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

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Abstract
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)

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