Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid.

Abstract

The underlying cause of anovulation in polycystic ovary syndrome is unknown. Circulating levels of immuno- and bioactive FSH are within the normal range, and the follicles contain measurable levels of bioactive FSH. The aim of this study was to compare estradiol (E2) production in response to FSH by granulosa cells from normal ovaries with those from polycystic ovaries derived from both anovulatory (anovPCO) and ovulatory subjects (ovPCO). Intrafollicular levels of immunoactive FSH, E2, and androstenedione in follicles of less than 12 mm were also measured. Follicular fluid steroid concentrations were obtained from 41 pairs of normal ovaries and 23 pairs of polycystic ovaries (8 anovPCO and 15 ovPCO). In size-matched follicles from each group there were no significant differences in follicular fluid FSH or E2 concentrations, but androstenedione levels were significantly higher in 5- to 11-mm follicles from ovPCO than in corresponding follicles from normal ovaries. Dose responses to FSH were determined in granulosa cells derived from 9 pairs of normal ovaries, 7 anovPCO, and 8 ovPCO. Cells from anovPCO produced 6- to 10-fold more E2 in response to FSH than normal cells, although there was no significant difference in the ED50 values. The response in cells from ovPCO was reduced compared to normal, but this difference did not reach significance. In summary, as judged by their FSH and E2 contents, polycystic ovaries do not have a higher proportion of atretic follicles than normal. Indeed, cells from anovPCO are hyperesponsive to FSH in vitro. This could be explained by stimulation of aromatase in vivo by either paracrine or, more probably, by endocrine factors, of which insulin is an arguable candidate.

Nutrition, insulin and polycystic ovary syndrome

“…The implication of these findings is that granulosa cells from insulinresistant women with PCOS are, effectively, exposed to higher than normal circulating concentrations of insulin and that this may be expected to enhance steroidogenesis. This would be consistent with the observation that granulosa cells from anovulatory PCOS subjects have a greater capacity to produce oestradiol in vitro than do cells from either normal ovaries or ovulatory PCOS (Mason et al, 1994). How can this proposed stimulatory effect of insulin be reconciled with the observation that PCOS is associated with disordered follicle maturation?…”

“…5-10 mm in diameter) may be effectively equivalent to that which, in the normal menstrual cycle, is attained only in mature follicles of about 20 mm in diameter. The predicted result would be enhanced oestradiol production (as indeed can be observed in studies in vitro, Mason et al, 1994) but inhibition of further growth and arrest of follicles at 5-10 mm (Fig. 6).…”

Luteal-phase inhibin A and follicular-phase inhibin B levels are not characteristic of patients with an elevated LH-to-FSH ratio

“…Since serum FSH concentrations are normal in PCOS patients and granulosa cells respond in a normal fashion to stimulation in vitro with FSH [27], local ovarian products might be involved in the follicular arrest characteristic of PCOS. In a recent report by Welt et al [28], decreased concentrations of inhibin A and B were found in follicular fluid samples from PCOS patients as compared to concentrations in size-matched follicles obtained from healthy volunteers.…”

The genetic basis of polycystic ovary syndrome

“…Immunohistochemical studies of polycystic ovaries could not detect aromatase in antral follicles of various sizes (53). On the other hand it has been found that granulosa cells from anovulatory polycystic ovaries are hyperresponsive to follicle-stimulating hormone (FSH) in vitro, displaying significantly greater oestradiol production than granulosa cells from normal ovaries, suggesting no functional deficiency of aromatase in polycystic ovaries (54).…”