Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020).

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to women's individual needs, take account of her personal circumstances, and have few or no side effects.

Increased Insulin Concentrations During Growth Hormone Treatment in Girls With Turner Syndrome Are Ameliorated by Hormone Replacement Therapy.

Objective: Turner syndrome (TS) is characterized by complete or partial loss of one sex chromosome and is commonly associated with short stature, metabolic changes (such as central obesity, abnormal glucose tolerance and high triglycerides) and premature ovarian insufficiency (POI). Primary management of TS during childhood and adolescence comprises treatment with human growth hormone (hGH) and, in cases with early loss of ovarian function, hormone replacement therapy (HRT). Given that metabolic parameters are altered when HRT is applied during menopause, we analyzed whether metabolic changes might be positively or negatively affected within 10 years after HRT and/or hGH in girls with TS. Design: Observational study. Methods: Data were collected from the medical records of 31 girls with TS attending two endocrinologic centers in Germany between 2000 and 2020. Descriptive statistics are reported as the mean ± SEM or percentages. Results: The mean age at first presentation was 99.06 ± 8.07 months, the mean height was 115.8 ± 3.94 cm, and the mean BMI 19.0 ± 0.99 was kg/m2. Treatment with hGH was given to 96.8% of the girls, starting at an average age of 99.06 ± 8.70 months, and was continued for 67.53 ± 6.28 months. HRT was administered to 80.6% of all patients and was started at a mean age of 164.4 ± 4.54 months. During the follow-up, we did not observe any significant absolute changes in lipid parameters, but we detected beneficial effects of childhood hGH: significantly lower cholesterol (-0.206/month; p = 0.006), lower low density lipoprotein cholesterol (-0.216/month; p = 0.004), and higher high density lipoprotein cholesterol (+0.095/month; p = 0.048). Insulin concentrations, showed a significant increase attributable to hGH treatment (+0.206/month; p = 0.003), which was ameliorated by concomitant or subsequent HRT (-0.143/month; p = 0.039). Conclusion: Treatment with hGH and HRT is provided to most girls with TS. Metabolic effects are associated with both modalities. Monitoring of metabolic changes appears to be important to detect unfavorable effects, and could guide treatment adjustment and duration.

Expression of the Peptidase "Fibroblast Activation Protein" on Decidual Stromal Cells Facilitating Tissue Remodeling.

INTRODUCTION: Expression of fibroblast activation protein (FAP) has been detected in activated fibroblasts participating in injury response, fibrotic and inflammatory conditions, and tumorigenesis. Human endometrium is equally characterized by rapid tissue remodeling events due to the reproductive tasks comprising the activity of proteolytic enzymes. OBJECTIVE: We therefore hypothesized that FAP-positive fibroblasts could also be involved in physiological processes requiring tissue remodeling, such as decidualization during early pregnancy. METHODS/RESULTS: The expression of FAP was analyzed by immunohistochemistry in frozen sections of decidual tissue from early pregnancy (gestational weeks: 6-12). All tissue samples clearly displayed a strong expression of FAP on the surface of stromal fibroblasts. Additionally, the percentage of FAP-positive fibroblasts freshly isolated from the decidua of the corresponding gestational weeks was calculated by applying FACS analysis. Decidual fibroblasts of different gestational weeks showed a significant decrease in FAP expression between the 6th and 7th weeks of gestation, which was followed by a steady slow reconstitution. By analyzing the expression of cytokines, chemokines, and growth factors of isolated FAP-positive decidual fibroblasts, we detected high levels of monocyte-attracting chemokines (growth-related oncogene alpha and monocyte chemoattractant protein-1 and -2), granulocyte-attracting chemokines (e.g., IL-8), proinflammatory factors (IL-1α and tumor necrosis factor alpha), and angiogenic substances (e.g., vascular endothelial growth factor and IL-8), which all promote an optimal microenvironment for implantation and growth of the conceptus. CONCLUSIONS: Our data demonstrate that the healthy early pregnancy decidua is characterized by a general occurrence of FAP-positive fibroblasts possibly participating in active tissue remodeling during implantation.

Factors Impacting on Decision-Making towards Prophylactic Surgeries in BRCA Mutation Carriers and Women with Familial Predisposition.

BACKGROUND/OBJECTIVES: BRCA mutation carriers and women at high risk of breast/ovarian cancer are faced with the intricate question to opt for prophylactic surgeries and/or a periodic screening. The aim of this study was therefore to identify objective and emotional factors that have an impact on the decision-making process. METHODS: Ninety-five women with BRCA mutations or women at increased breast/ovarian cancer lifetime risk were counseled at our outpatient department and either opted for prophylactic surgery or periodic screening. To identify the psychological factors that could have influenced the decision-making, a standardized questionnaire was applied. Additionally, clinical data were collected and were reviewed by a personal talk. RESULTS: Seventy-one of the patients opted for an increased surveillance only, 21 for prophylactic surgeries. Positive predictors for prophylactic surgeries were sociodemographic characteristics such as parity and objective variables such as verified mutation status. Hierarchical regression analysis revealed that the need for safety in health issues has been the only significant psychological predictor of surgery beyond the objective factors. Fear of surgical procedures, menopausal symptoms after surgery, loss of attractiveness, or fear of interferences with sexual life did not significantly affect decision-making. CONCLUSION: Decision-making towards prophylactic surgeries is influenced by objective but also emotional factors. Knowing that fear and anxiety also have an important impact on decision-making, distinct counselling about the procedures, the subsequent risk reduction as well as the psychological effects of prophylactic surgeries are essential.

Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.

The incidence of low (<6 oocytes) and high (>18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre (n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women (n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P-value: 0.853, 0.769-0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P-value: 0.871, 0.787-0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response.

Regular consumption of Lactobacillus reuteri-containing lozenges reduces pregnancy gingivitis: an RCT.

AIM: This randomized controlled trial assessed the impact of Lactobacillus reuteri on pregnancy gingivitis in healthy women. MATERIALS AND METHODS: Forty-five healthy women (24 test/21 placebo) with pregnancy gingivitis in the third trimester of pregnancy were enrolled. At baseline Gingival Index (GI) and Plaque Index (PlI) were assessed at the Ramfjord teeth and venous blood taken for TNF-α analysis. Subsequently participants were randomly provided with lozenges to be consumed 2 × daily until birth (approx. 7 weeks) containing ≥108 CFU L. reuteri ATCC PTA 5289 and ≥108 CFU L. reuteri DSM 17938 (test) or being devoid of L. reuteri (placebo). Within 2 days after birth recording of GI, PlI and blood sampling were repeated. RESULTS: At baseline, mean GI and mean PlI did not differ significantly between both groups. In the test group mean TNF-α serum level was significantly (p < 0.02) lower than in the placebo group. At reevaluation, mean GI and mean PlI of the test group were both significantly (p < 0.0001) lower than in the placebo group. Mean TNF-α serum level did no longer differ significantly between the groups. CONCLUSIONS: The consumption of L. reuteri lozenges may be a useful adjunct in the control of pregnancy gingivitis.

CD33(+) /HLA-DR(neg) and CD33(+) /HLA-DR(+/-) Cells: Rare Populations in the Human Decidua with Characteristics of MDSC.

PROBLEM: Human pregnancy needs a remarkable local immune tolerance toward the conceptus. Myeloid-derived suppressor cells (MDSC) are important players promoting cancer initiation and progression by suppressing T-cell functions and thus inducing immune tolerance. Therefore, MDSC were expected within decidua. METHODS: Subpopulations of CD33(+) immune cells were isolated from human early pregnancy decidua and characterized phenotypically and functionally by microscopy, FACS analysis, RT-PCR, Western blotting and in the coculture with T cells. RESULTS: Decidua harbors CD33(+) /HLA-DR(neg) and CD33(+) /HLA-DR(+/-) cells which both express arginase, iNOS and IDO and a typical cytokine profile. Both subtypes potently suppress T-cell proliferation and therefore fulfill the criteria of MDSC. CONCLUSION: We characterized a new population of CD33(+) /HLA-DR(neg) and CD33(+) /HLA-DR(+/-) cells in human early pregnancy decidua with properties of classical MDSC and thus potentially being an important player in immune tolerance in pregnancy.

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125.

BACKGROUND: Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z. METHODS: 69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.). RESULTS: In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69).HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective.As compared to AEZS 108, the Disorazol Z - LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment. CONCLUSION: The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125.

Quantification of the predominant immune cell populations in decidua throughout human pregnancy.

PROBLEM: To date, a multiplicity of factors contributing to the establishment and progression of a successful pregnancy have been postulated. There is emerging evidence that decidual leukocytes could be decisive factors during pregnancy. Despite numerous investigations on immune cells in human early pregnancy decidua, little is known about the physiological composition and proportion of the various immune cell populations during the different phases of pregnancy. In this study, we therefore analyzed the proportion of the dominant decidual leukocytes in human tissue samples derived from all phases of pregnancy. METHODS: Single cell suspensions were prepared from decidual samples from 205 patients at 6-40 weeks of gestation. Cell populations were analyzed by flow cytometry, and immune cell populations were quantified as percentage of decidual CD45(+) cells. RESULTS: There was generally no difference in immune cell counts comparing decidua of healthy gestations and those with systemic inflammation. Overall, the proportion of uNK cells continuously decreased, while the amount of monocytes, immature dendritic cells, and T cells increased until term. Striking modifications in cell counts were seen during the 7th week compared with the 6th and later weeks of gestation. CONCLUSION: Studying the proportion of decidual immune cells during pregnancy, we detected a unique pattern which could be useful to design novel therapies for pathological conditions during pregnancy.

Mechanisms of tumor immune escape in triple-negative breast cancers (TNBC) with and without mutated BRCA 1.

PURPOSE: Triple negative breast cancers (TNBC) are associated with an adverse outcome, although these tumors are sensitive to chemotherapy. In part, this phenomenon could be caused by tumor immune escape. The current study investigates immunogenicity of TNBC cells in vitro and the presence of immunosuppressive factors in the tumor microenvironment (pAKT and B7H1 expression, infiltration with regulatory T cells, [Tregs]). METHODS: Natural killer (NK)-cell induced lysis was evaluated in estrogen receptor (ER) positive MCF 7 breast cancers, in MDA-MB231 and MDA-MB468 and in HCC-1937 (BRCA 1 mutated) and HCC-1806 TNBC cells. Expression of pAKT, B7H1 and infiltration with Tregs were determined by immunohistochemistry in human specimens of benign and malignant breast disease. RESULTS: NK-cell induced lysis was significantly increased (p < 0.05) in four TNBC cell lines compared to ER + MCF 7 cells. Fibroadenomas and mastectomy samples were not infiltrated with Tregs. Infiltration with Tregs was 0.92 ± 0.21 in ER/PR + breast cancers and significantly higher in TNBC without (2.30 ± 0.34) and also significantly higher with mutation of BRCA 1 (2.10 ± 0.34). Expression of pAKT was absent in benign controls and 1.23 ± 0.36 in ER/PR + breast cancers, 1.78 ± 0.40 in TNBC without and 2.40 ± 0.30 with mutated BRCA 1. No significant differences of B7H1 expression occurred among the breast cancer subgroups. CONCLUSION: TNBC cell stimulate the NK-cell immune response significantly stronger than ER positive breast cancer cells. This could explain why infiltration with immunosuppressive Tregs is increased in human specimens of TNBC with and without mutated BRCA 1. Accordingly, immunomodulatory treatment strategies should be further explored in TNBC.

Effects of lobaplatin as a single agent and in combination with TRAIL on the growth of triple-negative p53-mutated breast cancers in vitro.

Lobaplatin as a single agent and in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is investigated in in-vitro models of p53-negative triple-negative breast cancers (TNBCs) and compared with a model of oestrogen receptor-positive p53-positive breast cancer. In addition, the induction of programmed cell death by lobaplatin is further explored. By using cell viability assays and western blotting, the cytotoxic effects of lobaplatin alone and in combination with TRAIL are compared with cisplatin in HCC 1806, HCC 1937, and MCF 7 cells. The multicaspase inhibitor z-VAD-fmk and necrostatin, an inhibitor of necroptosis, are used to demonstrate the mechanism of cell death caused by lobaplatin. Lobaplatin displayed antitumour activity in all three cell lines, which increased time dependently. Cotreatment of lobaplatin and TRAIL induced an increase in cytotoxicity by 30-50% in the different cell lines. The pan-caspase inhibitor z-VAD-fmk as well as necrostatin could weaken but not abolish the cytotoxic effect of lobaplatin and cisplatin. Lobaplatin showed substantial cytotoxic effects in two in-vitro models of p53-mutated TNBC. Cotreatment with TRAIL and platinum agents resulted in increased antitumour activity in the TNBC cell lines investigated. Cell death subsequent to treatment with cisplatin and lobaplatin occurred because of apoptosis. However, caspase-independent mechanisms of programmed cell death were also involved. It was also demonstrated that platinum compounds could induce necroptosis, although to a minor extent.

Dendritic cells: elegant arbiters in human reproduction.

The female reproductive tract represents a great challenge to the residing immune cells: Concomitantly, those immune-competent cells have to provide tolerogenic mechanisms favoring the development of a successful pregnancy while permitting protection against harmful pathogens. The predominant cell population facing this "double edged" regulatory capacity within the reproductive tract is that of dendritic cells (DC). There is evidence that DC represent a highly adaptive cell type, which can either be transformed in an immune-stimulatory phenotype after exposure to inflammatory or infectious signals, or in an immune inhibitory phenotype preventing T cell activation when located in an adequate antiinflammatory microenvironment. Thus, this review highlights this two-faced character of DC focusing on their morphology and function within the human reproductive tract and especially during pregnancy.

Human decidua and invasive trophoblasts are rich sources of nearly all human matrix metalloproteinases.

Trophoblast cell (CTB) invasion into the maternal endometrium plays a crucial role during human embryo implantation and placentation. As for all invasive cell types, the ability of CTB to infiltrate the uterine wall is facilitated by the activity of matrix metalloproteinases (MMPs), which is regulated by tissue inhibitors of MMPs (TIMPs). There is evidence for the expression of several MMPs and TIMPs in decidua. However, published data are limited. Therefore, to set a foundation for future research, we screened a panel of healthy human deciduas obtained during first, second and third trimester of pregnancy in addition to isolated decidual cell populations for the expression of all known human MMPs and TIMPs by RT-PCR, western blot and immunohistochemistry. In the decidual samples, we detected almost all MMPs and all four TIMPs at mRNA level. While the expression of proMMP-3 and active MMP-13 and -23 was down-regulated in the course of pregnancy, the pro forms of MMP-8, -19 and -23, active MMP-9, -10, -12, -15, -16, -26 and -28, and pro- and active MMP-14 increased towards the end of gestation. All MMPs and TIMPs were expressed in uterine natural killer cells, decidual fibroblasts and/or trophoblasts, with the exception of MMP-20 and -25. In summary, a remarkably broad spectrum of MMPs was expressed at the human feto-maternal interface, reflecting the highly invasive and remodelling effect on placenta formation. It can be speculated that expression of MMPs correlates with the invasive potential of CTBs together with a crucial role in activation of labour at term.

Cervical endometriosis associated with malignant pleural mesothelioma mimicking cervical cancer--Occam's razor or the "third man".

OBJECTIVE: To illustrate pitfalls in the diagnosis of endometriosis and cervical cancer. DESIGN: Case report. SETTING: University hospital, department of obstetrics and gynecology. PATIENT(S): A 45-year-old woman with menorrhagia, pelvic mass, right-sided hydronephrosis, and unexplained weight loss. INTERVENTION(S): Cervical biopsies were suggestive of cervical endometriosis. Laparoscopy confirmed endometriosis. Associated pleural effusion, without cytologic signs of malignancy, was interpreted as caused by thoracic endometriosis. The patient had a transabdominal hysterectomy and unilateral salpingo-oophorectomy. Histopathologic examination confirmed endometriosis and revealed a residual tubo-ovarian abscess. After surgery, the patient developed spontaneous seropneumothorax. Pleural biopsies revealed a well-differentiated epithelial malignant pleural mesothelioma. The patient underwent hypofractionated radiation of drain sites. She is now observed in our outpatient clinic. MAIN OUTCOME MEASURE(S): Steps to the correct diagnosis. RESULT(S): The patient had an association of cervical and pelvic endometriosis, residual tubo-ovarian abscess, and malignant pleural mesothelioma. CONCLUSION(S): Usually, the simplest diagnosis explaining a complex of symptoms and clinical and diagnostic findings is the one most likely to be correct. This is an application of Occam's razor to medicine. Our case illustrates that occasionally the simplest and therefore most probable diagnosis can be wrong, and on these occasions one should consider a "third man."

Pregnancy-triggered antiphospholipid syndrome in a patient with multiple late miscarriages.

Antiphospholipid syndrome (APS) is a multisystemic disorder of coagulation-causing thrombosis in the arterial and venous system as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery and pre-eclampsia. The disease is characterized by the autoimmune production of antibodies against phospholipid, a substance found in the cell membrane. We here report the case of a patient with four second trimester miscarriages, who apart from a heterozygous plasminogen activator-inhibitor-1 mutation, had no risk factors explaining her condition. In the subsequent pregnancy she was therefore put on low-molecular-weight heparin, aspirin and granulocyte colony-stimulating factor. Antiphospholipid antibodies (APL), which had been negative before gestation, increased and remained high throughout pregnancy, thus suggesting a pregnancy-induced or -aggravated APS. The patient was kept on the above-mentioned medication and delivered a healthy male baby by Caesarean section after an otherwise uneventful pregnancy. Thus, in order to diagnose and treat pregnancy-triggered APS in patients with unexplained recurrent miscarriage, screening for APL should also be performed at several time points after conception.

Antigen-presenting cells in pregnant and non-pregnant human myometrium.

PROBLEM: Inflammatory cells play a crucial role in human parturition. Different populations of leucocytes invade the reproductive tract. Numerous studies have described the decidual immune cell population in pregnant and non-pregnant endometrium. However, little is known about the presence of immune cells in human myometrium. METHOD OF STUDY: we herein analysed a spectrum of immune cells in human myometrium comparing tissue samples from non-pregnant (n = 8) and pregnant (n = 10) uteri. Applying immunohistochemistry with a panel of antibodies specific for T cells, monocytes, natural killer cells, B cells and antigen-presenting cells (CD4, CD8, CD14, CD15, CD16, CD19, CD56, CD68, CD83, HLA-DR, DC-Sign, mast cell tryptase), we characterized the immune cell population of human myometrium. RESULTS: a significantly higher number of CD14, CD15, CD16, DC-SIGN as well as CD4-positive cells were found in myometrium of pregnant compared to non-pregnant uteri, while mast cells were significantly reduced in pregnant myometrium. CONCLUSION: all markers found increased in pregnant myometrium indicate monocyte/macrophage lineage cells and thus suggest a possible involvement of these cells in healthy pregnancy maintenance. Monocytes/macrophages might produce a microenvironment that permits a controlled invasion of trophoblast cells into the myometrium while preventing a rejection of the semiallogenic conceptus and providing an important barrier against invading pathogenes.

Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia--a prospective observational study.

BACKGROUND: Changes in the balance of decidual leucocyte populations may lead to an unfavourable uterine microenvironment which may be associated with the development of preeclampsia (PE). In this study, we therefore investigated the leucocyte subpopulations in decidual tissues of 33 women with preeclampsia and 66 control patients. METHODS: Decidua was either obtained via curettage during cesarean section or dissected from the surface of the basal plate of the placenta after spontaneous delivery. We used FACS analysis to quantify decidual leukocytes (CD45), NK cells (CD56+/CD16+ and CD56++/CD16-), antigen presenting cells (HLA-DR, DC-Sign, CD14) and T/B cells (CD8, CD4, alpha-beta-T-cell receptor, gamma-delta-T-cell receptor, CD25, CD19). RESULTS: The number of decidual cytotoxic CD8+T-lymphocytes (P < 0.02), alpha-beta -T-cell receptor positive T cells (P < 0.03) and of CD56+/CD16+ NK cells (P < 0.03) was lower in decidua from women with PE than in decidua from control patients. CONCLUSION: The observed reduction of specific leucocyte subsets could create a microenvironment which is unfavourable for an appropriate placentation and could thereby be involved in the development of preeclamptic symptoms.

Impact of female sex hormones on the maturation and function of human dendritic cells.

PROBLEM: During pregnancy, the immune and the endocrine system cooperate to ensure that the fetal allograft develops without eliciting a maternal immune response. This is presumably in part achieved by dendritic cells (DCs) that play a dominant role in maintaining peripheral tolerance. In this study, we investigated whether female sex hormones, such as human chorionic gonadotropin (hCG), progesterone (Prog), and estradiol (E2), which are highly elevated during pregnancy, induce the differentiation of DCs into a tolerance-inducing phenotype. METHODS/RESULTS: Immature DCs were generated from blood-derived monocytes and differentiated in the presence of hCG, Prog, E2, or Dexamethasone (Dex) as a control. Unlike Dex, female sex hormones did not prevent the upregulation of surface markers characteristic for mature DCs, such as CD40, CD83, and CD86, except for hCG, which inhibited HLA-DR expression. Similarly, hCG, Prog, and E2 had any impact on neither the rearrangement of the F-actin cytoskeleton nor the enhanced chemokine secretion following DC maturation, both of which were strongly altered by Dex. Nevertheless, the T-cell stimulatory capacity of DCs was significantly reduced after hCG and E2 exposure. CONCLUSION: Our findings suggest that the female sex hormones hCG and E2 inhibit the T-cell stimulatory capacity of DCs, which may help in preventing an allogenic T-cell response against the embryo.

Upregulation of chemokine and cytokine production during pregnancy.

BACKGROUND: Following implantation, endometrial stroma is transformed into decidual tissue via a complex remodeling process. In parallel with that process, a significant increase in immune cells can be detected. Several studies suggest that chemokines and cytokines orchestrate the transformation of decidual tissue and the infiltration of leukocytes. In this study, we therefore compared chemokine and cytokine expression in the first- and third-trimester nonpregnant endometrium and decidua. METHODS: Investigation of the expression patterns of cytokines, chemokines and growth factors in endometrial tissue (after routine hysterectomy) and human decidual tissue (7-8 weeks of gestation and 38-40 weeks of gestation, respectively) was performed by protein array analysis. RESULTS: This analysis revealed a significant increase in monocyte-attracting chemokines (granulocyte-macrophage colony-stimulating factor, growth-related oncogene, growth-related oncogene-alpha and monocyte chemoattractant protein-2) , granulocyte-attracting chemokines (epithelial neutrophil activating peptide and interleukin 8) and proinflammatory factors (interleukin-1alpha, leptin) in decidual compared to endometrial tissue. Furthermore, concentrations of angiogenic substances (vascular endothelial growth factor and thrombopoietin) significantly peaked in first-trimester deciduas. CONCLUSION: This study demonstrates increased expression of chemokines and cytokines in decidual tissue compared to nonpregnant endometrium.

The glycoprotein-hormones activin A and inhibin A interfere with dendritic cell maturation.

BACKGROUND: Pregnancy represents an exclusive situation in which the immune and the endocrine system cooperate to prevent rejection of the embryo by the maternal immune system. While immature dendritic cells (iDC) in the early pregnancy decidua presumably contribute to the establishment of peripheral tolerance, glycoprotein-hormones of the transforming growth factor beta (TGF-beta) family including activin A (ActA) and inhibin A (InA) are candidates that could direct the differentiation of DCs into a tolerance-inducing phenotype. METHODS: To test this hypothesis we generated iDCs from peripheral-blood-monocytes and exposed them to TGF-beta1, ActA, as well as InA and Dexamethasone (Dex) as controls. RESULTS: Both glycoprotein-hormones prevented up-regulation of HLA-DR during cytokine-induced DC maturation similar to Dex but did not influence the expression of CD 40, CD 83 and CD 86. Visualization of the F-actin cytoskeleton confirmed that the DCs retained a partially immature phenotype under these conditions. The T-cell stimulatory capacity of DCs was reduced after ActA and InA exposure while the secretion of cytokines and chemokines was unaffected. CONCLUSION: These findings suggest that ActA and InA interfere with selected aspects of DC maturation and may thereby help preventing activation of allogenic T-cells by the embryo. Thus, we have identified two novel members of the TGF-beta superfamily that could promote the generation of tolerance-inducing DCs.