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H. M. Fraser

Introduction

The time of this symposium coincides with the tenth anniversary of the structural characterization of gonadotrophin-releasing hormone (GnRH) (Matsuo, Baba, Nair, Arimura & Schally, 1971). There were then high expectations that GnRH would not only be of help in the treatment of infertility but, with the synthesis of inhibitory analogues, could also hold the key to new methods of contraception (Guillemin, 1972). It is appropriate that we should now consider this 'old' peptide in a new light because in spite of all the varied predictions no-one could have foretold some of the ways the story of GnRH has developed. For example, GnRH and its stimulatory analogues have been of only limited success in the treatment of infertility, but they now constitute our most promising approach to contraception. Studies of the way in which GnRH can change from having a stimulatory to an inhibitory effect on the pituitary gland and

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R. M. Sharpe and H. M. Fraser

Summary. Daily treatment of immature (30-day-old) male rats for 40 days with 50 ng of an agonist of LH-RH impaired normal development of Leydig cell function. This treatment partly or completely inhibited maturational increases in (1) the serum levels of testosterone, (2) seminal vesicle weight, (3) the in-vitro steroidogenic responsiveness of the testis, and (4) the in-vitro testicular binding of125I-labelled hCG. In contrast, twice-weekly treatment of immature or adult rats with 50 ng LH-RH agonist had only minor effects on Leydig cell function, although hCG-binding was always significantly reduced. Testicular growth in immature rats was unaffected by daily injection of LH-RH agonist whereas twice-weekly treatment caused a small reduction in weight. None of the treatments had any major consistent effect on the pituitary or serum levels of gonadotrophins and prolactin, although daily treatment with the LH-RH agonist clearly reduced the responsiveness of the pituitary to the agonist, in terms of the amounts of LH and FSH released.

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R. M. Popkin and H. M. Fraser

Summary. The hypothalamic—pituitary—ovarian axis of female rats was disrupted at the site of LHRH stimulation by active immunization against LHRH or at the site of LH action by active immunization against LH. Active immunization against LH was associated with an increase in pituitary LHRH receptors to levels comparable to control values at pro-oestrus whereas immunization against LHRH led to a marked reduction in receptor numbers. Ovarian LHRH receptor concentrations were increased by both treatments. It is concluded, therefore, that (1) LHRH receptors in the pituitary and ovary are not concomitantly controlled, and (2) pituitary receptor numbers are primarily under positive autoregulatory control by LHRH and that ovarian LHRH receptor concentrations may be under long-term influence of LH.

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H. M. Fraser and A. S. McNeilly

Summary. Neutralization of LH-RH by injection of an ovine antiserum to LH-RH in ewes during the late follicular phase of the oestrous cycle resulted in an immediate blockade of pulsatile secretion of LH. Plasma concentrations of FSH gradually rose in the antiserum-treated ewes during the 36-h study period but levels declined in control ewes. These results show that, in the ewe, pulsatile LH secretion is dependent on LH-RH from the hypothalamus, while FSH is largely unresponsive to short-term reduction of LH-RH stimulation. Since reduction in LH secretion is likely to reduce ovarian function, the changes in FSH secretion may be attributed to the removal of a negative feedback influence of an ovarian factor, perhaps oestradiol, on FSH secretion.

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Rachel M. Popkin, H. M. Fraser, and R. G. Gosden

Summary. Hyperstimulation of pituitary function using daily injections of 50, 500 or 5000 ng LH-RH agonist for 3 weeks or hypostimulation by immunoneutralization of endogenous LH-RH led to disrupted oestrous cycles and profound changes in ovarian morphology. Despite this, the number of pituitary and ovarian LH-RH receptors remained within the range found in normally cyclic animals. Autoradiography confirmed that specific binding was located in theca, granulosa and luteal cells.

These results suggest that autoregulation of pituitary and ovarian LH-RH receptors is not of primary importance in the cyclic female rat.

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F. M. Young, P. J. Illingworth, and H. M. Fraser

The polypeptide ubiquitin covalently binds to cytoplasmic proteins and marks them for proteolytic degradation. Ubiquitin is upregulated during apoptosis in some systems. Apoptosis increases during luteolysis but it is not known whether ubiquitin is expressed in regressing corpora lutea. Marmoset ovaries were removed on day 10 of the luteal phase from animals that had received either no treatment, treatment with the PGF analogue cloprostenol 24 h earlier, or treatment with the GnRH antagonist antarelix for either 24 or 48 h before ovary collection. Ubiquitin was localized on ovarian sections by immunocytochemistry, and oligonucleosome formation characteristic of apoptosis was examined in isolated corpora lutea by electrophoresis of extracted [32P]DNA. Oligonucleosome formation was low in midluteal corpora lutea on day 10 but increased after induced luteal regression with PGF and GnRH antagonist. Nuclear ubiquitin immunoreactivity was found in 1.66 ± 0.66 steroidogenic cells and cytoplasmic staining was found in 0.4 ± 0.3 steroidogenic cells (per × 40 field of view) in midluteal phase corpora lutea on day 10. Luteolytic induction with PGF significantly increased the number of cells exhibiting cytoplasmic immunoreactivity to 12.24 ± 1.6 (P < 0.05). Ubiquitin immunoreactivity was not observed after GnRH-induced luteal regression. Apoptotic oligonucleosome formation was found after induced luteal regression with both PGF and GnRH antagonist, but ubiquitin upregulation only occurred after PGF-induced regression. These results indicate that ubiquitin expression is not specific for luteolysis and is not an indicator of luteal apoptosis, but that the polypeptide does play a role in luteal cellular responses to PGF.

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G. A. Lincoln, H. M. Fraser, and M. P. Abbott

Summary. Adult Soay rams were infused for 21 days with 50 μg buserelin/day, using s.c. implanted osmotic mini-pumps. The continuous treatment with this LHRH agonist induced a supraphysiological increase in the blood concentrations of LH (15-fold) and testosterone (5-fold) followed by a decrease below pre-treatment values after 10 days. The blood concentrations of FSH showed only a minimal initial increase but the subsequent decrease was dramatic, occurring within 1 day. By Day 10 of treatment, the blood concentrations of all 3 hormones were low or declining, LH pulses were absent in the serial profiles based on 20-min blood samples and the administration of LHRH antiserum failed to affect the secretion of LH or testosterone. By Day 21, the secretion of FSH, LH and testosterone was maximally suppressed. The i.v. injection of 400 ng LHRH was totally ineffective at stimulating an increase in the blood concentrations of LH while the i.v. injection of 50 μg ovine LH induced a normal increase in the concentrations of testosterone; this confirmed that the chronic treatment with the LHRH agonist had desensitized the pituitary gonadotrophs without markedly affecting the responsiveness of the testicular Leydig cells. The ratio of bioactive:radioimmunoactive LH did not change during the treatment. The long-term effect of the infusion was fully reversible as shown by the increase in the blood concentrations of FSH, LH and testosterone and the return of normal pulsatile fluctuations in LH and testosterone within 7 days of the end of treatment.

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G. A. Lincoln, H. M. Fraser, and T. J. Fletcher

Summary. Four sexually mature male red deer were actively immunized against LHRH and this caused 3 of the animals to cast their antlers prematurely in the autumn instead of the spring. Development of new antlers was initiated after casting, but the effects on the antler cycle were variable and correlated with the antibody titre, only the animal with the highest titre developed antlers that resembled those of a castrate and remained 'in velvet' for more than 6 months. In October, when all the immunized deer had peak circulating levels of LHRH antibodies, the testes were reduced in size compared to the maximum values of the controls. The blood levels of testosterone were reduced in the immunized animals, and there was a minimal increase in the circulating levels of testosterone in response to an i.v. injection of 100 μg ovine LH. The immunized stags showed no rutting behaviour in the autumn. The changes in the testes confirm that the immunizations were effective in blocking the secretion of the gonadotrophic hormones. The re-development of antlers in these animals indicates that gonadotrophins are not directly involved in stimulating antler growth.

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A. S. McNeilly, J. A. Jonassen, and H. M. Fraser

Summary. Active immunization of 6 Damline ewes against LHRH during seasonal anoestrus resulted in an inhibition of ovarian cyclicity throughout 2 subsequent breeding seasons. This was associated with a significant suppression of plasma LH and FSH concentrations but no significant effect on prolactin. The ovaries of LHRH-immunized ewes 30 months after primary immunization contained no follicles > 2·5 mm in diameter and a greater proportion of follicles between 1 and 2 mm were atretic than in control ewes (N = 8). In-vitro production of testosterone and androstenedione were similar in follicles 1–2 mm in both control and LHRH-immunized ewes (N = 6) and all had little or no ability to secrete oestradiol. However, basal and hCG-stimulated progesterone secretion was suppressed in the follicles from LHRH-immunized ewes. These results show that follicular development beyond 2·5 mm in the ewe is dependent on adequate stimulation by both LH and FSH.

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Susan C. Laing, R. G. Gosden, and H. M. Fraser

Summary. Graafian follicle overripening was induced in (1) adult mice by inhibiting the ovulatory discharge of gonadotrophins with antibodies to LH-RH and (2) immature mice by injection of PMSG to promote follicular maturation before the neuroendocrine system was competent to produce an ovulatory stimulus. The numbers of follicles capable of meiotic maturation after exogenous LH were sharply reduced during the period of overripening and there was a corresponding increase in the proportion of cystically enlarged follicles, many of which were undergoing atresia. Freshly ovulated ova were collected after delaying ovulation for 2 days and prepared for cytogenetic study of metaphase chromosomes. The incidence of non-disjunction and other errors was indistinguishable from that of ova collected after spontaneous ovulation during 4-or 5-day cycles.