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Title: The experimental manipulation of gonadotrophins in non-pregnant sheep by immunization against steroid hormones
Author: Martensz, N. D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1977
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The involvement of a steroid in the feedback systems controlling the hypothalamic-adenohypophyseal axis may be inferred if a reduction in the biologically active fraction of the steroid through antibody binding results in an alteration in the secretion of gonadotrophins. The present studies examined the effects of active immunization against bovine serum albumin (BSA) conjugates of four steroids known to be secreted by the sheep ovary (oestradiol-17p, oestrone, androstenedione and testosterone) on the release of LH and FSB in the non-pregnant ewe. Groups of five adult ewes were actively immunized against 17p-oestradiol6-(0-carboxymethyl)oxime-BSA (E2 6-BSA), oestrone-6-(O-carboxymethyl)oxime-BSA (E1-6-BSA), testosterone-3-(O-carboxymethyl)oxime-BSA (T-3-BSA), androstenedione-114-hemisuccinyl-BSA (A-11-BSA) and BSA (controls). The concentrations of LH and FSH were measured in samples of jugular venous blood taken from all animals during anoestrus and during the breeding season. The ewes were laparotomized during the breeding season and samples of jugulat venous and ovarian venous blood obtained for subsequent steroid analysis. The macroscopic appearance of the ovaries was noted and the ovaries removed. Ovine LH and FSB and oestradiol-17p(oestradiol), oestrone, androstenedione, testosterone and progesterone were all measured by specific radioimmunoassays. The binding of tritiated steroids by plasma was determined after the removal of unbound steroid by dextran-charcoal absorption and after equilibrium dialysis. The presence of elevated LH levels together with the absence of behavioural oestrus and the inhibition of ovulation in four of the five oestradiol-immunized ewes served to confirm the widely accepted concept of action of oestradiol on LH secretion in the ewe. Furthermore, multiple ovarian follicular development was evident in the four anovulatory oestradiol immunized ewes and reflected the elevated circulating levels of LH. A marked similarity between the oestradiol-immunized animals and the ewes immunized against T-3-BSA was apparent in terms of an elevated plasma level of LH, the absence of behavioural oestrus and the inhibition of ovulation accompanied by multiple follicular development. These findings coupled with the presence of significant oestradiol antibody titres and the failure of exogenous oestradiol to alter LH secretion during anoestrus in the testosterone-immunized animals led to the conclusion that immunization against T-3-BSA produced a non-specific reduction in the level of biologically active oestradiol. Active immunization against E1-6-BSA produced plasma levels of LH greater than those found in ovariectomized-hysterectomized animals. A further anomalous finding in the present study was the absence of follicular stimulation in the oestrone-immunized ewes in response to the elevated circulating levels of gonadotrophins. The effects of active immunization against E1-6-BSA in the ewe could not be satisfactorily explained at the present time. Active immunization against -A-11-BSA produced an increased frequency of spontaneous discharges of LH during anoestrus and an elevation in the plasma level of LH during the luteal phase of the oestrous cycle. Furthermore, the positive feedback action of oestradiol on LH secretion during anoestrus was delayed or absent in those ewes with high androstenedione antibody titres. Since the plasma binding of oestradiol was unaltered and oestrous cycles of normal length occurred in the androstenedione-immunized ewes, it is postulated that androstenedione, or its extra-ovarian metabolites, could modulate the feedback actions of oestradiol on LH secretion in the ewe. Exogenous oestradiol exerts a dual action on the release of FSH in an oestrou d and ovariectomized-hysterectomized ewes in a manner similar to the negative and positive feedback actions of this steroid on LH secretion. A significant elevation in the plasma concentration of FSH was observed in the two oestradiol immunized ewes with the highest titres of oestradiol antibodies. It is suggested that in these animals, the level of biologically active oestradiol was sufficiently reduced to lift the inhibitory control of FSH secretion. The presence of normal plasma FSH levels in the three remaining oestradiol-immunized animals suggests that incomplete neutralization of circulating oestradiol had left sufficient biologically active oestradiol available to exert an inhibitory action on FSH secretion. In contrast, a reduction in the levels of biologically active androstenedione and testosterone in the ewes immunized against A-11-BSA and T-3-BSA failed to produce an elevation in the plasma level of FSH. In fact, a significant reduction in the plasma concentration of FSH was present in the androstenedione immunized animals. It is tentatively suggested that androgens may enhance the release of FSH by a direct action on the anterior pituitary. In the light of recent evidence suggesting that FSH may enhance the aromatization of androgens to oestrogens by the ovary, it is postulated that the increased secretion of androgens by the ovary in response to LH may enhance the release of FSH. The elevated level of FSH would in turn lead to increased secretion of oestradiol thereby resulting in the suppression of LH and FSH secretion. The problems associated with the evaluation of the antibody specificity and the degree to which the biological actions of steroids are neutralized in the actively immunized animal emphasize the need for caution in the extrapolation of the findings described in the present studies to physiological events in the intact animal. The proposed action of androgens on the release of FSH awaits further examination.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available