Comparative Effects of Interferon Alpha-2b and Pegylated Interferon Alpha-2b on Menstrual Cycles and Ovarian Hormones in Cynomolgus Monkeys

BACKGROUND: The covalent modification of interferon (IFN) alpha 2b with monomethyoxy polyethylene glycol (PEG) reduces its clearance rate and increases its half-life. High doses of interferon (IFN) alpha 2b have previously been shown to affect maintenance of pregnancy in rhesus monkeys, Given the role of ovarian hormones in reproductive function and pregnancy, this study was conducted to assess the effects of PEG-IFN alpha 2b or IFN alpha 2b (comparative control) on ovarian hormones and menstrual cyclicity in cynomolgus monkeys. In addition, the potential for reversibility of PEG-IFN alpha 2b or IFN alpha 2b-related observations was assessed. METHODS: Monkeys were administered 3,105 mu g/m(2) human recombinant (hr) IFN alpha 2b or 52, 262, or 4,239 mu g/m(2) PEG-hr-IFN alpha 2b every other day for one menstrual cycle, followed by a post-dose period of up to two menstrual cycles, RESULTS: Monkeys administered 3,105 mu g/m(2) hr-IFN alpha 2b or 52, 262, or 4,239 mu g/m(2) PEG-hr-IFN alpha 2b exhibited transient decreases in food consumption, leukocyte and erythrocyte parameters. Monkeys administered 3,105 mu g/m(2) hr-IFN alpha 2b exhibited lengthened menstrual cycles that were associated with a delay in reaching peak ovarian hormone levels and lower respective peak concentrations. Similarly, monkeys administered 4,239 mu g/m(2) PEG-hr-IFN alpha 2b exhibited lengthened menstrual cycles and a delay in reaching peak ovarian hormone levels and slightly lower respective peak concentrations. Post-dosing menstrual cycle length, estradiol and progesterone profiles exhibited evidence of recovery in both the hr-IFN alpha 2b and the high-dose PEG-hr-IFN alpha 2b groups. CONCLUSIONS: Administration of hr-IFN alpha 2b or PEG-hr-IFN alpha 2b at high doses to cynomolgus monkeys resulted in similar effects on menstrual cycles, estradiol and progesterone profiles, and exhibited evidence of reversibility upon cessation of dosing. These results suggest that the previously observed high-dose IFN alpha-related effects on the maintenance of pregnancy in monkeys are likely the result of altered ovarian function. Birth Defects Res (Part B) 86:29-39, 2009. (C) 2009 Wiley-Liss, Inc.