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.