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Mode of Suppression of Pituitary and Gonadal Function After Acute or Prolonged Administration of a Luteinizing Hormone-Releasing Hormone Antagonist in Normal Men^*

SPYROS N. PAVLOU, GAIL WAKEFIELD, NICOLE L. SCHLECHTER, JILL LINDNER, KEVIN H. SOUZA, THEMIS C. KAMILARIS, SOCRATES KONIDARIS, JEAN E. RIVIER, WYLIE W. VALE and MARC TOGLIA

Department of Medicine, Vanderbilt University School of Medicine Nashville, Tennessee 37232
the Salk Institute La Jolla, California 92037

Address all correspondence and requests for reprints to: Spyros N. Pavlou, M.D., Division of Endocrinology, AA-4206 MCN, Vanderbilt University Medical Center, Nashville, Tennessee 37232.

LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadotropin secretion and, consequently, gonadal function. We studied the pituitary and gonadal suppression following single doses and short term administration (1–3 weeks) of a recently developed LHRH antagonist in normal men. First, the antagonist Nal-Glu ([Ac-D2Nal¹, D4ClPhe²,D3Pal³,Arg⁵,DGlu⁶(AA),DAla¹⁰]LHRH), was given as a single sc injection to five normal men at three dose levels of 1, 5, and 20 mg (study I). Serum FSH, immunoreactive LH (IRLH), bioactive LH (bio-LH), testosterone, and estradiol were measured before and at frequent intervals for 48 h after Nal-Glu administration. Mean serum FSH decreased (P < 0.001) by 28.9 ± 5.4/ (±SE), 38.2 ± 7.9/, and 44.5 ± 3.6/ after the 1-, 5-, and 20-mg doses, respectively. Mean serum IR-LH decreased (P < 0.001) by 39.0 ± 13.8/, 53.2 ± 10.0/, and 53.1 ± 14.4/ after the three doses. Serum bio-LH levels and the ratio of bio-LH/IR-LH decreased (P < 0.001) after the 20-mg dose by 87.8/ and 78.5/, respectively. Serum testosterone levels decreased (P < 0.001) more than 78.5/ after all Nal-Glu doses. The duration of testosterone suppression, but not the nadir reached, was dose dependent (P = 0.012). Serum estradiol levels also decreased (P < 0.001), but the rate of decrease was slower than that of serum testosterone. The apparent plasma disappearance half-life of Nal-Glu after administration of 5 mg was 12.8 ± 2.7 h.

The Nal-Glu antagonist also was given daily as a single sc injection of 5 mg to eight normal men for 21 days (study II) or twice daily to five men for 7 days (study III). In study II, serum FSH, IR-LH, bio-LH, testosterone, estradiol, and 17-hydroxyprogesterone were measured daily, immediately before the next injection, and on days 1, 7, and 21 in frequent blood samples drawn for 24 h. The mean serum testosterone level in study II decreased (P < 0.001) from 17.6 ± 2.2 to 4.1 ± 1.0 nmol/L on day 1, increased (P < 0.05) between days 2 and 8, and then progressively decreased to below 2 nmol/L from day 18 until 24 h after the end of the study. Serum FSH, IR-LH, and bio-LH levels paralleled those of testosterone. The serum pharmacokinetics of Nal-Glu on days 7 and 21 were almost identical. In study III serum testosterone levels decreased (P < 0.001) and remained suppressed throughout the entire study period. Serum estradiol levels also decreased (P < 0.001), whereas serum 17-hydroxy-progesterone levels did not change. No major sideeffects occurred during Nal-Glu administration in any of these studies other than minor local reactions at the injection sites. These results indicate that prolonged administration of the Nal-Glu LHRH antagonist effectively suppresses pituitary and gonadal function. The transient escape from suppression may be prevented by the use of higher or more frequent initial doses.

^* This work was supported by the Contraceptive Research and Development Program, Eastern Virginia Medical School (CONRAD-013) under a Cooperative Agreement with the United States Agency for International Development (AID; DPE-3044A-00-6063-00). The views expressed by the authors do not necessarily reflect the views of AID and CONRAD. Supported also by the following grants and grants-in-aid: Ford Foundation Grant 810-0297, Clinical Research Center Grantin-Aid 5-M01-RR-95, Population Center Grant-in-Aid HD-05797, and NIH Grant HD-13527 (to W.W.V. and J.E.R.). Research conducted in part by the Clayton Foundation for Research, California division.

Clayton Foundation Investigator.

Received June 24, 1988.

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