GnRH analogues—agonists and antagonists

doi:10.1016/j.anireprosci.2005.05.005

Animal Reproduction Science

Volume 88, Issues 1–2, August 2005, Pages 115-126

https://doi.org/10.1016/j.anireprosci.2005.05.005 Get rights and content

Abstract

GnRH analogues have achieved widespread clinical use for the control of reproduction in animals. Over 2000 analogues of GnRH have been developed and tested over the last 30 years. Paradoxical anti-fertility effects are seen when the more potent agonists are delivered continuously to animals. The evaluation of agonist potency depends largely on the model used and wide varying potencies are reported for the same agonist. The design of analogues has centered on improving the receptor-binding and subsequent activation for agonists. Antagonists have been produced with strong receptor binding but without activation. Deslorelin is classified as a superagonist, with a potency perhaps 100 times that of GnRH. The interactions between agonist potency, dose and duration of treatment largely determine whether pro- or anti-fertility effects are induced. Due to the peptide nature of the synthetic analogues oral administration and potential gastrointestinal enzymatic degradation poor bioavailability results necessitating a parenteral delivery system. Some GnRH antagonists have been associated with significant histamine release, inhibiting their widespread use. More recently, antagonists have been developed that avoid this side effect without compromising potency. However the GnRH antagonist development has lagged behind that of the agonists, in part related to their high cost of production. In conclusion, GnRH agonists have achieved widespread clinical use in animals for controlling reproduction in either pro- or anti-fertility roles, yet antagonist development has been slower.

Introduction

GnRH is the master hormone controlling mammalian reproductive physiology. Following the elucidation of the amino acid sequence of porcine GnRH (Schally et al., 1971) and the subsequent realisation that the decapeptide sequence was conserved across all mammals, interest then centered on developing modifications to the sequence in the expectation of greater potency and significant pro-fertility effects. The paradoxical anti-fertility effects of these more potent analogues were soon discovered and described. Agonists with the strongest receptor binding and activation along with slower degradation rates yielded the greatest anti-fertility effects. Antagonists with strong receptor-binding properties but without receptor activation became useful in avoiding the initial acute release (‘flare effect’) of gonadotrophins intrinsically associated with the agonists. Clarification of the biological properties of the GnRH agonists therefore required definition of the interactions between agonist potency, dose and duration of treatment. It is these attributes, which largely determine whether pro- or anti-fertility effects are induced.

Section snippets

Historical perspectives

The development of more potent GnRH analogues (both agonist and subsequently antagonist) depended largely on the improvements made in the science of peptide chemistry, notably in the area of peptide synthesis. Technological advances in solid phase peptide synthesis allowed for the automated production of short peptides (Merrifield, 1966). It has been estimated that over 2000 different analogs of GnRH have subsequently been synthesised (Karten and Rivier, 1986). The development has centered on

Potency evaluation models for GnRH analogues

To assess the biological response of an agonist requires consideration of its receptor affinity, in vivo absorption, distribution, and resistance to degradation and elimination profile. Consequently, the method used to ascertain an agonist's potency should be appreciated when considering comparison with other agonists. Assay systems are usually based on either in vivo or in vitro assessments of the agonist and these models have been reviewed in detail (Karten and Rivier, 1986, Hahn et al., 1984a

Structural and functional correlates

The primary structure of mammalian GnRH is given in Fig. 1. A fundamental feature of agonists is the substitution of l-isomers with d-isomers. Receptor-binding and activation (agonist) are properties of the NH₂- and COOH-terminal domains; although both are involved in binding. The terminal NH₂-domain residues are predominantly responsible for receptor activation (His² and Trp³, especially). Substitution of residues outside of the NH₂-terminal domain can affect receptor activation, possibly

Deslorelin—a GnRH superagonist

Peptides are often cited in journal publications, but non-uniformity in naming can lead to confusion as to the precise molecular structure. The correct nomenclature for expressing peptides has been briefly reviewed (Grant, 1995). Nomenclature, as recommended by The International Union of Pure and Applied Chemists (IUPAC–IUB, 1985) aims to prevent development of ambiguous peptide names. The prefix des-A^b refers to the deletion of an amino acid residue (A) at a particular position in the peptide (

Agonist delivery systems

The interactions between GnRH agonist potency, dose and duration of treatment largely determine whether pro- or anti-fertility effects are induced. The general approaches to controlled peptide delivery have been reviewed (Pitt, 1987). Long-term continuous delivery has been achieved in cattle through the use of mini-osmotic pumps (Gong et al., 1996), biocompatible cholesterol implants (D’Occhio et al., 2002, D’Occhio et al., 1996, Herschler and Vickery, 1981), polymer coated matrices (D’Occhio

Route of administration

Early studies of GnRH agonists primarily used parenteral routes of administration (i.v., s.c., i.m.). GnRH agonists are susceptible to gastrointestinal peptidase degradation, making oral administration unsuitable with only 0.1% bioavailability (Conn and Crowley, 1991, Chrisp and Goa, 1990). Intra-nasal administration is relatively inefficient and variable, with only 4–21% being available relative to s.c. or i.v. injection (Chrisp and Goa, 1990, Gudmundsson et al., 1984), necessitating frequent

Future directions for agonist development

The application of GnRH agonists to the treatment of human prostate cancer has proved to be beneficial with prolonged patient survival. Prostate cancer is one of the most common tumours of men and the pharmaceutical therapeutic market is estimated to be in the billions of dollar range. This market along with the control of stimulation programs for human assisted reproduction has led to the commercialisation of many agonists (Table 2).

The stimulatory actions of the agonists on the pituitary

GnRH antagonist overview

The development of highly potent antagonists has lagged behind that of the progress made with the superagonists. The essential features required of antagonists are a high affinity for the GnRH receptor (binding but without activation), low histaminergic properties and resistance to enzymatic degradation (Karten and Rivier, 1986). Evaluation of the inhibitory actions of the antagonists can be achieved using similar systems to the agonists. Pituitary cell cultures can be used to assay for a lack

Acknowledgements

This work was funded in part by the Dairy Research and Development Corporation UM-064 research grant.

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Cardiovascular (CV) disease is the leading cause of death in women, and it may manifest differently than in men, in part related to sex-specific CV risk factors. In females, assisted reproductive technologies (ARTs) are commonly used to treat infertility, and they utilize controlled ovarian stimulation involving the administration of exogenous sex hormones. ARTs, and especially controlled ovarian stimulation, have been associated with an increased pregnancy and short-term CV risk, although the long-term CV implications of these treatments in individuals treated with ARTs and their offspring remain unclear. This review endeavors to provide a comprehensive examination of what is known about the relationship between ART and CV outcomes for females treated with ARTs, as well as their offspring, and recommendations for future research. Novel insights into female-specific CV risk factors are critical to reduce the disproportionate burden of CV disease in Canadian women. ART has revolutionized reproductive medicine, offering hope to millions of individuals with infertility worldwide, and a further understanding of the CV implications of this important sex-specific CV risk factor is warranted urgently.
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To date, there have been no studies testing the capacity of GnRH analogs and respective doses to induce a LH peak in sheep. In this sense, the present study aimed to evaluate the capacity of different synthetic forms and doses of GnRH in inducing LH release in sheep, and the effect of GnRH administration at timed artificial insemination (TAI) on pregnancy per timed-AI. In experiment 1, ewes (n = 40) received an intravaginal device (IVD) of medroxyprogesterone acetate (MPA; 60 mg) for 7 d and prostaglandin F_2α analog on Day 5. On Day 7, the ewes were allocated randomly into one of eight groups (n = 5/group), which received a GnRH analog at a specific dose, as follows: lecirelin (12.5 or 25 μg), gonadorelin (50 or 100 μg), buserelin acetate (4.2 or 8.4 μg), or deslorelin (375 or 750 μg). Blood samples for LH determination were obtained at 0, 2, 4, and 6 h after GnRH and the IVDs were removed after the last blood collection. The maximal LH concentration induced by gonadorelin at doses of 50 μg and 100 μg (12.0 ± 2.4 ng/mL and 28.6 ± 7.1 ng/mL, respectively) was lower (P < 0.05) than serum LH induced by 8.4 μg of buserelin (78.9 ± 12.9 ng/mL), 375 μg and 750 μg of deslorelin (75.6 ± 7.4 ng/mL and 72.1 ± 10.6 ng/mL, respectively) and 12.5 μg and 25 μg of lecirelin (73.3 ± 17.8 ng/mL and 61.6 ± 5.9 ng/mL, respectively). However, the maximal LH concentration induced by 4.2 μg of buserelin (49.4 ± 5.9 ng/mL) was similar (P > 0.05) to the 100 μg of gonadorelin. The total release of LH (area under the curve – AUC) after treatment with 50 μg of gonadorelin (31.7 ± 5.9 ng h/mL) was lower (P < 0.05) than after other agonists. In a second experiment, 330 ewes were treated with IVD containing MPA for 7 d. Simultaneously with IVD removal, 250 μg of cloprostenol and 200 IU of eCG were administered. Then, ewes were assigned randomly to either no further treatment (control); or to receive 4.2 μg of buserelin acetate (GnRH group) at cervical TAI, which was performed with fresh semen 54 h after IVD withdrawal in all the animals. Higher pregnancy per timed-AI was observed for GnRH (50.3 %) compared to control (40.7 %). We conclude that buserelin acetate (8.4 μg), lecirelin (12.5 and 25 μg) and deslorelin (375 and 750 μg) induced a greater stimulatory effect on LH secretion than gonadorelin treatment. Furthermore, buserelin acetate treatment at TAI increased pregnancy per timed-AI in ewes previously treated with MPA and eCG.
Influence of GnRH analog and dose on LH release and ovulatory response in Bos indicus heifers and cows on day seven of the estrous cycle
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This study evaluated the influence of GnRH analogs (gonadorelin vs. buserelin) and doses (single vs. double) on LH release and ovulatory response in Bos indicus (Nelore) females on Day 7 of the estrous cycle. Cycling heifers and non-lactating cows were pre-synchronized: Day −10: progesterone (P4) implant insertion plus 2 mg of estradiol benzoate; Day −2: implant removal and 0.53 mg of cloprostenol sodium (PGF); Day 0: 25 μg of lecirelin (GnRH). Over four replicates, heifers (n = 57) and cows (n = 53) that ovulated to the GnRH treatment on Day 0, having a visible corpus luteum (CL) and a dominant follicle (DF) ≥ 8.5 mm, were allocated to receive the following GnRH treatments on Day 7: G-Single (100 μg of gonadorelin); G-Double (200 μg of gonadorelin); B-Single (10 μg of buserelin); and B-Double (20 μg of buserelin). At GnRH treatment, a P4 implant was inserted in heifers (0.5 g) and cows (1 g). Ultrasound examinations were done on Days −10, −2, 0, 2, 7, 9, 12, and 14 to evaluate DF diameter, ovulation and presence of CL. Blood samples were collected on Day 7 at 0, 2, and 4 h from GnRH treatment, to evaluate circulating P4 and LH concentrations. On Day 12, the P4 implant was removed, females received two PGF treatments (24 h apart), and 2 d later, 25 μg of GnRH was given to start the next replicate. In both heifers and cows, P4 concentrations were elevated on Day 7, and similar among groups (3.9 and 4.2 ng/mL, respectively). In heifers, buserelin induced greater LH peak (9.5 vs. 2.6 ng/mL; P < 0.01) and greater ovulation (88.9 [24/27] vs. 16.7% [5/30]; P < 0.01) than gonadorelin treatments, regardless of the dose. Similarly, in cows, buserelin induced greater LH peak than gonadorelin (9.9 vs. 4.9 ng/mL; P < 0.01). However, ovulation was only increased in cows from the B-Double group (90.9% [10/11]), whereas in the other groups the ovulatory response was similar (35.7% [15/42]). Regardless of treatment, heifers had similar P4 concentrations (P = 0.22), but smaller DF (P < 0.01) than cows on Day 7. Only in G-Double group the LH peak was lower (P = 0.05) in heifers than in cows, with no difference within other groups. In heifers, but not in cows, the single dose of buserelin resulted in high ovulatory response, equivalent to that produced by the double dose. In conclusion, in Bos indicus heifers and cows on Day 7 of the cycle, with elevated P4 concentrations, buserelin induced greater LH release and ovulatory response than gonadorelin treatments. Double doses increased the LH release, however, only resulted in greater ovulation in females treated with buserelin. Finally, although circulating P4 concentrations did not differ between parities, heifers were more likely to ovulate in response to a GnRH-induced LH peak than cows.
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^☆: This paper is part of the special issue entitled: GnRH in Domestic Animal Reproduction, Guest Edited by K.L. Macmillan and Jin-Gui Gong.

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GnRH analogues—agonists and antagonists☆

Abstract

Introduction

Section snippets

Historical perspectives

Potency evaluation models for GnRH analogues

Structural and functional correlates

Deslorelin—a GnRH superagonist

Agonist delivery systems

Route of administration

Future directions for agonist development

GnRH antagonist overview

Acknowledgements

Anal. Biochem.

Theriogenology

Biochem. Biophys. Res. Commun.

Theriogenology

Anim. Reprod. Sci.

Biochem. Biophys. Res. Commun.

Anim. Reprod. Sci.

Biochem. Biophys. Res. Commun.

Trends Endocr. Metab.

Contraception

J. Pharm. Sci.

Life Sci.

Regul. Toxicol. Pharmacol.

New antagonists of LHRH. IIInhibition and potentiation of LHRH by closely related analogues

Int. J. Pept. Prot. Res.

Metabolic clearance and plasma half-disappearance time of d-Trp6 and exogenous luteinsing hormone-releasing hormone

Clin. Endocr. Metab.

Metabolism of [d-Trp6]LHRH

Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinsing hormone releasing hormone (SB-75)

Neuroendocrinology

NafarelinA review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions

Drugs

Receptor-binding affinity of gonadotropin-releasing hormone analogs: analysis by radioligand-receptor assay

Endocrinology

Gonadotropin-releasing hormone and its analogues

N. Engl. J. Med.

Gonadotrophin releasing hormone analogues

Ann. Clin. Res.

Analogs of luteinising hormone releasing hormone with increased biological activity produced by D-amino acid substitution in position 6

J. Med. Chem.

Advantages and disadvantages in the use of GnRH analogues in an IVF program

Controlled, reversible suppression of estrous cycles in beef heifers and cows using agonists of gonadotropin-releasing hormone

J. Anim. Sci.

Enzymatic degradation of LHRH and analogs

Suppression in the secretion of follicle-stimulating hormone and luteinizing hormone, and ovarian follicle development in heifers continuously infused with a gonadotropin-releasing hormone agonist

Biol. Reprod.

Peptides, Synthetic

Biological assays utilized to characterize LHRH and its analogs