The Relationship Between Theca Cell Responses to hCG and Ovarian Morphology in Women With PCOS Compared to Normal Women

Rationale and Hypothesis We have previously reported that theca cells (TC) responses to hCG in women with PCOS represent a spectrum where some exhibit exaggerated increases of 17OHP while in others 17OHP responses resemble those of normal women (Maas KH et al, JCEM, 2015). The basis for this differential responsiveness is not clear. Earlier studies reported that 17OHP responses to gonadotropin stimulation were heterogeneous among PCOS women, which was attributed to the degree of hyperinsulinemia (Pasquali R et al, JCEM, 2007). However, assessment of the ovary was omitted in the analysis. In preliminary studies, we have found that in women with PCOS, insulin sensitivity was strongly correlated with insulin sensitivity index as assessed by the method of Matsuda and DeFronzo (Diabetes Care, 1999). However, the study lacked sufficient numbers. Further analysis of insulin sensitivity with respect to hCG stimulated theca cell responses is warranted.

We have also examined 17OHP responses to hCG in relationship to antral follicle count and anti-Müllerian hormone (AMH) in PCOS and normal women. In PCOS women, as expected, serum AMH correlated with antral follicle count. However, TC responses in PCOS were inversely related to AMH (Maas KH et al, JCEM, 2015). These novel observations suggested that in PCOS AMH production may reflect redistribution of the follicle population. In human ovaries maximal immunodetection of AMH is observed in small (< 4 mm) antral follicles followed by a rapid and progressive decline until an absence of the protein by 8 mm (Weenen C et al, Mol Hum Reprod, 2004). This consideration raises the issue of whether normal AMH levels represent more advanced follicle growth in some PCOS women compared with that of others with elevated AMH levels. An increased stage of follicle development would be accompanied by increased TC hyperplasia and may account for greater 17OHP responses to hCG stimulation. A comparison of TC responses to hCG with ovarian morphology has not be done in women with PCOS.

Based on these findings, we hypothesize that in PCOS, heterogeneous TC responses to hCG reflect differences in morphometric development of the follicle population. In addition, the positive correlation between insulin sensitivity and TC responses to hCG suggest an effect of hyperinsulinemia. We propose to investigate the relationship between theca cell responses to hCG, follicle morphology, and insulin sensitivity before and following treatment with an insulin lowering drug, metformin.