Estrogenic and antiestrogenic effects of enclomiphene and zuclomiphene on gonadotropin secretion by ovine pituitary cells in culture

17 beta-Estradiol (E2) alters gonadotropin secretions in ovine pituitary cell cultures by 1) augmenting the LH response to LHRH and 2) inhibiting the basal secretion of FSH. These responses were used to study the estrogenic and antiestrogenic effects of enclomiphene, zuclomiphene, and their commercial mixture, Clomid. In terms of the LH response to LHRH, Clomid and enclomiphene (10(-6) M) acted as E2 antagonists because they blocked the action of E2 (10(-10) M). By themselves they did not alter the LHRH response. Previous studies using rat pituitary cultures showed opposite results, since both enclomiphene and Clomid acted as estrogens in rat cultures. Apparently, species differences are involved. One conclusion from these data, therefore, is that it would be unwise to predict how Clomid acts in any species without direct experimentation. Zuclomiphene (10(-7)--10(-5) M) acted as a E2 agonist, in terms of the LH response to LHRH, because it sensitized cultures to LHRH. Surprisingly, all of the clomiphenes, including zuclomiphene, acted primarily as E2 antagonists when FSH secretion was observed. At a concentration of 10(-6) M, they blocked the inhibitory effects of E2 (10(-10 M) on FSH secretion, but enclomiphene and Clomid also exhibited minor estrogenic action when administered alone. The clear but unexpected role of zuclomiphene as both E2 agonist (as measured by LH secretion) and antagonist (as measured by FSH secretion) suggests that zuclomiphene may be an especially useful compound for dissociating the effects of E2 on FSH and LH in vivo, at least in sheep. Of more theoretical interest is the fact that zuclomiphene can affect two E2-responsive systems oppositely. Both systems appear to reside in the same subset of pituitary cells.