Prognostic significance and diagnostic value of PTEN and p53 expression in endometrial carcinoma. A retrospective clinicopathological and immunohistochemical study.

PURPOSE: To investigate the PTEN and p53 gene expression in endometrioid and serous papillary endometrial carcinomas and clarify their prognostic significance by studying the PTEN and p53 expression in relation to tumor stage and grade. METHODS: Archival pathological sections of 61 cases with endometrial cancer examined in a 5-year-period (January 2006-December 2010) were retrieved and re-examined. Immunohistochemical investigation was performed by the Ventana system. Anti-PTEN and anti-p53 monoclonal antibodies were used. Disease staging was made according to the FIGO staging system. RESULTS: Forty-nine (80.32%) cases were endometrioid adenocarcinomas. Patient age ranged from 39-75 years (mean 62.5). Grade 1 tumors:19/22 (86.3%) cases had stage Ib, 2/22 (9.09%) stage Ic and 1/22 (4.54%) stage IIIc. Eighteen of 22 (81.8%) cases were PTEN positive and 4/22 (18.2%) p53 positive. Grade 2 tumors: 17/ 23 (73.91%) cases had stage I b, 4/23 (17.39%) stage Ic and 2/23 (8.69%) stage IIIc. Seventeen of 23 (73.91%) cases were PTEN positive and 47sol;23 (17.3%) p53 positive. Grade 3 tumors: 2/4 (50%) cases had stage Ic and 2/4 (50%) stage IIIc. No case was PTEN positive and 2/4 (50%) were p53 positive. Twelve (19.35%) cases were serous papillary carcinomas. Patient age ranged from 63-79 years (mean 76). Five (41.66%) cases had stage Ic and 5 (41.66%) stage IIIc, with nodal metastases and peritoneal involvement. Two (16.66%) cases developed on endometrial polyps with minimal myometrial involvement (stage Ib) and in both cases elements of endometrioid adenocarcinoma were observed as well. Immunohistochemical study showed that 11 (91.66%) cases were p53 positive and 2 (16.66%) PTEN positive. CONCLUSION: PTEN and p53 immunoexpression helps both in accurate diagnosis and proper therapeutic approach of the various endometrial carcinomas. PTEN and p53 are also prognostic markers for these kind of tumors.

The effect of hormone therapy and tibolone on serum CD40L and ADAM-8 in healthy post-menopausal women.

BACKGROUND/AIM: The role of neutrophils and platelets in atherothrombotic disease is well established. The aim of our study was to investigate the effect of HT and tibolone on the soluble markers of neutrophil and platelet activation, "a disentigrin and metalloproteinase domain" (ADAM-8) and CD40 ligand (CD40L) respectively, in healthy post-menopausal women. SUBJECTS AND METHODS: One hundred and six healthy post-menopausal women were randomly allocated to: estradiol plus drospirenone (E2/DSP), E2 hemihydrate 1 mg plus norethisterone acetate (E2/NETA) 0.5 mg, and tibolone 2.5 mg. Serum ADAM-8 and CD40L were measured at baseline and at 6 months. RESULTS: Baseline values of ADAM-8 and CD40L were similar between groups. No significant correlation was revealed between ADAM-8 or CD40L and parameters related to cardiovascular risk factors in each group. No significant changes were observed between baseline values and values at 6 months (E2/DSP group: ADAM-8: 267.4±71.3 pg/ml vs 270.7±42.8 pg/ml, p=0.86, CD40L: 6.43±3.13 vs 6.79±2.70 ng/ml, p=0.67), (E2/NETA group: ADAM-8: 308.3±64.3 vs 294.7±57.7 pg/ml, p=0.40, CD40L: 9.68±2.81 vs 8.59±5.13 ng/ml, p=0.51), (tibolone group: ADAM-8: 307.5±87.5 vs 289±48.1 pg/ml, p=0.48, CD40L: 9.46±4.30 vs 9.26±4.60 ng/ml, p=0.99). CONCLUSIONS: Our study has not revealed an association between estrogen plus progestin treatment or tibolone on serum ADAM-8 and CD40L levels in healthy post-menopausal women. Larger prospective studies are needed to further investigate the effect of low-dose HT or tibolone on serum markers of neutrophil and platelet activation.

Fibronectin plasma levels in gynecological cancers.

PURPOSE: Fibronectin (FBN) is involved in the motility and migration of malignant cells. The purpose of this study was to investigate FBN plasma levels in gynecological cancers patients and in healthy women. METHODS: The study took place between 1998 and 2003. One hundred women with histologically diagnosed cancer of gynecological organs (cervix, ovary, endometrium, breast) formed the study group (group A), whereas the control group (group B) consisted of 100 healthy women. FBN plasma levels were measured with the radial immunodiffusion method. RESULTS: The average age of group A patients was 42.08 years (range 33-77), and of group B it was 41.1 years (range 32-65). Both groups were compared with the Student's-t test. The median plasma value of FBN in all gynecological malignancies was 258.4 mg/l (standard deviation/SD 163.9, p=0.0066, t-statistics: 2.768, (t95): 1.984, 95% CI: 225.4-290.9). The plasma levels were significantly elevated when compared to the control group (median=213 mg/l). The distribution of values showed a statistically important "tail" in high plasma levels (FBN >400 mg/l). Plasma levels of FBN were more increased in breast and cervical malignancies when compared to ovarian and endometrial cancers. CONCLUSION: FBN plasma levels were significantly increased in the total of group A patients, but not significantly increased in the endometrial and ovarian subgroup. Whether or not FBN could reliably be a marker for gynecological cancers should be confirmed in studies with larger number of patients.

Transvaginal sonography of the endometrium in women with postmenopausal bleeding.

OBJECTIVE: The purpose of this study was to determine the value of screening transvaginal ultrasonography for the evaluation of endometrial abnormalities in women with postmenopausal bleeding. MATERIALS AND METHODS: 250 women with postmenopausal bleeding underwent transvaginal ultrasonographic examinations before undergoing dilatation and curettage. Women who had any pelvic symptoms or were on hormone replacement therapy were excluded. RESULTS: In 151 women, the histologic diagnosis was atrophic endometrium. In these patients, the mean endometrial thickness was 3.4 +/- 1.2 mm. In 24 patients with endometrial carcinoma, the mean endometrial thickness was 16.5 +/- 6.2 mm. The measurement included both endometrial layers (i.e. double layer). Thirty six cases of other pelvic pathologic conditions were discovered on ultra sonography. CONCLUSIONS: We believe that is reasonable to have a cutoff limit for normal postmenopausal endometrium at 5 mm. Endovaginal ultrasound is a valuable diagnostic instrument, as sensitive as dilatation and curettage, for detecting pathological conditions in the uterine mucosa.

Effects of nasal administration of calcitonin in oophorectomized women: 2-year controlled double-blind study.

OBJECTIVE: The aim of this study was to assess the effects of nasal salmon calcitonin (SCT) administration on bone turnover in ovariectomized women. METHODS: Patients who had undergone bilateral ovariectomy 7 days previously, received either calcium supplementation (1000 mg/day, together with nasal SCT (100 IU/day) (n = 19) or the same calcium supplementation together with a placebo intranasal spray daily (n = 19), for 2 years. RESULTS: In the calcium-only-treated subjects, lumbar bone mineral density (BMD) was found to have decreased significantly (P < 0.001), 6 months after surgery and remained at this level until the end of the study. In the SCT-treated group, BMD remained stable during the 1st year and then decreased gradually, reaching a statistically significant level in the 2nd year. Mean serum osteocalcin concentration was unchanged during the 1st year of SCT treatment but was significantly elevated during the 2nd year (P < 0.01). The observed rise in serum osteocalcin concentration and urinary hydroxyproline excretion during the 2nd year of treatment with SCT was accompanied by a significant rise in serum calcitonin levels (P < 0.001 after 18 months and P < 0.01 after 24 months). CONCLUSION: This study shows that continuous treatment with intranasal SCT is able to prevent the bone loss that follows ovariectomy.

Prevention of post-oophorectomy bone loss with Tibolone.

The results of a 1-year placebo-controlled study in 25 women who had hysterectomy and bilateral oophorectomy receiving a daily oral dose of 2.5 mg of Tibolone (Org OD 14) are presented. Tibolone is a steroid compound with mild oestrogenic in additional to progestagenic effects. Post-oophorectomy bone loss has been reported to accelerate, at least during the first year after surgery. The efficacy of Tibolone to prevent this accelerated bone loss is questionable. All patients were scheduled to participate in the study before oophorectomy. Patients had a detailed pre-operative examination, including measurement of forearm bone density with an SP2 Lunar single photon absorptiometer and haematological and biochemical investigation. After surgery, patients were randomly allocated in two groups; 15 women received an oral dose of 2.5 mg of Tibolone and 1000 mg of Calcium, while 10 women had only 1000 mg of calcium daily. Patients were examined at the end of 6 and 12 months of observation. Bone density of the radial shaft was found to decrease significantly in the calcium group up to 6.12% (P < 0.01) at the end of 6 months and 12.4% (P < 0.001) at the end of 12 months. On the other hand, bone density of the radial shaft remained unchanged in the Tibolone-treated group during the 12 months of treatment. Bone density of the distal radius was found to decrease in the calcium-treated group up to 10.2% (P < 0.014) at the end of 6 months and up to 15.8% (P < 0.002) at the end of 12 months. Bone density of the distal radius remained almost unchanged in the Tibolone-treated group during the whole period of treatment. Urine hydroxyproline/creatinine ratio was found to increase in the calcium group at the end of 6 and 12 months (P < 0.009) and to decrease significantly (P < 0.05) in the Tibolone-treated group. It is concluded that Tibolone is effective in the prevention of the post-ovariectomy accelerated bone loss and in retaining the initial premenopausal bone mass, at least during the first post-oophorectomy year. As this period is the most crucial in developing osteoporosis, it seems that Tibolone is effective in preventing the post-oophorectomy bone loss. HRT is not obligatory in these patients, as Tibolone seems to cover the whole spectrum of post-oophorectomy consequences.

Corticosteroid treatment does not improve the results of intrauterine insemination in male subfertility caused by antisperm antibodies.

AIM: To determine whether corticosteroid immunosuppression (CS) administered to the male partner together with intrauterine insemination (IUI) is preferable compared to IUI alone in treating male autoimmune subfertility. MATERIALS AND METHODS: Thirty-six couples with proven male immunological subfertility were randomly assigned to begin CS + IUI (n = 18) or IUI (n = 18) treatment and progressed alternatively to receiving each treatment modality for three cycles unless pregnancy occurred. Each couple served as their own control. The administered corticosteroid was soluble prednisolone. RESULTS: Five pregnancies were achieved with 77 cycles of CS + IUI and seven pregnancies with IUI alone. The pregnancy rates per cycle were 6.5% with CS + IUI and 9.21% with IUI, while the pregnancy rates per couple were 16.13% with CS + IUI and 21.2% with IUI alone. These rates do not differ to a statistically significant degree (P > 10%). CONCLUSIONS: The addition of corticosteroid immunosuppression does not seem to significantly enhance the pregnancy rate in couples with male autoimmune subfertility treated with IUI as compared to the treatment with IUI alone. Considering the possible side-effects of corticosteroid intake, we conclude that IUI alone might be preferable to the combination of IUI with corticosteroid administration.

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in plasma/serum and urine of women during term and threatened preterm labor: a clinical approach.

OBJECTIVE: To explore the concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in plasma, serum and urine of women during term and threatened preterm labor. METHODS: Plasma and urine proMMP-9 as well as serum and urine TIMP-1 were evaluated in 60 healthy pregnant women; 20 of them presented in term labor following an uncomplicated pregnancy, 20 of them presented with threatened preterm labor and intact membranes at 24-36 gestational weeks and 20 of them were at 24-40 gestational weeks with no evidence of uterine contractions or other pregnancy complications. Data were analyzed with non-parametric statistical tests and cut-off values were determined with receiver operator characteristic curves. RESULTS: ProMMP-9 values were significantly higher and TIMP-1 values were significantly lower in cases with uterine term or preterm contractions compared to non-labor status; and in cases with preterm contractions that progressed to true preterm labor compared to those in which contractions were arrested. CONCLUSIONS: Alterations in the concentrations of proMMP-9 and TIMP-1 can be detected in plasma or serum and urine of pregnant women experiencing term or preterm uterine contractions. The altered values of proMMP-9 and TIMP-1 could possibly identify the inevitable progress of preterm contractions to true preterm labor.

Low-dose follicle-stimulating hormone treatment for polycystic ovarian disease.

OBJECTIVE: An attempt was made to induce ovulation with low-dose follicle-stimulating hormone (FSH) in clomifene-resistant women with anovulatory polycystic ovarian disease (PCOD). METHODS: Twenty-two PCOD patients were treated with a low-dose protocol of purified urinary FSH, starting with 75 IU/day and increasing every 7 days by 37.5 IU/day, if necessary. Monitoring was based on ultrasound scanning and estradiol measurements. RESULTS: Twenty-eight of the thirty-one cycles induced were ovulatory, the majority being uniovulatory (58%). No multiple pregnancies occurred. There was a small number of cancelled cycles (12.9%). The prevalence of complications was low, with one case of ovarian hyperstimulation syndrome. Ovulation was induced by a small amount of FSH (15.1 +/- 4.9 ampules). CONCLUSION: The use of the low-dose protocol permitted induction of ovulation safely and successfully in a selected group of PCOD patients. This therapy was associated with a high incidence of single dominant follicles and a very low multiple pregnancy rate.

Smoking and preterm labor.

The aim of the present study was to investigate the role of maternal smoking during pregnancy in the occurrence of the premature rupture of the membranes (PROM) and premature labor . Our study consisted of 1,133 women of which 283 (group A) had premature labor (gestation < or = 37 weeks), while 850 (group B) had term labor (gestation > 37 weeks). The two groups did not differ in their socioeconomic status and did not include women with serious complications during pregnancy. There were no apparent effects of smoking on the length of gestation. However, our results showed that smoking had a marked effect on preterm labor of less than 32 weeks; we also found a statistically significant correlation between PROM in premature deliveries and smoking during pregnancy, but no gradient was observed between the number of cigarettes smoked per day and the risk for PROM, in cases of premature labor. We conclude that smoking during pregnancy raises the risk of delivery before the 32nd week, as well as the PROM in premature deliveries, independently of the number of cigarettes smoked per day.

Hysteroscopy in the evaluation of habitual abortions.

OBJECTIVES: To evaluate the incidence of structural uterine anomalies (SUAs) in women with habitual abortion (HA) as diagnosed by means of hysteroscopy and to study hysteroscopy's therapeutic potential with regard to that pathology. METHODS: Forty-eight women with more than three consecutive pregnancy losses which occurred prior to the 20th week were included and hysteroscopy was performed on all of them. RESULTS: Twenty-five women (52%) had a normal hysteroscopy. The remaining 23 women (48%) presented SUAs: nine patients (19%) had intrauterine adhesions, four (8%) had submucous myomas, two (4%) had polyps and eight (17%) had congenital structural uterine anomalies (five cases of septate uterus and three of bicornuate uterus). Patients with abnormal hysteroscopy underwent appropriate therapy, when applicable. In the SUA group, 18 patients (78%) achieved a successful pregnancy, and five patients (22%) had another miscarriage. In the normal hysteroscopy group, eight patients (32%) achieved a successful pregnancy without additional treatment, 15 patients (60%) had recurrent miscarriages, and two patients (8%) had persistent secondary infertility. CONCLUSIONS: SUAs were detected in nearly half of the patients with HA. After appropriate treatment when applicable, 78% of patients with SUAs achieved a successful ongoing pregnancy. Hysteroscopy has much to offer in the diagnosis and treatment of SUAs.

The etiology in 77 primary amenorrhea patients.

This study is based upon an analysis of 77 cases of primary amenorrhea. The work-up included a complete endocrinological study, cytogenetics, laparoscopy, and gonadal biopsy. Of the total number of patients, 31 had a completely developed female phenotype, 22 had an insufficiently developed one, and the remaining 24 patients were characterized by infantilism. A positive sex chromatin was obtained in 59 patients, and negative in 18. Out of 77 patients, 25 had an abnormal karyotype or one corresponding to the opposite sex. In six patients, the existence of a Y chromosome in the karyotype was found in spite of the female phenotype. Five patients had the testicular feminisation syndrome.

Family planning and psychosocial support for infertile couples.

AIMS: The study was set up to analyze the psychological/emotional needs of women who undergo treatment for in vitro fertilization (IVF) and to emphasize the importance of the psychosocial support that family planning centers can provide to them. METHOD: This was a cohort study with closed questions. A total of 235 infertile women participating in an IVF program were studied. The statistical analysis of the findings was conducted by the Statistical Package for Social Sciences. RESULTS: The psychosocial support and the scientific information provided to those women who participate in IVF programs are insufficient. In order to succeed in an IVF program, the women must be assisted by a doctor with much medical experience. The study shows that 59.3% of the women studied sought more medical information and another 32.5% sought emotional support. These percentages varied with reference to education, age and origin. These kinds of services must be provided by family planning centers.

Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial.

The objective of this study was to compare the efficacy of flutamide and cyproterone acetate in the treatment of hirsutism. Twenty-two women with idiopathic hirsutism were randomized to receive either flutamide or cyproterone acetate. Each patient underwent a complete gynecological examination as well as an endocrinological profile and hematological, hepatic and renal function analyses. Hirsutism scores were determined using a modified Ferriman-Gallwey scoring system. These tests were then repeated at 3 and 9 months of therapy. Eleven patients received 250 mg of flutamide twice daily and 11 patients received 100 mg of cyproterone acetate on days 5-14 of the menstrual cycle. Ferriman-Gallwey scores were decreased significantly in both groups at the end of 9 months. There was a trend towards a better response with flutamide, that did not achieve significance. Another significant difference was the increased sex hormone-binding globulin in both groups. A statistically significant decrease was also observed for the levels of testosterone on both drugs. No subject withdrew from the study due to a side-effect. The data suggest that both flutamide and cyproterone acetate were similarly effective in treatment of hirsutism, and that the pure antiandrogen flutamide is a safe, well-tolerated and effective alternative in treatment.