Ovarian stromal hypertrophy

Polycystic ovary syndrome (PCOS) continues to stimulate lively debate and controversy on the subject of its pathogenesis. Marked heterogeneity of clinical, endocrine (Conway et al., 1989) and ultrasonographic features (Pache et al., 1992) has hindered the provision of strict diagnostic criteria so that variable combinations of parameters generally suffice. There are two diagnostic approaches to PCOS: one is primarily based on ovarian ultrasonographic appearances as defined by Adams et al. (1986) and combined with certain characteristic symptoms (Conway et al., 1989); in the alternative approach, detection of hyperandrogenic chronic anovulation (HCA) is considered sufficient for diagnosis regardless of ovarian scan appearances. When using ultrasonography, determination of the number and distribution of follicles is easier to achieve and therefore often forms the basis for diagnosis, particularly when the ovary is not enlarged (Franks, 1989). In practice, recognition of the typical dense central stroma is a notoriously subjective observation making valid clinical study comparisons very difficult. The importance of hyperandrogenaemia in PCOS is acknowledged and clear evidence now exists pin-pointing the ovary as its source. This has been proved directly from measurements of androgen metabolites (Kirschner et al., 1976) and by adrenal and ovarian vein catheterization (McNatty et al., 1980), and strongly inferred from the observed regression of hirsutism after ovarian suppression (Chang et al., 1983) and persistence of an abnormal hormone profile despite dexamethasone pretreatment (Barnes et al., 1989). The ability of theca interstitial cells to preferentially secrete androgens or progesterone under the influence of luteinizing hormone (LH) gives them a pivotal role in physiological and pathological ovarian mechanisms (Erickson et al., 1985). LH fluctuations during the ovarian cycle alter the activity of two key enzymes, 17a-hydroxylase and C 17,20 lyase, which catalyse the production of 17-hydroxyprogesterone (1 70HP) and androstenedione (A) respectively and are regulated by a single cytochrome, p-450 cl7. Barnes et al. (1989) reported excessive production of 170HP and A in women with PCOS after nafarelin administration. The specificity and consistency of these and subsequent results led Ehrmann et al. (1992) to postulate cytochrome p-450 cl7 dysregulation in PCOS and to suggest the short-term nafarelin test as a screening test to distinguish it from other causes of hyperandrogenism regardless of ultrasonographic features or the basal serum LH concentration. In their study, Dewailly et al. (1994) begin to address the pressing need for an objective quantitative method of ovarian stromal assessment by using a computerized ultrasonic technique to measure stromal and cyst areas. They correlated this information with serum androgen, insulin and gonadotrophin concentrations, showing that stromal area in hyperandrogenaemic women is significantly greater than in those with normal androgen levels and correlates positively with serum androstenedione (A) and 17-hydroxyprogesterone (1 70HP) concentrations, but not with basal LH, insulin or testosterone concentrations. The importance of their paper lies in the correlation of a quantitative stromal parameter with markers of androgenic dysfunction, thereby unifying the two diagnostic approaches. Cyst area did not correlate with hyperandrogenaemia despite being significantly increased in this group. As ultrasonic visualization and quantification of the stroma becomes more sophisticated, follicular pattern may become less important for diagnosis. Background normative data is obviously lacking at present, but two similarly sized control groups of normal and hypogonadotrophic women provide some illustration of the range of stromal areas encountered. Further studies are needed to clarify its limits. The group wisely validated each step of their analysis. Stromal area measurement consistently produced more variation within and between observers when compared to total ovarian area measurement which simply involved outlining the image. Variations were small, being generally less than 10%. Insulin resistance is closely associated with hyperandrogenaemia whether caused by insulin receptor disturbance or obesity (Poretsky & Kalim, 1987). In PCOS, this is expressed by a tendency to marked hyperinsulinaemia with increasing weight gain (Dunaif et al., 1989). The direct relation between insulin and thecal androgens suggested by in-vitro studies (Barbieri et af., 1988) and clinically (Conway et al., 1990) was not confirmed in this study since stromal area did not correlate positively with basal serum insulin or testosterone concentrations. Dunaif et al. (1989) also found no direct correlation of androgens