Ioannis Matalliotakis

CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis

OBJECTIVE To investigate the possibility of genetic contribution of CYP1A1, CYP19, GSTM1, and GSTT1 polymorphisms to endometriosis. DESIGN Genetic polymorphism analysis. SETTING Case-control study. PATIENT(S) A group of 275 women with sporadic endometriosis was compared with a group of 346 fertile, endometriosis-free women. INTERVENTION(S) Surgical, laparoscopic, and histological examination. MAIN OUTCOME MEASURE(S) Blood specimens were obtained from endometriosis cases and controls. Polymerase chain reaction-based assays were performed for the determination of individuals genotype. RESULT(S) The CYP19 VNTR, located in intron 4 (TTTA)(10) allele increases the risk for endometriosis development (odds ratio [OR], 4.99; 95% confidence interval [95% CI], 1.351 to 18.436). The combined genotype CYP1A1 wt/m1 or m1/m1 and GSTM1 null deletion adds to this risk (OR, 1.95; 95% CI, 1.266 to 2.995 and OR, 2.23; 95% CI, 0.631 to 7.906, respectively). In contrast, the CYP1A1 wt/wt genotype exhibits a protective effect, with a 38% reduction in the odds for endometriosis development (OR, 0.62; 95% CI, 0.440 to 0.883). CONCLUSION(S) Our data suggest that CYP19 VNTR (TTTA)(10) allele as well as the combined genotype CYP1A1 m1 polymorphism and GSTM1 null deletion associate with the endometriosis phenotype, whereas the GSTT1 null deletion does not.

Serum concentrations of growth factors in women with and without endometriosis: the action of anti-endometriosis medicines

Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis. Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis. Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease. In the present study, we investigate the soluble levels of vascular endothelial growth factor (VEGF), epidermal growth factor-receptor (EGF-R), granulocyte/macrophage-colony stimulating factor (GM-CSF), Insulin-like growth factor-1 (IGF-1) and interferon-gamma (IFN-gamma) in the serum of 28 women with and 20 without endometriosis. We also compared these levels before, during and after treatment with danazol and leuprorelin acetate depot, the two therapeutic regiments of choice concerning this disease. We found that only sVEGF levels were higher in women with endometriosis in comparison to controls (P < 0.001) while sEGF-R is not present. GM-CSF, IGF-1 and IFN-gamma soluble levels are not affected in either healthy or endometriotic subjects. The 6-month treatment with danazol decreased sVEGF levels (P < 0.02) and increased sEGF-R levels (P < 0.001). These observations support the view that VEGF may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold. However, future studies will be focused on the anti-angiogenic control of the action of VEGF in patients with endometriosis.

The role of leptin in fertility

The relationship between metabolism and reproduction remains a mystery in female endocrinology. Such substances as insulin, amino acids and IGFBP-I have been proposed as signals of body mass fat on the genital axis. Today this role is claimed by leptin, a protein hormone decoded from the obesity gene and is secreted exclusively from adipose tissue. This hormone acts on the central nervous system (CNS) to result in the suppression of food intake and increase in energy consumption. What is more, it also influences the capacity for reproduction. This paper reports findings with regard to the factors influencing the secretion of leptin and identification of the leptins hormonal receptors. Particular emphasis was placed on the relationship between secretion of leptin and disturbances in menstruation, the anticipated role of this hormone in the pathogenesis of the polycystic ovarian syndrome (PCOS) and its effects on the reproductive capacity.

Adenomyosis: what is the impact on fertility?

Purpose of review This review is timely and relevant for several reasons. The incidence of adenomyosis begins to rise from the mid-thirties. Moreover, more women are delaying their first pregnancy until later in their thirties or forties, and consequently adenomyosis is encountered more frequently in the fertility clinic during diagnostic work-up. Furthermore, it is difficult to diagnose adenomyosis before surgery, because there are no pathognomonic signs, symptoms or physical findings. Finally, reference data are very limited. Recent findings This review refers to adenomyosis of the uterus as a factor in female infertility. The clinical presentation of adenomyosis uteri is also reviewed, as well as animal and human studies concerning the effect of adenomyosis in female infertility. Different treatment options are discussed, especially those referring to patients who wish to maintain their fecundity. Summary Uterine adenomyosis remains a fairly frequent and debilitating disease that will be encountered with increasing incidence in the infertile female population. While spectacular advances have been made in recent years in the non-invasive diagnosis of the condition, non-surgical treatment options for infertile patients with adenomyosis arise but need to be confirmed in larger series.

Microsatellite DNA assays reveal an allelic imbalance in p16Ink4, GALT, p53, and APOA2 loci in patients with endometriosis

OBJECTIVE To detect allelic imbalance on specific genetic loci occurring in endometriosis. DESIGN Microsatellite analysis. SETTING Paraffin-embedded tissues histologically confirmed as endometriotic or normal endometrium. PATIENT(S) Premenopausal women undergoing laparoscopy for suspected endometriosis. INTERVENTION(S) Laparoscopic excision of specimens. MAIN OUTCOME MEASURE(S) Allelic imbalance and alterations of intensity of microsatellite alleles. RESULT(S) Five of 17 microsatellite DNA markers (29.4%) showed allelic imbalance. Eight samples (36.4%) showed allelic imbalance in at least one locus. Loci 9p21, 1q21, and 17p13.1 exhibited imbalance in 27.3%, 4.5%, and 4.5%, respectively. A 3-fold increase of the fractional allelic loss was observed from disease stage II to III and IV, whereas only 1.3-fold was found between patients of 41-50 and 20-40 years. CONCLUSION(S) We found that loss of heterozygosity on p16(Ink4), GALT, and p53, as well as on APOA2, a region frequently lost in ovarian cancer, occurs in endometriosis, even in stage II of the disease. The occurrence of such genomic alterations may represent important events in the development of endometriosis. The 9p21 locus may contain a gene associated with the pathogenesis of the disease, and therefore its loss may be a prognostic marker of the disease.

Impact of body mass index on IVF and ICSI outcome: a retrospective study

A group of 140 women with a body mass index (BMI) < or = 24 kg/m(2) undergoing 291 cycles was compared with a group of 138 women with a BMI >24 kg/m(2) in 291 cycles, with respect to duration of ovarian stimulation and dose of gonadotrophin, number of oocytes collected, cleavage and implantation rate, clinical pregnancy, miscarriage and delivery rates. Patients with a BMI > 24 kg/m(2) demonstrated a significant decrease in the number of follicles after stimulation (P = 0.01), a comparative increase in the number ampoules of gonadotrophin used (P = 0.03) and a lower number of eggs collected (P = 0.05). The mean number of embryos on days 1, 2 and 3 was significantly lower in the group with BMI > 24 kg/m(2) (P < 0.001). No significant difference was found in clinical pregnancy and miscarriage rates between the two groups. In spite of the lower response in women with BMI > 24 kg/m(2), the delivery rate per retrieval was not different (24.6 versus 24.8%). These results indicate a lower stimulation response in women with elevated BMI, but no adverse effect on IVF outcome. In relation to wellbeing, however, it is recommended that patients with a high BMI reduce their weight before IVF treatment.

Detection of interleukin-6, interleukin-8, and interleukin-11 in plasma from women with spontaneous abortion

OBJECTIVE To investigate the role of IL-6, IL-8, and IL-11 in the immune-regulatory mechanisms involved in the spontaneous abortion of the first trimester of pregnancy. STUDY DESIGN Plasma levels of IL-6, IL-8, and IL-11 were determined in 68 women who had a spontaneous abortion of unknown aetiology during the first trimester of pregnancy. They were compared with the corresponding levels of 73 age-matched pregnant women who had an uneventful pregnancy, and 52 age-matched non-pregnant women. All enrolled women presented without any severe disease, syndrome or recent infection. Cytokine levels were measured by a sensitive sandwich enzyme-linked immunoassay. RESULTS The women with spontaneous abortion had significantly decreased plasma levels of IL-6, IL-8 and IL-11 compared to those with normal pregnancies (P<0.05). The non-pregnant women had no detectable cytokine levels. CONCLUSIONS The reduced plasma levels of IL-6, IL-8 and IL-11 in women with spontaneous abortion may be related to the underlying aetiopathogenetic mechanisms, however, there is no sufficient evidence for their use as predictive markers of pregnancy outcome.

A case of sigmoid endometriosis difficult to differentiate from colon cancer

BackgroundAlthough endometriosis with sigmoid serosal involvement is not uncommon in women of childbearing age, the mucosal involvement is rare and differential diagnosis from colon cancer may be difficult due to the lack of pathognomonic symptoms and the poor diagnostic yield of colonoscopy and colonic biopsies.Case presentationWe present a case of a young woman with sigmoid endometriosis, in which the initial diagnostic workup suggested colon cancer. Histologic evidence, obtained from a second colonoscopy, along with pelvic ultrasound findings led to the final diagnosis of intestinal endometriosis which was confirmed by laparoscopy.ConclusionColonic endometriosis is often a diagnostic challenge and should be considered in young women with symptoms from the lower gastrointestinal tract.

Altered expression of interleukin-18 in the peritoneal fluid of women with endometriosis

OBJECTIVE Peritoneal fluid (PF) inflammatory factors may participate in the pathogenesis of endometriosis. The aim of this study was to investigate PF interleukin (IL)-18 levels in women with and without endometriosis. DESIGN Controlled clinical study. SETTING Women undergoing laparoscopy at a university hospital. PATIENT(S) Fifty women with previously untreated endometriosis, 8 women on GnRH agonists for endometriosis, and 18 control women with normal pelvic anatomy who were undergoing tubal ligation. INTERVENTION(S) Peritoneal fluid IL-18 levels as measured by ELISA. MAIN OUTCOME MEASURE(S) Peritoneal fluid IL-18 levels. RESULT(S) Peritoneal fluid IL-18 levels were significantly higher in women with previously untreated endometriosis (mean +/- SEM, 91.1 +/- 6.5 pg/mL) than in control women (59.4 +/- 2.0 pg/mL). Interestingly, women with superficial (100.0 +/- 10.2 pg/mL) and deep peritoneal implants (94.0 +/- 10.8 pg/mL) had significantly higher PF IL-18 levels than did women with endometriomas (57.8 +/- 1.8 pg/mL). Similarly, women with stage I-II endometriosis (97.3 +/- 8.0 pg/mL), but not women with stage III-IV endometriosis (74.9 +/- 9.9 pg/mL), had significantly higher PF IL-18 levels than did control women. Peritoneal fluid IL-18 levels were significantly higher in the luteal phase than in the follicular phase but did not discriminate between women with pelvic pain or infertility. CONCLUSION(S) Peritoneal fluid IL-18 is elevated in women with peritoneal, minimal- to mild-stage endometriosis.

Low-penetrance genes are associated with increased susceptibility to endometriosis

OBJECTIVE To investigate whether genetic polymorphisms of CYP1A1, GSTM1, and GSTT1 are associated with endometriosis. DESIGN Genetic polymorphism analysis. SETTING University department. PATIENT(S) A family with four women in two generations who had endometriosis and one member with suspected endometriosis in the third generation were compared with a group of fertile women. INTERVENTION(S) Laparoscopic examination. MAIN OUTCOME MEASURE(S) Blood specimens were obtained from fertile females and available affected female family members. Multiplex polymerase chain reaction (PCR) and restriction fragment length polymorphism PCR was done to determine each participants genotype. RESULT(S) All affected family members had genotype CYP1A1 wt/m1 and GSTM1 null deletion. The frequency of this genotype in 54 fertile women was 13%. A 17-year-old family member with suspected endometriosis had the same genotype. One affected member was also a carrier of a GSTT1 null deletion. This combination was not found in any of the fertile participants. The most frequent genotypes in the sample were CYP1A1 wt/wt, with GSTM1 null deletion and at least one functional allele of GSTT1, and CYP1A1 wt/wt, with at least one functional allele of GSTM1 and GSTT1 (33% and 31%, respectively). CONCLUSION(S) The combination of CYP1A1 m1 polymorphism and GSTM1 null deletion is closely associated with penetration of the endometriosis phenotype, whereas GSTT1 null deletion may add to the penetration of this trait.