Excess Metabolic and Cardiovascular Risk is not Manifested in all Phenotypes of Polycystic Ovary Syndrome: Implications for Diagnosis and Treatment.

AIM: To assess the potential differences in the metabolic and cardiovascular disease (CVD) risk between the distinct phenotypes of the Polycystic Ovary Syndrome (PCOS) according to the Rotterdam definition regardless of body mass index (BMI). PATIENTS-METHODS: The study included 300 women; 240 women with PCOS, according to the Rotterdam criteria and 60 controls without PCOS. All women were further subdivided, according to their BMI, into normal-weight and overweight/obese and PCOS women were furthermore subdivided to the 4 phenotypes of the syndrome. A complete hormonal and metabolic profile as well as the levels of high sensitivity C reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. OUTCOMES: Levels of surrogate markers of subclinical atherosclerosis (hsCRP and Lp-PLA2), levels of evaluated CVD risk score using risk engines, and several correlations of CVD risk factors. RESULTS: hsCRP levels were higher but not significantly so in PCOS women compared with controls. In lean PCOS patients, Lp-PLA2 levels were significantly higher, compared with lean controls, mainly in the 2 classic phenotypes. Overweight/obese patients in all 4 phenotypes had significantly higher Lp-PLA2 levels compared with overweight/obese controls. Evaluated CVD risk according to 4 risk engines was not different among phenotypes and between PCOS patients and controls. There were several correlations of risk factors with metabolic syndrome and non-alcoholic fatty liver disease requiring appropriate treatment. CONCLUSION: Only 2 of 4 Rotterdam phenotypes, identical with those of the classic PCOS definition, have excess cardiometabolic risk. These need to be treated to prevent CVD events.

Operator experience reduces the risk of second trimester amniocentesis-related adverse outcomes.

OBJECTIVE: To investigate the impact of operator experience on amniocentesis-related adverse outcomes. STUDY DESIGN: Retrospective study of mid-trimester amniocenteses performed by the same operator on singleton pregnancies in a single private institution during 1994-2007. Outcomes were hemorrhagic or dark amniotic fluid aspiration, insufficient volume aspiration, repeated puncture and fetal loss. Rates were estimated annually, as well as for every 10% of procedures up to the total number. The association of each outcome with epidemiological aspects was also examined. RESULTS: In total, 5913 amniocenteses were performed. The overall rate of adverse outcomes was 5.4%. The total adverse outcome rate reduced from 10.2% in the first 10% of cases to 3.0% in the last 10% (P=.001). The rate of hemorrhagic fluid gradually decreased from 4.4% to 1.5% (P=.05) over the same intervals. The fetal loss rate was also reduced from 0.5% during the first half to 0.3% in the second half of the study period (P=NS). Logistic regression analysis indicated no significant correlations between adverse outcomes with any of epidemiological parameters of women undergoing amniocentesis. CONCLUSION: Operator experience has a beneficial impact on preventing procedure-related adverse outcomes.

Comparative study of the intravenous chemoprophylaxix versus local Sulmycin® Implant E Sponge use in vaginal hysterectomy.

OBJECTIVE: The aim of this comparative study was to ascertain the efficacy of the Sulmycin® Implant E, an antiseptic sponge, on the incidence of peri- and postoperative morbidity in patients subjected to vaginal hysterectomy. MATERIAL AND METHODS: This eleven-year study included 228 patients undergoing vaginal hysterectomy. The patients were divided into two groups. Group A included 169 participants with benign diseases (fibroids, dysfunctional uterine bleeding and prolapse) and group B included 59 patients with early stage endometrial cancer or atypical hyperplasia. Women of both groups were further divided into three subgroups: (a) receiving a single dose of intravenous cefuroxime (2 gr) (group A: 55, group B: 19), (b) receiving three doses of intravenous cefuroxime (2 gr) (group A: 54, group B: 19), and (c) locally placed a collagen sponge containing gentamycin (Sulmycin® Implant E) (group A: 60, group B: 21). RESULTS: The number of postoperative infections (mainly urinary tract infections) did not differ between women of the three subgroups of patients in both groups. There were no important differences affecting the postoperative hospitalization, healing procedure and adhesion of the cuff between women of the three subgroups in both groups. CONCLUSION: The local chemoprophylaxis with Sulmycin® Implant E, a collagen sponge containing gentamycin and placed on the vaginal cuff, is well tolerated and equally effective as intravenous antibiotics.

Serum anti-Müllerian hormone (AMH) levels are differentially modulated by both serum gonadotropins and not only by serum follicle stimulating hormone (FSH) levels.

It is generally accepted that serum AMH levels are thought to reflect the size of the ovarian follicle pool. Therefore, an inverse correlation between serum AMH and Follicle Stimulating Hormone (FSH) levels has been noted in older women with abnormal or exhausted follicular development, such as menopause, leading to the use of serum AMH as a marker of ovarian reserve. In clinical practice the use of serum AMH for the assessment of ovarian reserve has been expanding to women irrespective of age, such as women in early menopause or women undergoing ovarian stimulation for in vitro fertilization (IVF). To our knowledge, this opinion article aims to show that serum AMH levels are differentially modulated by both serum gonadotropins, depending on the degree of ovarian reserve. For instance, in conditions of increased LH and normal to low FSH such as young PCOS women with hyperandrogenemia, serum AMH levels are increased and tend to be associated to serum LH, while in conditions of increased FSH such as premature ovarian failure, serum AMH levels are decreased and tend to be associated to serum FSH. The evidence that supports the theory of a link between AMH and LH in PCOS comes from both in vitro and in vivo experiments. Serum AMH levels have been directly linked to serum LH levels in the most severe forms of PCOS. LH has also been shown in vitro to directly increase serum AMH levels in PCOS derived granulosa cells. Finally, hyperandrogenism, obesity, insulin resistance and OCs administration, indirectly affect serum AMH levels, by modulating serum LH. Concerning PCOS, the correlation between AMH and LH can be used in the future for the assessment of the severity of PCOS, of the amelioration of PCOS under OCs treatment, as well as of the efficacy of infertility treatment in clomiphene resistant PCOS women. Apart from PCOS, the clinical implications of this theoretical approach might become important in a variety of medical conditions. For instance, serum AMH levels might be used in the future as a marker of cysts formation in the ovaries as well as of ovarian endometriosis, or as a marker of ovarian response to treatment of ovarian cysts or ovarian endometriosis by oral contraceptives, etc. Additionally, in infertile women with hypothalamic amenorrhea, serum AMH levels might be used for the assessment of ovarian recovery under treatment.

The clinical significance of anti-Müllerian hormone evaluation in gynecological endocrinology.

Anti-Müllerian hormone (AMH) is a homodimeric glycoprotein, a member of the transforming growth factor-ß superfamily. Over the last decade, a large number of studies examining the multiple roles of AMH have been published. AMH levels accurately reflect the ovarian follicular reserve and could, therefore, be considered as an extremely sensitive marker of ovarian aging and a valuable tool in the diagnosis and the recognition of recurrence of granulosa cell tumors. Furthermore, AMH evaluation is of clinical importance in predicting the success of in vitro fertilization (IVF). Additionally, AMH could be a surrogate diagnostic marker of polycystic ovary syndrome in cases in which ultrasonographic examination is not possible. This article is a review of the clinical usefulness of AMH evaluation in the fields of gynecological endocrinology, menopause, gynecological oncology and assisted reproduction. Special reference is made to the possible implications of AMH in the pathogenesis of polycystic ovary syndrome and the relationship between AMH and obesity.

Is the risk for cardiovascular disease increased in all phenotypes of the polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is a common disorder in women of reproductive age, affecting around 10% of them. Polycystic ovary syndrome is considered to be related to increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). There are 2 definitions for PCOS: one adopted in 1990 (classical PCOS with phenotypes A and B) and the other in 2003 (Rotterdam criteria with 4 phenotypes A to D). The latter is a wider definition including the 1990 phenotypes. There is mounting data suggesting that phenotypes C and D are not actually related to increased CVD risk, and thus screening for CVD risk factors of intervening for primary CVD prevention in young women is not cost-effective. There is an increasing number of suggestions to return to the 1990 criteria plus some metabolic parameters to identify real CVD risk in this population. However, such a strategy needs verification by large, prospective studies.

Phenotypic expression, body mass index and insulin resistance in relation to LH levels in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate LH levels in women with the classic (1990 criteria) and the newer (2003 criteria) PCOS phenotypes, and to examine the impact of BMI and insulin resistance indices on hormone levels. STUDY DESIGN: In this controlled clinical study 936 women with PCOS, classified as classic (n=729) and newer (n=207), and 204 controls were included. All women were divided into normal-weight (BMI<25 kg/m(2)) and overweight plus obese (BMI≥25 kg/m(2)). Serum LH, FSH, anthropometrics, androgens, fasting insulin and glucose, HoMA-IR, number of follicles, and ovarian volume were assessed. RESULTS: Women with classic PCOS presented significantly higher LH and LH/FSH ratios, and lower glucose/insulin levels than those with the newer phenotype and controls. Overweight plus obese women of all groups had lower LH levels than normal-weight women. Independent positive correlations between LH and androgens and negative correlation between LH and BMI were found. CONCLUSIONS: The higher LH concentrations of the classic phenotypes of PCOS could be attributed to the higher androgen levels, which desensitize the hypothalamus to the negative feedback regulation by progesterone. Moreover, the lower LH levels of overweight plus obese women of all groups could be attributed to the increased peripheral aromatization of androgens to estrogens in adipose tissue leading to suppression of LH secretion. CONDENSATION: Both normal-weight and overweight women with classic PCOS phenotypes present higher LH levels and LH-to-FSH ratios than women with similar BMI but the newer phenotypes.

Amniocentesis-related adverse outcomes in diamniotic twins: is there a difference compared to singleton pregnancies?

OBJECTIVE: To investigate whether diamniotic twin gestations are at increased risk of amniocentesis-related adverse outcomes compared to singleton pregnancies. STUDY DESIGN: This was a retrospective study of mid-trimester amniocenteses performed during the period 1993-2009. Cases were divided in two groups, one including singleton (Group 1) and the other diamniotic twin pregnancies (Group 2). All amniocentesis-related adverse outcomes were reviewed, including aspiration of insufficient amniotic fluid, aspiration of hemorrhagic amniotic fluid, repeated puncture and miscarriage. The incidence of these adverse outcomes was compared between the two groups. RESULTS: In total, 6270 cases were included in the study (Group 1, n=6150 and Group 2, n=120). Advanced maternal age was the main indication for amniocentesis in both singleton and twin pregnancies. There was no difference in the incidence of insufficient sample aspiration (0.2% in singletons vs. 0.0% in twins, P=NS), in the incidence of blood-stained amniotic fluid (3.7% in singletons vs. 4.6% in twins, P=NS), in the rate of need for second attempt (2.1% in singletons vs. 1.7% in twins, P=NS) or in the miscarriage rate (0.24% in singletons vs. 0% in twins). CONCLUSION: In our experience, the incidence of amniocentesis-related adverse outcomes is not increased in diamniotic twins compared to singleton pregnancies.

Hormone therapy and asymmetrical dimethylarginine in postmenopausal women.

Women present an estradiol-dependent cardiovascular risk profile. Based on various studies, it was considered that estrogen therapy (ET) in postmenopausal women could probably reduce the higher cardiovascular risk in this group. Assymetric dimethylarginine (ADMA) is an endogenous methylated arginine which inhibits nitric oxide (NO) synthesis by competing with the substrate of NO, L-arginine, leading to endothelial dysfunction and, consequently, to atherosclerosis. Moreover, ADMA has been considered as an independent risk factor for cardiovascular disease. It has also been found that hormone therapy (HT), and mainly oral estrogen therapy, lowers ADMA concentrations in healthy postmenopausal women. The effect of estrogens on ADMA levels, although small, is considered important, as physiological variation of ADMA is limited. Nevertheless, larger randomized trials are necessary to establish that estrogens substantially lower ADMA levels and that these changes really reflect improved cardiovascular prognosis in postmenopausal women.

Decreased active, total and altered active to total ghrelin ratio in normal weight women with the more severe form of polycystic ovary syndrome.

OBJECTIVE: To assess total, active and active to total serum ghrelin ratio in normal weight women with polycystic ovary syndrome (PCOS) and in healthy ovulatory control women. STUDY DESIGN: The study included 50 normal weight women with PCOS with a mean age of 23.70+/-4.99 years and 10 control women with a mean age of 30+/-5.80 years. The diagnosis of PCOS was based on the presence of biochemical hyperandrogenemia, chronic anovulation and polycystic ovarian morphology according to the Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Serum total and active ghrelin were measured by RIA, using commercially available kits. RESULTS: A significantly lower serum active/total ghrelin ratio was noted in the more severe form of PCOS with hyperandrogenemia, chronic anovulation and polycystic ovarian morphology. Both total and active serum ghrelin levels were negatively correlated to hirsutism score, to plasma glucose levels and to QUICKI and HOMA-IR indices of Insulin Resistance. A statistically significant difference was detected between the more severe and the milder forms of PCOS, concerning serum levels of total ghrelin (p=0.017), active ghrelin (p=0.007) and the active/total ghrelin ratio (p=0.026). CONCLUSIONS: The results of the present study demonstrate an altered active to total ghrelin ratio, as well as a tendency towards lower both total and active fasting serum ghrelin levels in normal weight PCOS, more pronounced in the more severe forms of the syndrome.

Adiponectin levels reflect the different phenotypes of polycystic ovary syndrome: study in normal weight, normoinsulinemic patients.

Diagnosis of polycystic ovary syndrome (PCOS), at present very common in women of reproductive age, is implicated with potential long-term metabolic consequences that are difficult to be investigated due to the heterogeneity in the manifestation of the syndrome. The present study constitutes an effort to explore the graduated metabolic impact of the different PCOS phenotypic groups through the levels of adiponectin, an adipose-derived hormone, in 100 normal weight, normoinsulinemic patients with PCOS.