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Pregnancy-specific stress predicts birth outcomes. We hypothesized that there is a maternal stress-GR interaction that can influence fetal birth weight. This study examined the relationship between mothers' stress and attitude towards their pregnancies, placental glucocorticoid receptors (GRs) and growth arrest-specific transcript 5 (GAS5) expression, and the status of GR polymorphism, with their infants' birth weights. GAS5 and GR α were the predominant transcripts in both term and preterm placentas, with GAS5 being primarily localized in the syncytiotrophoblasts. In an attempt to mimic moderate and high stress environment in vitro, BeWo and JEG-3 cytotrophoblast cell lines were treated with 10 nM-1000 nM cortisol. Only expression of GAS5 was significantly upregulated by cortisol in all treatments compared with basal levels, but none of the GRs changed expression significantly. In an attempt to assess a stress versus gene interaction, we studied four GR polymorphisms. In the homozygous group for Tth111I polymorphism, mothers with negative attitudes towards the pregnancy gave birth to infants with significantly lower birth weights compared to women with positive/neutral attitudes. None of the GR splice variants were associated with maternal stress. However, placental GAS5 levels were inversely correlated with maternal stress. This study points towards a potential gene-environment interaction that could be of predictive value for fetal weight.

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Pregnancy is associated with major physiological and future psychosocial changes, and maternal adaptation to these changes is crucial for normal foetal development. Psychological stress in pregnancy predicts an earlier birth and lower birth weight. Pregnancy-specific stress contributes directly to preterm delivery. The importance of nutrition and exercise during pregnancy with regard to pregnancy outcome has long been acknowledged. This importance has only been further emphasized by the recent changes in food quality and availability, lifestyle changes and a new understanding of foetal programming's effects on adult outcomes. We hypothesised that for a successful pregnancy certain events at a nutritional, immune, psycho-emotional and genetic level should be tightly linked. Therefore, in this study we followed an 'integrative' approach to investigate how maternal stress, nutrition, pregnancy planning and exercise influence pregnancy outcome. A key finding of our study is that there was a significant reduction in the intake of alcohol, caffeine-containing and sugary drinks during pregnancy. However, passive smoking in the household remained unchanged. In terms of immune profile, a significant inverse correlation was noted between difficulty to 'fight' an infection and number of colds (r=-0.289, P=0.003) as well as the number of infections (r=-0.446, P<0.0001) during pregnancy. The vast majority of the pregnant women acquired a more sedentary lifestyle in the third trimester. In planned, but not in unplanned, pregnancies stress predicted infant weight, independent of age and body mass index (BMI). Notably, in mothers with negative attitudes towards the pregnancy, those with an unplanned pregnancy gave birth to infants with significantly higher weights than those with planned pregnancies. Collectively these data suggest that there is a higher order of complexity, possibly involving gene-environment interactions that work together to ensure a positive outcome for the mother as well as the foetus.

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OBJECTIVE: Human leukocyte antigen-DR (HLA-DR) has been implicated in eutopic and ectopic glandular epithelial cells in endometriosis. We investigated the expression of HLA-DR in endometriotic and adenomyotic tissues within the stromal and glandular cells. Moreover, we correlate the HLA-DR expression according the transvaginal ultrasonography findings. METHODS: We studied operative and pathologic reports of 113 women who underwent laparoscopic or laparotomy treatment of endometrioma or adenomyosis. Tissues from 51 women with endometrioma and 62 women with adenomyosis were retrospectively evaluated. The distribution and intensity of the HLA-DR immunostaining was assessed using electron microscopy. Pathologic finding of the uterine junction zone and the size of endometrioma were evaluated with the laparoscopic results and the ultrasound findings. RESULTS: In adenomyosis tissues, the percentage of HLA-DR cells expression was significantly higher in stromal cells (83.9%) compared to glandular cells (25.8%), (p<0.001). The number of HLA-DR-positive endometriotic glandular cells was significantly higher than the total glandular adenomyotic cells (p<0.005). HLA-DR-positive cells was significantly different between stromal (p<0.016) and glandular cells (p<0.044) in each side of endometrioma. Finally, HLA-DR-positive percentage cells were significantly more frequent in the secretory phase than the proliferative in stromal and glandular cells in both groups. CONCLUSION: HLA-DR antigen expression in endometrium and adenomyotic tissues. However, HLA-DR expression is distributed preferentially in glandular epithelial cells in endometrioma and in the adenomyotic stroma. In both groups the HLA-DR expression was significantly higher in the secretory phase than the proliferative or glandular and stroma cells. Larger perspective studies are needed to establish the expression of HLA antigens in immune reactions which occur in adenomyosis and endometriosis.

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Age, BMI, lifestyle, menstrual status and obstetric history can modulate the endocrine system and, therefore, have been hypothesised to play a role in in-vitro fertilisation (IVF) outcome. We designed a retrospective study, set in a medical school hospital. We evaluated the medical files of 297 infertile women who underwent laparoscopy and consecutive IVF-ET treatment in the Yale IVF unit between 1996 and 2002. The study group consisted of 151 women who conceived after IVF-ET and the control group of 146 women who underwent 288 IVF-ET cycles without pregnancy. The main outcome measure was the impact of epidemiological factors on the IVF outcome. There was no association between IVF outcome and race, BMI, age at menarche, length of cycle, duration and amount of flow, menstrual symptoms, other medical problems, medical history of allergies, and family history of endometriosis and cancer. We found that the degree of smoking and alcohol use was not a factor when comparing women with and without pregnancy after IVF (34.5% vs 29.5%, and 33.7% vs 27%, respectively). The rate of duration of infertility tended to be lower in pregnant women (35.9+/-23.4 months) vs (42.3+/-30.2) non-pregnant women. As expected, we also confirmed the inverse association between the age of women and IVF outcome. Overall, body attributes, lifestyle, family history, menstrual and reproductive factors were not related to IVF-ET outcome.

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Placentally derived CRH seems to play a major role in the mechanisms controlling human pregnancy and parturition, via activation of specific receptors widespread in reproductive tissues. In the human placenta, CRH seems to modulate vasodilation, prostaglandin production, and ACTH secretion. It has also been suggested that CRH might act as a placental clock, determining the length of gestation. In addition, maternal plasma CRH concentrations are further elevated in pregnancies associated with abnormal placental function, such as preeclampsia and intrauterine growth retardation (IUGR). In this study, we sought to investigate the expression of CRH-R1 alpha levels in placentas from women who have undergone normal deliveries (control group) and patients who have been diagnosed as having preeclampsia or IUGR. Results showed that placental CRH-R1 alpha mRNA levels (as shown by quantitative RT-PCR) and protein levels (shown by Western blotting analysis) were significantly (P < 0.05) reduced in all of the complicated pregnancies. In contrast, levels of the angiotensin II receptor were elevated in preeclampsia and reduced in IUGR subjects, as shown by RT-PCR and Western blotting analysis. These findings might suggest that changes in receptor expression may contribute toward dysregulation of the dynamic balance controlling vascular resistance.

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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.

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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 participant's 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.

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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.

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BACKGROUND: Endometriosis is defined as an inflammatory condition of the female reproductive tract, a state often associated with infertility and miscarriage. Many exogenously administered factors (treatments) control the disease via as yet unknown pathways. Possible candidate molecules involved in these mechanisms could be the serum-soluble human leukocyte antigens (sHIA) that have been detected in a variety of human body fluids and that are associated with several diseases. AIMS: We here examine how danazol and leuprorelin acetate depot treatments exert their anti-inflammatory action. It is plausible that subtle alterations mediated by these treatments and in relation to sHLA may explain the pathophysiology of endometriosis and provide insights towards new therapeutic protocols. METHODS: Indirect enzyme-linked immunosorbent assay (ELISA), using specific monoclonal antibodies, determined serum-soluble class-I and class-II HLA levels. ELISA readings from treated women were compared with normal healthy subjects. RESULTS: Serum-soluble class-I and class-II HLA levels are statistically significantly lower (P < 0.001) in women with endometriosis than in the control groups. However, danazol but not leuprorelin acetate depot administration augments soluble HLA class I and class II (P < 0.01 and P < 0.001, respectively) to normal levels during the treatment period, an increase that may account for the anti-inflammatory effect and the remission observed. CONCLUSIONS: It is shown that one of the underlying causes of endometriosis may be the lack of both circulating class-I and class-II antigen levels. Danazol administration acts via an induced release of these antigens, whose presence correlates with the degree of the inflammatory alleviation obtained. We thus provide evidence that the inflammatory state of the disease appears to be associated with soluble HLA levels because, 3 months after ceasing therapy, the circulating antigens in the serum return to the same levels that correspond to the pathological condition.

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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.

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OBJECTIVE: To determine the Bcl-2 and Bax expressions in endometriotic and adenomyotic tissues. In addition, to evaluate the Bcl-2/Bax status during the menstrual cycle in these tissues. METHODS: A total of 56 women were retrospectively recruited from a University hospital setting. A total of 25 had endometriosis and 31 adenomyosis. Tissue samples were collected during gynaecological surgery and confirmed by histology to have endometriosis or adenomyosis. Bcl-2 and Bax expressions were investigated on 56 formalin-fixed and paraffin-embedded tissue by immunohistochemical staining and electron microscopy. RESULTS: The difference of Bcl-2-positive protein between endometriosis and adenomyosis was not significant. No significant difference was found between Bcl-2 expression and the proliferative and secretory phase of the cycle in women with endometriosis, but this comparison was highly significant (P<0.001) in women with adenomyosis. The difference of Bax-positive protein between endometriosis and adenomyosis was not significant. In addition, no significant differences were found between the various phases of the cycle. We have found a stronger inverse correlation between the expression of Bcl-2 and Bax in endometriosis than in adenomyosis. CONCLUSIONS: Our results suggest that the pathogenesis of ovarian endometriosis may be different from that of adenomyosis and the persistence of Bcl-2 and Bax expressions during both phases of the cycle in ovarian endometriotic tissues may have important implications for the survival and proliferation of the ectopic endometrial tissue.

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A 37-year old woman presented with severe endometriosis and the patient underwent a conservative operation. We investigated the effect of treatment with danazol on the levels of CA-125, CA-19-9, CA 15-3, SIL-2R, IL-6, IL-1a, TNE-a, SCD8 and SCD4 in this woman. Our findings suggest that severe endometriosis is a condition which induces a rise of tumor markers and cytokine levels that are suppressed on danazol treatment.

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Adenomyosis is a gynecological condition in which tissue histologically similar to that in endometrium is found within the myometrium in the uterus. Although, lesions of both adenomyosis and endometriosis are identical to their sources with respect to structure and function, they are generally regarded as separate and distinct nosologic processes. In this study, we used 17 microsatellite markers, in four tetraplex and one single PCR assay, to determine the incidence of loss of heterozygosity (LOH) in 31 cases of adenomyosis. The markers used are located close to tumor suppressor genes, DNA repair genes, and genes which are thought to be involved in endometriosis. Moreover, the markers were involved in regions frequently lost in ovarian cancer, on chromosomal arms 1p, 1q, 2p, 2q, 3p, 9p, 9q, 17p and 17q. Nine samples (29.0%) showed LOH in at least one locus. Loci 2p22.3-p16.1, 3p24.2-p22 and 9p21 exhibited imbalance (19.4%, 9.7% and 6.5% respectively). This is the first report, that LOH occurs in adenomyosis. The regional chromosomal losses were detectable early during the development of this condition. In addition, hMSH2, hMLH1, p16Ink4 and GALT genes were associated for the first time with adenomyosis and its pathogenesis.

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OBJECTIVE: To confirm the presence of L-carnitine in human seminal plasma, to show differences between L-carnitine concentrations in fertile and infertile subjects, and to show potential relationships between L-carnitine and semen quality. STUDY DESIGN: Seminal plasma from 101 men obtained by masturbation was examined for the presence of L-carnitine. Semen samples were divided as follows: (a) in eight groups according to the etiology of fertility, (b) in two groups on the basis of normal or abnormal spermiogram, (c) correlation of the amount of L-carnitine in seminal plasma with values of the spermiogram. RESULTS: We found the following: (1) L-carnitine levels differ significantly between controls and the patient groups (P < .0001) (2) The group with normal spermiogram has a mean value for L-carnitine of 478.4 while the abnormal one comes to 100.58. This difference is statistically significant (P < .0001). (3) There is a statistically significant, positive correlation between L-carnitine and the number of spermatozoa, the percentage of motile spermatozoa, and the percentage of normal forms (P < .0001). CONCLUSION: These findings suggest that determination of seminal carnitine values might provide the physician with an additional means of evaluating the infertile male.

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OBJECTIVE: This study was undertaken to evaluate serum leptin concentrations in women with endometriosis during treatment with danazol and with leuprolide depot. STUDY DESIGN: Twenty patients aged 18 to 42 years with regular menses and documented pelvic endometriosis were recruited from a university hospital setting. Treatment was 200 mg danazol 3 times daily for 6 months or 3.75 mg leuprolide depot every 28 days for 6 months. Serum leptin concentrations were measured before, during, and after treatment. A single blood sample was taken from each of 10 control women without endometriosis for comparison. Serum leptin level was measured with a radioimmunoassay kit with human leptin, and analysis of variance and paired t tests were used for statistical analysis. RESULTS: Serum leptin levels were almost the same among women with endometriosis as in the control group. Leptin levels were higher among women with endometriosis during treatment with danazol and leuprolide(P <.001). Three months after treatment, leptin values remained moderately higher than before treatment. CONCLUSION: Danazol and leuprolide increased serum leptin levels. The mechanism of leptin increase is unclear. Further studies are needed to determine whether an adipogonadal axis exists.

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The aim of this study was to confirm the presence of soluble interleukin-6 receptor (SIL-6R) in seminal plasma, to show eventual differences between SIL-6R concentrations in fertile and infertile men, and to evaluate the possible value of measuring these substances for the diagnosis of male accessory gland infection. SIL-6R levels were determined by "sandwich" enzyme immunoassay in the seminal plasma of 82 men divided into 7 groups according to the etiological diagnosis of fertility. The levels of SIL-6R in the seminal plasma of men with infection of the accessory genital glands were statistically significantly different in comparison with other groups (p < .001). The results suggest that urogenital infections may lead to elevated levels of SIL-6R in the seminal plasma. This measurement of SIL-6R in semen may provide clinically useful information for the diagnosis of male accessory gland infection.

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OBJECTIVE: To determine the effects of treatment with danazol and leuprolide acetate depot on serum-soluble CD23 concentrations in women with endometriosis. METHODS: This randomized trial involved 20 women 18-42 years old with regular menses and known pelvic endometriosis who were recruited from a university hospital between 1993 and 1998. Ten women took 200 mg of danazol three times daily for 6 months, and the remaining ten were given 3.75 mg of leuprolide acetate depot every 28 days for 6 months. Blood-soluble CD23 levels were measured before treatment, during the last 15 days of the 6-month treatment course, and 3 months after treatment. Only one blood sample was taken from ten women without endometriosis, between the 5th and 7th days of their menstrual cycles. For statistical analysis, we used independent and paired t tests with the Pearson correlation coefficient. RESULTS: Soluble CD23 levels were significantly higher in women with endometriosis before treatment than in ten normal controls. Levels decreased significantly during treatment with either danazol or leuprolide acetate. Three months after treatment, soluble CD23 values remained lower than before treatment. There was no correlation between soluble CD23 concentrations and severity of endometriosis. CONCLUSION: Our findings suggest that endometriosis increases soluble CD23 levels, which can be suppressed with either danazol or leuprolide acetate injection.

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Since increased levels of soluble CD23 (sCD23) were demonstrated in patients with autoimmune diseases, seminal plasma sCD23 levels were examined in 110 men divided into seven groups according to etiological diagnosis of infertility and two groups on the basis of normal or abnormal spermiogram. sCD23 was absent in the seminal plasma of normal men: According to the ANOVA results, all measurements were significantly different between the groups of patients examined (p<.01). Specifically, patients with idiopathic testicular lesion have a significantly higher mean value of sCD23 than all other patients. A statistically significant difference was noted in the sCD23 levels between men with normal and those with abnormal spermiograms, although with wide overlapping of the individual values. Men with idiopathic testicular lesion may be immunologically more active than other groups with subfertility.

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The present study was designed to investigate the participation of sCD23 and TNF-alpha in pregnant women in the first trimester. One hundred and forty-one patients were enrolled in the study. Women were classified into two groups. Serum sCD23 and TNF-alpha were measured in 73 normal pregnant women in the first trimester (Group I) and in 68 women with spontaneous abortion (Group II). We found that the mean values of TNF-alpha levels were higher in women with normal pregnancy than in women with spontaneous abortion (p < 0.05), whereas sCD23 levels of women in group II did not differ statistically from the controls. These results sustain the opinion that women with spontaneous abortion seem to have reduced TNF-alpha levels. However, determination of these immunological parameters provides no useful clinical information about disease activity and management.

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OBJECTIVE: The aim of the study was to establish if pregnancy belongs to pathological situations, if it changes SIL-2R, sCD4 and sCD8 levels, and to verify if these levels have a prognostic value in the evaluation of pregnancy. PATIENTS AND METHODS: Thirty pregnant women in the first trimester of pregnancy were studied. Ten of them had a normal evolution of pregnancy, ten had a threatened abortion with a bad outcome, and ten had an ectopic pregnancy. We determined SIL-2R, sCD4, and sCD8 levels in the serum and in the amniotic fluid in 10 pregnant women in their second trimester, and in 10 healthy women without pregnancy (control group). RESULTS: We found that (a) 50% of the pregnant women in their first trimester had abnormal SIL-2R values, and 90% had abnormal sCD8 values; (b) 9/10 women with threatened abortion and bad outcome had abnormal SIL-2R values; (c) SIL-2R levels were significantly higher in the amniotic fluid than in the serum (P <.001). CONCLUSION: Our results sustain the opinion that pregnancy must be included among those situations that increase SIL-2R, sCD4, and sCD8 levels. SIL-2R levels greater than 1,300 U/mL carried a bad prognosis in the evolution of pregnancy.

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