POTENT INHIBITORY ACTIVITY OF [D-LEU<sup>6</sup>, DES-GLY-NH<sub>2</sub>1Q]LHRH ETHYLAMIDE ON LH/hCG AND PRL TESTICULAR RECEPTOR LEVELS IN THE RAT

Auclair, C.; Kelly, Paul A.; Coy, D. H.; Schally, Andrew V.; Labrie, Fernand

doi:10.1210/endo-101-6-1890

Cited by 152 publications

(34 citation statements)

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“…This pattern of response was typical ofthat seen in man (14) and is in marked contrast to the pattern seen in the laboratory rat, perhaps because of the prolonged halflife ofhCG in man when compared with the rat (15,16). Stimulation of the rat testis in vivo leads to a testosterone response within 15 min and a 5-to 10-fold increase by [2][3][4][5][6][7][8][9][10][11][12] h, followed by a decline to normal levels within 1-2 d depending upon the administered dose of gonadotropin (1,2). The serum 17a-hydroxyprogesterone response of the hyperstimulated primate testes was similar to the pattern of testosterone response seen in the rat.…”

Section: Resultsmentioning

confidence: 56%

“…Furthermore, our data on desensitization of the primate LH receptor enhances the possibility of such a mechanism having a physiological role in the control and maintenance of human gonadal function. These data further suggest that negative regulation ofovarian and testicular function by gonadotropin-releasing hormone and its analogues (3,4) should also be effective in man, an approach that offers interesting possibilities for fertility control.…”

Section: Resultsmentioning

confidence: 80%

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Regulation of Primate Testicular Luteinizing Hormone Receptors and Steroidogenesis

Davies¹,

Hodgen²,

Dufau³

et al. 1979

J. Clin. Invest.

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A B S T R A C T The testicular luteinizing hormone (LH) receptors of the rhesus monkey and human have many features in common, including high equilibrium association constant, marked species specificity, and relatively low binding capacity. We have, therefore, used rhesus monkeys as models for human LH-receptor regulation in vivo during gonadotropin treatment. In four adult male monkeys, treated with 10,000 IU human chorionic gonadotropin (hCG), serum and testicular steroidogenic responses were monitored at 24-h intervals during the following 4 d, and LH-receptor concentrations were measured by '25I-hCG binding to 15,000-g particles preparedl from testis biopsy specimens. In treated animals, serum hCG was maximal on day 1 at 322±16 ng/ml and declined to 24.4±2.3 ng/ml by day 4. Serum testosterone was increased threefold during the subsequent 4 d (from 6.5±2.0 to 18.6±4.4 ng/ml) but serum progesterone remained unchanged. In contrast, serum 17a-hydroxyprogesterone increased 12-fold to 5.5±0.5 ng/ml at day 1 and was iincreased fourfold during the subsequent 3 d. The LHreceptor binding capacity of the primate testis was reduiced by 18.3±6.0% on day 1, 51.7+7.4% on day 2, and 45.3±2.4% on day 4. Occupancy of the LH receptors by endogenously bound hCG was significant on day 1 but was negligible by day 4. These data demonstrate that gonadotropin-induced LH-receptor depletion occurs in the rhesus testis and indicate that primate gonadotropin receptors are susceptible to the regulatory processes recently described in the rat. In addition, the simultaneous and disproportionate accumulation of 17a-hydroxyprogesterone indicates that 17,20-desmolase was rate-limiting under these conditions in the primate testis Leydig cell.

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 80%

Regulation of Primate Testicular Luteinizing Hormone Receptors and Steroidogenesis

Davies¹,

Hodgen²,

Dufau³

et al. 1979

J. Clin. Invest.

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“…A marked inhibition of pituitary and gonadal function that occurs after chronic administration of the D-Trp6 analog of luteinizing hormone-releasing hormone (LH-RH) and other LH-RH agonists (1)(2)(3)(4)(5)(6)(7)(8)(9) leads to a chemical castration and makes possible an additional approach for the treatment of sex hormone-dependent tumors (10,11). In previous studies we have shown that chronic administration of [D-Trp6]LH-RH suppressed prostate tumor growth in two different rat models (12,13).…”

mentioning

confidence: 99%

Long-acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of [D-Trp6]luteinizing hormone-releasing hormone from injectable microcapsules.

Redding¹,

Schally²,

Tice³

et al. 1984

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

132

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Intramuscular injection of [6-D-tryptophan]-luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) inmicrocapsules of poly(DL-lactide-co-glycolide), designed to release a controlled dose of the peptide over a 30-day period, decreased the weights of androgen-dependent Dunning prostate tumors in rats and suppressed serum testosterone levels more effectively than daily subcutaneous administration of equivalent or double doses of unencapsulated last from a few minutes to several hours. These modes of administration, with fluctuating blood levels of the peptide, may not achieve the optimal pharmacological effects. Consequently, higher-dosage regimens and greater frequency of administration may be needed to obtain these effects. A peptide administered by a controlled delivery system that would lead to a constant release over a prolonged period of time could provide a continuous biological effect. Recently, a polymer of poly(DL-lactide-co-glycolide) (PLG) has been used to formulate microcapsules with steroids for long-acting contraceptive delivery systems (22)(23)(24) MATERIALS AND METHODSMale (Copenhagen x Fisher) F1 rats bearing the androgendependent well-differentiated R3327H Dunning rat prostate adenocarcinoma were provided by Norman Altman (Papanicolaou Cancer Research Institute, Miami, FL). Approximately 150 days after the transplantation, the tumors were palpable and the experiment began. Tumors were measured weekly with microcalipers and tumor volumes were calculated as previously described (12, 13

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“…Desensitization of the gonads to gonadotropins is regarded as an important mechanism for the reduction in the sex hormone concentration caused by GnRH agonists (Auclair et al, 1978;Tcholakian et al, 1978;Fraser and Baird, 1987). Desensitization of the gonads is often associated with high serum gonadotropin concentrations (Bhasin & Swerdoff, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…GnRH agonists both stimulate and inhibit gonadal function depending on the dose and duration of treatment in man and laboratory animals (Auclair et al, 1978;Rivier et al, 1979;Bhasin & Swerdloff, 1986). The inhibition of gonadal function caused by chronic treatment with these potent GnRH agonists, i.e.…”

Section: Potentmentioning

confidence: 99%

Endocrinological Studies on TAP-144-SR, a Sustained-Release Formulation of a Potent GnRH Agonist (D-Leu6-(des-Gly10-NH2)-GnRH Ethylamide), in male Rats.

et al. 1990

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The paradoxical effects of TAP-144-SR, a biodegradable sustained-release formulation of a potent GnRH agonist (TAP-144, leuprolide acetate) were evaluated in male rats by comparing its potency with that of TAP-144 solution.A single sc injection of TAP-144-SR (equivalent to 0.1 mg/kg/day as TAP-144), prepared by encapsulating the agonist in microcapsules of copoly (DLlactic/glycolic acid), suppressed serum levels of androgens, and the levels remained suppressed for 4 weeks.The potency of the paradoxical effects of TAP-144-SR was evaluated 4 weeks after treatment by comparing it with that of TAP-144 solution administered daily for 4 weeks. Both daily injections of TAP-144 solution and a single injection of TAP-144-SR (equivalent to 0.02, 0.2 or 2 mg/kg/day as TAP-144) decreased the weight of the testes, prostates and seminal vesicles in a dose-dependent manner in a 4-week assay in male rats. TAP-144-SR was more effective than TAP-144 solution in reducing these organ weights. Serum and pituitary concentrations of LH and FSH and serum testosterone levels were also lower in TAP-144-SR-treated than in TAP-144 solution-treated rats. These results indicate that the paradoxical effects were more extensive upon TAP-144-SR treatment, suggesting that maintaining constant serum TAP-144 levels results in more extensive desensitization of the pituitary and testes. These results also suggest advantages of TAP-144-SR over TAP-144 solution in both efficacy and convenience as an anti-prostatic tumor agent.

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POTENT INHIBITORY ACTIVITY OF [D-LEU⁶, DES-GLY-NH₂1Q]LHRH ETHYLAMIDE ON LH/hCG AND PRL TESTICULAR RECEPTOR LEVELS IN THE RAT

Cited by 152 publications

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Regulation of Primate Testicular Luteinizing Hormone Receptors and Steroidogenesis

Regulation of Primate Testicular Luteinizing Hormone Receptors and Steroidogenesis

Long-acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of [D-Trp6]luteinizing hormone-releasing hormone from injectable microcapsules.

Endocrinological Studies on TAP-144-SR, a Sustained-Release Formulation of a Potent GnRH Agonist (D-Leu6-(des-Gly10-NH2)-GnRH Ethylamide), in male Rats.

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POTENT INHIBITORY ACTIVITY OF [D-LEU6, DES-GLY-NH21Q]LHRH ETHYLAMIDE ON LH/hCG AND PRL TESTICULAR RECEPTOR LEVELS IN THE RAT

Cited by 152 publications

References 0 publications

Regulation of Primate Testicular Luteinizing Hormone Receptors and Steroidogenesis

Regulation of Primate Testicular Luteinizing Hormone Receptors and Steroidogenesis

Long-acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of [D-Trp6]luteinizing hormone-releasing hormone from injectable microcapsules.

Endocrinological Studies on TAP-144-SR, a Sustained-Release Formulation of a Potent GnRH Agonist (D-Leu6-(des-Gly10-NH2)-GnRH Ethylamide), in male Rats.

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POTENT INHIBITORY ACTIVITY OF [D-LEU⁶, DES-GLY-NH₂1Q]LHRH ETHYLAMIDE ON LH/hCG AND PRL TESTICULAR RECEPTOR LEVELS IN THE RAT