Interest in women's reproductive variation within the subfield of Physical Anthropology known as Human Reproductive Ecology is dominated by energetic models for fecundity that disregard genetic variation as a potential cause of differences in reproduction. Further, a strong correlation between ovarian and uterine markers of fecundity is assumed, although this assumption is not supported by the available data. A polymorphism in the progesterone receptor gene, called PROGINS, shows diminished progesterone response in vitro and is associated with a number of uterine disorders in women. To elucidate the discrepancy between ovarian and uterine markers of fecundity, carriers of the PROGINS variant were compared to non-carriers with regard to endometrial thickness and menstrual cycle characteristics. Gene-environment interactions between PROGINS and life history, lifestyle factors, progesterone levels, anthropometric measures, and physical activity were also considered. The PROGINS polymorphism was found to impact both luteal phase length and menses duration, as well as to modify endometrial sensitivity to life history factors, progesterone levels, anthropometric measures, and physical activity. These results support the notion that PROGINS diminishes progesterone response, and indicate that the polymorphism also alters endometrial sensitivity to acute and chronic energetic stress. The findings of this study indicate that Human Reproductive Ecologists must consider genetically-based variation in sensitivity to energetic stress in future adaptive models of women's reproduction.