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Title: Gonadotropin and kisspeptin receptor function in granulosa cells from women with and without Polycystic Ovary Syndrome
Author: Owens, Lisa
ISNI:       0000 0004 8499 5075
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Polycystic ovary syndrome (PCOS) is a common, complex and heterogenous condition which affects 8-13% of women. The underlying aetiology is poorly understood and evidence suggests that it is multigenic disorder with strong epigenetic and environmental influences. Recent genome wide association studies have found hits close to loci encoding FSHR and LHCGR, implicating gonadotropin receptor action in the pathogenesis of the condition. I therefore studied the actions of the gonadotropin receptors in granulosa lutein cells (GLCs) from women with and without PCOS. I also studied the actions of receptors which have been shown to affect ovarian gonadotropin action, the androgen and kisspeptin receptors. Lastly, I examined gene expression of gonadotropin receptors, steroid enzymes and growth factors in granulosa cells (GCs) from small antral follicles from women with and without polycystic ovaries (PCO). Gonadotropin receptors are dependent on internalisation for the majority of gonadotropin receptor Gαs signal generation and LHR Gαs-cAMP signalling is enhanced in PCOS GLCs. This may be related to enhanced internalisation and trafficking of LHR to the very early endosome, as βarrestin-1 and GIPC expression are augmented. In PCOS LHR displays signal bias of Gαs over Gαq/11 but no difference in ERK signalling. Downstream there is augmented activation of cellular phosphoproteins and upregulation of LHR, but no difference in progesterone output into culture media. FSHR signalling is similar in control and PCOS GLCs but downstream phosphoprotein activation differs. In vitro androgen treatment enhances LH induced cAMP and ERK signalling. In vitro kisspeptin treatment activates kisspeptin receptor Gαq/11 and ERK signalling but does not contribute to steroidogenesis. In vivo kisspeptin given as an IVF maturation trigger in women with PCOS augments gonadotropin receptor and steroid enzyme gene expression. GCs from women with PCO display higher LHCGR in certain follicles, with higher steroid enzyme expression and lower FSHR and androgen receptor expression. In conclusion, GCs and GLCs from women with PCOS display distinct gonadotropin receptor signalling and regulation.
Supervisor: Franks, Stephen ; Hanyaloglu, Aylin ; Hardy, Kate Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral