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The minimal structural requirements for gonadotrophin releasing activity were studied with fragments of a highly active analogue of luteinizing hormone releasing hormone (LH-RH), [d-Ser(But)6]LH-RH(1–9)nonapeptide-ethylamide (Hoe 766). All fragments are related to the C-terminal structure of LH-RH and have increased enzyme stability. Ovulation in phenobarbitone-blocked rats was induced with a median effective dose/rat, of 1·9 μg of the (3–9)-heptapeptide, Trp-Ser-Tyr-d-Ser(But)-Leu-Arg-Pro-ethylamide and 6·8, 18·0 and 38·3 μg for the (4–9), (5–9) and (6–9) fragments respectively. The (3–9)-heptapeptide and (4–9)-hexapeptide induced release of LH and FSH in phenobarbitone-blocked rats with a ratio similar to that of LH-RH. Degradation of LH-RH by enzyme preparations of liver, kidney and hypothalamic or anterior pituitary tissue was not modified by addition of the (3–9)-heptapeptide fragment. The organ distribution of the 125I-labelled (3–9)-heptapeptide fragments was similar to LH-RH, but not to Hoe 766. The peptide accumulated in liver and kidney, but was eliminated from the anterior pituitary gland 15 min after i.v. injection, whereas Hoe 766 showed progressive accumulation in the pituitary gland (tissue: plasma ratio = 6·6 after 60 min). In contrast to C-terminal fragments of LH-RH, the corresponding fragments of nonapeptide analogues retained significant biological activity, and the minimal structural requirements for LH release may be related to the C-terminal sequence of LH-RH.
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Immunization against luteinizing hormone releasing hormone (LH-RH) in adult male rats produced a progressive decline in LH and FSH in the circulation to low or non-detectable levels. d-Serine-tertiary-butyl6,des-glycine-NH2 10 LH-RH ethylamide is an analogue of LH-RH having highly active LH-RH properties in the normal rat. Because it is also immunologically different from LH-RH it can stimulate gonadotrophin release from the anterior pituitary gland of rats immunized against LH-RH without interference from the antibody. The analogue stimulated LH and FSH release in rats 15 weeks after immunization against LH-RH when antibody titre was highest, and after long-term (35 weeks) immunization against LH-RH. d-Serine-tertiary-butyl6,des-glycine-NH2 10 LH-RH ethylamide and related analogues are therefore potentially useful for reversing the effects of immunization against LH-RH.
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ABSTRACT
Continuous administration of LH-releasing hormone (LHRH) agonists is an effective method of suppressing testosterone secretion in the male. The effect of the LH-releasing hormone (LHRH) agonist, buserelin, administered to bulls by constant infusion from osmotic minipumps was studied. In one experiment with four treated and one control bull, 109 pg buserelin/day were administered for 22 days. Immediately after implantation, serum testosterone concentrations rose from below 35 nmol/l to 35-105 nmol/l, and all four buserelin-infused bulls showed increased testosterone secretion during the treatment period. After removal of the minipumps, testosterone concentrations decreased to pretreatment levels. In a second experiment bulls were infused for 42 days (four treated and one control), and identical results were obtained. Testosterone secretion was stimulated (52-87 nmol/l serum) during the entire treatment period. These results demonstrate that conditions for stimulation of the pituitary-testicular axis may vary between species. Infusion of low doses of LHRH-agonists in bulls has an extended stimulatory effect without immediate desensitization of gonadotrophin release.
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Male rats aged 30 days were injected once daily for between 1 and 7 days with 50 ng (d-serine t-butyl6, des-glycine-NH2 10) luteinizing hormone releasing hormone ethylamide (LH-RH agonist), and pituitary and testicular function were assessed. Treatment for 7 days significantly (P < 0·02) inhibited maturational increases in the pituitary content and serum concentration of gonadotrophins, testicular luteinizing hormone (LH)-receptor concentration and the testicular capacity to secrete testosterone; the pituitary content and serum concentration of prolactin, the hypothalamic content of LH-RH and testicular weight were unaffected. In rats treated with LH-RH agonist, the initial (2 to 3 days) reduction in testicular LH-receptors and the capacity to secrete testosterone probably resulted from acutely raised levels of LH in the blood, whilst later effects may have resulted from the apparently chronic reduction in serum gonadotrophin levels. The latter may reflect a decrease in pituitary responsiveness to repeated stimulation with LH-RH agonist. Despite the extensive loss of testicular LH-receptors and diminished responsiveness, the concentration of HCG which significantly (P < 0·05) increased testosterone secretion by the testis in vitro was the same (2 pmol/l) as that for testes from control rats.
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ABSTRACT
The use of pituitary desensitization by an LHRH agonist (buserelin) to examine pituitary-testicular function was investigated in a New World primate. Six adult male marmoset monkeys were injected s.c. with an LHRH agonist implant (1·5 mg in a rod 0·5 cm long). Pharmacokinetics, determined by radioimmunoassay of urinary buserelin, revealed a rapid initial release of the agonist followed by a steady decline during a 200-day period. The LHRH agonist treatment resulted in a rapid initial rise in plasma LH followed by a return to mean values similar to those seen in the control samples by 7 days after implantation. Using the present protocol, no evidence of subsequent pituitary desensitization or suppression of testicular function was observed, plasma concentrations of LH and testosterone remaining within the normal range during the 200-day study period.
In contrast, pituitary-testicular function was suppressed in the male marmoset after blockade of pituitary LHRH receptors by an LHRH antagonist. Five adults were treated with a single s.c. injection of the antagonist [Ac-d-Nal(2)1,d-pCl-Phe2,d-Trp3,d-Ser(Rha)6,AzGlyNH2 10]-LHRH at a dose of 300 μg/kg. The LHRH antagonist induced a marked suppression of plasma LH and testosterone by 6–8 h, the low levels being maintained for 24–48 h.
These results show that, whereas treatment with an LHRH antagonist can inhibit pituitary-testicular function in the male marmoset, it may be that desensitization cannot be induced by the LHRH agonist used.
Journal of Endocrinology (1990) 125, 233–239
