Mullerian Inhibiting Substance (MIS) is a member of the transforming growth factor beta superfamily of growth factors, which causes regression of the Mullerian duct in male embryos, and is believed to act in a paracrine fashion after birth to regulate granulosa cell and oocyte function. MIS appears to be an important regulator of primordial follicle recruitment, and is also capable suppressing androgen production. Abnormal ovarian function is implicit in polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, and recent reports indicate that MIS is raised in the circulation of PCOS women. The role of MIS in PCOS was explored by measuring MIS and other factors in the circulation of 82 obese women with PCOS before and during 8 months treatment with metformin.
Prior to treatment, MIS concentrations were elevated (mean = 7.9 ng/ml) compared with normal laboratory data (upper limit = 7.9 ng/ml), and showed positive correlations with total ovarian follicle number (TFN) and circulating androstenedione concentrations, and a negative correlation with age. A multiple regression model, including all 3 variables showed only TFN remained significantly related to MIS concentrations (p=0.02; r2 of the model = 0.18).
Metformin treatment increased menstrual frequency, achieved reductions in weight, androstenedione and also MIS, with no effect on TFN or testosterone.
Patients responding to metformin by establishing normal menses ('Responders') were compared with those who retained their oligomenorrhoea ('Non-responders'). Both groups underwent similar reductions in MIS during treatment. The TFN of the 'Responders' declined to a smaller number than the 'Non-responders'. However there was no difference between the groups in either the decline in MIS concentrations, nor the final concentrations of MIS.
The data suggest that circulating MIS reflects the cohort size of specific categories of follicles, and that metformin treatment leads to a shift in the dynamics of follicle activities, including small, androgen secreting follicles. MIS may be a reliable marker for PCOS.
22 - 24 Mar 2004
British Endocrine Societies