SEX STEROID MODULATION OF AT(2) RECEPTORS IN HUMAN MYOMETRIUM

In contrast to the abundant expression of the AT(2) subtype of angiote nsin II (AII) receptors during fetal development, AT(2) receptor in ad ult life is expressed in few tissues. We now report studies on the pre sence and hormonal regulation of AT(2) receptor in human pregnant and nonpregnant myometrium obtained from a large study population (n = 50) . AT(2) receptor subtypes have been characterized using self- and cros s-competition curves among [I-125]CGP42112A (a selective AT(2) ligand) , [I-125](Sar(1),Ile(8))AII (a unselective antagonist), the correspond ing unlabeled ligands, and several peptidic and nonpeptidic analogs wi th different affinities for the AT(1) and AT(2) receptor subtypes. We found that the human nonpregnant uterus expresses almost exclusively t he AT(2) subtype, and that [I-125]CGP42112A a selective probe to study human AT(2) receptor. By using [I-125]CGP42112A, we demonstrated that the density of AT(2) receptor in human myometrium is dramatically aff ected by the hormonal milieu. Indeed, in the estrogen-dominant uterus of normal cycling women in the proliferative phase and that of perimen opausal women with anovulatory cycles, the density of binding sites wa s very high [1565 +/- 246 fmol/mg protein (n = 11) and 2176 +/- 429 (n = 7), respectively]. The concomitant presence of progestogens blunted the estrogen effect [term pregnancy, 61 +/- 12 fmol/mg protein (n = 5 ); secretive phase of the cycle, 453 +/- 154 (n = 10); combined oral c ontraceptive, 243 +/- 74 fmol/mg protein (n = 6)]. Very low concentrat ions of binding sites are also present in the sex steroid-deprived ute rus of postmenopausal women (100 +/- 12 fmol/mg protein; n = 8) and th e uterus of fertile women chronically treated with GnRH agonists (199 +/- 100 fmol/mg protein; n = 3). Hence, these data confirm the presenc e of AT(2) receptors in human uterus and indicate their regulation by sex steroids.