Anastasios Makedos

Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome

BACKGROUND The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed. METHODS A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. RESULTS A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77-1.21)], Hcy [2.25 (1.46-3.03)], PAI-1 antigen [16.96 (7.25-26.28)], PAI-1 activity [0.71 (0.18-1.23)], VEGF [1.72 (0.96-2.48)], ADMA [0.19 (0.08-0.3)], AGEs [3.91 (2.36-5.45)] and Lp(a) [0.81 (0.58-1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07-1.44)], ET-1 [1.06 (0.52-1.59)] and fibrinogen [0.20 (0.01-0.39)], whereas no difference was detected for IL-6 [0.71 (-0.16 to 1.59)]. CONCLUSIONS Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.

Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial

STUDY QUESTION Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? SUMMARY ANSWER A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. WHAT IS KNOWN ALREADY Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. STUDY DESIGN, SIZE, DURATION Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). PARTICIPANTS/MATERIALS, SETTING, METHODS Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. MAIN RESULTS AND THE ROLE OF CHANCE The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2-4, 2-3, respectively, P = 0.26]. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1. A multivariable analysis adjusting for all the potential baseline differences confirmed this finding. No significant difference was observed regarding the probability of live birth between the corifollitropin alfa and the follitropin beta group (live birth per patient reaching oocyte retrieval: 7.9 versus 2.6%, respectively, difference +5.3%, 95% CI: -6.8 to +18.3). LIMITATIONS, REASONS FOR CAUTION The present study was not powered to test a smaller difference (e.g. 1 COC) in terms of COCs retrieved as well as to show potential differences in the probability of pregnancy. Moreover, it would be interesting to assess whether the continuation of stimulation in the long acting FSH arm, where necessary, with 200 IU instead of 450 IU of follitropin beta would have altered the direction or the magnitude of the effect of the type of FSH, observed on the number of COCs retrieved. WIDER IMPLICATIONS OF THE FINDINGS Corifollitropin alfa simplifies IVF treatment because it is administered in a GnRH antagonist protocol and replaces seven daily FSH injections with a single one of a long acting FSH without compromising the outcome. It could greatly reduce the burden of treatment for poor responders and this deserves further investigation.

Serum High-Sensitivity C-Reactive Protein and Homocysteine Changes During Hormonal Therapy in Women With Polycystic Ovary Syndrome: A Prospective, Matched Study

The study evaluated the effect of 5 hormonal regimes on serum levels of high-sensitivity C-reactive protein (hsCRP) and homocysteine (Hcy) in women with polycystic ovary syndrome (PCOS). Women with PCOS received (1) conjugated estrogens and cyproterone acetate (n = 22), (2) 17β-estradiol and cyproterone acetate (n = 17), (3) ethinyl-estradiol and cyproterone acetate (high dose; n = 20), (4) ethinyl-estradiol plus cyproterone acetate (low dose; n = 12), or (5) ethinyl-estradiol plus desogetrel (n = 12). Both hsCRP and Hcy levels were measured at baseline and after 4, 7, and 12 months. The 17β-estradiol/cyproterone acetate regime resulted in significant reduction of both hsCRP and Hcy levels (P < .001). The other 4 regimes only resulted in a reduction of Hcy levels (P < .001). In conclusion, the 17β-estradiol/cyproterone acetate regime had the most favorable effects in women with PCOS regarding serum levels of hsCRP and Hcy.

Adhesion Prevention Strategies in Laparoscopic Surgery

Adhesions are defined as abnormal attachments between tissues and organs [1]. Intra-ab‐ dominal adhesions may be classified as congenital or acquired [2]. Congenital adhesions are a consequence of embryological anomaly in the development of the peritoneal cavity. Ac‐ quired adhesions result from the inflammatory response of the peritoneum that arises after intra-abdominal inflammatory processes (e.g. acute appendicitis, pelvic inflammatory dis‐ ease, exposure to intestinal contents and previous use of intrauterine contraceptive devices), radiation and surgical trauma [3]. It has been reported that the majority of acquired adhe‐ sions (about 90%) are post-surgical [2].

Is the time interval between HCG administration and oocyte retrieval associated with oocyte retrieval rate

The aim of this study was to evaluate whether prolongation of the time interval between HCG administration and oocyte retrieval, from 36 h to 38 h, affects oocyte retrieval rate in women undergoing ovarian stimulation with gonadotrophins and GnRH antagonists for IVF. One hundred and fifty-six normo-ovulatory women were randomized to have oocyte retrieval performed 36 h (n = 78) or 38 h (n = 78) following HCG administration. Oocyte retrieval rate was defined as number of cumulus-oocyte-complex (COC) retrieved/follicle ≥ 11 mm present on day of HCG administration. No significant differences were observed between the groups regarding baseline characteristics. Moreover, no significant difference was observed between the groups regarding oocyte retrieval rate (difference: + 1.2%, 95% CI for difference between medians: -4.5 to +12.1). The median (95% CI for the median) was not significantly different between the groups regarding number of cumulus-oocyte-complexes (COCs) retrieved: 5.5 (5.0-7.0) versus 6.0 (5.0-6.2), respectively, and fertilization rates: 57.7% (50.0-66.7) versus 50.0% (44.8-65.5), respectively. Live birth rates were similar between the groups (20.5% versus 16.7%, RD: + 3.8%, 95% CI: -8.5 to +16.1, respectively). Prolongation of time interval between HCG administration and oocyte retrieval from 36 h to 38 h does not affect oocyte retrieval rate.

Prevalence of occult leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of leiomyomas in reproductive-age women

STUDY QUESTION What is the prevalence of leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of fibroids in reproductive age women? SUMMARY ANSWER No case of leiomyosarcomas but seven atypical leiomyomas were found in 1216 subjects. WHAT IS KNOWN ALREADY Although uterine sarcoma is a rare entity affecting usually older peri- or post-menopausal women, the Food and Drug Administration discourages use of laparoscopic power morcellation of uterine fibroids. STUDY DESIGN, SIZE, DURATION Retrospective review of data extracted from a single center database of 1216 consecutive women who underwent laparoscopic morcellation of 2582 unsuspicious leiomyomas between June 2003 and December 2015 and were followed-up until December 2016. PARTICIPANTS/MATERIALS, SETTINGS, METHODS A total of 1216 women, aged 18-45 years, underwent laparoscopic morcellation of 2582 apparently benign leiomyomas by the same surgeon and all specimen slides were examined by the same experienced pathologist. MAIN RESULTS AND THE ROLE OF CHANCE The prevalence of leiomyosarcomas and atypical leiomyomas was 0% (95% CI: 0-0.3%) and 0.6% (95% CI: 0.23-1.18%) (six atypical-bizarre and one mitotically active leiomyoma) respectively. In addition, there were identified 34 cases of adenomyomas, 45 leiomyomas with infarcts, 81 cellular leiomyomas and 133 degenerated leiomyomas. No morcellator-associated complication was recorded and none of the patients included in this study required conversion to laparotomy. LIMITATIONS, REASONS FOR CAUTION Retrospective and single referral center study design. WIDER IMPLICATIONS OF THE FINDINGS Laparoscopic morcellation of unsuspicious leiomyomas after careful preoperative work up seems to be safe in women of reproductive age. STUDY FUNDING/COMPETING INTEREST(S) None.

Uterine manifestations of tuberous sclerosis complex as a random finding at laparoscopy.

Tuberous sclerosis complex is a genetic disease inherited by the autosomal dominant pattern that causes nonmalignant tumors to multiple organs, such as the brain, kidneys, heart, eyes, and skin [1]. Symptoms are relevant to the target organs. The existing literature is limited regarding uterine manifestations; and the behavior of uterine lesions is generally benign, although a few cases have been reported in the literature with local aggressive behavior and distant metastases [2]. A 33-year-old woman presented to the Gynecology Outpatient Clinic in May 2012 with primary infertility of 18 months’ duration. The patient had been diagnosed with tuberous sclerosis complex involving the brain and both kidneys, but had no pertinent gynecological history other than dysmenorrhea. During transvaginal ultrasound, a 4-cm left ovarian cyst was detected thatwas consistentwith endometrioma. Routine diagnostic hysteroscopy was performed and there were no abnormal findings. During laparoscopy, the uterus was observed to have multiple hemorrhagic subserous cysts (Fig. 1), a left ovarian endometrioma, and scattered endometriosis on the right ovary and both lateral pelvic walls. The ovarian endometriomawas removed and the scattered endometriosis was vaporized with a carbon dioxide laser. Biopsies were taken from the uterine hemorrhagic cysts and sent for immediate histopathologic examination, where endometriosis and malignancy were excluded. Owing to excessive bleeding during biopsy sampling it was decided that the uterine lesions should not be removed without assessment of the depth of involvement into the myometrium. The final pathology report was lymphangiomyomatosis with contributions of lymphatic, muscle, and vascular tissue. Lymphangiomyomatosis is a common finding of tuberous sclerosis complex in the lungs, where the lung parenchyma can be replaced by multiple cysts. Subsequent CT scan of the lung revealed no abnormal findings. The management decision was not to remove the uterine lesions owing to the excessive bleeding during biopsy and because they had been asymptomatic. In addition, the patient had not provided written consent for a further procedure, other than for surgical management of endometriosis.