This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by MONROE, S. E. Articles by JAFFE, R. B. Search for Related Content PubMed PubMed Citation Articles by MONROE, S. E. Articles by JAFFE, R. B.

Dose-Dependent Inhibition of Pituitary-Ovarian Function during Administration of a Gonadotropin-Releasing Hormone Agonistic Analog (Nafarelin)^*

SCOTT E. MONROE, ZEEV BLUMENFELD, JANICE L. ANDERYKO, ELDON SCHRIOCK, MILAN R. HENZL^¶ and ROBERT B. JAFFE

Reproductive Endocrinology Center, Department of Obstetrics, Gynaecology and Reproductive Sciences, University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Scott Monroe, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California School of Medicine, Room HSW 1404B, San Francisco, California 94143.

To determine if treatment with the GnRH agonistic analog nafarelin could reliably block ovulation while only partially disrupting ovarian estrogen production, three degrees of pituitary-ovarian inhibition were investigated. Thirty-two women with ovulatory menstrual cycles were given 125 ¶g (group (Gp) I), 250 ¶g (Gp II), or 1000 (¶g (Gp III) nafarelin daily by intranasal spray. Twenty-seven women completed 6 months of treatment. Basal serum FSH concentrations decreased (P < 0.01) in all groups. Suppression of serum LH was dose dependent and significant (P < 0.01) only in Gps II and III. Pituitary desensitization to nafarelin developed in all groups. Peak LH responses to nafarelin decreased by about 70% (Gps I and II) and 95% (Gp III). Basal serum estradiol levels after 1 month of treatment were approximately 70 pg/ml (Gp I) and 25 pg/ml (Gps II and III). Serum estradiol levels increased acutely in Gps I an d II, but not in Gp III, in response to each dose of nafarelin. Thus, average daily estradiol levels in Gp II were higher than those in Gp III. Serum testosterone and androstenedione levels decreased slightly (P < 0.05; Gp II) or by 50% (P < 0.01; Gp III) during treatment. The effects of nafarelin on ovulatory function also were dose-dependent. In Gp I there were four ovulations (progesterone, b4 ng/ml) and seven instances of luteinization (progesterone, 2–4 ng/ml) during 73 months of nafarelin administration. In contrast, there were no ovulations during 58 and 44 months in Gps II and III, respectively. After discontinuance of nafarelin, ovulatory menstrual function returned rapidly in all women.

In summary, inhibition of pituitary-ovarian function by daily intranasal nafarelin administration is dose dependent. Gonado-troph sensitivity to 125 ¶g is variable, and there is inconsistent inhibition of ovulation. Daily doses of 250 or 1000 fig analog reliably inhibit ovulation, but are associated with either moderate (Gp II) or marked (Gp III) reduction of ovarian estradiol secretion. The effects of these reduced levels of circulating estradiol on bone are not known. Further investigation, with dosage adjusted according to individual patient sensitivity, may lead to the development of a clinically acceptable contraceptive which consistently inhibits ovulation while maintaining serum estradiol levels sufficient to prevent osteoporosis. (J Clin En-docrinolMetab63:1334,1986)

^* This work was supported in part by Contracts NOl-HD-0-2811 and NO1-HD-3-2831 of the NICHHD (Bethesda, MD).

Postdoctoral fellow. Present address: Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel.

Postdoctoral fellow. Supported by the Medical Research Council of Canada. Present address: Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada.

Postdoctoral fellow. Present address: Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, Nashville, Tennessee 38163.

^¶ Syntex Research, Palo Alto, California 94304.

Received February 4, 1986.

This article has been cited by other articles:

				S. Palomba, F. Orio Jr, T. Russo, A. Falbo, T. Cascella, P. Doldo, C. Nappi, G. Lombardi, P. Mastrantonio, and F. Zullo Long-term effectiveness and safety of GnRH agonist plus raloxifene administration in women with uterine leiomyomas Hum. Reprod., June 1, 2004; 19(6): 1308 - 1314. [Abstract] [Full Text] [PDF]

				S. Palomba, F. Orio Jr., M. Morelli, T. Russo, M. Pellicano, C. Nappi, P. Mastrantonio, G. Lombardi, A. Colao, and F. Zullo Raloxifene Administration in Women Treated with Gonadotropin-Releasing Hormone Agonist for Uterine Leiomyomas: Effects on Bone Metabolism J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4476 - 4481. [Abstract] [Full Text] [PDF]

				T. Mizutani, A. Sugihara, K. Nakamuro, and N. Terada Suppression of Cell Proliferation and Induction of Apoptosis in Uterine Leiomyoma by Gonadotropin-Releasing Hormone Agonist (Leuprolide Acetate) J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1253 - 1255. [Abstract] [Full Text]

				K. E. Anderson, I. M. Spitz, C. W. Bardin, and A. Kappas A Gonadotropin Releasing Hormone Analogue Prevents Cyclical Attacks of Porphyria Arch Intern Med, July 1, 1990; 150(7): 1469 - 1474. [Abstract] [PDF]