In vivo and in vitro Studies on the Opioidergic Control of the Secretion of Gonadotrophin-Releasing Hormone and Luteinizing Hormone in Sexually Immature and Adult Male Rats

1991 ◽  
Vol 53 (6) ◽  
pp. 579-588 ◽  
Author(s):  
Gordana Leposavic ◽  
Patricia O. Cover ◽  
Julia C. Buckingham
Keyword(s):  
Luteinizing Hormone ◽  
Adult Male ◽  
In Vitro Studies ◽  
Male Rats ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone

Evolution of Design and Achievement of Inhibitors of the Luteinizing Hormone-Releasing Hormone as Inhibitors of Ovulation

1982 ◽  
Vol 37 (2) ◽  
pp. 246-259 ◽  
Author(s):  
Karl Folkers ◽  
John Humphries ◽  
Cyril Y. Bowers
Keyword(s):  
Luteinizing Hormone ◽  
Adult Male ◽  
Subcutaneous Tissue ◽  
Female Rats ◽  
Male Rats ◽  
Luteinizing Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Lh Rh

Abstract Detailed structure-activity studies on inhibitors of the luteinizing hormone releasing hormone (LH-RH) have been described. The most potent ovulation inhibitors have substitutions in positions 1, 2, 3, and 6. Currently four basic structural requirements for potent antiovulatory activity are: a D-aromatic amino acid, such as D-Trp or D-Phe, in position 6; a D-Phe residue in position 2; substitutions in positions 1 and 3. For inhibitors based on substitutions in positions 2, 3, and 6, the substitution of a Pro, N-Me-Leu or D-Trp residue in position 3 is equally acceptable, and gives analogues which inhibit ovulation at 750 ^g/rat. For inhibitors based on substitutions in positions 1, 2, 3, and 6, D-Trp appears necessary in position 3 in order for ovulation to be inhibited at 200 μ/rat. Many analogues based on the [residue1, D-Phe2, D-Trp3, D-Trp6]-LH-RH sequence are known which inhibit ovulation at 200 μ/rat. These include those analogues having D- <Glu, Ac-Pro, N-Ac-Hyp and N-Ac-Thr in position 1. The choice between L- or Dresidues in this position is structure dependent (Ac-L-Pro > Ac-D-Pro, D- <Glu >L- <Glu, etc.). In addition, a "protected" N-terminal residue having some polar character appears to be important. Substitution of the dipeptide residue, <Glu-Pro-, into position 1 has produced a new category of potent ovulation inhibitors based on linear peptides longer than decapeptides. Continued studies on other analogues in this later class could provide more potent inhibitors by (1) utilizing new binding sites on or in the vicinity of the LH-RH receptor(s); (2) altering transportation properties; (3) producing "pro-drugs". The substitution of N-Me-Leu into position 7 was not advantageous, presumably because of the presence of bulky D-aromatic amino acids in position 6. Nonapeptide ethylamide analogues also had very low antiovulatory potencies. The analogue [chlorambucil1, Leu2, Leu3, D-Ala6]-LH-RH acted as an agonist, but also inhibited in a modified assay in vitro. Comparative assays measuring the inhibition of LH-RH, and inhibition of ovulation have emphasized other factors of importance to inhibitor design. Although all ovulation inhibitors active at 750 or 200 /μg/rat strongly inhibited in vivo, at a ratio of analogue to LH-RH of 166:1, other analogues of comparable in vitro potency have displayed a range of antiovulatory activities. Similar discrepancies have been observed in the results of in vivo LH-RH inhibition assays. The most potent ovulation inhibitors always inhibited LH-RH at 333:1 in adult male chimpanzees, and at 100:1 in adult male rats. The dissociation of the results of the LH-RH and antiovulatory assays have been rationalized in two cases. The Cpc-analogues were active in inhibiting LH-RH in rats and in chimpanzees when given i.V., but were inactive in rats when given s.c. which is the mode of administration in the antiovulatory assay. The results for inhibition of LH-RH in vivo paralleled the results for inhibition of ovulation, and raised a question as to differences in absorption of peptides though the lipid layers of subcutaneous tissue. The reduced in vivo activities of the L-Trp3 analogues in both the LH-RH and antiovulatory assays suggest an increase in enzymatic inactivation for these compounds. [D-Phe2, Pro3, D-Phe6]-LH-RH can inhibit endogenous LH-RH in the Rhesus monkey and inhibit ovulation. Infusion of [D-Phe2, Pro3, D-Trp6]-LH-RH at 375 ^ug/day for 4 days from a s.c. implanted minipump completely inhibited ovulation in cycling female rats and decreased serum LH levels in castrated rats. In contrast with LH-RH or des-Gly10- [D-Ala6]-LH-RH ethylamide the Pro3 analogue did not block uterine implantation sites of mated rats, indicating a difference in the mechanism of contraception for LH-RH agonists and inhibitors

In vivo Release of Dopamine, Luteinizing Hormone-Releasing Hormone and Thyrotropin-Releasing Hormone in Male Rats Bearing a Prolactin-Secreting Tumor

1987 ◽  
Vol 46 (2) ◽  
pp. 110-116 ◽  
Author(s):  
James L. Voogt ◽  
Wim J. de Greef ◽  
Theo J. Visser ◽  
Jurien de Koning ◽  
Jan T.M. Vreeburg ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Thyrotropin Releasing Hormone ◽  
Male Rats ◽  
Luteinizing Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
In Vivo Release

Stimulatory effect of thyrotrophin-releasing hormone (TRH) on the release of luteinizing hormone (LH) from rat anterior pituitary cells in vitro

1983 ◽  
Vol 61 (2) ◽  
pp. 186-189 ◽  
Author(s):  
Noboru Fujihara ◽  
Masataka Shiino
Keyword(s):  
Luteinizing Hormone ◽  
Anterior Pituitary ◽  
Pituitary Cells ◽  
Thyrotrophin Releasing Hormone ◽  
Releasing Hormone ◽  
Anterior Pituitary Cells ◽  
Lh Release ◽  
Lh Rh

The effect of thyrotrophin-releasing hormone (TRH, 10−7 M) on luteinizing hormone (LH) release from rat anterior pituitary cells was examined using organ and primary cell culture. The addition of TRH to the culture medium resulted in a slightly enhanced release of LH from the cultured pituitary tissues. However, the amount of LH release stimulated by TRH was not greater than that produced by luteinizing hormone – releasing hormone (LH–RH, 10−7 M). Actinomycin D (2 × 10−5 M) and cycloheximide (10−4 M) had an inhibitory effect on the action of TRH on LH release. The inability of TRH to elicit gonadotrophin release from the anterior pituitary glands in vivo may partly be due to physiological inhibition of its action by other hypothalamic factor(s).

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