Comparison of the Potential for Therapeutic Utilities with Gonadotropin-Releasing Hormone Agonists and Antagonists

Vickery, B. H.

doi:10.1210/edrv-7-1-115

Cited by 103 publications

(61 citation statements)

References 103 publications

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“…The disappearance of LH from the blood was similar to that observed after passive immunization of pigs against GnRH (Esbenshade et ai, 1986), indicating that the GnRH antagonist was effective in blocking LH secretion from the pituitary gland. Similar results have been shown for the rat (Grady et ai, 1985;Kartun & Schwartz, 1987), primate (Pineda et ai, 1980) and sheep (Matwijiw & Faiman, 1987) 1983; Jennes et ai, 1984;Vickery, 1986 (Huhtaniemi et ai, 1984a) and in the monkey (Kenigsberg et ai, 1984] when a GnRH antagonist was given for a prolonged period of time. In the present study, FSH concentrations in gilts decreased more slowly over the treatment period and were suppressed to 5% of the values in control animals by the end of the experiment.…”

Section: Discussionsupporting

confidence: 64%

Effects of a gonadotrophin-releasing hormone antagonist on gonadotrophin secretion and gonadal development in neonatal pigs

Ziȩcik¹,

Esbenshade²,

Britt³

1989

Reproduction

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Summary. Male GnRH*HOAc; 1 mg/kg body weight) at 14 days of age. The GnRH antagonist caused LH to decline (P < 0\m=.\01) from 1\m=.\7 ng/ml at 0 h to <0\m=.\5 ng/ml during 4\p=n-\32 h in males and females. Concentrations of FSH in gilts declined slowly from 75 \ m=+-\ 8 to 56 \ m=+-\ 5 ng/ ml (P < 0\m=.\05) at 32 h. In males FSH was low (5\m=.\7 \m=+-\0\m=.\5 ng/ml) at 0 h and did not change significantly.To observe the effect of long-term treatment with GnRH antagonist, 10 male and 10 female pigs, 3 days of age, were treated with saline or 1 mg GnRH antagonist per kg body weight every 36 h for 21 days. Concentrations of LH were reduced (P < 0\m=.\01) to 0\ m=. \ 2\ p=n-\ 0\ m=. \ 4 ng/ml throughout the experimental period in male and female piglets treated with GnRH antagonist. Plasma FSH increased in control females, but remained suppressed (P < 0\m=.\001) in females treated with GnRH antagonist. Treatment with the GnRH antagonist suppressed FSH levels in males on Days 8 and 16 (P < 0\m=.\05), not on Day 24. Treatment of females with the GnRH antagonist did not influence (P > 0\m=.\10)oestradiol-17\g=b\ concentrations. Administration of GnRH antagonist to males suppressed testosterone and oestradiol-17\g=b\ values (P < 0\m=.\01) and reduced testicular weight (P < 0\m=.\01). Concentration of LH/hCG receptors in testes of boars treated with GnRH antagonist was lower (P < 0\m=.\10) than in controls, but concentration of FSH receptors was not affected. Basal and potassium-stimulated release of GnRH from the stalk median eminence and medial basal hypothalamus in vitro did not differ between treatment groups. The amount of residual GnRH in hypothalamic tissue was not different in control gilts and in gilts receiving the GnRH antagonist, but it was lower (P < 0\m=.\05) in boars treated with GnRH antagonist than in control boars.

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Section: Discussionsupporting

confidence: 64%

Effects of a gonadotrophin-releasing hormone antagonist on gonadotrophin secretion and gonadal development in neonatal pigs

Ziȩcik¹,

Esbenshade²,

Britt³

1989

Reproduction

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“…LH-RH antagonists act on the same receptor sites as LH-RH and produce an immediate inhibition of the release of LH, FSH, and sex steroids (3,4,6,7,9,14,15,26,29). The mode of action of LH-RH antagonists varies in some aspects from that of the agonists inasmuch as down-regulation of receptors is not required for an inhibitory effect, which is immediate, due to occupancy of receptors (12,30). Nevertheless, recent evidence from our laboratory showed that prolonged treatment with modem LH-RH antagonist Cetrorelix causes a marked down-regulation of pituitary LH-RH receptors in rats (12,14,15).…”

Section: Chemicals Lh-mentioning

confidence: 98%

Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.

Halmos¹,

Schally²,

Pinski³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Antagonists of luteinizing hormone-releasing hormone (LH-RH), unlike the LH-RH agonists, suppress gonadotropins and sex steroid secretion immediately after administration, without initial stimulatory effects. [Ac-DNal(2)1,D-Ph(4C1)2,D-Pal(3)3,D-Cit6,D-Ala"]LH-RH Cetrorelix) is a modern, potent antagonistic analog of LH-RH. In this study, the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries were investigated after a single injection of Cetrorelix at a dose of 100 ,ug per rat. More than 20 years have passed since the isolation, determination of structure, and synthesis of the hypothalamic hormone controlling the secretion of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary (1). In the past 2 decades, >3000 agonists and antagonists of this decapeptide, called luteinizing hormonereleasing hormone (LH-RH) have been synthesized in view of their expected therapeutic applications (2-4). While repeated chronic administration of LH-RH agonists is required to induce a suppression of LH and FSH and reduction in the levels of sex steroids, similar effects can be obtained after a single injection of LH-RH antagonists (2-7). During the past few years, several highly potent antagonistic analogs of LH-RH containing neutral amino acids D-citrulline or D-homocitrulline at positions 6 and free of edematogenic and anaphylactoid reactions were synthesized by our group and tested in vitro andThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. in vivo (3,4,8,9). Among these analogs [Ac-D-Nal (2) It is well established that chronic administration of LH-RH agonists reduces the number of pituitary receptors for LH-RH, a phenomenon that has been called down-regulation, and induces desensitization of the pituitary gonadotrophs (2-4, 10, 11). Although the principal mechanism of action of LH-RH antagonists was thought to be the competitive blockade of LH-RH receptors, recent data indicate that prolonged treatment with potent LH-RH antagonist Cetrorelix also downregulates pituitary LH-RH receptors in rats (12)(13)(14)(15).The purpose of this study was to investigate the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries after a single injection of Cetrorelix. The pattern of changes in number and affinity of receptors for LH-RH was defined after administration of Cetrorelix followed by in vitro desaturation of LH-RH antagonist from its receptors by chaotropic agents, such as manganous chloride (MnCl2) and ammonium thiocyanate (NH4SCN) (16,17). The use of such techniques allows estimation of total LH-RH receptor concentration and not only of measurable free receptors. The timing of receptor events after administration of Cetrorelix was compared with the sequel of inhibitory effects on gonadotropin and sex steroid secretion in male rats...

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“…In the past few years, a large number of antagonists of luteinizing hormone-releasing hormone (LHRH) has been synthesized and evaluated for therapeutic use (1)(2)(3)(4)(5)(6). These analogues may have various practical applications, including treatment of gynecologic disorders and hormone-sensitive tumors such as prostate and breast cancers (1,2,(7)(8)(9).…”

mentioning

confidence: 99%

Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

Csernus¹

1992

Proc. Natl. Acad. Sci. U.S.A.

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Antagonistic analogues of luteinizing hormone-releasing hormone (LHRH) belong to a class of compounds that can be utilized for treatment of some hormonedependent cancers and gynecologic disorders. Recently, we synthesized and tested a large number of LHRH analogues for LHRH antagonistic activity in the dispersed pituitary cell superfusion system. This fast, reliable, and dynamic system made it possible for us not only to evaluate the relative amounts of an analogue required for suppression of the LH-releasing activity of exogenous LEIRH but also provided quantitative data on dynamic interactions between the LHRH analogue, LHRH receptors, and LH secretion. Three experimental paradigms were used: (i) LHRH responses after preincubation with the antagonist, (ii) pulsatile, simultaneous infusion of LHRH and the antagonistic analogue, and (iW) effects of the analogues on ongoing, continuous LH secretion induced by prolonged stimulation with LHRH. From the data obtained, we conclude that (') the suppression of the LHRH-induced LH release was more effective and longer lasting when the cells were preincubated with the antagonistic analogues before the LBRH stimulation than in the case of simultaneous exposure; (ui) not only the potency but also the time of onset and the duration of the LH release-suppressing activity varied according to the different peptides used, resulting in different shapes of response curves; and (ii) from the accurate data obtained in this dynamic system, quantitative parameters of the in vivo interactions between the antagonists and LBRH on the LHRH receptor can be calculated.In the past few years, a large number of antagonists of luteinizing hormone-releasing hormone (LHRH) has been synthesized and evaluated for therapeutic use (1-6). These analogues may have various practical applications, including treatment of gynecologic disorders and hormone-sensitive tumors such as prostate and breast cancers (1, 2, 7-9). Although chronic administration of LHRH agonists is necessary for inhibition of LH, a single dose of a potent LHRH antagonist is sufficient to evoke the same effect (1, 2, 5-13).

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Comparison of the Potential for Therapeutic Utilities with Gonadotropin-Releasing Hormone Agonists and Antagonists

Cited by 103 publications

References 103 publications

Effects of a gonadotrophin-releasing hormone antagonist on gonadotrophin secretion and gonadal development in neonatal pigs

Effects of a gonadotrophin-releasing hormone antagonist on gonadotrophin secretion and gonadal development in neonatal pigs

Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.

Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

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