Effects of a long-acting analogue of LH releasing hormone on human and rat corpora lutea

Richardson, M. C.; Hirji, M R; Thompson, Anna M.; Masson, G. M. C.

doi:10.1677/joe.0.1010163

Cited by 19 publications

(8 citation statements)

References 16 publications

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“…Very high concentrations of mammalian GnRH or its analogues were needed to bind to the receptor or to produce progesterone inhibition. In many studies of the ovarian receptor, the affinity of mammalian GnRH was low (ϳ10 Ϫ6 ) [10,38,39]. Only after cells are in culture for 4 days have low concentrations produced a response [40,41].…”

Section: Discussionmentioning

confidence: 99%

Action of Gonadotropin-Releasing Hormone II on the Baboon Ovary1

Siler-Khodr

Grayson

Eddy

2003

Biology of Reproduction

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The content, binding affinity, and bioactivity of chicken II GnRH (GnRH II) and a stable analogue of GnRH II (GnRH II analogue) in the baboon ovary were studied. Although mammalian GnRH is rapidly degraded by baboon ovarian extracts, we designed a GnRH II analogue that is stable to ovarian enzymatic degradation. This analogue binds to the ovarian membranes with high affinity (41 +/- 3 nM), having 20-fold the affinity of a potent mammalian GnRH analogue. The bioactivity of GnRH II and this GnRH II analogue on the regulation of ovarian progesterone release was compared with that for a potent mammalian GnRH analogue using a baboon granulosa cell culture system. Both GnRH II and GnRH II analogue produced significant inhibition of progesterone release from the granulosa cells (P < 0.03 and P < 0.005, respectively), with a greater reduction observed using the GnRH II analogue. After 24 h in culture, this GnRH II analogue produced a 59% +/- 5% inhibition of progesterone with a concentration as low as 1 nM. Maximal inhibition of 75% +/- 1% was attained with 10 nM GnRH II analogue. The endogenous GnRH II content in the baboon ovary was 5-14 pmoles/g protein. The release of endogenous GnRH II from granulosa cells was observed throughout the 48 h in culture. These studies demonstrated the presence of high enzymatic activity for the degradation of mammalian GnRH in the ovary, whereas this GnRH II analogue was stable. High-affinity binding sites for this GnRH II analogue were also found. GnRH II and this GnRH II analogue can regulate progesterone production from baboon granulosa cells, suggesting that GnRH II is a potent regulator of ovarian function.

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Section: Discussionmentioning

confidence: 99%

Action of Gonadotropin-Releasing Hormone II on the Baboon Ovary1

Siler-Khodr

Grayson

Eddy

2003

Biology of Reproduction

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“…The correlations between GnRH agonist binding and a number of important indices of luteal function suggest a physiological role for GnRH-like factors in the human corpus luteum. INTRODUCTION We have demonstrated specific binding of gonadotrophin-releasing hormone (GnRH) and its agonist analogues to human corpus luteum homo- (Clayton & Huhtaniemi, 1982;Richardson, Hirji, Thompson & Masson, 1984) had certain crucial differ¬ ences in binding assay methodology which probably account for the differences observed (Fraser, Bramley, Miller & Sharpe, 1986). Human luteal GnRH binding sites had an impressive specificity for GnRH and its analogues (Bramley, Menzies & Baird, 1986) and, like rat pituitary and gonadal receptors, required both the N-and C-terminal regions of the molecule for binding.…”

mentioning

confidence: 99%

Specific binding sites for gonadotrophin-releasing hormone, LH/chorionic gonadotrophin, low-density lipoprotein, prolactin and FSH in homogenates of human corpus luteum. II: Concentrations throughout the luteal phase of the menstrual cycle and early pregnancy

Bramley¹,

Stirling²,

Swanston³

et al. 1987

Journal of Endocrinology

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Corpora lutea were obtained from 52 women undergoing laparotomy during the luteal phase of the menstrual cycle. In addition, stromal, thecal and granulosa cell preparations were obtained from seven women undergoing ovariectomy during the late follicular-preovulatory phase of the cycle. The specific binding of a 125I-labelled gonadotrophin-releasing hormone (GnRH) agonist [D-Ser(But)6] GnRH(1-9)-ethylamide (buserelin) and of human chorionic gonadotrophin (hCG), human FSH (hFSH), human prolactin (hPRL) and human low-density lipoprotein (hLDL) to tissue homogenates was measured under optimal conditions. Bound LH/hCG was estimated by elution with acid-citrate buffer, followed by radioimmunoassay of released hormone. Binding of GnRH agonist, though variable, was highest in mid-luteal corpus luteum and high binding was also present in three out of four corpora lutea of pregnancy. Binding of LH/hCG increased significantly with luteinization, reaching maximal levels in the mid-luteal phase before falling significantly. Occupancy of LH receptors by bound LH was relatively constant throughout the luteal phase (10.7-35.3%), but occupancy increased to greater than 90% in corpora lutea from early pregnancy. Binding of hFSH was variable, with only five out of 50 corpora lutea having binding greater than 10 pg/micrograms DNA. Similarly, hPRL binding varied markedly with only six out of 44 having binding greater than 50 pg/micrograms DNA. Binding of LDL was highest in the early- to mid-luteal phases of the cycle. In corpora lutea from all stages of the menstrual cycle (excluding corpora albicantia), GnRH agonist binding was highly correlated with the levels of unoccupied and occupied LH receptors (P less than 0.001; n = 49 and n = 48 respectively) and with LDL receptors (P less than 0.002; n = 49). Binding of GnRH agonist was also correlated with PRL binding (P less than 0.05; n = 21) but not with FSH receptors (P greater than 0.4; n = 25). In addition, LDL binding was associated with PRL (P less than 0.005; n = 21) and FSH receptors (P less than 0.05; n = 25) and with endogenously bound LH (P less than 0.03; n = 48), but not with unoccupied LH receptors (P = 0.8; n = 49). Moreover, in corpora lutea from the mid-luteal phase, there was a strong association between GnRH agonist binding and LDL receptors (P less than 0.02; n = 23). The correlations between GnRH agonist binding and a number of important indices of luteal function suggest a physiological role for GnRH-like factors in the human corpus luteum.

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“…A significant decrease in progesterone secretion was reported following incubation of 1 0 -9~ agonist for 96 h (Tureck et al 1982) but other studies found ~O-'M agonist or native LHRH had no effect on FSH stimulated oestrogen and progesterone secretion (Casper et al 1982). Basal and hCG-stimulated progesterone release from cultured human luteal cells was unaffected by agonist (Casper et al 1984;Richardson et al 1984). Finally, M D-Trp6-LHRH did not alter the gonadotrophinstimulated increase in adenyl cyclase activity in a cell-free system prepared from human corpus luteum cells (Rojas & Asch 1985).…”

Section: Direct Gonadal Effectsmentioning

confidence: 98%

“…Specific binding of iodinated LHRH to human luteal tissue has been reported demonstrating only low affinity binding sites (Popkin et al 1983). Others have failed to find even this low level of binding in human (Clayton & Huhtaniemi 1982;Richardson et al 1984) or non-human primate gonadal tissue (Asch et al 1981).…”

Section: Direct Gonadal Effectsmentioning

confidence: 99%

Clinical aspects of LHRH analogues in gynaecology: a review

McLachlan

Healy

Burger

1986

BJOG

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LHRH agonists are synthetic peptide analogues of hypothalamic luteinizing hormone releasing hormone (LHRH) with superior potency and longer duration of gonadotrophin release. Paradoxically, repeated administration causes pituitary desensitization with diminished gonadotrophin and oestradiol secretion. A state of hypogonadotrophic hypogonadism is reversibly induced; plasma oestrogen can be reduced to castrate levels. LHRH agonists reliably induce anovulation but are unlikely to replace existing contraceptive methods in most normal women. By contrast these agents offer, for the first time, the prospect of inducing a reversible pseudomenopause essentially free of side-effects. LHRH analogues promise to have a profound impact upon the management of a diverse range of oestrogen-dependent gynaecological diseases both benign and malignant. In particular, they may shortly become the gynaecological treatment of choice in endometriosis, as well as becoming part of the management of common gynaecological disorders such as dysfunctional uterine bleeding and uterine fibroids. R.

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Effects of a long-acting analogue of LH releasing hormone on human and rat corpora lutea

Cited by 19 publications

References 16 publications

Action of Gonadotropin-Releasing Hormone II on the Baboon Ovary1

Action of Gonadotropin-Releasing Hormone II on the Baboon Ovary1

Specific binding sites for gonadotrophin-releasing hormone, LH/chorionic gonadotrophin, low-density lipoprotein, prolactin and FSH in homogenates of human corpus luteum. II: Concentrations throughout the luteal phase of the menstrual cycle and early pregnancy

Clinical aspects of LHRH analogues in gynaecology: a review

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