Opposite Changes of Pituitary and Ovarian Receptors for LHRH in Ageing Rats: Further Evidence for a Direct Neural Control of Ovarian LHRH Receptor Activity

Abstract

Hypophyseal and ovarian receptors for the neurohormone LHRH (LHRH-R) have been measured in young (3-4 months), middle-aged (8-11 months), constant estrous (CE, 10-14 months) and pseudopregnant (PR, 16-18 months) rats in order to study whether changes in hypothalamic and/or peripheral LHRH-like peptide production might precede and/or accompany the onset of reproductive failure observed in aging rats. Furthermore, we have investigated whether the neural efferent system from the brain to the ovary is affected with aging. The pattern of pituitary LHRH-R modifications during the estrous cycle of middle-aged rats shows lower LHRH-R levels on the second day of diestrus, resulting in a shift of the maximal LHRH binding capacity in the morning of proestrus. On the other hand, when comparing pituitary LHRH-R of animals exhibiting constant vaginal cornification (CVC) or repetitive PP with young estrus rats, no significant difference could be observed. Young rats responded to electrical stimulation (ES) of the medial preoptic area with an acute elevation of LHRH-R while ES performed in CVC, or PP animals resulted in a significant increase of hypophyseal LHRH binding capacity similar to the one observed in young estrous controls, indicating an impairment in the neural signals impinging in the pulse generating system, in old rats, and not an intrinsic defect of the LHRH-R per se. Ovarian LHRH-R concentration is higher in middle-aged cycling animals on the day of vaginal proestrus, compared to levels measured in young animas at any phase of the estrous cycle. Similarly, CE rats displaying CVC as well as PP animals show significantly higher numbers of LHRH-R with no change in affinity, than young estrus rats. CVC and PP rats receiving unilaterally an intraovarian injection of the potent LHRH antagonist, Ac-D-Cl-Phe1,2, D-Trp3,D-Phe6,D-Ala10, LHRH, showed an acute drop of LHRH-R measured within the treated ovary with no significant changes taking place in the vehicle-treated contralateral gland, suggesting that changes of endogenous ovarian LHRH-like peptide might participate in the mechanism(s) responsible for LHRH receptor increase observed in agining rats. In order to investigate the participation of a direct neural efferent pathway in ovarian LHRH-R regulation, young and old rats were subjected to spinal cord transection (above T10-T11). Bilateral transection of the spinal cord in young animals in the morning of proestrous markedly increased ovarian LHRH-R concentration in the afternoon (17.00 h) of the same day. When spinalectomy was performed unilaterally, a marked increase of ovarian LHRH-R capacity in the gonad ipsilateral to the intervention was measured, with no effect taking place in the contralateral gland. On the other hand, the same intervention did not modify the already stimulated LHRH-R levels measured in old rats. It is suggested that an increase of ovarian LHRH-R activity might trigger the neuroendocrine mechanisms leading to reproductive dysfunction in aging female rats. Furthermore, present data also suggest that the establishment of a central defect in aging animals might directly interfere with ovarian function, by means of neural signal, modulating ovarian LHRH-R activity, which further reinforces our view that the brain and the gonads can directly communicate via a neural pathway.