Combined effect of follicle-follicle interactions and declining follicle-stimulating hormone on murine follicle health in vitro

Follicle selection occurs throughout an adult female's reproductive life, w ith selected, dominant follicle(s) developing to the preovulatory stage whe reas the remaining, subordinate follicles within the growing cohort instead undergo atresia and die. To date, most research into follicle dominance ha s concentrated on its endocrine regulation, although it seems likely that i ntraovarian mechanisms are also involved in its regulation. We demonstrate here that the response of singly cultured murine follicles to declining con centrations of FSH depends on their developmental stage, with follicles at an earlier stage of development being much more susceptible than mature fol licles to a lowering of FSH levels. We then extrapolate this information to follicle cocultures, in which a large dominant follicle was grown with a s mall subordinate follicle in a manner that maintained a dominant/subordinat e relationship, with follicle health assessed by a terminal transferase-med iated 2 ' -deoxyuracil 5 ' -triphosphate nick end-labeled reaction on whole -follicle mounts. Our investigations show a combined negative effect of coc ulture and FSH withdrawal on small subordinate follicles, such that subordi nate follicles cocultured with dominant follicles and subjected to a loweri ng of FSH levels during the culture period exhibit a greatly increased inci dence of apoptosis in the granulosa cells (750% increase) compared with tha t exhibited by the dominant follicles (97% increase). We suggest that a sim ilar interaction between endocrine and intraovarian factors regulates folli cular dominance in vivo, such that dominant follicles, in addition to bring ing about a fall in FSH levels via the hypothalamic-pituitary axis, exert l ocal, direct effects on subordinate follicles, with both of these influence s combining to induce atresia in subordinate follicles.