS: Besides hyperandrogenemia, abdominal obesity, and young age are independently associated with the presence of hirsutism. In contrast, the relationship between IR and hirsutism appears to be mediated by the more severe obesity of insulin-resistant patients with PCOS.

Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility.

Obesity is frequently present in patients with polycystic ovary syndrome (PCOS) and plays an important role in the pathogenesis of the metabolic, endocrine, and reproductive abnormalities associated with this syndrome. We aimed to summarize the effects of lifestyle changes and anti-obesity pharmacotherapy in patients with PCOS. We reviewed the literature regarding the effects of lifestyle changes and anti-obesity agents on the metabolic and endocrine abnormalities of PCOS. Lifestyle changes, including diet, exercise, and behavioral modification, appear to improve the metabolic and reproductive abnormalities of overweight and obese patients with PCOS. Therefore, lifestyle changes appear to represent the first-line management for all overweight and obese patients with PCOS. However, the optimal composition of diet and the optimal type of exercise in these patients are unknown. Anti-obesity agents that have been studied in PCOS include orlistat, sibutramine, and rimonabant. However, the latter two agents have been withdrawn from the market because of side effects. Long-term studies with orlistat in overweight and obese diabetic patients showed greater weight loss and metabolic and cardiovascular benefits than those achieved with lifestyle changes alone. However, there are limited data on the efficacy of orlistat in women with PCOS. In conclusion, lifestyle changes (diet, exercise and behavioral modification), particularly when combined with anti-obesity agents, exert beneficial effects on the endocrine abnormalities of obese patients with PCOS and improve metabolic parameters.

Association between menstrual cycle irregularities and endocrine and metabolic characteristics of the polycystic ovary syndrome.

OBJECTIVE: Insulin resistance (IR) is frequent in polycystic ovary syndrome (PCOS) and contributes to the increased risk for type 2 diabetes mellitus and cardiovascular disease of this population. Several markers of IR are used but most are expensive or have limited sensitivity and specificity. Preliminary data suggest that the menstrual cycle pattern correlates with IR in PCOS but existing studies are small. We aimed to assess the relationship between the type of menstrual cycle irregularities and IR in PCOS. DESIGN: Prospective study. METHODS: We studied 1285 women with PCOS, divided according to the menstrual cycle pattern. RESULTS: Patients with isolated secondary amenorrhea and those with secondary amenorrhea alternating with regular menstrual cycles were more insulin resistant than patients with regular cycles (Group D). Patients with isolated oligomenorrhea were also more insulin resistant than Group D. However, patients with oligomenorrhea alternating with regular cycles, secondary amenorrhea, or polymenorrhea had comparable levels of markers of IR with Group D. Moreover, patients with oligomenorrhea alternating with regular cycles were less insulin resistant than patients with secondary amenorrhea alternating with regular cycles. Finally, patients with isolated polymenorrhea and those with polymenorrhea alternating with regular cycles had comparable levels of markers of IR with Group D. CONCLUSIONS: Amenorrhea is associated with more pronounced IR in PCOS, and oligomenorrhea portends a less excessive risk for IR than amenorrhea whereas polymenorrhea appears to be even more benign metabolically. Therefore, the type of menstrual cycle abnormality appears to represent a useful tool for identifying a more adverse metabolic profile in PCOS.