Effect of a New LH-RH Analogue (D-Ser(TBU)⁶-EA¹⁰-LH-RH) on Gonadotrophin and Gonadal Steroid Secretion in Men

Abstract

The effect of a new analogue of the gonadotrophin-releasing hormone LH-RH, D-Ser(TBU)⁶-EA¹⁰-LH-RH, on the secretion of LH, FSH, as well as testosterone, oestrone, oestradiol, HGH, prolactin, TSH, and cortisol was studied in normal men. The same subjects were injected intravenously in 4-day intervals with 1.0, 2.5, 5.0, and 10.0 µg of this substance. A significant LH but no FSH release was seen after doses of 1.0 and 2.5 µg LH-RH analogue, while after 5.0 and 10.0 µg dose-dependent increases of LH and imposed elevations of FSH were observed. Peak levels of LH were reached after 30 min, those of FSH after intravenous injection after 120 min. LH and FSH remained elevated for 8–10 h. LH peak levels after 5 µg of LH-RH analogue were comparable to those seen after injection of 100 µg of the decapeptide LH-RH. Following the release of LH and FSH after doses of 5.0 and 10.0 µg LH-RH analogue, there was a late stimulating effect in testosterone and oestradiol secretion. HGH, TSH, prolactin, and cortisol were not influenced by the LH-RH analogue.

Inactivation of Two Hyperactive LH-RH Analogues by Rat Hypothalamic Peptidases

“…The eventual loss of biological activity by the two analogues would indicate, though, that other less specific peptidases can act elsewhere in the decapeptide structure, and have the ability to do so with much less ease than more specific peptidases acting on the -Gly-Leu-and Pro-Gly NH2 bonds. Wiegelmann et al (1976) have already suggested that the increased specific activity of £>-Ser(TBU)6-EA'°-LH-RH may be due to an increased binding affinity for the anterior pituitary LH-RH receptor sites or to decreased enzymic inactivation: the results obtained here would certainly indicate that their second proposal may be the case. The fact that D-Leu6-EA10-LH-RH tends to be more resistant to the hypothalamic enzymes than the £>-Ser(TBU)6EA10-LH-RH but is less active in terms of gonadotrophin-releasing ability (Sandow et al , 1976) would infer that the decreased susceptibility to enzyme action is not the only reason for the analogues' greater LH-and FSH-releasing activity.…”

“…The lack of more positive results from stimulation of FSH release is probably due to tire fact that blood samples were taken from the test animals 15 min after injection of the test solutions, a time at which a maximum LH release in response to LH-RH occurs (Arimura et al, 1972). With FSH release, however, a maximum response to both LH-RH and the DSer(TBU)6-analogue may occur at 60-90 min ( Wiegelmann et al, 1976), which would account for the discrepancy between the LI1 and FSH results. The findings do indicate, though, that both analogues keep their activity much longer than LH-RH in tire presence of potent hypothalamic peptidases, and if tire analogues are compared with each other, the £>-Leu'-EA10-LH-RH is more resistant to this enzyme action than the Z)-Ser(TBU)6-EAl0-LH-RH.…”

“…Recently, a new LH-RH analogue, ¿>-Ser(TBU)6EA10-LH-RH (Hoe 766) (table I) has been synthesized and found to be about 130-150 times more active in the ovarian ascorbic acid assay (Sandow et al, 1976;Rechenberg et al, 1977). Wiegelmann et al (1976) suggest that the increased activity of £)-Ser(TBU)6-EAI0-LH-RH over the original LH-RH decapeptide may be due to an increased affinity for the pituitary receptor sites or decreased enzymic inactivation.…”

Acute Effects of a New Stimulatory Luteinizing Hormone-releasing Hormone Analogue D-Ser(TBU)6-EA10-LRH on the Gonadotrophin and Gonadal Steroid Secretion in Women with Amenorrhoea

“…This analogue has previously proved to be high effective in raising gonadotrophin secretion in experimental animals and normal male volunteers (3, 13, 18). Wiegelmann et al (18) found significant L H increases after injection of 1 and 2.5 pg and dose-dependent LH increases after 5 and 10 pg of the analogue with peaks at 30 min after intravenous administration into normal men. FSH increases were only observed after the 5 and 10 pg doses with peaks after 120 min (18).…”

“…Wiegelmann et al (18) found significant L H increases after injection of 1 and 2.5 pg and dose-dependent LH increases after 5 and 10 pg of the analogue with peaks at 30 min after intravenous administration into normal men. FSH increases were only observed after the 5 and 10 pg doses with peaks after 120 min (18). Kuhl et al (3) found that a subcutaneous injection of 5 pg of the analogue was as effective as 100 pg of LRH.…”