Georgios Koumantakis

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.

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.

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.

Soluble ICAM-1 levels in the serum of endometriotic patients appear to be independent of medical treatment

Adhesion molecules regulate the interaction of cells with the extracellular matrix and/or other cells. The intercellular adhesion molecule-1 (ICAM-1; CD54) is a member of the immunoglobulin superfamily and expressed by several cell types, including leukocytes and endothelial cells. A circulating form of the usually membrane-bound molecule was identified and characterized in normal human serum and in sera from patients with endometriosis. In the present study, we established the serum-soluble ICAM-1 (sICAM-1) levels in patients with endometriosis. We also studied the effect of danazol and leuprorelin acetate depot on the levels of sICAM-1. Thirty-eight women, 18-45 years of age, with regular menses and documented pelvic endometriosis were recruited from a University Hospital setting. Twenty-two women with endometriosis were randomly divided into two groups. Danazol (600 mg) were given every day for 6 months, and 3.75 mg of leuprorelin acetate depot every 28 days for 6 months. Serum sICAM-1 concentrations were measured before, during and after treatment, and its quantitative determination was performed by an ELISA technique using a specific immunoassay. We found that (1) sICAM-1 levels were higher in women with endometriosis in comparison to healthy subjects; (2) the 6 month treatment with danazol or leuprorelin acetate depot increased sICAM-1 levels (P<0.001); (3) 3 months after termination of both treatments, sICAM-1 levels were unchanged. Although the mechanism leading to the increase of sICAM-1 needs to be further clarified, any benefits of medical treatment of endometriosis such as danazol or leuprorelin appear to be independent of changes in ICAM-1 serum levels.

The familial risk of breast cancer in women with endometriosis from Yale series

OBJECTIVE Few studies examining the association of endometriosis with the risk of breast cancer. Our goal was to investigate the familial risk of breast cancer in women with endometriosis. DESIGN Retrospective study. SETTING University-based endometriosis referral center. PATIENTS Three hundred fifty-two women with endometriosis and 180 infertile women without endometriosis were studied using laparoscopy between August 1996 and February 2002. The endometriosis group was further subdivided into a group of women with 94 positive and 268 negative family histories of breast cancer. MAIN OUTCOME MEASURE(S) The overall risk of familial breast cancer among first- and second-degree relatives in patients with endometriosis and the association between potential risk factors was estimated by chi(2) and by crude adjusted odds ratios (95% CI). RESULTS Positive family history of breast cancer was detected in (26.7%) 94/352 of endometriosis group and in (5%) 9/180 of controls. The relative risk of women with endometriosis and positive family history of breast cancer was (OR=6.9 (95% CI, 3.4-14.1), chi(2)=34.6, P<0.001). Endometriosis was associated with the risk of first-degree relatives of breast cancer (OR=5.69 (95% CI, 2.4-13.3), P<0.001). Moreover, endometriosis was significantly associated with the risk of breast cancer in mothers (OR=6.3 (95% CI, 2.2-17.8), P<0.001) and in maternal aunts (OR=5.9 (95% CI, 1.3-72.9), P<0.001). The two groups are similar in age, race height, main complaints, age of menarche, cycle length, days of flow, estimated blood loss, stage of endometriosis and the presence of endometrioma. CONCLUSION(S) This study found an elevated risk associated with family history of breast cancer among women with endometriosis. A familial clustering interaction with a familial history of breast cancer in women with endometriosis is possible, but should be investigated further.

Diagnostic role of inhibin B in resistant ovary syndrome associated with secondary amenorrhea

To report two rare cases of gonadotropin-resistant ovary syndrome associated with secondary amenorrhea and normal levels of inhibin B. Case report. Two university teaching hospitals. Two women presenting with secondary amenorrhea and infertility. The control group for the inhibin B levels consisted of 30 cycling women of reproductive age. Medical history, physical examination, laboratory data, histologic findings, and IVF results. Diagnosis and treatment of resistant ovary syndrome. Case 1 was a 25-year-old woman with secondary amenorrhea and primary infertility. She had high serum levels of FSH and LH, low E(2) levels, and normal inhibin B levels (62 pg/mL). Karyotype was 46,XX, and ovarian biopsy showed primordial follicles with oocytes. Administration of GnRH analogue with hMG for 15 days did not affect E(2) levels. She had a successful pregnancy with IVF using donor oocytes. Case 2 was a 24-year-old woman with secondary amenorrhea. She had elevated serum levels of FSH and LH, low E(2) levels, and normal inhibin B levels (57 pg/mL). Karyotype was 46,XX and ovarian biopsy showed primordial follicles. Administration of GnRH analogue with hMG for 12 days did not affect E(2) levels. Both women were given estrogen-progestin replacement therapy. Inhibin B has a diagnostic role in women with gonadotropin-resistant ovary syndrome associated with secondary amenorrhea. A review of the literature confirms the uniqueness of the diagnostic role of inhibin B in these cases.

Pulmonary endometriosis in a patient with unicornuate uterus and noncommunicating rudimentary horn

OBJECTIVE To report a rare case of a patient with catamenial hemoptysis, secondary infertility, and endometriosis associated with a unicornuate uterus and noncommunicating rudimentary horn. DESIGN Case report. SETTING University hospital. PATIENT(S) A 29-year-old woman who developed progressive catamenial hemoptysis and secondary infertility was evaluated at the University Hospital of Crete. INTERVENTION(S) The complete history, laboratory data, laparoscopic findings, and chest magnetic resonance image of this patient were analyzed. A GnRH agonist, leuprolide acetate, was successfully administered. MAIN OUTCOME MEASURE(S) Diagnosis and appropriate treatment of pulmonary endometriosis in a patient with rudimentary uterine horn. RESULT(S) Treatment with a GnRH agonist achieved suppression of both menstruation and hemoptysis. After 6 months of normal menstrual activity, the symptoms reappeared. The patient was again treated with leuprolide acetate (3.75 mg/mo IM) for 6 months and remained asymptomatic. In fact, the patient became pregnant after cessation of therapy. Finally, the patient was treated successfully with removal of the rudimentary uterine horn during cesarean section. Three-year follow-up showed disappearance of the chest symptoms. CONCLUSION(S) Pulmonary endometriosis and unicornuate uteri are rare. To our knowledge, this is the first case of catamenial hemoptysis with a congenital müllerian anomaly. We describe successful management using a combination of GnRH agonist and surgical resection of the rudimentary uterine horn.

Increased pregnancy-associated plasma protein-A (PAPP-A) concentrations in peritoneal fluid of women with endometriosis.

PROBLEM:  Pregnancy‐associated plasma protein‐A (PAPP‐A) belongs to a group of glycoproteins isolated from extracts of human placenta. Healthy ovarian and uterine tissues are also known to express PAPP‐A. We hypothesized that PAPP‐A levels might also be elevated in the peritoneal fluid (PF) of women with endometriosis, and examined variations in PF PAPP‐A during the menstrual cycle and with the severity of the disease.