During the menstrual cycle, the endometrium undergoes cyclic changes of cellular proliferation, differentiation, and death, an essential preparation of the endometrium for its interaction with the ...implanting embryo. In particular, the differentiation of endometrial stromal cells, named decidualization, ensures the formation of a proper feto-maternal interface for a regulated trophoblast invasion and correct placental orientation and growth. Interestingly, autophagy, an intracellular degradation process of great importance for the maintenance of cellular homeostasis, plays an important role in cell proliferation, differentiation, and growth. In the endometrium, increased detection of autophagy markers correlates with the progression of the menstrual cycle. However, until now, it was unknown whether autophagy contributes to the proper function of the endometrium. In this study, we show that autophagy is increased during in vitro decidualization of human endometrial stromal cells. Furthermore, we demonstrate that the knockdowns of two important autophagy-related (ATG) proteins, ATG7 and ATG5, impaired decidualization, confirming a positive role of these proteins and of autophagy for the correct decidualization of human endometrial stromal cells. In conclusion, in this work, we describe a previously unknown functional connection between autophagy and endometrial physiology.
Endometriosis is often associated with severe dysmenorrhea, pelvic pain and dyspareunia and has a high impact on daily life as well as sexuality. Quality of partnership positively influences the ...course of various diseases and ability to cope with emotional and physical distress. However, studies focusing on the male partners of endometriosis patients are rare, and even less is known about the reciprocal relationship in these couples. Therefore, this study aims to explore the interrelations in couples with endometriosis in matters of psychological distress, sexual and partnership satisfaction and social support.
The cross-sectional study was conducted in two university-affiliated fertility centres in Germany and Austria with n = 104 female/male couples affected by endometriosis. Participants completed a questionnaire regarding endometriosis, partnership, sexuality, stress, anxiety, depression and social support. Both women and men were asked about the impact of women's endometriosis-related pain (IEP) on their everyday life (e.g. leisure time). Data were analysed using the Actor-Partner-Interdependence Model.
Significant partner effects were evident: High depression, anxiety and stress scores in women were associated with a higher IEP in men (all p ≤ 0.01), reciprocally high stress and depression scores in men were correlated with a higher IEP in women (all p ≤ 0.05). Less sexual satisfaction in women was associated with a higher IEP in men (p = 0.040). There was a significant reciprocal association between the perceived lack of understanding from the social environment and a higher IEP, for both women (p = 0.022) and men (p = 0.027).
The male partner should be taken into account when counselling or treating women with endometriosis. Our study shows a high interdependence and reciprocal influence from both partners-positively and negatively-concerning psychological distress and sexual satisfaction. Furthermore, there ought to be more awareness for the psychosocial impact of endometriosis, especially in regard to social support and understanding. Talking about and improving sexual satisfaction as well as enhancing stress reducing techniques may hold great benefits for dealing with endometriosis. Registration number The study is registered with the German Clinical Trials Register (DRKS), number DRKS00014362.
Abstract Objective Time to therapy initiation in patients requiring gonadotoxic therapy is crucial. This article evaluates the efficiency of random start ovarian stimulation in affected women. Study ...Design Retrospective anonymous registry data analysis from 85 university and non-university fertility centres participating in the international network FertiPROTEKT. The study comprised 684 women undergoing ovarian stimulation for fertility preservation from 2007-2013. According to the time of stimulation initiation, days of ovarian stimulation, total dose of gonadotropins used, gonadotropin dose used per day, number of oocytes retrieved and incidence of ovarian hyperstimulation syndrome were analysed. Statistical analysis was performed using analysis of variance in case of continuous outcome variables and chi-square tests in case of categorical variables. Results Among 684 women who underwent ovarian stimulation prior to gonadotoxic therapy 472 (69.0%) started ovarian stimulation between menstrual cycle day 1-5 (group A), 109 (15.9%) between day 6-14 (group B) and 103 (15.1%) after day 14 (group C). The days of stimulation (A: 10.8 ±2.4, B: 10.6 ±2.7, C: 11.5 ±2.2) and total dose of gonadotropins (A: 2496 IU ±980, B: 2529 IU ±940, C: 2970 IU ±1145) were significantly increased in group C. Numbers of obtained oocytes (Group A: 11.6 ±7.7, B: 13.9 ±9.1, C: 13.6 ±7.9) were significantly increased in group B and C, while the overall incidence of ovarian hyperstimulation syndrome III° was 0.15%. Conclusion The outcome of ovarian stimulation is similar after stimulation initiation during any phase of the menstrual cycles, supporting the concept of random-start ovarian stimulation before gonadotoxic therapy without disadvantage for the patient concerning later fertility preservation.
Does the use of an online decision aid (DA) about fertility preservation (FP), in addition to standard counselling by a specialist in reproductive medicine, reduce decisional conflict compared to ...standard counselling alone?
Female cancer patients who could make use of the online DA had a significantly lower short-term decisional conflict score.
Nowadays, female cancer patients have several options for preserving fertility, but having to decide whether to opt for FP within a short time frame after cancer diagnosis and before the start of treatment is challenging. According to previous studies focussing mainly on breast cancer patients, decisional conflict among these women is high, and they have expressed the need for additional support.
The study was a randomized controlled trial including female cancer patients who were referred by their treating oncologist to a specialist in reproductive medicine for fertility counselling. Participants were randomly assigned to the control group (counselling only) or to the intervention group (counselling and additional use of the online DA immediately after counselling). Recruitment was ongoing from July 2016 to December 2017 at eight fertility centres in Switzerland and Germany.
The online DA was developed by an interdisciplinary team of specialists in reproductive medicine, gynaecologists, oncologists and psychologists. Of 79 recruited participants, 59 completed the first assessment and could therefore be enrolled in the study. They were asked to complete an online questionnaire at three time points: at T1, after counselling (control group, n = 27) or after counselling and the additional use of the DA (intervention group, n = 24); at T2, 1 month later (N = 41: control group, n = 23; intervention group, n = 18); and at T3, 12 months later (N = 37: control group, n = 20; intervention group, n = 17). The survey comprised questions about fertility-related knowledge, attitude towards FP, willingness to undergo FP and socio-demographic data, as well as the decisional conflict and decisional regret scales.
All participants showed low decisional conflict scores. Women who used the online DA in addition to counselling (intervention group) showed a significantly lower total score on the Decisional Conflict Scale (DCS) compared to the control group at T1 (P = 0.008; M = 12.15, SD = 4.38; 95% CI, 3.35-20.95) and at T2 (P = 0.043; M = 9.35, SD = 4.48; 95% CI, 0.31-18.38). At T3, the mean total score of the DCS was still lower in the intervention group compared to the control group; however, this group difference was no longer significant (P = 0.199, M = 6.86, SD = 5.24; 95% CI, -3.78 to 17.51). The majority of participants had already made a decision regarding FP (yes or no) at T1 (72.5%): 91.7% in the intervention group compared to 55.6% in the control group (P = 0.014). Those who had decided already at T1 showed significantly lower decisional conflict (P = 0.007; M = 13.69, SD = 4.89; 95% CI, 3.86-23.52). The average number of DA sessions per user was 2.23, and 80.8% of the participants completed the DA's value clarification exercises. Participants in the intervention group were satisfied with the DA and would recommend it to other patients.
The recruitment of participants was challenging because of the emotionally difficult situation patients were in. This led to the limited sample size for final analysis. Education levels were high in two-thirds of the participants. It is difficult to say whether the DA would be equally effective in women with a lower educational background.
There is evidence that the DA served as a helpful complement to the decision-making process for young female cancer patients qualifying for FP. This is, to our knowledge, the first randomized controlled trial evaluating a DA targeted at patients with several cancer types and in a language other than English (i.e. German). This study contributes to extending the range of the still limited number of DAs in the context of FP.
The study was supported by a research grant of the Swiss Cancer Research. The authors declare that no competing interests exist.
Clinicaltrials.gov, trial no. NCT02404883.
19 March 2015.
4 July 2016.
The incidence of endometrial cancer (EC) has increased over the past years and mainly affects women above the age of 45 years. Metabolic diseases such as obesity and type II diabetes mellitus as well ...as associated conditions like polycystic ovary syndrome (PCOS), insulin resistance and hyperinsulinemia lead to elevated levels of circulating estrogens. Increased estrogen concentrations, in turn, further trigger the proliferation of endometrial cells and thus promote EC development and progression, especially in the absence of progesterone as seen in postmenopausal women. Elevated blood glucose levels in diabetic patients further contribute to the risk of EC development. Metformin is an insulin-sensitizing biguanide drug, commonly used in the treatment of type II diabetes mellitus, especially in obese patients. Besides its effects on glucose metabolism, metformin displayed anti-cancer effects in various cancer types, including EC. Direct anti-cancer effects of metformin target signaling pathways that are involved in cellular growth and proliferation, e.g. the AKT/PKB/mTOR pathway. Further proteins and pathways have been suggested as potential targets, but the underlying mechanism of action of metformin's anti-cancer activity is still not completely understood. In the present study, the effects of metformin on protein expression were investigated in the human EC cell line HEC-1A using an affinity proteomic approach. Cells were treated with 0.5 mmol/L metformin over a period of 7 days and changes in the expression pattern of 1,300 different proteins were compared to the expression in untreated control cells as well as insulin-treated cells. Insulin treatment (100 ng/mL) was incorporated into the study in order to implement a model for insulin resistance and associated hyperinsulinemia, conditions that are often observed in obese and diabetic patients. Furthermore, the culture medium was supplemented with 10 nmol/L ß-estradiol (E2) during treatments to mimic increased estrogen levels, a common risk factor for EC development. Based on the most prominent and significant changes in expression, a set of 80 proteins was selected and subjected to a more detailed analysis. The data revealed that metformin and insulin targeted similar pathways in the present study and mostly acted on proteins related to proliferation, migration and tumor immune response. These pathways may be affected in a tumor-promoting as well as a tumor-suppressing way by either metformin treatment or insulin supplementation. The consequences for the cells resulting from the detected expression changes were discussed in detail for several proteins. The presented data helps identify potential targets affected by metformin treatment in EC and allows for a better understanding of the mechanism of action of the biguanide drug's anti-cancer activity. However, further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, CCND2, CD63, CD81, GFAP, IL5, IL17A, IRF4, PI3, and VTCN1. Further proteins might be of interest, where metformin counteracted unfavorable effects that have been induced by hyperinsulinemia.
The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates early follicular activation and follicular pool maintenance in female germline cells. Fragile X mental ...retardation 1 (FMR1) regulates folliculogenesis and it is variably expressed in patients with Premature Ovary Insufficiency. FMR1 expression is supposed to be linked to AKT/mTOR signaling in an ovarian response dependent manner as demonstrated in recent in vitro and in vivo studies in the female germline in vitro and in vivo.
We evaluated changes in the expression of AKT/mTOR signaling pathway genes by real time PCR in the peripheral blood of 74 patients with Premature Ovarian Insufficiency and 56 fertile controls and correlated their expression with FMR1 expression.
Expression of the genes AKT1, TSC2, mTOR, and S6K was significantly more abundant in patients with POI than in the controls. For AKT1, TSC2 and mTOR, gene expression was not affected by FMR1-CGG repeat number in the 5´-untranslated region. FMR1 and S6K expression levels, however, were significantly upregulated in patients with POI and an FMR1 premutation. Independent of a premutation, expression of mTOR, S6K, and TSC2 was significantly correlated with that of FMR1 in all patients. Furthermore, when grouped according to ovarian reserve, this effect remained significant only for mTOR and S6K, with higher significance note in patients with Premature Ovarian Insufficiency than in the controls.
In Premature ovarian insufficiency patients, activation of AKT/mTOR signaling pathway is remarkable and putatively pathognomonic. Additionally, it seems to be triggered by an FMR1/mTOR/S6K linkage mechanism, most relevant in premutation carriers.
Purpose
Endometriosis (EM) is a common gynecological disease affecting 10–15% of women of reproductive age. However, molecular mechanisms and pathogenesis are still not completely understood. ...Furthermore, due to the absence of a reliable clinical biomarker, the only viable method for the often-delayed definitive diagnosis is laparoscopic surgery. Our objective was to analyze molecular differences of selected endometrial proteins and genes of women suffering from different stages of EM compared with healthy women to evaluate potential clinical biomarkers.
Methods
We analyzed eutopic endometrial tissue samples from women undergoing a laparoscopic surgery (
n
= 58). mRNA gene expression of progranulin (
GRN
), neurogenic locus notch homolog protein (
NOTCH3
), fibronectin (
FN1
), and PTEN-induced kinase 1 (
PINK1
) was analyzed using qRT-PCR. Protein expression was determined using ELISA and immunohistochemistry.
Results
Significant differences in gene expression between the different stages of the disease were noted for GRN, NOTCH3, FN1, and PINK1 (
p
< 0.05). The endometrium of women with minimal EM (ASRM I) showed the highest mRNA expression. Protein levels of GRN and FN1 on the other hand were significantly decreased in the endometrium of women with EM compared with those of healthy controls. Furthermore, for GRN and FN1, we could detect a correlation of protein expression with the severity of the disease.
Conclusion
Our findings suggest a potential use of GRN and FN1 as clinical biomarkers to detect endometriosis. In addition, GRN, NOTCH3, FN1, and PINK1 could potentially be useful to differentiate between the underlying stages of the disease. However, a validation with a larger study population is needed.
We report a unique case of a rare utilization of IVM. This case shows the successful retrieval of immature oocytes followed by in vitro maturation (IVM) for fertility preservation in a patient ...undergoing chronic progestin contraception. A 24-year-old patient with anaplastic astrocytoma requiring chemotherapy with temozolomide for 12 cycles as soon as possible with wish for fertility preservation while using a long acting etonogestrel birth control implant presented in our unit for fertility preservation in May 2017. The currently used implant should be preserved for further contraception. As the ovaries presented with a high, pco-like, antral follicle count, IVM was offered; the patient agreed. A transvaginal follicular puncture in general anesthesia without any hormonal intervention and IVM of gained oocytes was performed. As the patient actually had no spouse, she decided to freeze unfertilized metaphase II stage oocytes (MII). Thirteen oocytes were obtained, eight of them could be matured and cryopreserved. IVM could be a possibility for fertility preservation in patients with polycystic ovaries when no time is available for stimulation for conventional in vitro fertilization. Even use of continuous progestin application for contraception is no obstacle.
Spontaneous abortion is one of the most common complications in early pregnancy. A preventive test to identify women who will experience a miscarriage, even before first symptoms occur, is not ...established. Activation of maternal immunological tolerance seems to be essential for early fetal development and various cytokines have been described in different stages of pregnancy. Therefore, we aimed to investigate if chemokine levels at the time of pregnancy testing relative to human Choriogonadotropin (hCG) are altered in patients who will experience a miscarriage in this pregnancy.
We obtained blood samples from 39 women. Dependent on the follow-up, patients with a positive pregnancy test were subsequently divided in two groups: ongoing pregnancy (n = 22) and miscarriage (n = 17) in this pregnancy. Immunological and endocrine profiling of maternal plasma at the time of pregnancy testing (5th week of gestation) was performed for each group at the time of pregnancy test using Multiplex and ELISA analysis.
hCG was significantly decreased in patients with abortion whereas levels of IL-1ra, MIP-1a and TNF-alpha were significantly increased. GCSF/ IL-1ra-ratio was 1.66-fold increased in patients with ongoing pregnancy. TGF-beta /MIP1a-ratio was significantly 3.45-times higher in patients with miscarriage. Comparing patients with ongoing pregnancy to patients experiencing a miscarriage, we could demonstrate significant alterations of the ratios MIP1a/hCG, IL-1ra/hCG, TNFalpha/hCG, MCP1/hCG, IL-6/hCG, TPO/hCG and TGF-beta1/hCG. The strongest effects were seen for the ratio MIP1a/hCG, IL-1ra/hCG and TNFalpha/hCG.
We have shown that cytokines in relation to hCG after 4 weeks of gestation are significantly altered in women with miscarriage, promising potential as a prognostic biomarker.
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