Gonadotropin-releasing hormone receptor mRNA expression by human pituitary tumors in vitro.
An important question in the pathogenesis and regulation of human gonadotroph adenomas is whether heterogeneous gonadotropin responses to gonadotropin-releasing hormone (GnRH) are due to dysregulation of GnRH receptor biosynthesis and/or cell-signaling pathways. We investigated gonadotropin responsiveness to pulsatile GnRH in 13 gonadotroph adenomas. All tumors had evidence of follicle-stimulating hormone (FSH) beta and alpha subunit biosynthesis using reverse transcriptase/polymerase chain reaction (RTPCR) techniques. Four tumors significantly increased gonadotropin and/or free subunit secretion during pulsatile 10(-8) M GnRH administration. The GnRH antagonist Antide (10(-6) to 10(-8) M) blocked secretory increases in all GnRH-responsive tumors. Gonadotropin and/or free subunit secretion increased after 60 mM KCl, confirming that GnRH nonresponsiveness was not due to intracellular gonadotropin depletion. We hypothesized that GnRH nonresponsiveness in these tumors may be due to GnRH receptor (GnRH-Rc) biosynthetic defects. RTPCR analyses detected GnRH-Rc transcripts only in responsive tumors and normal human pituitary. This is the first demonstration of a cell-surface receptor biosynthetic defect in human pituitary tumors. We conclude (a) one third of gonadotroph tumors respond to pulsatile GnRH in vitro, (b) GnRH-Rc mRNA is detected in human gonadotroph adenomas and predicts GnRH responsiveness, and (c) GnRH-Rc biosynthetic defects may underlie GnRH nonresponsiveness in gonadotroph tumors.
Alexander
J M
JM
Neuroendocrine Unit, Massachusetts General Hospital, Boston 02114.
Klibanski
A
A
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010911:Pituitary Neoplasms / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis*; D011966:Receptors, LHRH / Q000235:genetics*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone