Suppression and recovery of pituitary gonadotrophin secretion in intact and orchidectomized rats treated neonatally with a gonadotrophin-releasing hormone antagonist

1989 ◽  
Vol 122 (2) ◽  
pp. 519-526 ◽  
Author(s):  
K.-L. Kolho ◽  
I. Huhtaniemi
Keyword(s):  
Gnrh Antagonist ◽  
Recovery Period ◽  
Neonatal Rat ◽  
Male Rats ◽  
Minor Role ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Serum Lh ◽  
Gonadotrophin Secretion ◽  
Gonadotrophin Releasing Hormone

ABSTRACT Suppression of neonatal rat pituitary-testis function by gonadotrophin-releasing hormone (GnRH) antagonists results in delayed sexual maturation and infertility. Since the mechanism is not understood, the acute effects of a GnRH antagonist on gonadotrophin secretion in neonatal male rats has been studied in more detail. Treatment with a GnRH antagonist analogue, N-Ac-d-Nal(2)1,d-p-Cl-Phe2,d-Trp3,d-hArg(ET2)6,d-Ala10-GnRH (2 mg/kg per day) on days 1–10 of life had prolonged effects on gonadotrophin secretion; serum LH and FSH recovered in 1 week, but the pituitary content took 2 weeks to recover. Likewise, LH and FSH responses to acute in-vivo stimulation with a GnRH agonist were still suppressed 1 week after the treatment. Interestingly, a rebound (86% increase) in basal serum FSH was found 16 days after treatment with the antagonist. Whether testis factors influence gonadotrophin secretion during treatment with the GnRH antagonist and/or in the subsequent recovery period was also assessed. Neonatal rats were castrated on days 1, 5 or 10 of the 10-day period of antagonist treatment. Orchidectomy on days 1 and 5 only marginally affected gonadotrophin secretion. When orchidectomy was performed at the beginning of the recovery period, no effects on pituitary recovery were seen within 1 week of castration. After 16 days, serum LH and FSH in the antagonist-treated and control castrated rats were equally increased but the pituitary contents of the antagonist-treated rats were still suppressed. Finally, the effect of testosterone treatment on the recovery of gonadotrophin secretion after antagonist suppression was studied in intact and orchidectomized animals. The rats were implanted with testosterone capsules for 7 days after treatment with the GnRH antagonist in the neonatal period. Testosterone suppressed pituitary LH contents similarly in all groups of animals, but had no effects on serum LH. Paradoxically, serum FSH was suppressed 50% by testosterone in intact and castrated antagonist-treated rats and in castrated controls but not in intact controls. These findings suggest that suppression of FSH by testosterone is only seen in neonatal animals with low endogenous levels of this androgen, whether due to GnRH antagonist treatment or castration. It is concluded that neonatal treatment with a GnRH antagonist results in prolonged suppression of LH and FSH secretion, that testis factors play only a minor role in pituitary modulation during the antagonist suppression and that more disturbances are observed in the post-treatment recovery of FSH secretion than in that of LH. Journal of Endocrinology (1989) 122, 519–526

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

Acute and chronic effects of a gonadotrophin-releasing hormone antagonist on pituitary and testicular function in monkeys

1985 ◽  
Vol 104 (3) ◽  
pp. 345-354 ◽  
Author(s):  
F. Bint Akhtar ◽  
G. F. Weinbauer ◽  
E. Nieschlag
Keyword(s):  
Gnrh Antagonist ◽  
Primate Species ◽  
Testicular Function ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Serum Lh ◽  
End Of Treatment ◽  
Complete Disruption ◽  
Gonadotrophin Releasing Hormone ◽  
The Individual

ABSTRACT The effects of a potent gonadotrophin-releasing hormone (GnRH) antagonist, (N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10)-GnRH (Org 30276), on pituitary and testicular function of adult macaque monkeys were investigated. After a study to find the correct dose in castrated monkeys, five intact adult male animals were treated with daily s.c. injections of 5 mg antagonist for 9 weeks. The treatment resulted in an immediate decline in serum LH and testosterone in three out of five animals. The two hormones remained suppressed during the 9-week treatment period. Testosterone and LH responses to a bolus injection of GnRH (50 μg i.v.) were blunted or abolished during the antagonist treatment. Testicular volumes decreased markedly and ejaculates obtained at the end of treatment were azoospermic or contained only few dead sperm. Histological examination of the testes showed complete disruption of seminiferous epithelium in these animals. A decrease of body weight was observed in the treated animals. When the treatment was ceased, all inhibitory effects of GnRH antagonists were reversible. In the other two animals no consistent suppression of pituitary or testicular function could be observed during this period, nor was a doubling of the treatment dose for a further 8 weeks capable of fully suppressing endocrine and seminal parameters in these monkeys. It is concluded that GnRH antagonist treatment is capable of rapidly decreasing serum LH and testosterone and disrupting spermatogenesis in this primate species. Suppression effected by antagonist treatment is more rapid than that caused by GnRH agonists. The individual responses to the tested doses, however, vary markedly. J. Endocr. (1985) 104, 345–354

Effects of administration of testosterone and gonadotrophin-releasing hormone (GnRH) antagonist on basal and GnRH-stimulated gonadotrophin secretion in orchidectomized monkeys

1991 ◽  
Vol 129 (3) ◽  
pp. 363-370 ◽  
Author(s):  
S. Khurshid ◽  
G. F. Weinbauer ◽  
E. Nieschlag
Keyword(s):  
Gnrh Antagonist ◽  
Combined Treatment ◽  
High Dose ◽  
Similar Response ◽  
Primate Model ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Gonadotrophin Secretion ◽  
Gonadotrophin Releasing Hormone ◽  
Range Study

ABSTRACT The aim of the present investigation was to investigate the effects of testosterone on basal and gonadotrophin-releasing hormone (GnRH)-stimulated gonadotrophin secretion in the presence and absence of a GnRH antagonist in a non-human primate model (Macaca fascicularis). Orchidectomized animals were used in order to avoid interference by testicular products other than testosterone involved in gonadotrophin feedback. Concomitant and delayed administration of testosterone at doses that provided serum levels either within the intact range (study 1) or markedly above that range (study 2) did not influence the suppression of basal gonadotrophin release induced by the GnRH antagonist during a 15-day period. To assess the possible effects of testosterone treatment at the pituitary level (study 3) GnRH stimulation tests (500 μg) were performed before and on days 8 and 15 of treatment with high-dose testosterone and GnRH antagonist alone or in combination. Testosterone alone abolished the gonadotrophin responses to exogenous GnRH observed under pretreatment conditions. With GnRH antagonist alone, an increased responsiveness (P <0·05) to GnRH was seen on day 8 and a similar response compared with pretreatment on day 15. Following combined treatment with GnRH antagonist and testosterone, GnRH-induced gonadotrophin secretion was consistently lower compared with that after GnRH antagonist alone (P <0·05), but was increased compared with that after testosterone alone (P<0·05). Thus, in the presence of a GnRH antagonist the feedback action of testosterone on LH and FSH was diminished. The present work in GnRH antagonist-treated orchidectomized monkeys demonstrates that (I) unlike in rats, testosterone fails to stimulate FSH secretion selectively, (II) the negative feedback action of testosterone on GnRH-stimulated LH and FSH secretion is altered in the presence of a GnRH antagonist and (III) GnRH antagonists induce a transient period of increased responsiveness of gonadotrophic hormone release to exogenous GnRH. The observation that a GnRH antagonist reduced the feedback effects of testosterone suggests that testosterone action on pituitary gonadotrophin release, at least in part, is mediated via hypothalamic GnRH. Journal of Endocrinology (1991) 129, 363–370

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

Hyperprolactinaemia attenuates the gonadotrophin releasing hormone receptor response to gonadectomy in rats

1982 ◽  
Vol 95 (2) ◽  
pp. 267-274 ◽  
Author(s):  
R. N. Clayton ◽  
L. C. Bailey
Keyword(s):  
Female Rats ◽  
Male Rats ◽  
Serum Prolactin ◽  
Intact Male ◽  
Adult Rats ◽  
Releasing Hormone ◽  
Receptor Response ◽  
Serum Lh ◽  
Gonadotrophin Releasing Hormone ◽  
Qualitative Index

Measurement of pituitary gonadotrophin releasing hormone (Gn-RH) receptor content provides a qualitative index of prior exposure of the pituitary gland to endogenous Gn-RH. The effect of moderate hyperprolactinaemia (serum prolactin = 95–250 μg/l), achieved with three pituitary grafts beneath the renal capsule, on the pituitary Gn-RH receptor content and serum LH responses to gonadectomy of adult rats has been studied. In males the presence of hyperprolactinaemia for 7 days completely prevented the increase in Gn-RH receptor content 3 days after castration and inhibited the serum LH rise by 45%. By 6 days after castration, Gn-RH receptors had increased in the hyperprolactinaemic castrated animals but values were 33% lower than in sham-grafted controls, while the serum LH increase was attenuated by 30%. Pituitary LH content was also lower in grafted castrated animals 6 days after castration. Hyperprolactinaemia for 3 weeks had no effect on Gn-RH receptors or pituitary LH content of intact male rats, although basal serum LH was decreased by 50%. Hyperprolactinaemia also attenuated the increases in Gn-RH receptors, serum LH and pituitary LH which occurred 6 days after ovariectomy in female rats. In all experiments the pituitary content of prolactin was reduced by 80–90% in animals bearing pituitary grafts. These results suggest that hyperprolactinaemia restricts the Gn-RH receptor response to gonadectomy by decreasing endogenous hypothalamic Gn-RH secretion.

Sexual maturation of male rats treated postnatally with a gonadotrophin-releasing hormone antagonist

1988 ◽  
Vol 116 (2) ◽  
pp. 241-246 ◽  
Author(s):  
K.-L. Kolho ◽  
H. Nikula ◽  
I. Huhtaniemi
Keyword(s):  
Sexual Maturation ◽  
Gnrh Antagonist ◽  
Prolactin Receptor ◽  
Male Rats ◽  
Delayed Puberty ◽  
Testis Weight ◽  
Adult Rats ◽  
Releasing Hormone ◽  
Treatment Groups ◽  
Gonadotrophin Releasing Hormone

ABSTRACT Postnatal secretion of gonadotrophin by male rats was inhibited by a potent gonadotrophin-releasing hormone (GnRH) antagonist analogue (N-Ac-4-Cl-d-Phe1,4-Cl-d-Phe2,d-Trp3,d-Phe6,des-Gly10-GnRH-d-alanylamide; Org 30039; 2 mg/kg s.c. twice daily) on days 1–5, 6–10, 11–15 or 16–20 of life. The onset of puberty was determined by monitoring the separation of the preputium from the glans penis, i.e. balanopreputial separation (BPS). Rats treated on days 1–5 matured normally, whereas all treatments between days 6 and 20 delayed BPS (P < 0·01). In adult rats (between 110 and 160 days of age), testis weights were reduced by 21–35% (P < 0·01) in groups treated between days 1 and 15, although weights of the accessory sex glands were normal. Testicular FSH receptors were decreased by 31–47% (P < 0·01) in all treatment groups, whereas the LH receptor content was decreased only in rats treated between days 1 and 5 (18%; P < 0·05) and prolactin receptor content decreased only in rats treated up to day 10 (31–33%; P < 0·01). Concentrations of serum testosterone, LH and FSH, and pituitary contents of LH and FSH were unaffected by neonatal treatment with Org 30039. Animals treated with Org 30039 had reduced fertility which was most pronounced (88%; P < 0·01) in rats treated between days 1 and 5. However, motile sperm were detectable in the cauda epididymis of the infertile rats. In conclusion, postnatal gonadotrophin deprivation induced with a GnRH antagonist for different 5-day periods during the first 15 days of life delayed puberty, reduced adult testis weight and impaired fertility. Some effects of the antagonist were largely independent of the timing of gonadotrophin suppression. Other effects, including suppression of testicular LH and prolactin receptors and the delay in the onset of puberty, were found only in the younger and older treatment groups respectively. These findings emphasize the importance of neonatal hypothalamic-pituitary-gonadal function for subsequent sexual maturation. J. Endocr. (1988) 116, 241–246

Can testosterone alone maintain the gonadotrophin-releasing hormone antagonist-induced suppression of spermatogenesis in the non-human primate?

1994 ◽  
Vol 142 (3) ◽  
pp. 485-495 ◽  
Author(s):  
G F Weinbauer ◽  
A Limberger ◽  
H M Behre ◽  
E Nieschlag
Keyword(s):  
Gnrh Antagonist ◽  
High Dose ◽  
Partial Recovery ◽  
Primate Model ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Testosterone Substitution ◽  
Gonadotrophin Releasing Hormone ◽  
Group 2 ◽  
Human Primate

Abstract The combination of gonadotrophin-releasing hormone (GnRH) antagonist and delayed testosterone substitution provides a promising approach towards male contraception. However, the GnRH antagonists used clinically so far cause side-effects and have to be administered continuously. We therefore used the non-human primate model to see whether the GnRH antagonist cetrorelix (which exhibits a favourable benefit-to-risk ratio in terms of anti-gonadotrophic action in normal men) induces complete and reversible suppression of spermatogenesis and whether GnRH antagonist-induced suppression of spermatogenesis can be maintained by testosterone alone. Four groups of adult cynomolgus monkeys (Macaca fascicularis; five per group) were injected daily with 450 μg cetrorelix/kg ([N-acetyl-d-2-naphthyl-Ala1, d-4-chloro-Phe2, d-pyridyl-Ala3, d-Cit6, d-Ala10]-GnRH). Group 1 received the GnRH antagonist for 7 weeks followed by vehicle administration for another 11 weeks; group 2 was treated with GnRH antagonist for the entire 18 weeks with each animal receiving a single testosterone implant during weeks 11–18 to restore the ejaculatory response to electrostimulation; group 3 received the GnRH antagonist for 18 weeks and testosterone buciclate (TB) was injected during week 6 of GnRH antagonist treatment; group 4 was subjected to GnRH antagonist administration for 7 weeks and received TB (200 mg/animal) during week 6. Under GnRH antagonist treatment alone serum concentrations of testosterone were suppressed. TB maintained testosterone levels two- to fourfold above baseline levels in groups 3 and 4 and prevented the recovery of LH secretion for about 20 weeks after GnRH antagonist withdrawal, whereas inhibin levels increased significantly from week 8 onwards. Group 2 animals were azoospermic during weeks 12–18 of GnRH antagonist administration. The TB-replaced groups developed azoospermia or became severely oligozoospermic. Quantitation of cell numbers by flow cytometry during weeks 6 and 18 revealed that TB (groups 3 and 4) had prevented a further decline of germ cell production compared with group 2 but had maintained the spermatogenic status present at week 6 (onset of TB substitution). All inhibitory effects of cetrorelix and/or TB were reversible after cessation of treatment. These findings demonstrate that cetrorelix reversibly inhibits spermatogenesis in a non-human primate model. Although TB maintained the GnRH antagonist-induced suppression of spermatogenesis, azoospermia was not achieved. This latter effect may reflect either a direct spermatogenesis-supporting effect of the high dose of TB or the partial recovery of inhibin secretion (indirectly reflecting FSH secretion) or a combination of both. Thus, maintenance of GnRH antagonist-induced spermatogenic inhibition by testosterone alone appears theoretically possible. Whether this regimen will, however, permit the induction of sustained azoospermia remains to be seen, preferably in human studies. Journal of Endocrinology (1994) 142, 485–495

Testosterone maintains pituitary and serum FSH and spermatogenesis in gonadotrophin-releasing hormone antagonist-suppressed rats

1986 ◽  
Vol 108 (1) ◽  
pp. 101-107 ◽  
Author(s):  
M. A. Rea ◽  
G. R. Marshall ◽  
G. F. Weinbauer ◽  
E. Nieschlag
Keyword(s):  
Serum Testosterone ◽  
Treated Group ◽  
Male Rats ◽  
Testis Weight ◽  
Releasing Hormone ◽  
Serum Lh ◽  
Hypophysectomized Rats ◽  
Gonadotrophin Releasing Hormone ◽  
Vehicle Treated Control

ABSTRACT Groups of adult male rats were treated continuously for 30 days with either vehicle or the potent gonadotrophin-releasing hormone (GnRH) antagonist, (N-Ac-d-Nal(2)1,d-pCl-Phe2,d-Trp3,d-hArg (Et2)6,d-Ala10)-GnRH (RS 68439; 35 μg/day). In addition, groups of vehicle- and antagonist-treated rats received s.c. testosterone implants sufficient to maintain serum testosterone concentrations 3·5- to 5-fold higher than those of vehicle-treated control rats. After 30 days of antagonist treatment serum LH, FSH and testosterone concentrations were at or below the detection limits of their respective assays and pituitary FSH content and GnRH receptor binding were reduced, relative to control animals, by 77 and 98% respectively. Testis weight in antagonist-treated rats was reduced by 75% and spermatogenesis was suppressed to an extent comparable to that observed in hypophysectomized rats. Testosterone, which caused a 40% reduction in serum FSH relative to control animals, prevented the antagonist-induced fall in both serum and pituitary FSH, but not GnRH receptors, below that observed in the vehicle plus testosterone-treated group. Furthermore, spermatogenesis in the antagonist plus testosterone-treated group was indistinguishable from that observed in control animals. It is concluded that testosterone is capable of maintaining serum and pituitary FSH levels in vivo, under conditions which presumably render the pituitary insensitive to hypothalamic GnRH. J. Endocr. (1986) 108, 101–107

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