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Developmental Changes in Pituitary Adenylate Cyclase Activating Polypeptide Expression during the Perinatal Period: Possible Role in Fetal Gonadotroph Regulation

Department of Anatomical Sciences and Neurobiology (J.P.M.), Division of Endocrinology and Metabolism (J.P.M., B.C.V., S.J.W.), and Departments of Medicine and Anesthesiology (C.A.U.), University of Louisville School of Medicine, Louisville, Kentucky 40202

Address all correspondence and requests for reprints to: Joseph P. Moore Jr., Ph.D., Department of Anatomical Sciences and Neurobiology, University of Louisville, School of Medicine, Louisville, Kentucky 40292. E-mail: jpmoor03{at}louisville.edu.

Normal reproductive functioning may require secretion of LH independently of FSH. Variation in GnRH pulse frequency and inhibin negative feedback are mechanisms for differential gonadotropin regulation; however, the first instance of differential regulation in rats is during fetal development, prior to the establishment of GnRH connections, when LH accumulates appreciably 2–4 d prior to FSH. Pituitary adenylate cyclase activating polypeptide (PACAP) can differentially regulate the gonadotropins in vitro by stimulating -subunit transcription, lengthening LHβ transcripts and decreasing FSHβ mRNA levels, probably through stimulation of follistatin transcription. These experiments are the first to examine whether PACAP influences gonadotroph function in perinatal pituitaries. In vivo, pituitary PACAP mRNA and peptide levels were high at embryonic d 19 and declined by 94 and 85%, respectively, after parturition. This was accompanied by a decrease of 65 and 96% in total follistatin and follistatin-288 mRNAs. These changes were temporally associated with a 20- and 6.5-fold rise in FSHβ and GnRH receptor mRNAs, respectively, with no significant increase in LHβ mRNA. In pituitary cell cultures from fetal and postnatal male rats, PACAP mRNA levels were likewise highest in fetal cultures in which the PACAP 6-38 antagonist decreased -subunit and increased FSHβ mRNA. PACAP 6-38 also reduced basal and GnRH-stimulated LH secretion with little effect on FSH. These data support the hypothesis that PACAP expressed at high levels in the fetal pituitary stimulates -subunit expression and LH secretion and restrains FSH synthesis relative to LH and that a decline in PACAP allows for the neonatal rise in FSH and GnRH receptor because follistatin is decreased.