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Edinburgh, United Kingdom

Maybin J.A.,Queens Medical Research Institute | Hirani N.,Center for Inflammation Research | Brown P.,Human Reproductive science Unit | Jabbour H.N.,Human Reproductive science Unit | Critchley H.O.D.,Queens Medical Research Institute
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F 2α synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF 2α, and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor. Design and Results: Endometrial biopsies were collected (n = 47) with ethical approval and consent. VEGF mRNA, quantified by quantitative RT-PCR, was increased during menstruation (P < 0.01).VEGF protein was maximally secreted from proliferative endometrial explants. Treatment of an endometrial epithelial cell line and primary human endometrial stromal cells with 100 nM PGF 2α or hypoxia (0.5%O 2) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF 2α and hypoxia simultaneously (P < 0.05-0.001). Secretory phase endometrial explants also showed an increase in VEGF with cotreatment (P<0.05). However, proliferative-phase explants showed no increase in VEGF on treatment with PGF 2α and/or hypoxia. Proliferative tissue was induced to increase VEGF mRNA expression when exposed to progesterone and its withdrawal in vitro but only in the presence of hypoxia and PG. Hypoxia-inducible factor-1α (HIF-1α) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF 2α-induced VEGF expression. Conclusions: Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF 2α, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1α to increase VEGF, whereas PGF 2α acts in a HIF-1α-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair. Copyright © 2011 by The Endocrine Society.

Young J.M.,Human Reproductive science Unit | McNeilly A.S.,Human Reproductive science Unit
Reproduction | Year: 2010

Theca cells function in a diverse range of necessary roles during folliculogenesis; to synthesize androgens, provide crosstalk with granulosa cells and oocytes during development, and provide structural support of the growing follicle as it progresses through the developmental stages to produce a mature and fertilizable oocyte. Thecal cells are thought to be recruited from surrounding stromal tissue by factors secreted from an activated primary follicle. The precise origin and identity of these recruiting factors are currently not clear, but it appears that thecal recruitment and/or differentiation involves not just one signal, but a complex and tightly controlled combination of multiple factors. It is clear that thecal cells are fundamental for follicular growth, providing all the androgens required by the developing follicle(s) for conversion into estrogens by the granulosa cells. Their function is enabled through the establishment of a vascular system providing communication with the pituitary axis throughout the reproductive cycle, and delivering essential nutrients to these highly active cells. During development, the majority of follicles undergo atresia, and the theca cells are often the final follicular cell type to die. For those follicles that do ovulate, the theca cells then undergo hormone-dependent differentiation into luteinized thecal cells of the corpus luteum. While the theca is an essential component of follicle development and ovulation, we do not yet fully understand the control of recruitment and function of theca cells, an important consideration since their function appears to be altered in certain causes of infertility. © 2010 Society for Reproduction and Fertility.

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