A ROLE FOR NEUROTRANSMITTERS IN EARLY FOLLICULAR DEVELOPMENT - INDUCTION OF FUNCTIONAL FOLLICLE-STIMULATING-HORMONE RECEPTORS IN NEWLY FORMED FOLLICLES OF THE RAT OVARY

The initiation of follicular grow th in the mammalian ovary is a gonad otropin-independent phenomenon. Although some of the intraovarian sign aling molecules that control the later phases of this process have bee n recently identified, the factors involved in the acquisition of gona dotropin receptors by early growing follicles have not been fully defi ned. In the rat, development of the ovarian innervation precedes the o nset of folliculogenesis and occurs before follicles acquire responsiv eness to gonadotropins. Because vasoactive intestinal polypeptide (VIP ) and norepinephrine (NE), two of the neurotransmitters contained in o varian nerves, are present in the ovary before the gland becomes respo nsive to gonadotropins, we sought to determine if VIP and/or NE are ab le to act on early follicles to facilitate the process of molecular di fferentiation that leads to gonadotropin dependency. In vitro exposure of 2-day-old rat ovaries to isoproterenol (ISO), a beta-adrenorecepto r agonist, or VIP, a neurotransmitter contained in both sympathetic an d sensory nerves, increased the steady state levels of the messenger R NAs encoding cytochrome P-450 aromatase (P-450(arom)) and FSH receptor s (FSHR) within 8 h of treatment. A similar effect was observed follow ing forskolin-induced activation of cAMP formation. In situ hybridizat ion experiments revealed that both the P-450(arom) and FSHR hybridizat ion signals were localized to follicles. The increase in FSHR messenge r RNA was accompanied by formation of functional receptor molecules, a s demonstrated by the ability of FSH to stimulate cAMP formation in ov aries preexposed to either ISO or VIP, but not in untreated ovaries. T he stimulatory effect of ISO and VIP on the formation of FSHR coupled to the cAMP generating system was not reproduced by phenylephrine, an alpha-adrenergic agonist, err secretin, a member of the VIP family not recognized by ovarian VIP receptors. Treatment of VIP-primed ovaries with FSH resulted in follicular growth, demonstrating that exposure of the gland to the neurotransmitter led to the formation of a functiona l complement of FSH receptors. These results suggest that ovarian nerv es, acting via neurotransmitters coupled to the cAMP generating system , contribute to the differentiation process by which newly formed prim ary follicles acquire FSH receptors and responsiveness to FSH. Follicl es that begin to grow in more densely innervated ovarian regions, may have a selective advantage over those not exposed to neurotransmitter- activated, cAMP-dependent signals and, thus, may become more rapidly s ubjected to gonadotropin control.