Endocrine Abstracts (2006) 11 OC13

Anti-Müllerian hormone (AMH) production by granulosa cells from anovulatory PCO is 100 times higher than from normal ovaries, but is inhibited by metformin

L Pellatt1, L Hanna1, D Feldman2, P Malloy2, H Brain1, S Whitehead1 & H Mason1

1St George’s University of London, London, United Kingdom; 2Stanford University, CA, United States.

AMH causes regression of Müllerian ducts during male fetal development. Recently, AMH was detected in the adult ovary, principally in granulosa cells (GCs). Studies have demonstrated a 1.5–5 fold increase in serum AMH in women with PCOS compared to normal ovulatory women. The AMH rise was assumed to be secondary to increased numbers of follicles. Interestingly, the insulin sensitiser metformin, which is in widespread use in PCOS, caused a significant reduction in serum AMH levels after protracted treatment. The aim of this study was to compare AMH production per cell between normal and PCO and to investigate effects of metformin. AMH levels in medium conditioned by GCs from normal, ovulatory (ovPCO) and anovulatory PCO (anovPCO) cultured for 48 hrs at 5×104 cells/well were measured by ELISA (DSLabs). In a parallel study, cells were incubated +/− metformin (10−7 M) for 48 hrs and the AMH protein and mRNA in cell lysates assessed by ELISA (DSL) and qPCR. AMH levels in GCs from anovPCO were significantly increased compared to normal and ovPCO (P<0.001): mean anovPCO 27.4 ng/ml (n=6, range, 17.2–42.7), ovPCO 1.4 (n=12, range, 0.025–7.6) and normal ovaries 0.29 (n=14, range, 0.025–1.7). FSH (5 ng/ml) significantly reduced AMH levels in GCs from PCO (P=0.008) (n=8), but not from normal ovaries. Both mRNA and protein levels of AMH from granulosa-luteal cell lysates were significantly reduced by metformin (n=4, P< 0.05).

In summary, AMH production per cell is greatly increased in anovPCO and was reduced by FSH. In addition, metformin inhibited both mRNA and protein in cell extracts.

In conclusion, as AMH-knockout mice have been shown to have an increased sensitivity to FSH, this data has important implications for a role for AMH in the anovulation associated with PCOS. The ability of metformin to reduce AMH production indicates a further possible mechanism of action for this drug in PCOS.

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