Can TSH level and premenstrual spotting constitute a non-invasive marker for the diagnosis of endometriosis?

Background!#!To date, there is no reliable non-invasive marker for the early detection and diagnosis of endometriosis available possibly resulting in a delayed diagnosis and consequently an unnecessary long ordeal for the individual woman. Therefore, the primary objective of the current study was to evaluate whether the combination of a thyroid-stimulating hormone (TSH) level > 2.5 µlU/ml and premenstrual spotting could serve as non-invasive markers of endometriosis. A secondary objective was to determine whether typical symptoms of endometriosis like dysmenorrhea and/or dyspareunia could increase the diagnostic reliability.!##!Methods!#!We conducted a retrospective, case-control study with 167 female patients at the Department of OB/GYN and REI (UniKiD) of the medical center of the University of Düsseldorf, between January 2015 and December 2016. 107 women with surgically confirmed endometriosis were compared to 60 without endometriosis (controls). To evaluate the diagnostic accuracy, we considered sensitivity, specificity and predictive values. In order to assess the association between the non-invasive markers and endometriosis an odds ratio (OR) with a 95% confidence interval was calculated.!##!Results!#!In our cohort, diagnosis of endometriosis with non-invasive markers according to their sensitivity yielded the following ranking: increased TSH level, premenstrual spotting, combination of both previous parameters, addition of dysmenorrhea, addition of dyspareunia and combination of all parameters.!##!Conclusion!#!The existence of endometriosis should be taken into consideration when a patient suffers from thyroid dysfunction and premenstrual spotting. Apart from an increased TSH level, the presence of premenstrual spotting underlines the possible diagnosis of endometriosis with non-invasive markers and therefore, the patient´s history needs to be taken into account carefully. Trial registration The retrospective study was approved by the Ethics Committee of the medical faculty of the Heinrich-Heine University, Düsseldorf, Germany, Registration number Düsseldorf: 5371R (approved: April 04th, 2016). Since the design of the study was retrospective no written informed consent was necessary

Uveitis: From diagnosis to treatment [Uvéites : du diagnostic au traitement]

cited By 0International audienc

Progesterone-induced progesterone receptor membrane component 1 rise-to-decline changes are essential for decidualization

Abstract Background Decidualization of endometrial cells is the prerequisite for embryo implantation and subsequent placenta formation and is induced by rising progesterone levels following ovulation. One of the hormone receptors contributing to endometrial homeostasis is Progesterone Receptor Membrane Component 1 (PGRMC1), a non-classical membrane-bound progesterone receptor with yet unclear function. In this study, we aimed to investigate how PGRMC1 contributes to human decidualization. Methods We first analyzed PGRMC1 expression profile during a regular menstrual cycle in RNA-sequencing datasets. To further explore the function of PGRMC1 in human decidualization, we implemented an inducible decidualization system, which is achieved by culturing two human endometrial stromal cell lines in decidualization-inducing medium containing medroxyprogesterone acetate and 8-Br-cAMP. In our system, we measured PGRMC1 expression during hormone induction as well as decidualization status upon PGRMC1 knockdown at different time points. We further conferred proximity ligation assay to identify PGRMC1 interaction partners. Results In a regular menstrual cycle, PGRMC1 mRNA expression is gradually decreased from the proliferative phase to the secretory phase. In in vitro experiments, we observed that PGRMC1 expression follows a rise-to-decline pattern, in which its expression level initially increased during the first 6 days after induction (PGRMC1 increasing phase) and decreased in the following days (PGRMC1 decreasing phase). Knockdown of PGRMC1 expression before the induction led to a failed decidualization, while its knockdown after induction did not inhibit decidualization, suggesting that the progestin-induced ‘PGRMC1 increasing phase’ is essential for normal decidualization. Furthermore, we found that the interactions of prohibitin 1 and prohibitin 2 with PGRMC1 were induced upon progestin treatment. Knocking down each of the prohibitins slowed down the decidualization process compared to the control, suggesting that PGRMC1 cooperates with prohibitins to regulate decidualization. Conclusions According to our findings, PGRMC1 expression followed a progestin-induced rise-to-decline expression pattern during human endometrial decidualization process; and the correct execution of this expression program was crucial for successful decidualization. Thereby, the results of our in vitro model explained how PGRMC1 dysregulation during decidualization may present a new perspective on infertility-related diseases

Physiological and anatomical aspects of the reproduction of mice with reduced Syndecan-1 expression

Abstract Background Syndecan-1 is a heparan sulfate proteoglycan acting as a co-receptor for cytokines and growth factors mediating developmental, immunological and angiogenic processes. In human, the uteroplacental localization of Syndecan-1 and its reduced expression in pregnancy-associated pathologies, such as the intrauterine growth restriction, suggests an influence of Syndecan-1 in embryo-maternal interactions. The aim of the present study was to identify the effect of a reduced expression of Syndecan-1 on the reproductive phenotype of mice and their progenies. Methods Reproductive characteristics have been investigated using animals with reduced Syndecan-1 and their wildtype controls after normal mating and after vice versa embryo transfers. Female mice were used to measure the estrus cycle length and the weight gain during pregnancy, as well as for histological examination of ovaries. Male mice were examined for the concentration, motility, viability and morphology of spermatozoa. Organs like heart, lung, liver, kidney, spleen, brain and ovaries or testes and epididymis of 6-month-old animals were isolated and weighed. Statistical analyses were performed using two-tailed students t-test with P < .05 and P < .02, chi square test (P < .05) and Fisher’s Exact Test (P < .05). A linear and a non-linear mixed-effects model were generated to analyze the weight gain of pregnant females and of the progenies. Results Focusing on the pregnancy outcome, the Syndecan-1 reduced females gave birth to larger litters. However, regarding the survival of the offspring, a higher percentage of pups with less Syndecan-1 died during the first postnatal days. Even though the ovaries and the testes of Syndecan-1 reduced mice showed no histological differences and the ovaries showed a similar number of primary and secondary follicles and corpora lutea, the spermatozoa of Syndecan-1 reduced males showed more tail and midpiece deficiencies. Concerning the postnatal and juvenile development the pups with reduced Syndecan-1 expression remained lighter and smaller regardless whether carried by mothers with reduced Syndecan-1 or wildtype foster mothers. With respect to anatomical differences kidneys of both genders as well as testes and epididymis of male mice with reduced syndecan-1 expression weighed less compared to controls. Conclusions These data reveal that the effects of Syndecan-1 reduction are rather genotype- than parental-dependent

Biological age of the endometrium using DNA methylation

Age has a detrimental effect on reproduction and as an increasing number of women postpone motherhood, it is imperative to assess biological age in terms of fertility prognosis and optimizing fertility treatment individually. Horvath’s epigenetic clock is a mathematical algorithm that calculates the biological age of human cells, tissues or organs based on DNA methylation levels. The clock, however, was previously shown to be highly inaccurate for the human endometrium, most likely because of the hormonal responsive nature of this tissue. The aim of this study was to determine if epigenetically based biological age of the human endometrium correlated with chronological age, when strictly timed to the same time point in the menstrual cycle. Endometrial biopsies from nine women were obtained in two consecutive cycles, both strictly timed to the LH surge (LH + 7) and additionally, peripheral whole blood samples were analyzed. Using the Illumina HumanMethylation 450 K array and Horvath’s epigenetic clock, we found a significant correlation between the biological age of the endometrium and the chronological age of the participants, although the endometrial biological age was accelerated by comparison with blood and chronological age. Moreover, similar biological ages were found in pairs of consecutive biopsies, indicating that an endometrial biopsy does not alter the biological age in the following cycle. In conclusion, as long as endometrial samples are timed to the same time point in the menstrual cycle, Horvath’s epigenetic clock could be a powerful new biomarker of reproductive aging in the human endometrium.</jats:p

Additional file 1 of Progesterone-induced progesterone receptor membrane component 1 rise-to-decline changes are essential for decidualization

Additional file 1: Supplementary Fig. 1. Rise-to-decline expression pattern of PGRMC1 is linked to the decidualization program. (A) PGRMC1 protein expression changes during 9 days of decidualization were measured by western blot in the St-T1 cell line. (B) PGRMC1 protein expression changes during 10 days of stimulation with MPA, cAMP, and DMSO, respectively, were measured by western blot in T-HESCs. (C) PGRMC1 protein expression levels on day 6 and day 10 when cultured with DMSO, nomegestrel (NOM), P4, cAMP, MPA/cAMP (M + A), and MPA, respectively, measured by western blot in T-HESCs. Supplementary Fig. 2. PGRMC1 is effectively downregulated by siRNA on protein level. (A) The PGRMC1 protein expression on day 2 and day 10 after transfection of T-HESCs with either 10 nM anti-PGRMC1 siRNA (siPGRMC1) or unspecific scrambled-control siRNA (siCTL). (B) A comparison of the PGRMC1 protein expression changes within 10 days after transfection of T-HESCs with either 10 nM siPGRMC1 or 10 nM siCTL. Supplementary Fig. 3. PGRMC1-downregulation before decidualization induction impairs morphological remodeling of T-HESCs. The cellular morphology changes of the T-HESCs induced with either DMSO (upper panel) or MPA/cAMP (down panel) after 10 days of siRNA treatment (siCTL, left panel; siPGRMC1, right panel). Scale bar: 200 µm. Supplementary Fig. 4. PGRMC1-downregulation after decidualization induction does not impair morphological remodeling of T-HESCs. The cellular morphology changes of the T-HESCs induced with either DMSO (non-induction, column 1) or MPA/cAMP (Induction, columns 2–4). I (column 3) and II (column 4) indicate that siRNA treatment on T-HESCs was conducted on day 2 or day 4 of decidualization induction, respectively. Scale bar: 200 µm. Supplementary Fig. 5. PGRMC1-downregulation after progestin induction does not impair decidualization in the St-T1 cell line. The mRNA expression levels of PGRMC1 (A, C) and PRL (B, D) in St-T1 treated with MPA/cAMP for decidualization induction (red line), and non-induction (black line). The mRNA expression levels of PGRMC1 and PRL in St-T1 cells transfected with 10 nM siPGRMC1 (blue line) on the second (A, B) and fourth day (C, D) after decidualization induction, respectively. Results are shown as the mean ± SEM from three independent biological replicates. Statistical analysis was performed by a two-way ANOVA test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. The red * indicates the comparison between the red and black lines. The blue * indicates the comparison between the red and blue lines. Supplementary Fig. 6. PGRMC1 and PHB1/PHB2 co-localize in T-HESCs. Double Immunofluorescence staining for PGRMC1 (red) and PHB1 (green) or PHB2 (green) in T-HESCs treated with DMSO (A) as control or MPA/cAMP (B) for decidualization induction. Magnification: 40x. Scale bar: 20 µm. Supplementary Fig. 7. PGRMC1 does not interact with PHBs without induction. The interactions between PGRMC1 and PHB1 (A) and PHB2 (B) in T-HESCs without induction were analyzed with proximity ligation assay from day 2 to day 10. Each red spot represents a single interaction. Nuclear stain: DAPI. Magnification 40X. Supplementary Fig. 8. PGRMC1 co-precipitate with PHB1/PHB2 upon decidualization induction. PGRMC1 was immunopurified from native whole cell lysates of T-HESCs using anti-PGRMC1 antibody. Western blot analyses of co-immunoprecipitated PHB1 (upper) and PHB2 (bottom) in T-HESCs with and without decidualization induction. Supplementary Fig. 9. Morphological changes during decidualization upon PHBs downregulation. The cellular morphology changes of the T-HESCs induced with either DMSO (non-Induction) or MPA/cAMP (Induction) upon either PHBs knockdown alone or both. Scale bar: 200 µm. Supplementary Fig. 10. Overview over the role of PGRMC1 in human endometrial decidualization. Upon stimulation with progesterone or MPA, the PGRMC1 rise-to-decline changes are essential for successful decidualization of the human endometrial cells (upper panel). With downregulated PGRMC1 expression before induction, the decidualization program cannot be carried out, leading to decidualization failure (bottom panel)