In Vivo Effects of a Potent GnRH Antagonist ORG 30850

Abstract

OBJECTIVE: Our purpose was to determine the pituitary responsiveness to exogenous GnRH in GnRH antagonist-suppressed ovariectomized monkeys.

METHODS: This was a prospective experimental non-human primate study performed at the research laboratories of The Jones Institute for Reproductive Medicine . Seventeen long-term ovariectomized cynomolgus monkeys were studied.

INTERVENTIONS: The GnRH antagonist ORG 30850 was administered to long-term ovari ectomized monkeys assigned to one of six groups: single subcutaneous injections in group A (n = 4), 0.3 mg/kg; group B (n = 4), 1.0 mg/kg; and group C (n = 3), 3.0 mg/kg; and six consecutive daily subcutaneous injections in group D (n = 2), 0.3 mg/kg; group E (n = 2), 1.0 mg/kg; and group F (n = 2), 3.0 mg/kg. Blood samples were collected daily from 10 days before treatment until 22 days after treatment, then weekly for 6 additional weeks. Intravenous GnRH stimulation tests (10 μglkg) were performed on the day after vehicle injection (control) and the day after completion of treatment(s), and then at weekly intervals. The main outcome measures were serum levels of LH, FSH, and ORG 30850.

RESULTS: Administration of ORG 30850 resulted in suppression (P < .05) of LH and FSH in all treatment groups. Long-term suppression (greater than 2 weeks) was evident in all primates receiving a cumulative dose of at least 1 mg/kg. Paradoxically, the responsiveness of the pituitary to exogenous GnRH was accentuated during the time of maximal tonic LHlFSH suppression.

CONCLUSIONS: ORG 30850 is a potent long-acting GnRH antagonist. Furthermore, the present in vivo demonstration of heightened pituitary responsiveness to exogenous GnRH em phasizes the divergent mechanisms of action of GnRH antagonists and GnRH agonists . (J Soc Gynecol Invest 1994;1: 290-6)

Keywords

GnRH antagonist non-human primate ORG 30850 down-regulation GnRH receptors.

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References

Kenigsberg D. , Littman BA , Hodgen GD Medical hypophysectomy: I. Dose-response using a gonadotropin-releasing hormone antagonist. Fertil Steril 1984;42:112-5.

Meldrum DR , Wisot A. , Hamilton F. , Gutlay AL , Kempton W. , Huynh D. Routine pituitary suppression with leuprolide before ovarian stimulation for oocyte retrieval. Fertil Steril 1989 ;51:455-9.

Oehninger S. , Brzyski RG , Muasher SJ , Acosta AA , Jones GS In vitro fertilization and embryo transfer in patients with endometriosis: Impact of a gonadotropin releasing hormone agonist. Hum Reprod 1989 ;4:541-4.

Gordon K. , Hodgen GD

GnRH agonists and antagonists in assisted reproduction. Ballieres

Clin Obstet Gynaecol 1992; 6:247-65.

Gordon K. , Hodgen GD

Basis for differential therapeutic roles of GnRH agonists versus antagonists in clinical practice. Infertil Reprod

Med Clin North Am 1993;4:201-213.

Clayton RN Gonadotropin-releasing hormone: Its actions and receptors. J Endocrinol 1989;120:11-9.

Huckle WR , Conn PM Molecular mechanism of gonadotropin releasing hormone action. II. The effector system. Endocr Rev 1988;9:387-95.

Meldrum DR , Tsao Z. , Monroe SE , et al. Stimulation of LH fragments with reduced bioactivity following GnRH agonist administration in women. J Clin Endocrinol Metab 1984;58:755-7.

Chillik CF , Itskovitz J. , Hahn DW , McGuire JL , Danforth DR , Hodgen GD Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: Tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment . Fertil Steril 1987;48: 480-5.

10.

Schmidt F. , Sundaram K. , Thau RB , Bardin CW [Ac-D-Nal(2)1, 4FD-Phe2, D-Trp3, DArg6]-LHRH. A potent antagonist of LHRH, produces transient edema and behavioral changes in rats. Contraception 1984;29:283-9.

11.

Ljungqvist A. , Feng D-M. , Tang P-F. , et al. Design, synthesis and bioassays of antagonists of LHRH which have high antiovulatory activity and release negligible histamine. Biochem Biophys Res Commun 1987;148:849-56.

12.

Bajusz S. , Kovacs M. , Gazdag M. , et al. Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects. Proc Natl Acad Sci USA 1988;85: 1637-41.

13.

Karten MJ An overview of GnRH antagonists development: Two decades of progress . In: Crowley WF , Conn PM , eds. Modes of action of GnRH and GnRH analogs. New York: Springer Verlag, 1992:277-97.

14.

Cassidenti DL , Sauer MV , Paulson RJ , et al. Comparison of intermittent and continuous use of a gonadotropin-releasing hormone antagonist (Nal-Glu) in in vitro fertilization cycles: A preliminary report. Am J Obstet Gynecol 1991;165:1806-10.

15.

Ditkoff EC , Cassidenti DL , Paulson RJ , et al. The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women. Am J Obstet Gynecol 1991;165:1811-7.

16.

Frydman R. , Cornel C. , deZiegler D. , Taieb J. , Spitz IM , Bouchard P. Prevention of premature LH and progesterone rise with a gonadotropin-releasing hormone antagonist (Nal-Glu) in controlled ovarian hyperstimulation. Fertil Steril 1991;56:923-7.

17.

Frydman R. , Cornel C. , deZiegler D. , Taieb J. , Spitz IM , Bouchard P. Spontaneous luteinizing hormone surges can be reliably prevented by the timely administration of a gonadotropin-releasing hormone antagonist (Nal-Glu) during the late follicular phase. Hum Reprod 1992 ;7:930-3.

18.

Dubourdieu S. , Le Nestour E. , Spitz IM , Charbonnel B. , Bouchard P. The combination of gonadotropin-releasing hormone (GnRH) antagonist and pulsatile GnRH normalizes luteinizing hormone secretion in polycystic ovarian disease but fails to induce follicular maturation . Hum Reprod 1993;8:2056-60.

19.

Pavlou SN , Brewer K. , Farley MG , et al. Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido. J Clin Endocrinol Metab 1991 ;73: 1360-9.

20.

Bremner WJ , Bagatell CJ , Steiner RA Gonadotropin-releasing hormone antagonist plus testosterone: A potential male contraceptive. J Clin Endocrinol Metab 1991 ;73: 465-9.

21.

Tom L. , Bhasin S. , Salamek W. , et al. Induction of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing hormone antagonist and testosterone enanthate. J Clin Endocrinol Metab 1992;75:476-83.

22.

Behre HM , Klein B. , Steinmeyer E. , McGregor GP , Voigt K. , Neischlag E. Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist Cetrorelix (SB-75) in normal men. J Clin Endocrinol Metab 1992 ;75:393-8.

23.

Gordon K. , Williams RF , Danforth DR , Hodgen GD A novel regimen of GnRH antagonist plus pulsatile GnRH: Controlled restoration of gonadotropin secretion and ovulation induction. Fertil Steril 1990;54:1140-5.

24.

Kenigsberg D. , Hodgen GD Ovulation inhibition by administration of weekly gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 1986;62:734-8.

25.

Leal JA , Gordon K. , Williams RF , Danforth DR , Roh SI , Hodgen GD Probing studies on multiple dose effects of Antide (Nal-Lys) GnRH antagonist in ovariectomized monkeys. Contraception 1989 ;40:623-33.

26.

Deckers Ghj , DeGraaf JH , Kloosterboer HJ , Loozen Hjj. Properties of a potent LHRH antagonist (ORG 30850) in female and male rats. J Steroid Biochem Molec Biol 1992; 42:705-12.

27.

Goodman AL , Descalzi CD , Johnson DK , Hodgen GD Composite patterns of circulating LH, FSH, estradiol and progesterone during the menstrual cycle in cynomolgus monkeys. Proc Soc Exp Biol Med 1977;155:479-81.

28.

Goodman AL , Nixon WE , Johnson DK , Hodgen GD Regulation of folliculogenesis in the cycling rhesus monkey: Selection of the dominant follicle. Endocrinology 1977 ;100:155-61.

29.

Hodgen GD , Tullner WW , Vaitukaitis JL , Ward DN , Ross GT Specific radioimmunoassay of chorionic gonadotropins during implantation in rhesus monkeys. J Clin Endocrinol Metab 1974 ;39:457-64.

30.

Leal JA , Williams RF , Danforth DR , Gordon K. , Hodgen GD Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist . J Clin Endocrinol Metab 1988;67:1325-7.

31.

Danforth DR , Gordon K. , Leal JA , Williams RF , Hodgen GD Extended presence of Antide (Nal-Lys GnRH antagonist) in circulation: Prolonged duration of gonadotropin inhibition may derive from Antide binding to serum proteins. J Clin Endocrinol Metab 1989;70:554-6.

32.

Nett TM , Crowder ME , Moss GE , Duello TM GnRHreceptor interaction. V. Down-regulation of pituitary receptors for GnRH in ovariectomized ewes by infusion of homologous hormone. Biol Reprod 1981;24:1145-55.

33.

Mann DR , Gould KG , Collins DC Influence of continuous gonadotropin-releasing hormone (GnRH) agonist treatment on luteinzing hormone and testosterone secretion, the response to GnRH, and testicular response to human gonadotropin in male rhesus monkeys . J Clin Endocrinol Metab 1984;58:262-7.