Use of the gonadotrophin-releasing hormone antagonist azaline B to control the oestrous cycle in the koala (Phascolarctos cinereus)

2016 ◽  
Vol 28 (11) ◽  
pp. 1686 ◽  
Author(s):  
K. Ballantyne ◽  
S. T. Anderson ◽  
M. Pyne ◽  
V. Nicolson ◽  
A. Mucci ◽  
...  
Keyword(s):  
Gnrh Antagonist ◽  
Day Treatment ◽  
Dependent Manner ◽  
Phascolarctos Cinereus ◽  
Subcutaneous Injections ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone ◽  
June July ◽  
Dose Dependent ◽  
Cessation Of Treatment

The present study examined the effectiveness of the gonadotrophin-releasing hormone (GnRH) antagonist azaline B to suppress plasma LH and 17β-oestradiol concentrations in koalas and its potential application for oestrous synchronisation. In Experiment 1, single subcutaneous injections of azaline B successfully blocked the LH response to exogenous mammalian (m) GnRH in a dose-dependent manner; specifically, 0 mg (n = 4) did not suppress the LH response, 1 mg azaline B (n = 6) suppressed the LH response for 24 h (P < 0.05), 3.3 mg azaline B (n = 8) suppressed the LH response significantly in all animals only for 3 h (P < 0.05), although in half the animals LH remained suppressed for up to 3 days, and 10 mg azaline B (n = 4) suppressed the LH response for 7 days (P < 0.05). In Experiment 2, daily 1 mg, s.c., injections of azaline B over a 10-day period during seasonal anoestrus (June–July; n = 6) suppressed (P < 0.01) the LH response to mGnRH consecutively over the 10-day treatment period and, 4 days after cessation of treatment, the LH response had not recovered. Experiment 3 was designed to test the efficacy of daily 1 mg, s.c., azaline B over 10 days to suppress plasma LH and 17β-oestradiol concentrations and ultimately synchronise timed return to oestrus during the breeding season. Although azaline B treatment did not suppress basal LH or 17β-oestradiol, oestrus was delayed in all treated females by 24.2 days, but with high variability (range 9–39 days). Overall, the present study demonstrates that the GnRH antagonist azaline B is able to inhibit the LH response in koalas to exogenous mGnRH and successfully delay the return to oestrus. However, although azaline B clearly disrupts folliculogenesis, it has not been able to effectively synchronise return to oestrus in the koala.

Gonadotrophin-releasing hormone (GnRH) overcomes GnRH antagonist-induced suppression of LH secretion in primates

1986 ◽  
Vol 110 (1) ◽  
pp. 145-150 ◽  
Author(s):  
G. R. Marshall ◽  
F. Bint Akhtar ◽  
G. F. Weinbauer ◽  
E. Nieschlag
Keyword(s):  
Gnrh Antagonist ◽  
Receptor Occupancy ◽  
Gnrh Receptor ◽  
Dependent Manner ◽  
Response Curves ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Gonadotrophin Secretion ◽  
Gonadotrophin Releasing Hormone ◽  
Lh Secretion

ABSTRACT If the suppressive effects of gonadotrophin-releasing hormone (GnRH) antagonists on gonadotrophin secretion are mediated through GnRH-receptor occupancy alone, it should be possible to restore serum gonadotrophin levels by displacing the antagonist with exogenous GnRH. To test this hypothesis, eight adult crab-eating macaques (Macaca fascicularis), weight 4·7–7·6 kg, were subjected to the following treatment regimens. A GnRH-stimulation test was performed before and 4, 12 and 24 h after a single s.c. injection of the GnRH antagonist (N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10)-GnRH (ORG 30276). The stimulation tests were performed with 0·5, 5·0 or 50 μg GnRH given as a single i.v. bolus. Blood was taken before and 15, 30 and 60 min after each bolus for analysis of bioactive LH and testosterone. The GnRH-challenging doses were given as follows: 0·5 μg GnRH was injected at 0 and 4 h, followed by 5·0 μg after 12 h and 50 μg after 24 h. One week later, 5·0 μg GnRH were given at 0 and 4 h, followed by 50 μg after 12 h and 0·5 μg after 24 h. Finally, after another week, the GnRH challenges began with 50 μg at 0 and 4 h, followed by 0·5 μg at 12 h and 5·0 μg at 24 h. This design permitted comparison of the LH and testosterone responses with respect to the dose of GnRH and the time after administration of GnRH antagonist. The areas under the response curves were measured and statistical evaluation was carried out by means of non-parametric two-way analysis of variance followed by the multiple comparisons of Wilcoxon and Wilcox. Four hours after the antagonist was injected, the LH and testosterone responses to all three doses of GnRH were suppressed. At the lowest dose of GnRH (0·5 μg) the responses remained reduced even after 24 h, whereas the higher doses of GnRH elicited an LH and testosterone response at 12 and 24 h which was not significantly different from that at 0 h. These data demonstrate that the suppression of LH secretion by a GnRH antagonist in vivo can be overcome by exogenously administered GnRH in a dose- and time-dependent manner, thus strongly supporting the contention that GnRH antagonists prevent gonadotrophin secretion by GnRH-receptor occupancy. J. Endocr. (1986) 110, 145–150

Exogenous gonadotrophin-releasing hormone (GnRH) stimulates LH secretion in male monkeys (Macaca fascicularis) treated chronically with high doses of a GnRH antagonist

1992 ◽  
Vol 133 (3) ◽  
pp. 439-445 ◽  
Author(s):  
G. F. Weinbauer ◽  
P. Hankel ◽  
E. Nieschlag
Keyword(s):  
Gnrh Antagonist ◽  
Prolonged Exposure ◽  
Receptor Occupancy ◽  
Gnrh Receptor ◽  
Dependent Manner ◽  
Releasing Hormone ◽  
Testosterone Secretion ◽  
Stimulation Tests ◽  
Gonadotrophin Releasing Hormone ◽  
Lh Secretion

ABSTRACT We reported previously that after a single injection of a gonadotrophin-releasing hormone (GnRH) antagonist to male monkeys, exogenous GnRH stimulated LH secretion in a time- and dose-dependent manner, indicating that GnRH antagonist-induced blockade of LH secretion resulted from pituitary GnRH receptor occupancy. The present study was performed to investigate whether GnRH can also restore a blockade of LH and testosterone secretion during chronic GnRH antagonist administration. Four adult male cynomolgus monkeys (Macacafascicularis) received daily s.c. injections of the GnRH antagonist [N-Ac-d-pCl-Phe1,2,d-TRP3,d-Arg6,d-Ala10]-GnRH (ORG 30276) at a dose of 1400–1600 μg/kg for 8 weeks. Before the GnRH antagonist was given and during weeks 3 and 8 of treatment, pituitary stimulation tests were performed with 0·5, 5, 50 and 500 μg synthetic GnRH, administered in increasing order at intervals of 24 h. At 8 weeks, a dose of 1000 μg GnRH was also given. All doses of GnRH significantly (P < 0·05) stimulated serum concentrations of bioactive LH (3- to 8-fold) and testosterone (2·6- to 3·8-fold) before the initiation of GnRH antagonist treatment. After 3 weeks of GnRH antagonist treatment, only 50 and 500 μg GnRH doses were able to increase LH and testosterone secretion. Release of LH was significantly (P < 0·05) more elevated with 500 μg compared with 50 μg GnRH. After 8 weeks, only the highest dose of 1000 μg elicited a significant (P < 0·05) rise in LH secretion. Basal hormone levels just before the bolus injection of GnRH were similar (P > 0·10–0·80). This finding eliminated the possibility that the increasing doses of GnRH had primed the pituitary thereby resulting in higher stimulatory effects of the larger doses of GnRH. In conclusion, the present data indicate that, even after prolonged exposure to a GnRH antagonist, the pituitary retains some degree of responsiveness to GnRH. This observation supports the view that the inhibitory effects of chronic GnRH antagonist treatment are also mediated, at least in part, by occupancy of the pituitary GnRH receptor rather than by receptor down-regulation. Journal of Endocrinology (1992) 133, 439–445

Suppression of pituitary-testis function in rats treated neonatally with a gonadotrophin-releasing hormone agonist and antagonist: acute and long-term effects

1989 ◽  
Vol 123 (1) ◽  
pp. 83-91 ◽  
Author(s):  
K.-L. Kolho ◽  
I. Huhtaniemi
Keyword(s):  
Body Weight ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Long Term Effects ◽  
Adult Rats ◽  
Releasing Hormone ◽  
Serum Lh ◽  
Accessory Sex Organs ◽  
Gonadotrophin Releasing Hormone

ABSTRACT The acute and long-term effects of pituitary-testis suppression with a gonadotrophin-releasing hormone (GnRH) agonist, d-Ser(But)6des-Gly10-GnRH N-ethylamide (buserelin; 0·02, 0·1, 1·0 or 10 mg/kg body weight per day s.c.) or antagonist, N-Ac-d-Nal(2)1,d-p-Cl-Phe2,d-Trp3,d-hArg(Et2)6,d-Ala10-GnRH (RS 68439; 2 mg/kg body weight per day s.c.) were studied in male rats treated on days 1–15 of life. The animals were killed on day 16 (acute effects) or as adults (130–160 days; long-term effects). Acutely, the lowest dose of the agonist decreased pituitary FSH content and testicular LH receptors, but with increasing doses pituitary and serum LH concentrations, intratesticular testosterone content and weights of testes were also suppressed (P< 0·05–0·01). No decrease was found in serum FSH or in weights of accessory sex organs even with the highest dose of the agonist, the latter finding indicating continuing secretion of androgens. The GnRH antagonist treatment suppressed pituitary LH and FSH contents and serum LH (P< 0·05–0·01) but, as with the agonist, serum FSH remained unaltered. Testicular testosterone and testis weights were decreased (P <0·01) but testicular LH receptors remained unchanged. Moreover, the seminal vesicle and ventral prostate weights were reduced, in contrast to the effects of the agonists. Pituitary LH and FSH contents had recovered in all adult rats treated neonatally with agonist and there was no effect on serum LH and testosterone concentrations or on fertility. In contrast, in adult rats treated neonatally with antagonist, weights of testis and accessory sex organs remained decreased (P <0·01–0·05) but hormone secretion from the pituitary and testis had returned to normal except that serum FSH was increased by 80% (P <0·01). Interestingly, 90% of the antagonist-treated animals were infertile. It is concluded that treatment with a GnRH agonist during the neonatal period does not have a chronic effect on pituitary-gonadal function. In contrast, GnRH antagonist treatment neonatally permanently inhibits the development of the testis and accessory sex organs and results in infertility. Interestingly, despite the decline of pituitary FSH neonatally, neither of the GnRH analogues was able to suppress serum FSH values and this differs from the concomitant changes in LH and from the effects of similar treatments in adult rats. Journal of Endocrinology (1989) 123, 83–91

Relationship between gonadotrophin subunit gene expression, gonadotrophin-releasing hormone receptor content and pituitary and plasma gonadotrophin concentrations during the rebound release of FSH after treatment of ewes with bovine follicular fluid during the luteal phase of the cycle

1992 ◽  
Vol 8 (2) ◽  
pp. 109-118 ◽  
Author(s):  
J. Brooks ◽  
W. J. Crow ◽  
J. R. McNeilly ◽  
A. S. McNeilly
Keyword(s):  
Follicular Fluid ◽  
Luteal Phase ◽  
Gnrh Receptor ◽  
Mrna Levels ◽  
Α Subunit ◽  
Luteal Regression ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone ◽  
Lh Secretion ◽  
Cessation Of Treatment

ABSTRACT The modulation of FSH secretion at the beginning and middle of the follicular phase of the cycle represents the key event in the growth and selection of the preovulatory follicle. However, the mechanisms that operate within the pituitary gland to control the increased release of FSH and its subsequent inhibition in vivo remain unclear. Treatment of ewes with bovine follicular fluid (bFF) during the luteal phase has been previously shown to suppress the plasma concentrations of FSH and, following cessation of treatment on day 11, a rebound release of FSH occurs on days 12 and 13. When luteal regression is induced on day 12, this hypersecretion of FSH results in an increase in follicle growth and ovulation rate. To investigate the mechanisms involved in the control of FSH secretion, ewes were treated with twice daily s.c. injections of 5 ml bFF on days 3–11 of the oestrous cycle and luteal regression was induced on day 12 with prostaglandin (PG). The treated ewes and their controls were then killed on day 11 (luteal), or 16 or 32h after PG and their pituitaries removed and halved. One half was analysed for gonadotrophin and gonadotrophin-releasing hormone (GnRH) receptor content. Total pituitary RNA was extracted from the other half and subjected to Northern analysis using probes for FSH-β, LH-β and common α subunit. Frequent blood samples were taken and assayed for gonadotrophins. FSH secretion was significantly (P<0.01) reduced during bFF treatment throughout the luteal phase and then significantly (P<0.01) increased after cessation of treatment, with maximum secretion being reached 18– 22h after PG, and then declining towards control values by 32h after PG. A similar pattern of LH secretion was seen after bFF treatment. Pituitary FSH content was significantly (P<0.05) reduced by bFF treatment at all stages of the cycle. No difference in the pituitary LH content was seen. The increase in GnRH receptor content after PG in the controls was delayed in the treated animals. Analysis of pituitary mRNA levels revealed that bFF treatment significantly (P<0.01) reduced FSH-β mRNA levels in the luteal phase. Increased levels of FSH-β, LH-β and α subunit mRNA were seen 16h after PG in the bFF-treated animals, at the time when FSH and LH secretion from the pituitary was near maximum. These results suggest that the rebound release of FSH after treatment with bFF (as a source of inhibin) is related to a rapid increase in FSH-β mRNA, supporting the concept that the rate of FSH release is directly related to the rate of synthesis.

90 Effect of the gonadotrophin-releasing hormone antagonist on the sheep follicular population

2021 ◽  
Vol 33 (2) ◽  
pp. 152
Author(s):  
H. C. Ferreira ◽  
G. B. Vergani ◽  
J. R. Bevilaqua ◽  
N. V. Rodrigues ◽  
M. E. F. Oliveira
Keyword(s):  
Gnrh Antagonist ◽  
Population Data ◽  
Average Diameter ◽  
Placebo Treatment ◽  
Releasing Hormone ◽  
Treatment Administration ◽  
Gonadotrophin Releasing Hormone ◽  
Post Hoc ◽  
Different Doses ◽  
Synchronization Protocol

The present study was designed to study the follicular population dynamics followed or not by treatment with different doses of the GnRH antagonist in sheep. A total of 18 ewes were submitted to short-term oestrus synchronization protocol (Oliveira et al. 2009 Proc. Braz. Congr. Anim. Reprod.). The animals were 2 or 3 years old, multiparous, and had a body score of 3 to 3.5. On Day 7 after ovulation of synchronized oestrus, females were randomly divided into groups (n=6/group) according to the dose of the gonadotrophin-releasing hormone (GnRH) antagonist (Firmagon®, Ferring Pharmaceuticals) subcutaneously administered: G-control: placebo treatment (administration of saline solution); G-lower dose: 215 µg/kg; and G-higher dose: 235 µg/kg of bodyweight. B-mode ultrasound exams of the ovaries were conducted daily from 1 day before treatment with GnRH antagonist until the females showed oestrous behaviour. Ultrasound equipment (MyLab Vet®, Esaote) was used coupled to a transrectal linear transducer with a frequency of 6 and 8MHz to assess the ovarian population. Data were compared between groups, evaluation days, and their interaction by ANOVA with post hoc using Tukey’s test (P&lt;0.05). There was no interaction (P&gt;0.05) between the studied effects (treatments and evaluation days). The number of small follicles (2–3.49mm) was higher (P=0.0002) in the G-lower dose (5.4±0.4) compared with the G-control (4.1±0.3) and G-higher dose (3.5±0.2). The number of large follicles (≥4.5mm) was lower (P=0.01) in the G-higher dose (0.2±0.0) compared with the G-control (0.5±0.1) and G-lower dose (0.4±0.1). The number of medium follicles (3.5– 4.49mm) and the average diameter of the follicles in the 3 categories of diameter did not differ (P&gt;0.05) between groups. The number of medium follicles differed (P=0.0131) between Days 8 and 15 after synchronized oestrus ovulation. The number of large follicles on Day 6 differed (P=0.0002) of Days 8, 9, 10, 11, 12, 16, and 17. The average diameter of medium follicles differed (P=0.0095) between Days 8 and 10. The number of small follicles and the average diameter of small and large follicles did not differ (P&gt;0.05) between days. In conclusion, the administration of the GnRH antagonist at a higher dose in sheep suppressed the development of large tertiary or antral follicles, whereas at a lower dose, it led to an increase in the population of small follicles.

Modulation of Pacemaker Activity by Salmon Gonadotropin-Releasing Hormone (sGnRH) in Terminal Nerve (TN)-GnRH Neurons

2000 ◽  
Vol 83 (5) ◽  
pp. 3196-3200 ◽  
Author(s):  
Hideki Abe ◽  
Yoshitaka Oka
Keyword(s):  
Late Phase ◽  
Gonadotropin Releasing Hormone ◽  
Pacemaker Activity ◽  
Dependent Manner ◽  
Releasing Hormone ◽  
Terminal Nerve ◽  
Bath Application ◽  
Gnrh Neurons ◽  
G Protein Coupled ◽  
Dose Dependent

The terminal nerve (TN)-gonadotropin-releasing hormone (GnRH) neurons project widely in the brain instead of the pituitary and show endogenous pacemaker activity that is dependent on the physiological conditions of the animal. We suggest that the TN-GnRH system may act as a putative neuromodulator that is involved in the regulation of many long-lasting changes in the animal's behavior. In the present study, we find that the pacemaker activity of TN-GnRH neurons is modulated by salmon GnRH (sGnRH), which is the same molecular species of GnRH peptide produced by TN-GnRH neurons themselves. Bath application of sGnRH (2–200 nM) transiently decreased (early phase) and then subsequently increased (late phase) the frequency of pacemaker activity of TN-GnRH neurons in a dose-dependent manner. These biphasic changes of pacemaker activities were suppressed by intracellular application of guanosin 5′-0-(2-thiodi-phosphate) (GDP-β-S). The results suggest that G-protein coupled receptors are present on the cell surface and play a triggering role in modulating the frequency of pacemaker activities in TN-GnRH neurons. Because the TN-GnRH neurons make tight cell clusters with no intervening glial cells, it may be further suggested that GnRH released from GnRH neurons regulates the activities of their own (autocrine) and/or neighboring GnRH neurons (paracrine).

The effect of a potent gonadotrophin-releasing hormone antagonist on ovarian secretion of oestradiol, inhibin and androstenedione and the concentration of LH and FSH during the follicular phase of the sheep oestrous cycle

1990 ◽  
Vol 126 (3) ◽  
pp. 377-384 ◽  
Author(s):  
B. K. Campbell ◽  
A. S. McNeilly ◽  
H. M. Picton ◽  
D. T. Baird
Keyword(s):  
Gnrh Antagonist ◽  
Venous Blood ◽  
Hormone Secretion ◽  
Experimental Period ◽  
Follicular Phase ◽  
Oestrous Cycle ◽  
Blood Samples ◽  
Releasing Hormone ◽  
Inhibitory Feedback ◽  
Gonadotrophin Releasing Hormone

ABSTRACT By selective removal and replacement of LH stimulation we sought to examine the relative importance of inhibin and oestradiol in controlling FSH secretion, and the role of LH in the control of ovarian hormone secretion, during the follicular phase of the oestrous cycle. Eight Finn–Merino ewes which had one ovary removed and the other autotransplanted to a site in the neck were given two injections of a gonadotrophin-releasing hormone (GnRH) antagonist (50 μg/kg s.c.) in the follicular phase of the cycle 27 h and 51 h after luteal regression had been induced by cloprostenol (100 μg i.m.). Four of the ewes received, in addition, i.v. injections of 2·5 μg LH at hourly intervals for 23 h from 42 to 65 h after GnRH antagonist treatment. Ovarian jugular venous blood samples were taken at 10-min intervals for 3 h before and 5 h after the injection of antagonist (24–32 h after cloprostenol) and from 49 to 53 h after antagonist (74–78 h after cloprostenol). Additional blood samples were taken at 4-h intervals between the periods of intensive blood sampling. The GnRH antagonist completely inhibited endogenous pulsatile LH secretion within 1 h of injection. This resulted in a marked decrease in the ovarian secretion of oestradiol and androstenedione (P<0·001), an effect that was reversible by injection of exogenous pulses of LH (P<0·001). The pattern of ovarian inhibin secretion was episodic, but removal or replacement of stimulation by LH had no effect on the pattern or level of inhibin secretion. Peripheral concentrations of FSH rose (P<0·01) within 20 h of administration of the antagonist and these increased levels were maintained in ewes given no exogenous LH. In ewes given LH, however, FSH levels declined within 4 h of the first LH injection and by the end of the experimental period the levels of FSH were similar to those before administration of antagonist (P<0·01). These results confirm that ovarian oestradiol and androstenedione secretion, but not inhibin secretion, is under the acute control of LH. We conclude that oestradiol, and not inhibin, is the major component of the inhibitory feedback loop controlling the pattern of FSH secretion during the follicular phase of the oestrous cycle in ewes. Journal of Endocrinology (1990) 126, 377–384

THE EFFECTS OF TESTOSTERONE AND ITS 5α-REDUCED METABOLITES ON PITUITARY RESPONSIVENESS TO GONADOTROPHIN-RELEASING HORMONE (Gn-RH)

1977 ◽  
Vol 86 (4) ◽  
pp. 728-732 ◽  
Author(s):  
Y. Epstein ◽  
B. Lunenfeld ◽  
Z. Kraiem
Keyword(s):  
Pituitary Gland ◽  
Mature Male ◽  
Male Rats ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone ◽  
Low Levels ◽  
High Doses ◽  
Dose Dependent ◽  
Stimulation Of

ABSTRACT The aim of this study was to investigate effects of androgens on gonadotrophin release in response to gonadotrophin-releasing hormone (Gn-RH) stimulation in vitro. Hemipituitaries of mature male rats were pre-incubated for 90 min with T, DHT, 3α- or 3β-diol (4 ng or 4 μg/ml medium), and the incubation continued for 240 min after adding Gn-RH (1 ng/ml medium). Gn-RH caused a 4-5-fold rise in the secretion of LH and a 2-fold rise in FSH secretion. The effect of the androgens was dose-dependent. At low levels, T and DHT exerted no effect on Gn-RH-stimulated gonadotrophin release, whereas the two androstanediols (3α- and 3β-diol) augmented the Gn-RH stimulation of both gonadotrophins, though preferentially LH. With high doses of androgens, the results obtained showed: a) no effect of T; b) DHT suppression of the Gn-RH-stimulated FSH release; c) suppression of Gn-RH stimulation by 3α- and 3β-diol regarding both LH and FSH. It is concluded that T exerts through its reduced metabolites a feedback effect on the pituitary gland responsiveness to Gn-RH stimulation.

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