To study the cellular patterns of gene expression of the insulin-like growth factor (IGF) system in human endometrium during the menstrual cycle, we used in situ hybridization histochemistry to localize messenger ribonucleic acids (mRNAs) encoding IGF-I and -II, their receptors, and their binding proteins (IGFBPs) in fresh-frozen endometrial tissue obtained from cycling women. IGF-I and IGF-II mRNAs are both expressed diffusely throughout endometrial stroma and are not detected in endometrial epithelium. Endometrial IGF-I mRNA is significantly more abundant during the proliferative than the secretory phase of the menstrual cycle, whereas the reverse is true for IGF-II. Type I and type II IGF receptor mRNAs are both present in endometrial stroma, but are relatively more abundant in endometrial epithelium, and neither shows distinctive cyclic changes. IGFBP-2, -4, -5, and -6 mRNAs demonstrate a diffuse stromal pattern of expression, whereas IGFBP-1 and -3 are more focally concentrated in selected subpopulations of endometrial cells. IGFBP-1 mRNA is not detected in proliferative endometrium and demonstrates a very heterogeneous pattern of expression in secretory endometrium, where it is intensely abundant in a patchy distribution of stromal and epithelial cells. IGFBP-3 mRNA is primarily concentrated in endometrial capillaries and is increased in the secretory phase, largely due to the intense vascularization of endometrial glands during this phase. IGFBP-5 mRNA is more abundant in the proliferative phase, but all other IGFBP mRNAs are relatively increased in the secretory phase of the menstrual cycle. These findings support the view that the IGF system plays a fundamental role in endometrial biology, acting via autocrine and/or paracrine mechanisms, with IGF-I and IGFBP-5 being dominant in the proliferative phase, and IGF-II and the other IGFBPs predominant in the secretory phase of the menstrual cycle.