Correction to: Recurrent pregnancy loss is associated to leaky gut: a novel pathogenic model of endometrium inflammation?

Following publication of the original article [1], the authors reported updated affiliations for five of the authors. The updated affiliations are shown below and reflected in the affiliation list of this Correction.

Recurrent pregnancy loss is associated to leaky gut: a novel pathogenic model of endometrium inflammation?

BACKGROUND: Recurrent pregnancy loss (RPL) occurs in 3-5% in about 30% of cases no cause can be found. Women with RPL show higher prevalence of undiagnosed gut disorders. Furthermore, in endometrial tissues of RPL women, higher expression of pro-inflammatory cytokines and Nalp-3 inflammasome has been observed. Aim of this study was to investigate whether an abnormal gut permeability might occur in RPL women and allow passage into systemic circulation of pro-inflammatory molecules able to induce endometrial inflammation. METHODS: 70 women with idiopathic RPL and 30 healthy women were recruited at the Recurrent Pregnancy Loss Outpatient Unit of the Gemelli Hospital of Rome from March 2013 to February 2017. Enrolled women underwent 51Cr-ethylene-diamine-tetraacetic acid absorption test to evaluate intestinal permeability. Sera obtained from enrolled women were analysed for lipopolysaccharide (LPS) by ELISA. Anxiety and depression state were evaluated by administering STAI-Y and Zung-SDS tests, respectively. Of all recruited individuals, 35 women with idiopathic RPL and 20 healthy controls accepted to undergo diagnostic hysteroscopy and endometrial biopsy. Endometrial lysates were investigated for inflammasome Nalp-3 by Western blot analysis, and caspase-1, IL-1ß and IL-18 by ELISA, respectively. RESULTS: Higher prevalence of abnormal intestinal permeability (P < 0.0001), increased circulating levels of LPS (P < 0.05), anxiety (P < 0.05) and depression (P < 0.05) were observed in RLP women compared to controls. Endometrial expression of Nalp-3, caspase-1 and IL-1ß was significantly increased in RPL group (P < 0.0001; P < 0.05 and P < 0.001, respectively). IL-18 endometrial levels were not found to be higher in RPL cases. Statistically significant association between higher intestinal permeability and abnormally increased expression of endometrial Nalp-3, was observed in RPL (P < 0.01). Furthermore, higher LPS serum levels, a bacterial-derived activator of Nalp-3 complex, was shown to be statistically associated to abnormal endometrial expression of Nalp-3 inflammasome (P < 0.01) in RPL women. CONCLUSIONS: In women with RLP, leaky gut might occur and allow passage into circulation of immune triggers, potentially able to elicit endometrial innate immune response and, thus, to contribute to miscarriage pathogenesis. Diagnosis and treatment of intestinal disorders underlying leaky gut might improve endometrial environment and pregnancy outcome.

Non-hormonal treatment of vulvo-vaginal atrophy-related symptoms in post-menopausal women.

In post-menopausal period vulvo-vaginal atrophy (VVA)-related symptoms may seriously affect women's quality of life. Hormonal replacement therapy effectively relieves these symptoms but it is not always safe or accepted, and a non-hormonal treatment is often needed instead. Over a period of 12 weeks, we tested the effect of a twice-a-week vulvo-vaginal application of a hyaluronic acid, AC collagen, isoflavones and vitamins-based cream (Perilei Pausa) on 35 women in post-menopausal period, reporting VVA-related symptoms. After 12 weeks of treatment with Perilei Pausa a significant improvement in vaginal dryness, vulvo-vaginal itching, dyspareunia (P < 0.001), dysuria (P = 0.02), nocturia (P = 0.009) and pollakiuria (P = 0.005) was reported by the women. Colposcopical score assessing the intensity of atrophic colpitis, cervico-vaginal paleness and petechiae was also reduced (P = 0.037, P = 0.016 and P = 0.032, respectively). No significant difference in terms of maturation value of cervico-vaginal epithelium was observed. In conclusion, Perilei Pausa may represent an effective and safe alternative treatment of symptomatic VVA in post-menopausal women.

Effect of pravastatin on endothelial function and endothelial progenitor cells in healthy postmenopausal women.

PURPOSE: Coronary heart disease is the leading cause of morbidity and mortality in postmenopausal women. Among statins, pravastatin has been shown to significantly reduce fatal and non-fatal cardiovascular events in primary and secondary prevention trials. The aim of the present research was to investigate whether treatment with pravastatin can modify some indices of cardiovascular risk in healthy postmenopausal women such as significant reductions in total and LDL cholesterol and triglyceride levels. METHODS: 20 patients were randomized in double-blind fashion to treatment for eight weeks with either pravastatin 40 mg/day or placebo, and subsequently, after one-week wash-out, crossed-over to the alternative treatment (placebo or pravastatin) for the following eight weeks. We performed clinical and laboratory investigations, before and at the end of each treatment period, to evaluate patient response to the treatment with pravastatin. RESULTS: After eight weeks pravastatin therapy reduced the median low density lipoprotein (LDL) and total cholesterol (p < 0.01 in both cases). In contrast, insulin level and insulin sensitivity did not show any difference with regard to values observed after placebo treatment. The absolute number of endothelial progenitor cells-colony forming unit (EPC-CFU) was significantly increased by pravastatin treatment (30.6% increase, p < 0.05) and the number of senescent cells was significantly decreased. However pravastatin did not increase tube-like formation by EPC and did not improve endothelial function. CONCLUSIONS: Despite beneficial effect on lipids and EPC, short term pravastatin does not seem to improve other cardiovascular risk factors, at least in healthy postmenopausal women.

Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation.

OBJECTIVE: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) plays a role in blastocyst implantation and is down-regulated in preeclampsia and in hypertensive pregnancy disorders associated with defective extravillous trophoblast invasion. Defective placentation and severe preeclampsia are also features of the antiphospholipid syndrome (APS). The purpose of this study was to investigate whether abnormal HB-EGF expression plays a pathogenic role in antiphospholipid antibody (aPL)-mediated defective placentation. METHODS: HB-EGF expression in placental tissue was evaluated by Western blotting and messenger RNA analysis in normal and APS placentae. Polyclonal IgG fractions or monoclonal beta(2)-glycoprotein I-dependent aPL and their respective controls were investigated for the following 4 features: their binding to human trophoblast monolayers, as determined by cell enzyme-linked immunosorbent assay (ELISA); their effect on HB-EGF expression by Western blotting in trophoblast cell extracts as well as by ELISA as a protein secreted in the culture supernatants; their inhibitory effect on in vitro trophoblast invasiveness, as evaluated by Matrigel assay; and their inhibitory effect on matrix metalloproteinase (MMP) levels, as measured by gelatin zymography. Experiments were also performed in the presence of serial concentrations of heparin or recombinant HB-EGF. RESULTS: Placental APS tissue displayed reduced expression of HB-EGF. Polyclonal and monoclonal aPL bound to trophoblast monolayers and significantly reduced the in vitro synthesis and secretion of HB-EGF. Heparin inhibited aPL binding and restored HB-EGF expression in a dose-dependent manner. Addition of recombinant HB-EGF reduced the in vitro aPL-induced inhibition of Matrigel invasiveness as well as MMP-2 levels. CONCLUSION: These preliminary findings suggest that the reduction of aPL-mediated HB-EGF represents an additional mechanism that is responsible for the defective placentation associated with APS and that heparin protects from aPL-induced damage by inhibiting antibody binding.

Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view.

Antiphospholipid antibodies (aPL) are associated with recurrent miscarriages and pregnancy complications, however their pathogenic mechanisms are still matter of research. Thrombotic events at the placental level cannot explain all of the clinical manifestations. It has been suggested that aPL may be responsible for a local acute inflammatory response mediated by complement activation and neutrophil infiltration eventually leading to fetal loss. However histological and immunohistological studies on human placental samples do support such a mechanism only in part and with no any clear relationship with the pregnancy outcome. A direct effect of aPL on both maternal and fetal placental tissues has been reported through the reactivity of the antibodies with beta2 glycoprotein I (beta2GPI) expressed on the cell membranes. These events do not require an inflammatory response and can be in part related to the inhibition of growth factors favouring a physiological placentation. Understanding the different pathogenic mechanisms of aPL-associated miscarriages may help in improving our therapeutic approach particularly in recurrent cases not responsive to the usual treatment.

Recurrent miscarriage and fetal congenital malformations: Is there a neglected causal association?

OBJECTIVE: The aim of the present study is to investigate the correlation between pregnancies complicated by morphological or chromosomal fetal anomalies and an obstetric history of two or more pregnancy losses, analyzing the association with any maternal risk factor. STUDY DESIGN: Retrospective analysis of women who had access to the Day Hospital Clinic of Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome from 2012 to 2018 for a pregnancy complicated by fetal malformation and/or abnormal karyotype, and who had an obstetric history of at least one pregnancy loss. Patients were divided into four groups depending on the number of miscarriages and the presence of a genetic anomaly: Group 0 included women with <2 miscarriages and fetal malformations, Group 1 included women with ≥2 miscarriages and fetal malformations, Group 2 included women with <2 abortion, fetal malformations and the presence of genetic anomalies; Group 3 included women with 2 ≥ abortions, fetal malformations and genetic anomalies. Statistical analysis was performed using the SAS v. 9.4 (SAS Institute Inc., Cary, NC, USA). RESULTS: A total of 466 patients were included in the present analysis. Out of these, 379 patients belonged to Group 0; 40 patients entered in Group 1; Group 2 included 42 patients, and 5 patients were part of Group 3. Pregnancies complicated by fetal congenital malformations in patients with two or more pregnancy losses were significantly associated with maternal trombophilic disease and previous birth defects. Recurrent miscarriage and fetal structural anomalies were also significantly correlated with advanced maternal age. CONCLUSIONS: An adequate periconceptional counseling regarding the risk of fetal congenital anomalies may be indicated in patients affected by thrombophilic disease, as well as in those of advanced maternal age and with a pregnancy history of fetal malformations. The screening for thrombophilia may be advisable in patients with an obstetric history of congenital birth defects.

The interplay between immune system and microbiota in gynecological diseases: a narrative review.

OBJECTIVE: The vaginal microbiome is a dynamic environment, depending on the results of a complex interplay between microbiota and the host. In physiological conditions, Lactobacillus species are the most represented, regulating glycogen metabolism in order to maintain normal pH. Vaginal flora has been divided into five subtypes. Pattern recognition receptors are present on both squamous epithelial cells lining the vagina and columnar cells lining the upper female genital tract. They respond directly to bacterial product expressed by vaginal microbiome. The vagina contains different immune related cells and receptors which can recognize and react with the microbial environment. Altered microbiota and altered interplay between microbiota and immune system underlie several gynecologic diseases. MATERIALS AND METHODS: In this review, literature data related to vaginal microbiota, vaginal inflammation, immune system and menopause, preterm labor and miscarriage, were summarized. Relevant publications were retrieved from: PubMed, Medline, Scopus and Web of Science. RESULTS: The vaginal microbiome and the relationship with immune system has been analyzed in different gynecologic conditions. Menopause is associated to estrogen loss which causes vaginal atrophy, reduced abundance of Lactobacilli and increased amount of other bacterial species. Estrogens influence vaginal immunity through known and unknown mechanisms. In bacterial vaginosis (BV), due to many bacterial species, there has been found an inhibition of the chemotaxis and cytokine secretion. A decreased concentration of Lactobacilli seems to be playing a role in preterm labor as well as the increased levels of pro-inflammatory cytokines. Finally, the disequilibrium in the Th1/Th2 immune adaptive response, with a shift from Th2 to Th1, appears to be playing a role in miscarriage. CONCLUSIONS: The interplay between microbiota and the host closely involves the immune system. In particular, the vaginal microbiota is classically characterized by Lactobacilli even if vaginal microbiome of asymptomatic woman of reproductive age includes multiple aerobic and facultative or obligate anaerobic species. The role of microbiota and immune system in determining gynecological and obstetric events has been studied throughout recent years reaching new advancements. Therefore, additional studies are needed to better comprehend the complexity of the issue.

HLA-DR is aberrantly expressed at feto-maternal interface in pre-eclampsia.

In normal pregnancy, villous cytotrophoblast and syncytiotrophoblast do not express HLA Class I and Class II molecules, while invasive extravillous trophoblast only express class I HLA-C and the atypical class Ib antigens, HLA-G, -E and -F. Inadequate maternal tolerance of invasive trophoblast has been proposed as a possible immunologic trigger of poor trophoblast invasion and subsequent occurrence of pre-eclampsia. This study aimed to investigate possible aberrant expression of class II HLA-DR on placentae and syncytiotrophoblast-derived extracellular vesicles (STEVs), obtained by dual placental perfusion, from pre-eclampsia (n = 23) and normal pregnant (n = 14) women. Here we demonstrate that HLA-DR can be detected in syncytiotrophoblast from a significant proportion of pre-eclampsia but not control placentae. HLA-DR was also observed, by flow cytometry, on STEVs and associated with placental alkaline phosphatase to validate their placental origin. HLA-DR positive syncytiotrophoblast was detected in placental biopsies from pre-eclampsia but not normal control cases, using immunohistochemistry. The HLA may be fetal or maternal origin. In the latter case a possible mechanism of acquisition is trogocytosis.

Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors.

Heparin is used widely for the prevention of pregnancy loss in pregnant women with thrombophilia. However, it is still unknown if heparin may be able to affect trophoblast functions. Therefore, we investigated the hypothesis that low-molecular weight heparin (LMWH) might regulate in vitro trophoblast invasiveness and placental production of matrix metalloproteinases (MMPs) and tissue inhibitors (TIMPs). In the first-trimester placental tissue, the MMP-9 expression was observed in both villous and extravillous cytotrophoblast cells, and MMP-2 mainly in villous cytotrophoblast. In human choriocarcinoma cells (JAR), MMP-2 was the dominant form. Heparin significantly enhanced both pro-MMPs and the active forms, and increased Matrigel invasiveness of extravillous trophoblast and choriocarcinoma cells. In choriocarcinoma cells the heparin effect was also indirect, inducing a significant decrease in TIMP-1 and TIMP-2 protein expressions and mRNAs. The present data suggest that the increase in trophoblast invasion by heparin is due to a specific protein playing a role in placental invasion. These observations may help in understanding the effects of heparin treatment during pregnancy.

Activin regulates betaA-subunit and activin receptor messenger ribonucleic acid and cellular proliferation in activin-responsive testicular tumor cells.

Activin, a member of the transforming growth factor-beta superfamily of growth and differentiation factors, has a number of actions in embryonic as well as adult tissues. These actions are mediated via a family of receptors containing two subtypes and at least two members of each subtype. Recent evidence demonstrates that activin-responsive cell lines containing different subsets of these receptors are valuable models for dissecting functional relationships among receptor subtype, signal transduced, and response obtained. TT cells, derived from a p53(-/-)/alpha-inhibin(-/-) mouse testicular tumor, respond to activin by proliferating, a response that can be inhibited by follistatin (FS) treatment. Using semiquantitative RT-PCR methods, we characterized steady state messenger RNA (mRNA) levels for the inhibin/activin subunits, FS, and activin receptor subtypes under basal conditions and in the presence of activin or FS. These cells produced ample immunoreactive activin A and FS, necessitating higher treatment doses to observe any modulation of cellular proliferation. Furthermore, in the presence of exogenous activin, mRNA levels for activin receptor type IIA (ACTRIIA) and betaA were significantly and profoundly suppressed. In addition, both ACTR1B and ACTRIIB were detectable and down-regulated by exogenous activin, although not to the degree observed for ACTRIIA and betaA. Finally, activin treatment at the higher doses, which decreased activin receptor mRNA levels, resulted in inhibition of cellular proliferation. Taken together with previous observations, our results support the model that these tumor cells respond to an autocrine activin signal by proliferating, whereas exogenous or excess activin results in down-regulation of activin receptor and activin biosynthesis, suggesting a potential autocrine/paracrine mechanism by which activin can modulate its own signal.

Characterization of inhibin/activin subunit, follistatin, and activin type II receptors in human ovarian cancer cell lines: a potential role in autocrine growth regulation.

Although ovarian cancer is the most common gynecological malignancy with a relatively poor 5-yr survival record, the mechanism(s) by which these tumors arise is not well understood. A role for inhibins and activins in regulating this transformation is suggested by the detection of circulating alpha or dimeric inhibin in some patients with ovarian cancer and by the alpha inhibin knockout mouse, in which development of gonadal tumors in 100% of homozygotes is associated with greatly elevated activin levels. To develop diagnostic tools with greater specificity for ovarian cancers, the present study was targeted at characterizing the biosynthetic capacity of the epithelial ovarian cancer cell lines from the American Type Culture Collection with respect to inhibin, activin, the related activin-binding protein follistatin (FS), and activin receptor type II. In addition, the functional capacity of this system was investigated by examining the ability of activin and FS to modulate cellular proliferation. All six cell lines contained abundant messenger RNA (mRNA) for activin receptor type II, but no inhibin alpha-subunit mRNA was detected in any cell line. Two cell lines contained mRNA for activin beta B-subunit (CaOV4 and SKOV3), one cell line contained beta A-subunit mRNA (SW626), and one cell line contained both (ES2); the latter also contained FS mRNA. FS mRNA was detected in another cell line (PA-1) that contained no detectable activin beta-subunit mRNA. Finally, one cell line (CaOV3) contained neither beta-subunit nor FS mRNA. Protein secretion was also examined. Consistent with the mRNA studies, the two cell lines containing FS mRNA secreted FS (PA-1 and ES2 cells), whereas three of the remaining lines secreted activin (A or B). In the cell line containing neither FS nor beta-subunit mRNA, no FS or activin could be detected. Finally, none of the cell lines secreted detectable immunoreactive inhibin. The effects of exogenous activin and FS on cellular proliferation were examined in these cell lines. No response was detected in the two cell lines that secreted FS (PA-1 and ES2). For the four cell lines not synthesizing FS, treatment with activin (1-100 ng/ml) resulted in an increase, whereas FS treatment (1-100 ng/ml) resulted in a decrease in cellular proliferation, as determined by [3H]thymidine incorporation. The response to activin correlated negatively with endogenous activin production, suggesting that autocrine activin production may be involved with cell proliferation. The differential expression and production of inhibin/activin subunits, activin receptors, and follistatin as well as the range of responses to exogenous activin among six ovarian epithelial cancer cell lines suggest that this family of hormones may be important in regulating cell proliferation in the ovary. Whether primary tumors have the same profile and the degree to which these results can be generalized to additional forms of ovarian cancer remain to be determined.

In vitro effect of antiphospholipid antibody-containing sera on basal and gonadotrophin releasing hormone-dependent human chorionic gonadotrophin release by cultured trophoblast cells.

Our objective was to evaluate whether antiphospholipid antibody-containing sera could play a regulatory role in signal transduction induced by gonadotrophin releasing hormone (GnRH) when incubated with normal human trophoblast cells. To test this hypothesis we established an in vitro placental culture system in which GnRH addition in the presence of normal human serum resulted in a significant increase in human chorionic gonadotrophin (hCG) secretion. When GnRH was added to the culture medium with antiphospholipid antibody-containing sera, the hCG increase was inhibited. These results suggest the possibility that antiphospholipid antibody-positive sera can exert their effect on GnRH-induced signal transduction. Further studies are needed to explain their exact site of action.

Interleukin-3 and human trophoblast: in vitro explanations for the effect of interleukin in patients with antiphospholipid antibody syndrome.

OBJECTIVE: To examine the effect of interleukin (IL)-3 on in vitro trophoblast differentiation, hormone production, and invasiveness affected by antiphospholipid antibodies. DESIGN: Primary cytotrophoblast cell cultures. SETTING: Obstetrics and Gynecology Department of the Catholic University, Rome, Italy. PATIENT(S): Five normal pregnant women underwent uncomplicated vaginal delivery at 36 weeks of gestation. INTERVENTION(S): Immunoglobulin (Ig) G antibodies were isolated from the plasma of two patients with antiphospholipid syndrome and two normal control subjects with the use of protein-G Sepharose columns. Cytotrophoblast cells were dispersed in Ringer's bicarbonate buffer containing trypsin and DNAseI, filtered, and layered over a Percoll gradient in Hank's balanced salt solution. MAIN OUTCOME MEASURE(S): We investigated the effects of IL-3 and antiphospholipid antibodies on trophoblast cell invasiveness, differentiation, and hormone secretion. RESULT(S): IgG obtained from patients with antiphospholipid syndrome bound to trophoblast cells, with inhibitory effects on the cells' invasiveness, differentiation, and hCG secretion. IL-3 was able to restore in vitro placental functions. CONCLUSION(S): These results imply that IL-3 favorably affects human trophoblast implantation and development.

Human growth hormone enhances progesterone production by human luteal cells in vitro. II. Evidence of a distinct effect on two luteal cell types.

OBJECTIVE: To examine the differential effect of human GH (hGH) on basal and hCG-stimulated production by cultured small and large human luteal cells. DESIGN: Distinct cultures of small and large luteal cells from early and midluteal phase. SETTING: All corpora lutea were obtained from the Obstetrics and Gynecology Department of the Catholic University, a public care center in Rome, Italy. PATIENTS, PARTICIPANTS: Ten nonpregnant women between 31 and 43 years of age underwent surgery for various nonendocrine disorders such as leiomyomatosis. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. MAIN OUTCOME MEASURES: Small and large luteal cells were incubated with or without hCG and/or hGH at different concentrations. RESULTS: Human GH neither at 250 nor at 500 micrograms/L increased basal P production by small luteal cells, whereas from 1,000 micrograms/L, P concentration in media was significantly increased. The concomitant treatment with ineffective doses of hCG (30 and 60 IU/L) and hGH (250 and 500 micrograms/L) enhanced P production to that obtained with the highest doses of hGH (1,000 micrograms/L or more) or hCG (125 to 250 IU/L) alone. Human GH addition did not change the amount of P release by large luteal cells at any concentration. CONCLUSIONS: These results indicate a distinct and differential effect of hGH on in vitro luteal steroidogenesis by the two luteal cell types.

Human growth hormone enhances progesterone production by human luteal cells in vitro: evidence of a synergistic effect with human chorionic gonadotropin.

OBJECTIVE: To examine the possible direct effect of human growth hormone (hGH) on basal and human chorionic gonadodotropin (hCG)-stimulated progesterone (P) production by cultured human luteal cells. DESIGN: Cultures of human luteal cells from early and midluteal phase. SETTING: All corpora lutea were obtained from the Obstetrics and Gynecology Department of the Catholic University, a public care center. PATIENTS, PARTICIPANTS: Twelve nonpregnant women between 35 and 47 years of age underwent surgery for various nonendocrine disorders such as leiomyomatosis. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. MAIN OUTCOME MEASURE: Luteal cells were incubated with or without hCG and/or hGH at different concentrations. RESULTS: Human growth hormone neither at 250 nor at 500 ng/mL increased basal P production, whereas from 1,000 ng/mL P concentration in media was significantly increased (P less than 0.05). The concomitant treatment with uneffective doses of hCG (6 and 12 ng/mL) and hGH (250 and 500 ng/mL) enhanced P production similarly to that obtained with the highest doses of hGH (1,000 ng/mL or more) or hCG (25 to 50 ng/mL) alone. CONCLUSIONS: These results indicate a direct effect of hGH on the luteal steroidogenesis in vitro.

Effect of activin-A on progesterone synthesis in human luteal cells.

OBJECTIVE: To examine the effect of activin-A on basal and hCG-stimulated P production by human luteal cells. DESIGN: Mixed luteal cell cultures and distinct cultures of two luteal cell types: small and large luteal cells from early and midluteal phase. SETTING: Corpora lutea (CL) were obtained from the Obstetrics and Gynecology Department of the Catholic University, Rome, Italy. PATIENTS: Fifteen nonpregnant women between 30 and 45 years of age underwent surgery for nonendocrine gynecological diseases. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. The luteal cells were dispersed in Ham's F-12 medium containing collagenase at 37 degrees C in shaking water bath for 2 hours, filtered, centrifuged, and resuspended in fresh medium. MAIN OUTCOME MEASURES: The cells diluted to a final concentration of 60,000 to 100,000 cells/mL of medium. After 24 hours, the cells attached to the wells and were incubated with or without hCG and/or activin-A at different concentrations. RESULTS: Activin-A starting from 25 micrograms/L significantly decreased basal and hCG (250 mIU/mL [conversion to SI unit, 1.00])-induced P production by mixed luteal cells. The small luteal cells responded to hCG (250 mIU/mL), and the treatment with activin-A (from 25 to 100 micrograms/L) reduced their basal and hCG-induced P production. Activin-A addition did not change the amount of P release by large luteal cells at any concentration. CONCLUSIONS: These results imply that activin-A plays a role in the local regulation of human CL.

Insulin-like growth factor (IGF)-I and IGF-II stimulate progesterone production by human luteal cells: role of IGF-I as mediator of growth hormone action.

OBJECTIVE: To examine the possible direct effect of insulin-like growth factor (IGF)-I and IGF-II on basal and hCG-stimulated P production by cultured human luteal cells. The possible role of IGF-I as mediator of GH action on luteal steroidogenesis also was investigated. DESIGN: Cultures of human luteal cells from early and midluteal phase. SETTING: All corpora lutea were obtained from the Obstetrics and Gynecology Department of the Universita Cattolica, a public care center. PATIENTS: Eight nonpregnant women between 35 and 47 years of age underwent surgery for various nonendocrine disorders such as leiomyomatosis. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. MAIN OUTCOME MEASURES: Luteal cells were incubated with IGF-I or IGF-II with or without hCG at different concentrations. Growth hormone also was used alone and with an anti-IGF-I-antibody. RESULTS: We found that IGF-I and IGF-II were able to stimulate directly the P production at all used concentrations and that both of them significantly amplified the steroidogenic hCG effect. Finally, IGF-I was shown to mediate the positive GH action on P synthesis.

Polycystic ovary disease. A risk factor for gestational diabetes?

We investigated the impact of pregestationally elevated insulin plasma levels on glycemic control in pregnant women with polycystic ovary disease (PCOD). Twelve patients with PCOD who became pregnant within six months following evaluation of their metabolic status were the study subjects. Four were obese and six (two obese) had a hyperinsulinemic response to the oral glucose tolerance test (OGTT). They were tested with the OGTT at 28-30 weeks of gestation. We also tested 12 normal patients and 10 consecutive patients with gestational diabetes; all were at the same gestational age. Plasma levels of insulin and glucose were determined in the samples collected for a period of four hours after glucose load (100 g). All PCOD patients significantly increased their insulin secretion in pregnancy. The hyperinsulinemic PCOD patients developed gestational diabetes (two patients) and impaired gestational glucose tolerance (three patients). The area under the insulin curve was greater in PCOD patients than in control and gestational diabetes patients (P < .01). In spite of their large increase in insulin secretion observed during pregnancy, patients with PCOD may develop a derangement of glycemic control, probably related to their pregestational insulinemic status.

Alterations of maternal plasma HTRA1 level in preeclampsia complicated by IUGR.

We evaluated the presence of HtrA1 in maternal plasma of normal pregnancies and of pregnancies complicated by preeclampsia (PE) without and with Intrauterine Growth Restriction (IUGR). We demonstrate that HtrA1 maternal plasma levels show significant different concentrations in first, second and third trimester of gestation and that HtrA1 concentration increases in maternal plasma of gestations complicated by PE with IUGR compared with control maternal plasma matched for gestational age. Based on these data high maternal plasma levels of HtrA1 could be considered as a possible marker of an occurring IUGR in preeclamptic women.