The mechanisms responsible for reproductive abnormalities in transgenic female mice overexpressing human IGF binding protein-1 (IGFBP-1) in the liver have been investigated. At 2 months of age, none of these transgenic mice exhibited ovar- ian cyclicity. Genital tract and ovary tissue weights were re- duced in transgenic mice, this weight reduction being dispro- portionate with the reduction of body weight. Examination of ovarian follicular population revealed a marked decrease in the number of corpora lutea and gonadotropin-dependent fol- licles, suggesting an alteration of terminal follicular growth and ovulation. Stimulation of ovaries by exogenous gonado- tropins revealed that ovaries from transgenic mice ovulated less oocytes than nontransgenic mice. This lower responsive- ness of ovaries from transgenic mice to gonadotropins was not associated with a decrease in FSH-, LH- or IGF-I receptor expression. Transgenic and nontransgenic mice have similar circulating LH and FSH concentrations at dioestrus, after castration, 46 h after equine CG administration, or 15 min after GnRH injection. However, LH concentrations were 8-fold higher in pituitaries from transgenic vs. nontransgenic mice. Moreover, the size of LH-immunoreactive cells was re- duced and their number was increased, suggesting a subtle alteration of LH secretion. Overall, these data indicate that reduced fertility in trans- genic female mice overexpressing human IGFBP-1 are mainly due to an alteration of terminal follicular growth leading to a decrease in natural and induced ovulation rate, likely due to an impairment of IGF-I action on follicular cells. Increased circulating IGFBP-1 concentrations may additionally lead to altered GnRH and LH pulsatility and thereby exacerbate the ovulation defect. (Endocrinology 143: 1801-1808, 2002)