Predictors of partnership and sexual satisfaction and dyadic effects in couples affected by endometriosis and infertility.

PURPOSE: Endometriosis and infertility are associated with impaired partnership and sexuality of the patients, but also of their male partners. Also, endometriosis is one of the most common causes of infertility, resulting in a large overlap of both pathologies. The aim of this study was to determine the association of different predictors of partnership and sexual satisfaction and dyadic effects in couples with endometriosis and infertility. METHODS: A cross-sectional study was conducted with n = 62 women with endometriosis and n = 46 partners, including a total of n = 44 couples, some of whom were affected by infertility. The questionnaire included items on partnership, sexuality, depression, social support, and desire for a child. Multiple linear regression and the actor-partner-interdependence-model were used for analysis. RESULTS: Significant dyadic effects only occurred in couples with both endometriosis and infertility. Depression showed a significant negative actor effect in men for partnership satisfaction and a negative actor and partner effect in women for sexuality satisfaction (p < .05). For women, social support showed a significant positive actor effect for partnership satisfaction (p < .05), age showed a significant actor and partner effect for sexuality satisfaction (p < .05). CONCLUSION: The results show a significant association of endometriosis and infertility with partnership and sexuality satisfaction. Infertility could be a decisive factor. However, the large overlapping of both endometriosis und infertility in many couples support the importance of further studies to differentiate between the both effects. TRIAL REGISTRATION: German Clinical Trials Register DRKS00014362 on the 29.03.2018.

Patient- and cycle-specific factors affecting the outcome of frozen-thawed embryo transfers.

PURPOSE: This study attempted at identifying the main parameters influencing the outcome of frozen embryo transfers. METHODS: This is a single-center retrospective cohort study of 830 frozen-embryo-transfer cycles performed at a German university hospital from January 2012 to December 2016. Main outcome parameters were the clinical pregnancy and live birth rate. Twelve patient- and cycle-dependent factors were analyzed in terms of their influence on the outcome of frozen embryo transfers. Multivariate logistic regression analysis was used for the modelling of the dependency of the different parameters on outcomes. RESULTS: The clinical pregnancy rate in our study was 25.5%, the live birth rate was 16.1% with an average maternal age of 34.2 years at the time of the oocyte retrieval. In the univariate analysis age, number of transferred embryos, blastocyst versus cleavage stage transfer, embryo quality and mode of endometrial preparation affected the birth rate significantly. The birth rate after artificial endometrial preparation was significantly lower than the birth rate after transfers in modified natural cycles (12.8 versus 20.6% with p = 0.031). The multivariate logistic regression analysis showed a significant independent influence of age, number of transferred embryos, culture duration and mode of endometrial preparation on the frozen embryo transfer success rates. Body mass index, nicotine abuse, a history of PCO syndrome or endometriosis and the co-transfer of a second poor-quality embryo to a good-quality embryo appeared to be irrelevant for the outcome in our collective. CONCLUSION: Age, number of transferred embryos, embryo culture duration and the mode of endometrial preparation are independent predictive factors of frozen embryo transfer outcomes.

Activation of AKT/mammalian target of rapamycin signaling in the peripheral blood of women with premature ovarian insufficiency and its correlation with FMR1 expression.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Partners matter: The psychosocial well-being of couples when dealing with endometriosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Glucose and fatty acids catabolism during in vitro decidualization of human endometrial stromal cells.

The differentiation of endometrial stromal cells, named decidualization, is essential for the proper formation of the materno-fetal interphase. One important feature of decidualization is the increased glucose consumption and its utilization by endometrial cells to produce energy. Besides glucose, fatty acids are another important energy source for living cells and it has been described that endometrial stromal cells rely on the proper function of the oxidation of fatty acids for the correct decidualization. It is, however, unknown whether the turn-over of fatty acid degradation is modified during decidualization. Furthermore, it is also unknown how the final products of glucose and fatty acid catabolism are related to the function of the tricarboxylic acid cycle for the efficient ATP production. In this study, we evaluated the content levels of different intermediate metabolites and the expression of the key enzymes related to the degradation of glucose and fatty acids during the in vitro decidualization of human endometrial stromal cells. Our results suggest that human endometrial stromal cells undergo energetic metabolic changes during decidualization and that decidualizing and non-decidualizing cells differ in the level of activation of different metabolic pathways and, probably, in the use of intermediate metabolites.

Long-term effectiveness of an online decision aid for female cancer patients regarding fertility preservation: Knowledge, attitude, and decisional regret.

INTRODUCTION: The decision, whether to undergo fertility preservation or not is highly demanding for cancer patients. Decision aids may act as an additional source of support. So far, only a limited number of decision aids regarding fertility preservation for female cancer patients exist and have been evaluated systematically. This paper presents the results of secondary analyses of the first randomized controlled trial evaluating an online decision aid for female cancer patients affected by different types of cancer. It focuses on fertility-related knowledge, attitude toward fertility preservation, and long-term effectiveness regarding decisional regret. MATERIAL AND METHODS: Young female cancer patients between 18 and 40 years of age were recruited after fertility counseling with a reproductive specialist. They were assigned to either the control group (counseling only) or the intervention group (counseling followed by the additional use of the decision aid). Both groups had to complete a questionnaire after counseling as well as 1 and 12 months later, covering topics such as fertility-related knowledge, attitude towards fertility preservation, decisional conflict and regret. Recruitment was ongoing during 18 months in eight fertility centers located in Switzerland and Germany. RESULTS: Mean age of participating women was 29.31 years (SD 4.57). Of the entire sample (n = 51) 53% were affected with breast cancer, 27.4% with lymphoma, and 19.6% with various other types of cancer. Knowledge regarding the most common fertility preservation methods was high and comparable in both groups. Positive attitude significantly exceeded negative attitude among all participants (p = 0.001). Although the altogether low scores for decisional regret were on a higher level in the control group (T2: mean = 19.00, SD = 13.24; T3: mean = 22.0, SD = 20.67) than in the intervention group (T2: mean = 14.12, SD = 11.07; T3: mean = 12.94, SD = 13.24), there were no statistically significant differences between and within both groups. There was a positive association between decisional conflict and decisional regret at T3 (p = 0.001, r = 0.510). CONCLUSIONS: This decision aid was suitable as an additional source of knowledge and may positively impact decisional regret in the long term. Results suggest that the provision of an online decision aid as a complement to fertility counseling may facilitate decision-making.

[Endometriosis and Menopause]. / Endometriose und Klimakterisches Syndrom.

Endometriosis and Menopause Abstract. Endometriosis is supposed to affect only women in their reproductive years, but endometriotic lesions can reactivate in menopause and cause significant complaints in these patients. Altered needs and co-morbidities of the women request a different approach in therapy than in the younger ages. Reduction in chronic pain on the one hand and alleviation of climacteric symptoms, like hot-flushes and vaginal dryness, on the other hand, are main concerns to the physician in charge. Consequently, keeping the balance between the hypoestrogenic state, which is necessary to reduce activity and size of endometriotic lesions, and hormone replacement therapy (HRT) to relief menopausal complaints, depicts the key in treating these women. Progesterons, GnRH-analoga (with addback) and intrauterine devices depict the basic therapeutic strategy in perimenopausal women. In case of uncertain sonographic findings or intractable symptoms, a surgical approach (and histology) should be performed. Aromatase inhibitors, melatonin, oral GnRH-antagonists and ablation of the endometrium (in bare dysmenorrhea) represent promising alternatives to the established therapy. Requesting an HRT, it is important to add progesterone for at least two years, even in the patients with a prior hysterectomy to avoid a recurrence of residual lesions.

Resveratrol enhances decidualization of human endometrial stromal cells.

The differentiation of endometrial stromal cells (ESC), named decidualization, is essential to regulate trophoblast invasion and to support pregnancy establishment and progression. Decidualization follows ESC proliferation and it has been described that cell cycle arrest contributes to a proper decidualization. Interestingly, resveratrol, a natural compound derived from grapes with antioxidant properties, has been widely studied in relation to endometrial health. However, little is known about the effect of resveratrol supplementation during decidualization. Therefore, in this study we evaluate the effect of resveratrol supplementation during decidualization. We used primary and immortalized human ESC and we decidualized them in vitro with a decidualization cocktail containing medroxyprogesterone acetate, estradiol and 8-Bromo-cyclic AMP. Pre-decidualized cells were further treated with the decidualization cocktail supplemented with resveratrol. Our results show that resveratrol supplementation increased, in a dose-dependent manner, the expression levels of prolactin and IGFBP1 (RT-PCR and ELISA), indicating an enhanced in vitro decidualization of human ESC. This enhanced decidualization was accompanied by a decrease in cell proliferation (crystal violet and CellTiter proliferation assay) and by changes in the mRNA levels of key cell cycle regulators (RT-PCR). Furthermore, resveratrol supplementation seemed to enhance decidualization by reinforcing the effect of the decidualization cocktail. We believe that resveratrol could to be an effective supplementation to reinforce hormone action during human ESC decidualization and that further insights into resveratrol action and its interaction with estradiol and progesterone signaling pathways could facilitate the identification of new therapeutic strategies for the improvement of women's health.

GRN, NOTCH3, FN1, and PINK1 expression in eutopic endometrium - potential biomarkers in the detection of endometriosis - a pilot study.

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.

In vitro maturation of immature oocytes from ovarian tissue prior to shipment to a cryobank.

PURPOSE: Female fertility preservation prior to gonadotoxic therapies can be achieved by the cryopreservation of ovarian cortical tissue. Immature oocytes may be recovered during the preparation, matured in vitro and lead to live births, thereby providing an additional option for fertility preservation. The purpose of this study was to test the feasibility of this approach in a setting with unilateral biopsy of a small piece of ovarian tissue and minimal tissue preparation prior to shipment to an external cryobank. METHODS: A prospective observational clinical study in an academic center was performed from January 2018 through December 2019. Ovarian tissue was obtained laparoscopically. Immature oocytes were recovered by minimal preparation of the tissue before shipment to an external cryobank for cryopreservation. In vitro maturation was performed on recovered immature oocytes. RESULTS: Twelve patients were enrolled. Immature oocytes could be recovered for all. The maturation rate was 38.9% (n = 14/36). Metaphase II (MII) were either directly used for intracytoplasmic sperm injection (ICSI) with a fertilization rate of 66.6% (n = 4/6) or vitrified (n = 8). PNs were cryopreserved (n = 4). Vitrified MII were warmed with a post-warming vitality rate of 75.0% (n = 3/4) and used for ICSI with a fertilization rate of 33.3% (n = 1/3). CONCLUSIONS: Immature oocytes can be successfully retrieved from ovarian tissue through minimal tissue preparation prior to shipment to a cryobank, matured in vitro, fertilized and cryopreserved for potential future fertility treatments. The total number of oocytes available for fertility preservation can be increased even without controlled ovarian stimulation in a situation where only ovarian biopsy for cryopreservation is performed. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00013170. Registered 11 December 2017, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013170 .

Randomized controlled trial on the effect of an online decision aid for young female cancer patients regarding fertility preservation.

STUDY QUESTION: 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? SUMMARY ANSWER: Female cancer patients who could make use of the online DA had a significantly lower short-term decisional conflict score. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a research grant of the Swiss Cancer Research. The authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, trial no. NCT02404883. TRIAL REGISTRATION DATE: 19 March 2015. DATE OF FIRST PATIENT'S ENROLMENT: 4 July 2016.

Successful in vitro maturation for urgent fertility preservation despite hormonal contraception by continuous progestin application.

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.

Endometrial expression of receptivity markers subject to ovulation induction agents.

PURPOSE: Implantation rates differ according to ovulation induction agents in ART. This study investigates the different local endometrial effects of LH- versus hCG-induced ovulation. METHODS: Endometrial stromal cells from healthy patients were cultured with hCG or LH in different concentrations, supplemented with 250 ng/mL hCG and progesterone after 2 and 5 days. In addition after decidualization induction, cells were treated with hCG (50 or 250 ng/mL) or LH (10 or 50 ng/mL) for 3 days. Receptivity markers expression was evaluated by real-time quantitative PCR on day 3 and 6. RESULTS: On day 3, non-decidualized cells treated with LH showed an increased expression of IGFBP1, IL-8 and CXCL12 compared to hCG. The expression pattern changed on day 6, where cells treated with hCG showed higher expression of implantation markers compared to LH-treated cells. Furthermore, on day 3, decidualized cells treated with hCG250 showed an increased IL8 and CXCL12 expression compared to LH10. CONCLUSIONS: LH seems to modulate the local endometrial expression of receptivity markers earlier compared to hCG; however, the effect is not sustained over time in cells without prior decidualization. Though, in decidualized cells, pattern changed and an earlier positive effect of hCG was shown on IL-8 and CXCL12.

Decreased Autophagy Impairs Decidualization of Human Endometrial Stromal Cells: A Role for ATG Proteins in Endometrial Physiology.

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.

Cytokines in relation to hCG are significantly altered in asymptomatic women with miscarriage - a pilot study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve.

BACKGROUND: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5'-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55-200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. METHODS: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. RESULTS: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). CONCLUSION: Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future.

Fertility protection: complications of surgery and results of removal and transplantation of ovarian tissue.

Fertility-preserving measures are becoming important for patients receiving oncological treatment. One method involves cryopreservation of ovarian tissue and transplanting it when treatment is completed. We report complications resulting from surgical and fertility medicine, and the results of procedures for the removal and transplantation of ovarian tissue carried out within the FertiProtekt network. A survey using a structured questionnaire was conducted among the FertiProtekt network centres between November 2015 and June 2016. The analysis included surgical techniques used to remove and transplant ovarian tissue, surgical complications and results. Laparoscopic removal and transplantation of ovarian tissue have a low risk of complications. Surgical complications occurred in three of the network's 1373 ovarian tissue removals (n = 1302) and transplantations (n = 71); two complications (0.2%) occurred during removal and one during transplantation. Menstruation resumed in 47 out of 58 women (81%) who underwent ovarian tissue transplantation. Hormonal activity occurred in 63.2% of transplantations with a follow-up of 6 months or over. Sixteen pregnancies occurred in 14 patients, with nine births. The risks and complications of removal and transplantation of ovarian tissue are similar to those of standard laparoscopy. These procedures are becoming standard for fertility protection in cancer patients.

Expression of semaphorin class 3 is higher in the proliferative phase on the human endometrium.

PURPOSE: The semaphorins are related to angiogenesis and cell proliferation depending on the tissue. The purpose of this study was to assess gene expression of class 3 semaphorin (SEMA3A-F) and protein expression of semaphorin 3A (SEMA3A) within human endometrium throughout the menstrual cycle. METHODS: Gene expression of SEMA3A-F was analyzed by real-time PCR (qRT-PCR) and protein expression of SEMA3A was analyzed by ELISA in endometrial biopsies in the proliferative and secretory phase of the menstrual cycle. RESULTS: Gene expression of SEMA3A, SEMA3C, SEMA3D, and SEMA3E was statistically significant decreased in secretory compared to proliferative phase endometrium (p < 0.05). Accordingly, SEMA3A protein expression in the secretory phase was lower than protein expression in proliferative phase endometrium (p ≤ 0.05). CONCLUSION: SEMA3A, 3C, 3D, and 3E are possibly related to cell proliferation in the endometrium, being more expressed in the proliferative phase of the cycle. This finding may stimulate studies of class 3 semaphorins as a possible target for treatment of endometrial pathologies.

Serum levels of Pentraxin 3 differ significantly at the time of blastocyst transfer depending on implantation success: a pilot study.

OBJECTIVE: Many approaches try to identify the underlying molecular mechanisms to detect new potential biomarkers for successful artificial reproductive therapies. One factor has been described as a possible regulator of inflammation during implantation: Pentraxin 3 (PTX3), which seems to be essential for female fertility on one hand, but whose overexpression has been described in many obstetric complications based on abnormal placentation on the other hand. Therefore, we investigated if serum levels of PTX3 at the time of embryo transfer differ between women with an ongoing pregnancy compared to those without implantation. METHODS/DESIGN: During in vitro fertilization cycles of 51 patients, PTX3 levels at the time of embryo transfer were compared between patients without implantation (n = 26) and those with ongoing pregnancy (n = 25) using an enzyme-linked immunosorbent assay. Statistical analysis was performed using the Kolmogorov-Smirnov test, Fisher's exact test and Student's t test RESULTS: No significant differences were found concerning possible confounders (patients age, smoking pattern, embryo quality, number of embryos transferred and prior IVF attempts). Patients without implantation presented with significantly higher serum levels of PTX3 at the time of embryo transfer compared to women who became pregnant (0.781 ± 0.074 ng/ml vs. 0.578 ± 0.055 ng/ml, p < 0.05). CONCLUSIONS: PTX3 could present as a possible biomarker for ART success. The main limitation of this pilot study is its small sample size that needs validation with a larger study population.