Project description:Human granulosa cells are follicular cells surrounding the oocyte. Human granulosa cells are retrieved during in vitro fertilization a process where patients undergo hormonal stimulation including FSH and LH/hCG stimulation. Under the influence of the luteinizing hormone (LH) a process called luteinization they differentiate to luteal cells and contribute to the corpus luteum. Therefore, this cellular system is a good model for human corpus luteum (CL). To study processes within the human CL, IVF-derived GCs from patients were cultured for two to five days and then analyzed with mass spectrometry based shotgun proteomics.
Project description:This study was designed to provide a genome-wide analysis of the effects of luteinizing hormone (LH) ablation/replacement versus steroid ablation/replacement on gene expression in the developed corpus luteum (CL) in primates during the menstrual cycle. Naturally cycling, female rhesus monkeys were left untreated (Control; n = 4) or received one of the following treatments for three days beginning on Day 9 of the luteal phase: daily injection of the gonadotropin-releasing hormone (GnRH) antagonist (Antide; n = 5), Antide + recombinant human LH (A+LH; n = 4), Antide + LH + the 3b-HSD antagonist Trilostane (A+LH+TRL; n = 4), and Antide + LH + TRL + progesterone replacement with a synthetic progestin R5020 (A+LH+TRL+ R5020; n = 5). On Day 12 of the luteal phase, CL were removed and samples of RNA from individual CL were fluorescently labeled and hybridized to Affymetrix™ rhesus macaque total genome microarrays. The greatest number of altered transcripts was associated with the ablation/replacement of LH, while ablation/replacement of progestin affected fewer transcripts. Replacement of LH during Antide treatment restored expression of most transcripts to control levels. Real-time PCR validation of a subset of transcripts revealed that most expression patterns were similar between microarray and real-time PCR. Analysis of protein levels were subsequently determined for 2 of the transcripts differentially expressed by real-time PCR. This is the first genome-wide analysis of LH and steroid regulation of gene transcription in the developed primate CL. Further analysis of novel transcripts identified in this data set can clarify the relative role for LH and steroids in CL maintenance and luteolysis. Keywords: LH/steroid ablation/replacement in primate mid-late luteal phase corpora lutea 22 samples from Rhesus Macaque corpus luteum hybridized to individual Rhesus Affymentrix Gene Chip Arrays. 5 treatment groups, with at least 4 replicates per treatment.
Project description:Microarray analysis of the transcriptome in the primate corpus luteum during chorionic gonadotropin administration simulating early pregnancy.
Project description:Effects of steroid ablation and progestin replacement on the transcriptome of the primate corpus luteum during simulated early pregnancy.
Project description:Corpus luteum (CL) is an ephemeral gland whose main function is to secrete progesterone required for the establishment and maintenance of pregnancy. It is very well established that development and maintenance of CL function in primates requires action of luteinizing hormone (LH) but the extent and mechanism by which LH contributes to the maintenance of CL function through out the luteal phase is not known. To study the nuclear actions mediated by LH, we evaluated global genomic changes in CL of monkeys treated with GnRH receptor antagonist to inhibit pituitary LH secretion. Affymetrix microarray analysis was performed on RNA samples from CL obtained from VEH or CET treated monkeys. Results demonstrate that LH regulates expression of a number of genes which might be important for maintenance of CL structure and function. Keywords: CL, LH, CET, gene expression
Project description:Roblitz2013 - Menstrual Cycle following GnRH analogue administration
The model describes the menstrual cycle feedback mechanisms. GnRH, FSH, LH, E2, P4, inbibins A and B, and follicular development are modelled. The model predicts hormonal changes following GnRH analogue administration. Simulation results agree with measurements of hormone blood concentrations. The model gives insight into mechanisms underlying gonadotropin supression.
This model is described in the article:
A mathematical model of the human menstrual cycle for the administration of GnRH analogues.
Röblitz S, Stötzel C, Deuflhard P, Jones HM, Azulay DO, van der Graaf PH, Martin SW.
J. Theor. Biol. 2013 Mar; 321: 8-27
Abstract:
The paper presents a differential equation model for the feedback mechanisms between gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), development of follicles and corpus luteum, and the production of estradiol (E2), progesterone (P4), inhibin A (IhA), and inhibin B (IhB) during the female menstrual cycle. Compared to earlier human cycle models, there are three important differences: The model presented here (a) does not involve any delay equations, (b) is based on a deterministic modeling of the GnRH pulse pattern, and (c) contains less differential equations and less parameters. These differences allow for a faster simulation and parameter identification. The focus is on modeling GnRH-receptor binding, in particular, by inclusion of a pharmacokinetic/pharmacodynamic (PK/PD) model for a GnRH agonist, Nafarelin, and a GnRH antagonist, Cetrorelix, into the menstrual cycle model. The final mathematical model describes the hormone profiles (LH, FSH, P4, E2) throughout the menstrual cycle of 12 healthy women. It correctly predicts hormonal changes following single and multiple dose administration of Nafarelin or Cetrorelix at different stages in the cycle.
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Project description:This study was designed to provide a genome-wide analysis of the effects of luteinizing hormone (LH) ablation/replacement versus steroid ablation/replacement on gene expression in the developed corpus luteum (CL) in primates during the menstrual cycle. Naturally cycling, female rhesus monkeys were left untreated (Control; n = 4) or received one of the following treatments for three days beginning on Day 9 of the luteal phase: daily injection of the gonadotropin-releasing hormone (GnRH) antagonist (Antide; n = 5), Antide + recombinant human LH (A+LH; n = 4), Antide + LH + the 3b-HSD antagonist Trilostane (A+LH+TRL; n = 4), and Antide + LH + TRL + progesterone replacement with a synthetic progestin R5020 (A+LH+TRL+ R5020; n = 5). On Day 12 of the luteal phase, CL were removed and samples of RNA from individual CL were fluorescently labeled and hybridized to Affymetrix™ rhesus macaque total genome microarrays. The greatest number of altered transcripts was associated with the ablation/replacement of LH, while ablation/replacement of progestin affected fewer transcripts. Replacement of LH during Antide treatment restored expression of most transcripts to control levels. Real-time PCR validation of a subset of transcripts revealed that most expression patterns were similar between microarray and real-time PCR. Analysis of protein levels were subsequently determined for 2 of the transcripts differentially expressed by real-time PCR. This is the first genome-wide analysis of LH and steroid regulation of gene transcription in the developed primate CL. Further analysis of novel transcripts identified in this data set can clarify the relative role for LH and steroids in CL maintenance and luteolysis. Keywords: LH/steroid ablation/replacement in primate mid-late luteal phase corpora lutea
Project description:Luteolysis of the corpus luteum (CL) during non-fertile cycles involves a cessation of progesterone (P4) synthesis (functional regression) and subsequent structural remodeling. The molecular processes responsible for initiation of luteal regression in the primate CL are poorly defined. Therefore, a genomic approach was utilized to systematically identify differentially expressed genes in the rhesus macaque CL during spontaneous luteolysis. CL were collected prior to (days 10-11 post-LH surge, mid-late [ML] stage) or during (days 14-16, late stage) functional regression. Based on P4 levels, late stage CL were subdivided into functional late (FL, serum P4 > 1.5 ng/ml) and functionally-regressed late (FRL, serum P4 < 0.5 ng/ml) groups (n=4 CL/group). Total RNA was isolated, labeled and hybridized to Affymetrix genome microarrays that contain elements representing the entire rhesus macaque transcriptome. With the ML stage serving as the baseline, there were 681 differentially expressed transcripts (>2-fold change; p< 0.05) that could be categorized into three primary patterns of expression: 1) increasing from ML through FRL, 2) decreasing from ML through FRL, and 3) increasing ML to FL, followed by a decrease in FRL. Ontology analysis revealed potential mechanisms and pathways associated with functional and/or structural regression of the macaque CL. Quantitative real-time PCR was used to validate microarray expression patterns of 13 genes with the results being consistent between the two methodologies. Protein levels were found to parallel mRNA profiles in 4 of 5 differentially expressed genes analyzed by Western blot. Thus, this database will facilitate the identification of mechanisms involved in primate luteal regression. Keywords: time course plus functional state of corpus luteum