Radiation injury of the hypothalamicipituitary-axis (H/P-A) can compromise the quality of survival of patients treated for brain tumors. We have identified a population of female adolescents and women who are oligo- or amenorrheic and hypoestrogenemic, but have normal or near normal basal and stimulated luteinizing hormone (LH) levels. This suggests normal intrinsic pituitary function in these patients, but a gland which is not appropriately stimulated by hypothalamic releasing hormone (GnRH). A radiation lesion in the hypothalamus disrupting its neurosecretory pattern would best explain the complex of observed hormonal events.
The specific aims of this proposal intend to (1) identify the pattern of LH pulsatility in post-pubertal women who were irradiated to the H/P-A by comparing their secretory dynamics with that of normal women, and (2) further explore the mechanism by which this might occur by pharmacologically intervening in the catecholamine and opiate systems which chemically mediate relevant neurosecretory events in the H/P-A. If such a strategy is successful, then gonadotropin secretion could be corrected; chronic pharmacologic intervention would offer the possibility of restoring fertility to some women. The evaluative (and potentially the interventional) strategies could also be extended to girls who were irradiated prior to puberty and are failing to develop sexually. Finally the pathophysiology of radiation damage of the H/P-A would be better understood, offering a basis to proceed with additional clinical and laboratory investigations. The specific protocol will involve 3 conditions (C) which will be examined in 3 groups (G) of 10 patients each defined as follows: Cl=determination of LH pulse frequency, height and volume during nighttime sleep at 15 minute intervals, and then peak LH response to GnRH to evaluate pituitary responsiveness; C2=as in C1 but in the presence of the opiate receptor antagonist naloxone; G1=women irradiated to the H/P-A for non H/P-A brain tumors whose H/P,gonadal axis is dysfunctional; G2=as in G1 but with a normal H/P-gonadal axis; G3=healthy volunteers. Groups and conditions will be compared using a deconvolution analysis which has been designed specifically to investigate the secretory process.
