Clinical Focus


  • Obstetrics and Gynecology

Academic Appointments


Professional Education


  • Fellowship:UCSF Dept of Obstetrics and Gynecology and REI (2017) CA
  • Residency:UCSF Dept of Obstetrics and Gynecology and REI (2014) CA
  • Residency:Baylor College of Medicine Registrar (2012) TX
  • Karolinska Institute (2006) Sweden
  • Yerevan State Medical Univercity (1999) Armenia
  • Medical Education:Yerevan State Medical Univercity (1996) Armenia

All Publications


  • The Protein Kinase A Pathway-Regulated Transcriptome of Endometrial Stromal Fibroblasts Reveals Compromised Differentiation and Persistent Proliferative Potential in Endometriosis ENDOCRINOLOGY Aghajanova, L., Horcajadas, J. A., Weeks, J. L., Esteban, F. J., Nezhat, C. N., Conti, M., Giudice, L. C. 2010; 151 (3): 1341-1355

    Abstract

    Intrinsic abnormalities in transplanted eutopic endometrium are believed to contribute to the pathogenesis of pelvic endometriosis. Herein we investigated transcriptomic differences in human endometrial stromal fibroblasts (hESFs) from women with (hESF(endo)) vs. without (hESF(nonendo)) endometriosis, in response to activation of the protein kinase A (PKA) pathway with 8-bromoadenosine-cAMP (8-Br-cAMP). hESF(nonendo) (n = 4) and hESF(endo) (n = 4) were isolated from eutopic endometrium and treated +/- 0.5 mm 8-Br-cAMP for 96 h. Purified total RNA was subjected to microarray analysis using the whole-genome Gene 1.0 ST Affymetrix platform. A total of 691 genes were regulated in cAMP-treated hESF(nonendo) vs. 158 genes in hESF(endo), suggesting a blunted response to cAMP/PKA pathway activation in women with disease. Real-time PCR and ELISA validated the decreased expression of decidualization markers in hESF(endo) compared with hESF(nonendo). In the absence of disease, 8-Br-cAMP down-regulated progression through the cell cycle via a decrease in cyclin D1, cyclin-dependent kinase 6, and cell division cycle 2 and an increase in cyclin-dependent kinase inhibitor 1A. However, cell cycle components in hESF(endo) were not responsive to 8-Br-cAMP, resulting in persistence of a proliferative phenotype. hESF(endo) treated with 8-Br-cAMP exhibited altered expression of immune response, extracellular matrix, cytoskeleton, and apoptosis genes. Changes in phosphodiesterase expression and activity were not different among experimental groups. These data support that eutopic hESF(endo) with increased proliferative potential can seed the pelvic cavity via retrograde menstruation and promote establishment, survival, and proliferation of endometriosis lesions, independent of hydrolysis of cAMP and likely due to an inherent abnormality in the PKA pathway.

    View details for DOI 10.1210/en.2009-0923

    View details for Web of Science ID 000274711600054

    View details for PubMedID 20068008

    View details for PubMedCentralID PMC2840687

  • Increased Mitogen-Activated Protein Kinase Kinase/Extracellularly Regulated Kinase Activity in Human Endometrial Stromal Fibroblasts of Women with Endometriosis Reduces 3 ',5 '-Cyclic Adenosine 5 '-Monophosphate Inhibition of Cyclin D1 ENDOCRINOLOGY Velarde, M. C., Aghajanova, L., Nezhat, C. R., Giudice, L. C. 2009; 150 (10): 4701-4712

    Abstract

    Endometriosis is characterized by endometrial tissue growth outside the uterus, due primarily to survival, proliferation, and neoangiogenesis of eutopic endometrial cells and fragments refluxed into the peritoneal cavity during menses. Although various signaling molecules, including cAMP, regulate endometrial proliferation, survival, and embryonic receptivity in endometrium of women without endometriosis, the exact molecular signaling pathways in endometrium of women with disease remain unclear. Given the persistence of a proliferative profile and differential expression of genes associated with the MAPK signaling cascade in early secretory endometrium of women with endometriosis, we hypothesized that ERK1/2 activity influences cAMP regulation of the cell cycle. Here, we demonstrate that 8-Br-cAMP inhibits bromodeoxyuridine incorporation and cyclin D1 (CCND1) expression in cultured human endometrial stromal fibroblasts (hESF) from women without but not with endometriosis. Incubation with serum-containing or serum-free medium resulted in higher phospho-ERK1/2 levels in hESF of women with vs. without disease, independent of 8-Br-cAMP treatment. The MAPK kinase-1/2 inhibitor, U0126, fully restored cAMP down-regulation of CCND1, but not cAMP up-regulation of IGFBP1, in hESF of women with vs. without endometriosis. Immunohistochemistry demonstrated the highest phospho-ERK1/2 in the late-secretory epithelial and stromal cells in women without disease, in contrast to intense immunostaining in early-secretory epithelial and stromal cells in those with disease. These findings suggest that increased activation of ERK1/2 in endometrial cells from women with endometriosis may be responsible for persistent proliferative changes in secretory-phase endometrium.

    View details for DOI 10.1210/en.2009-0389

    View details for Web of Science ID 000270021700025

    View details for PubMedID 19589865

    View details for PubMedCentralID PMC2754675

  • MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis MOLECULAR HUMAN REPRODUCTION Burney, R. O., Hamilton, A. E., Aghajanova, L., Vo, K. C., Nezhat, C. N., Lessey, B. A., Giudice, L. C. 2009; 15 (10): 625-631

    Abstract

    Endometriosis is a common gynecologic disorder characterized by pain and infertility. In addition to estrogen dependence, progesterone resistance is an emerging feature of this disorder. Specifically, a delayed transition from the proliferative to secretory phase as evidenced by dysregulation of progesterone target genes and maintenance of a proliferative molecular fingerprint in the early secretory endometrium (ESE) has been reported. MicroRNAs (miRNAs) are small noncoding RNAs that collectively represent a novel class of regulators of gene expression. In an effort to investigate further the observed progesterone resistance in the ESE of women with endometriosis, we conducted array-based, global miRNA profiling. We report distinct miRNA expression profiles in the ESE of women with versus without endometriosis in a subset of samples previously used in global gene expression analysis. Specifically, the miR-9 and miR-34 miRNA families evidenced dysregulation. Integration of the miRNA and gene expression profiles provides unique insights into the molecular basis of this enigmatic disorder and, possibly, the regulation of the proliferative phenotype during the early secretory phase of the menstrual cycle in affected women.

    View details for DOI 10.1093/molehr/gap068

    View details for Web of Science ID 000270005200005

    View details for PubMedID 19692421

    View details for PubMedCentralID PMC2744474