Delay of Puberty and Inhibition of Reproductive Processes in the rat by a Gonadotropin-Releasing Hormone Agonist Analog

Johnson, Eddie; Gendrich, R.; White, W. F.

doi:10.1016/s0015-0282(16)41963-1

Cited by 119 publications

(44 citation statements)

References 11 publications

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“…Similar to the original observations of delay of puberty in rats with these agents (Johnson, Gendrich & White, 1976) we have shown a prevention of oestrus in prepubertal bitches. Although pregnancy was not achieved at the first oestrus after cessation of treatment, it is possible that normal fertility may occur at the next oestrus.…”

Section: Introductionsupporting

confidence: 88%

Long-term reversible suppression of oestrus in bitches with nafarelin acetate, a potent LHRH agonist

McRae¹,

Roberts²,

Worden³

et al. 1985

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Summary. Adult A return to oestrus was observed in all 3 bitches between 3 and 18 weeks after cessation of treatment: 2 of the bitches mated at those times and produced normal litters.Another 2 bitches were similarly treated with 32 \ g=m\ ganalogue/day; they were mated at the oestrus at start of treatment and dosing was continued for about 63 days. One of the bitches conceived and produced a normal litter. Nafarelin acetate treatment begun during anoestrus resulted in an induced heat 1\p=n-\2weeks after the start of treatment. The induced heat consisted of pro-oestrous vaginal discharge, oestrous vaginal cytology, and ovulation (judged by increased circulating levels of progesterone). Three bitches mated at the induced heat and treated for the normal duration of gestation did not litter. Nafarelin treatment of 3 bitches before puberty did not induce signs of oestrus and prevented the occurrence of oestrus through 18 months of treatment. The first oestrus in these bitches occurred 3\ m=. \ 5\ p=n-\ 4 months after cessation of treatment, but mating at that time did not result in pregnancy. These studies have established the feasibility of and dosage requirement for the use of the LHRH agonist as a contraceptive in the bitch.

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Section: Introductionsupporting

confidence: 88%

Long-term reversible suppression of oestrus in bitches with nafarelin acetate, a potent LHRH agonist

McRae¹,

Roberts²,

Worden³

et al. 1985

Reproduction

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“…In the ovary, desensitization of adenylate cyclase has been observed in Graafian follicles and corpus luteum after endogenous elevations of gonadotropin secretion during the estrus cycle and pregnancy in rats and rabbits (19)(20)(21), as well as after injection of hCG (22). Finally, the inhibition of ovarian function (23), ovulation (24), and endocrine-dependent mammary tumors (25) …”

Section: Resultsmentioning

confidence: 99%

Gonadotropin-induced regulation of luteinizing hormone receptors and desensitization of testicular 3':5'-cyclic AMP and testosterone responses.

Hsueh¹,

Dufau²,

Catt³

1977

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

204

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Administration of human chorionic gonadotropin (hCG) to male rats was followed by dose-related changes in luteinizing hormone (LH) receptors in the testis. After treatment with a low dose of hCG (10 international units), the number of LHI receptors increased slightly over the first 24 hi, then fell to about 30o of the control value. These changes occurred with occupancy of only 8% of the available receptors, and were initially accompanied by increased basal testosterone production in vitro with no change in basal 3':5'-cyclic AMP production. (3,4). Recently, we have observed a sustained loss of testicular LH receptors in rats after systemic administration of ovine LH or hCG (6). The ability of gonadotropins to induce loss of their own receptors is analogous to the regulation of receptors for insulin, somatotropin (growth hormone), thyrotropin releasing hormone, and catecholamines by the respective hormones (7-13). Loss of receptors in adrenergic systems has been shown to be accompanied by refractoriness or desensitization of adenylate cyclase,.indicating that changes in hormone receptors influence the regulation of target cell responses (12,13). In this report, we describe the functional relations between negative regulation of LH/hCG receptors and desensitization of cyclic AMP and steroidogenic responses in the testes of rats treated with exogenous gonadotropin. MATERIALS AND METHODSAdult male rats (250-300 g), obtained from Charles River Laboratories, Wilmington, Mass., were given subcutaneous injections of hCG [Pregnyl, Organon; 3000 international units (IU)/mg], dissolved in 0.5 ml of phosphate-buffered saline containing 0.1% bovine serum albumin. Animals were killed by decapitation at selected intervals, sera were collected for hCG assay, and testes were decapsulated for determination of tissue-bound hCG, available LH/hCG receptor sites, and responsiveness to gonadotropin in vitro. Highly purified hCG (CR 117,10,000 IU/mg) for radioiodination and receptor binding assays was provided by Dr. R. Canfield, Columbia University, New York.Decapsulated testes were homogenized in phosphate-buffered saline for 1 min in a tissue blender at 13,000 rpm. After centrifugation at 20,000 X g for 15 min, the pellet was resuspended in 40 ml of phosphate-buffered saline, centrifuged again, and rehomogenized in phosphate-buffered saline at a concentration of 100-200 mg/ml. Testicular LH/hCG receptors were determined by incubating serial dilutions of homogenate with a saturating concentration of labeled hormone, using 1251-labeled purified hCG prepared by enzymatic radioiodination (14). The following reagents were added to 12 X 75 mm glass tubes: 100 IAI of phosphate-buffered saline containing 0.1% bovine serum albumin with or without 100 IU of hCG; 50 0d of 125I-labeled hCG (200,000 cpm, 5-10 ng) in phosphate-buffered saline-0.1% bovine serum albumin; and 100 Al of testis homogenate. Three serial 1:1 dilutions of the homogenate were incubated in triplicate at room temperature for 16-18 hr, then diluted with 5 ml of i...

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“…It is well known that consecutive administration of the potent LHRH agonist leuprorelin [D-Leu6-(des-Gly10-NH2)-LHRH ethylamide] (Fujino et al, 1974), suppresses gonadotropin release and reduces function of the ovary and testis in rats (Johnson et al, 1976a;Rippel and Johnson, 1976;Hsueh and Jones, 1981;Okada et al, 1983a;Okada et al, 1989). These effects of leuprorelin suggest the possibility that this agent can be used in the treatment of sex hormone-dependent diseases, such as sex hormone-dependent tumors or endometriosis.…”

mentioning

confidence: 99%

Histological Studies on the Therapeutic Effect of Sustained-Release Microspheres of a Potent LHRH Agonist (Leuprorelin Acetate) in an Experimental Endometriosis Model in Rats.

et al. 1990

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The therapeutic effect of sustained-release microspheres of a potent LHRH agonist (leuprorelin acetate) on experimental endometriosis in female rats was examined histologically.Endometriosis was produced in rats by autotransplantation of endometrial tissue obtained from the left uterine horn into the renal subcapsular space.In the nontreated rats, the transplants were well established and had formed large cysts containing fluid.The walls of the cysts were composed of epithelium and stroma resembling that of normal endometrium.In the rats which received the microspheres of leuprorelin acetate, growth of the transplant was markedly suppressed as evidenced by the reduced size of the cystic cavity and the flattened and pyknotic epithelium. Also, the uterine and ovarian weight decreased significantly.In the ovariectomized rats, growth of the transplant was also markedly suppressed, and the uterine weight decreased.The present results clearly indicate that a single injection of the sustainedrelease microspheres of leuprorelin acetate markedly suppresses growth of the transplant and produces uterine and ovarian atrophy in the rats.

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Delay of Puberty and Inhibition of Reproductive Processes in the rat by a Gonadotropin-Releasing Hormone Agonist Analog

Cited by 119 publications

References 11 publications

Long-term reversible suppression of oestrus in bitches with nafarelin acetate, a potent LHRH agonist

Long-term reversible suppression of oestrus in bitches with nafarelin acetate, a potent LHRH agonist

Gonadotropin-induced regulation of luteinizing hormone receptors and desensitization of testicular 3':5'-cyclic AMP and testosterone responses.

Histological Studies on the Therapeutic Effect of Sustained-Release Microspheres of a Potent LHRH Agonist (Leuprorelin Acetate) in an Experimental Endometriosis Model in Rats.

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