Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Endometrial Transcriptome Changes Following Short-Term Liraglutide Treatment in Infertile Women with PCOS and Obesity

ABSTRACT: The aim of the study was to investigate if the use of a 12 weeks liraglutide treatment change the endometrial gene expression during the implantation window in infertile obese women with polycystic ovary syndrome (PCOS) undergoing in-vitro fertilization (IVF). This was a cross-sectional study involving treated and non-treated subjects. Endometrial biop-sies were collected from 20 infertile women with PCOS and BMI ≥30 kg/m2 before the IVF procedure. Endometrium transcriptome of 10 participants who had been pretreated with low-dose liraglutide 1.2 mg QD for 12 weeks and achieved at least a 5% reduction in body weight was compared to endometrium transcriptome of 10 treatment-naive participants who had a sta-ble body weight over the last 12 weeks. Next-generation sequencing was conducted to analyze RNA samples. The resulting data were processed to discern key canonical pathways and pre-dict activations or inhibitions. Gene networks were constructed based on established published associations.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Aleš Maver

PROVIDER: E-MTAB-14282 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Context: Endometrium in polycystic ovary syndrome (PCOS) presents altered gene expression indicating progesterone resistance and predisposing to reduced endometrial receptivity and endometrial cancer. Objective: We hypothesized that an altered endocrine/metabolic environment in PCOS may result in an endometrial M-bM-^@M-^\disease phenotypeM-bM-^@M-^] affecting the gene expression of different endometrial cell populations, including stem cells and their differentiated progeny. Design and setting: A prospective study conducted at an academic medical center. Patients and Main Outcome Measures: Proliferative phase endometrium was obtained from 6 overweight/obese PCOS (NIH criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting (FACS)-isolated endometrial epithelial cells (eEP), endothelial cells (eEN), stromal fibroblasts (eSF) and mesenchymal stem cells (eMSC). Gene expression data were validated using microfluidic Q-RT-PCR and immunohistochemistry (IHC). Results: The comparison between eEPPCOS and eEPCtrl showed dysregulation of inflammatory genes and genes with oncogenic potential (CCL2, IL-6, ORM1, TNAIFP6, SFRP4, SPARC). eSFPCOS and eSFCtrl showed upregulation of inflammatory genes (C4A/B, CCL2, ICAM1, TNFAIP3). Similarly, in eMSCPCOS vs. eMSCCtrl the most upregulated genes were related to inflammation and cancer (IL-8, ICAM1, SPRR3, LCN2). IHC scoring showed increased expression of CCL2 in eEPPCOS and eSFPCOS compared to eEPCtrl and eSFCtrl and IL-6 in eEPPCOS compared to eEPCtrl. Conclusions: Isolated endometrial cell populations in women with PCOS showed altered gene expression revealing inflammation and pro-oncogenic changes, independent of BMI, especially in eEPPCOS and eMSCPCOS, compared to controls. The study reveals an endometrial M-bM-^@M-^\disease phenotypeM-bM-^@M-^] in women with PCOS with potential negative effects on endometrial function and long-term health. Proliferative phase endometrium was obtained from 6 overweight/obese PCOS (NIH criteria) and 6 overweight/obese controls. Microarray analysis was performed on fluorescence-activated cell sorting (FACS)-isolated endometrial epithelial cells (eEP), endothelial cells (eEN), stromal fibroblasts (eSF) and mesenchymal stem cells (eMSC). Tissue samples were obtained through the National Institute of Health (NIH)/University of California, San Francisco (UCSF), Human Endometrial Tissue and DNA Bank in accordance with the guidelines of the Declaration of Helsinki. Informed consent was obtained from all participants in the UCSF Center for Reproductive Health, and the study was approved by the UCSF Committee on Human Research. The clinical summary of the study participants is shown in Table 1. Eleven proliferative phase endometrial biopsies (Pipelle, Cooper Surgical Shelton, Connecticut) and one curettage specimen were collected from over-weight (Body Mass Index [BMI, kg/m2] M-bM-^IM-% 27 < 29.9; n=1) and obese (BMI M-bM-^IM-% 30; n=5) women with PCOS (age 30.5M-BM-1 2.1 yrs, BMI 34.13M-BM-1 2.2, NIH criteria (17) and overweight (n=2) and obese (n=4) control women (age 36.50M-BM-11.70 yrs, BMI 35.73M-BM-13.96). All PCOS subjects had normal 17-hydroxyprogesterone, prolactin and thyroid hormone levels. Control samples were obtained from healthy volunteer and women undergoing benign gynecological surgery. All controls reported menstrual cycles with regular interval (25-35 days) and no clinical evidence of having PCOS. Neither PCOS nor control subjects were exposed to hormonal medications for at least 2 months prior to tissue sampling and were confirmed not pregnant.

Project description:Infertility and subfertility represent major problems in domestic animals and humans, and the majority of embryonic loss occurs during the first month of gestation that involves pregnancy recognition and conceptus implantation. The critical genes and physiological pathways in the endometrium that mediate pregnancy establishment and success are not well understood. In Study One, 270 predominantly Angus heifers were classified based on fertility using four rounds of serial embryo transfer (ET) to select animals with intrinsic differences in pregnancy loss. In each round, a single in vitro-produced high-quality embryo was transferred into heifers on day 7 post-estrus and pregnancy was determined on days 28 and 42 by ultrasound and then terminated. Heifers were classified based on pregnancy success as high fertile (HF), subfertile (SF), or infertile (IF). In Study Two, fertility-classified heifers were resynchronized and bred with semen from a single high fertility bull. Blood samples were collected every other day from days 0 to 36 post-mating. Pregnancy rate was determined on day 28 by ultrasound and tended to be higher in HF (70.4%) and SF (46.7%) than IF (0%) heifers. Progesterone concentrations in serum during the first 20 days post-estrus were not different in non-pregnant heifers and also not different in pregnant heifers among fertility groups. In Study Three, a single in vivo-produced embryo was transferred into fertility-classified heifers on day 7 post-estrus. The uteri were flushed on day 14 to recover embryos, and endometrial biopsies were obtained from the ipsilateral uterine horn. Embryo recovery rate and conceptus length and area were not different among the heifer groups. RNA was sequenced from the day 14 endometrial biopsies of pregnant HF, SF and IF heifers (n=5 per group) and analyzed by edgeR robust analysis. There were 26 differentially expressed genes (DEG) in the HF compared to SF endometrium, 12 DEG for SF compared to IF endometrium, and 3 DEG between the HF and IF endometrium. Many of the DEG encoded proteins involved in immune responses and are expressed in B cells. Results indicate that pre-implantation conceptus survival and growth to day 14 is not compromised in SF and IF heifers. Thus, the observed difference in capacity for pregnancy success in these fertility-classified heifers is manifest between days 14 and 28 when pregnancy recognition signaling and conceptus implantation must occur for the establishment of pregnancy. Endometrial biopsies were subjected to RNA sequencing from high fertile (HF; n=5), subfertile (SF; n=5) and infertile (IF; n=5) classified heifers on day 14 of pregnancy.

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Endometrial Transcriptome Changes Following Short-Term Liraglutide Treatment in Infertile Women with PCOS and Obesity

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