An integrated series of basic and clinical investigative studies is planned to evaluate factors involved in the etiology of prolactinomas and the mechanisms by which prolactin (PRL) affects the hypothalamic-pituitary-ovarian axis. Studies will be performed to 1) study the relationship between alterations in vascular supply of the pituitary gland and pituitary tumors; 2) assess facets of hypothalamic regulation of PRL in normal women and those with prolactinomas; and 3) evaluate mechanisms involved in the development of amenorrhea in hyperprolactinemic women. 1) To study the role of vascular changes, the """"""""arteriogenic"""""""" response in rats with estrogen-induced tumors will be characterized, determining whether the direct arterial blood supply to the anterior pituitary gland (AP) is reversible; is inhibited by dopamine agonists; is partially dependent on endogenous estrogen; occurs in E2-treated male rats; is located in areas of the AP with hyperplasia of lactotrophs; occurs during the formation of prolactinomas in aging or pregnant rats and can be identified histologically. Whether the formation of new arteries is dependent upon an angiogenic-like factor will be determined. The effect of removal of dopamine inhibition on the rate and incidence of tumor formation in E2-treated rats will be assessed. The time course of E2 induction of AP hemorrhage will be determined and related to pituitary infarction and autoimmune changes. An attempt will be made to induce autoimmune changes in the AP of rats by immunization with AP cells. Whether prolactinoma formation in humans is associated with arteriogenesis will be assessed by evaluating tumor specimens histologically; injecting microspheres into the carotid artery at autopsy; and determining whether tumors produce an arteriogenic factor. In addition, whether antibodies to AP cells are found in patients with lymphocytic adenohypophysitis will be determined. 2) To assess facets of hypothalamic regulation of PRL, a) alterations in PRL response to dopamines caused by E2 will be determined; b) alteration of PRL response to dopamine infusion caused by suppression of endogenous opioids will be evaluated; and c) possible CRF-mediated PRL responses will be assessed and compared with insulin-induced hypoglycemic PRL responses. Further, the predictive value of provocative testing of PRL responses will be correlated with prolactinoma recurrence. 3) To study mechanisms involved in hyperprolactinemic amenorrhea the following will be assessed: a) the effects of dopamine infuson on pulsatile gonadotropin release; b) the effectiveness of pulsatile GnRH administration on ovulation induction; c) temporal changes in pituitary and ovarian hormones following discontinuance of bromocriptine. Prolactinomas are common tumors, frequently associated with disruption of reproductive funtion and may have significant consequences in terms of estrogen deprivation, osteoporosis, tumor extension and infertility.
