Inhibition of the Pre-Ovulatory Proestrous Gonadotropin Surge, Ovulation and Pregnancy with a Peptide Analogue of Luteinizing Hormone Releasing Hormone

Corbin, Alan; Cw, Beattie

doi:10.3109/07435807509053836

Cited by 81 publications

(39 citation statements)

References 15 publications

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“…In addition, leiomyomas in women of reproductive age are commonly treated with hormone ablative therapies such as GnRH agonists [11]. Treatment with these agents results in the shutdown of ovarian hormone production by inhibiting the release of gonadotropins by the pituitary and the halting of follicular development in ovaries [12,13].…”

Section: Introductionmentioning

confidence: 99%

Altered Hormonal Responsiveness of Proliferation and Apoptosis During Myometrial Maturation and the Development of Uterine Leiomyomas in the Rat1

Burroughs

Fuchs-Young

Davis

et al. 2000

Biology of Reproduction

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Uterine leiomyomas are responsive to the ovarian steroids, estrogen and progesterone; however, a mechanistic understanding of the role of these hormones in the development of this common gynecologic lesion remains to be elucidated. We have used the Eker rat uterine leiomyoma model to investigate how ovarian hormones regulate or promote the growth of these tumors. Proliferative and apoptotic rates were quantitated in normal uterine tissues and leiomyomas in response to endogenous ovarian steroids. In 2- to 4-mo-old animals, cell proliferation in the normal uterus corresponded with high serum levels of steroid hormones during the estrous cycle, and apoptosis occurred in the rat uterus in all cell types following sharp, cyclical declines in serum hormone levels. It is interesting that the responsiveness of uterine mesenchymal cells changed between 4 and 6 mo of age, with significant decreases in both proliferative and apoptotic rates observed in myometrial and stromal cells of cycling animals. Leiomyomas displayed much higher levels of proliferation than did age-matched myometrium; however, their apoptotic index was significantly decreased in comparison with normal myometrium. This disregulation between proliferative and apoptotic responses, which were tightly regulated during ovarian cycling in the normal myometrium, may contribute to the disruption of tissue homeostasis and underlie neoplastic growth of these tumors.

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Section: Introductionmentioning

confidence: 99%

Altered Hormonal Responsiveness of Proliferation and Apoptosis During Myometrial Maturation and the Development of Uterine Leiomyomas in the Rat1

Burroughs

Fuchs-Young

Davis

et al. 2000

Biology of Reproduction

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“…In addition to the ability of such analogs to stimulate or inhibit LH and FSH release, both antagonist and superagonist analogs have potent antigonadal and antifertility actions, suggesting that these compounds may be useful as reversible contraceptive agents (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Receptor-Binding Affinity of Gonadotropin-Releasing Hormone Analogs: Analysis by Radioligand-Receptor Assay

1980

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A recently developed radioligand-receptor assay for pituitary gonadotropin-releasing hormone (GnRH) receptors, employing a radioiodinated superagonist analog as the ligand, was used to analyze the receptor-binding properties of several GnRH analogs. This receptor assay is specific for GnRH and related peptides with agonist or antagonist activity. All superagonist analogs had equilibrium association constants (Ka) between 4-and 8-fold greater than that of the natural GnRH decapeptide (Ka = 6.6 x 10 8 M~'). Conversely, weak agonists and inactive analogs were bound with affinities 0.003-0.05 times that of GnRH. Weak antagonists, such as [D-Phe 2 ]GnRH and [DPhe 2 , D-Phe 6 ]GnRH, had lower binding constants, while the most potent antagonist, [D-pGlu 1 , D-Phe 2 , D-Trp 3 ' 6 ]GnRH, exhibited 8-fold higher affinity than GnRH for pituitary receptors. There was a general positive correlation between receptor-binding affinity and relative biological activity, whether agonist or antagonist, for the several GnRH analogs tested. However, the observed increases in receptor affinity (4-to 8-fold) did not account for the 30-to 100-fold greater LH-releasing activity of the superagonists. The relatively high bioactivity of such analogs in comparison to their binding constants is attributable to their increased resistance to degradation in addition to their increased binding affinity. Comparison of receptor binding data with structural features of the GnRH analogs revealed that the three Nterminal amino acids are critical for receptor recognition, while the C-terminal des-Gly 10 ethylamide modification does not enhance binding affinity. The radioligand assay provides a rapid and reliable method for evaluating the contribution of receptorbinding affinity to the agonist or antagonist actions of new GnRH analogs. This procedure also permits systematic determination of the structural requirements for GnRH receptor recognition. (Endocrinology 106: 1154, 1980)

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“…At a single dose of 400 µg, Peptides 1, 2 and 5 exhibited considerable intrinsic activity (Table 2). Corbin & Beattie (1975) also reported that Peptide 3 possessed agonistic as well as antagonistic activity, but the agonistic activity was not strong enough to induce ovulation in Nembutal-blocked pro-oestrous rats, even when the i.v. dose was as high as 100 µg.…”

Section: Rat Experimentsmentioning

confidence: 99%

“…Several analogues based on the original decapeptide sequence have been synthesized and found to have weak but significant inhibitory properties (Vilchez-Martinez et ai, 1974a). However, it was the discovery of several agonistic analogues of LH-RH that were far more potent than the natural hormone that enabled a variety of relatively strongly active antagonistic peptides to be developed with structures based on the super-active analogues (Coy et ai, 1973(Coy et ai, , 1974VilchezMartinez et ai, 1974b;de la Cruz et ai, 1975de la Cruz et ai, , 1976aCorbin & Beattie, 1975). Most of these ana¬ logues, however, possess residual inherent LH-RH activities, which may overcome their LH releaseinhibiting activities, resulting only in partial blockade or no blockade of ovulation in animals.…”

Section: Introductionmentioning

confidence: 99%

Suppression of LH-RH-induced ovulation in hamsters and rats by synthetic analogues of LH-RH

Nishi

Coy

et al. 1976

Reproduction

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20\m=.\9ng/ml) to suppress ovulation. However, the extent of suppression of ovulation did not correlate with the serum LH levels < 5 ng/ml. The incidence ofovulation induced by the intrinsic LH-RH activity of some of these analogues was similar to or greater than that resulting from administration of LH-RH plus analogue, suggesting that the activity of LH-RH itself was eliminated by pretreatment with the analogues.

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Inhibition of the Pre-Ovulatory Proestrous Gonadotropin Surge, Ovulation and Pregnancy with a Peptide Analogue of Luteinizing Hormone Releasing Hormone

Cited by 81 publications

References 15 publications

Altered Hormonal Responsiveness of Proliferation and Apoptosis During Myometrial Maturation and the Development of Uterine Leiomyomas in the Rat1

Altered Hormonal Responsiveness of Proliferation and Apoptosis During Myometrial Maturation and the Development of Uterine Leiomyomas in the Rat1

Receptor-Binding Affinity of Gonadotropin-Releasing Hormone Analogs: Analysis by Radioligand-Receptor Assay

Suppression of LH-RH-induced ovulation in hamsters and rats by synthetic analogues of LH-RH

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