Doctoral Dissertation Improvement: The Role of the Progesterone Receptor, Energetic, and Life History Variables in Women

Temple University, Philadelphia PA

Investigators

Abstract

Variation in human female reproductive function likely reflects the action of natural selection in our evolutionary past. The capacity to vary ovarian steroid production with ecological or energetic conditions is well known but underlying genetic variation that could also impact reproductive phenotypes is less well studied. This research project will examine whether a physiologically significant, high frequency genetic variant of the human progesterone receptor gene (PROGINS) impacts uterine function. PROGINS consists of three genetic markers that are in complete linkage-disequilibrium. One of the three markers, a single nucleotide non-synonomous substitution in exon 4, causes a valine to leucine amino acid substitution in the resulting protein. This amino acid substitution may account for the diminished response to progesterone attributed to PROGINS-encoded progesterone receptors. A phenotypic affect of PROGINS is also suggested by numerous epidemiological studies that identify it as a risk factor for reproductive disorders and cancers. In this project uterine function will be assessed indirectly by the study of menstrual cycle characteristics (total menstrual cycle length, follicular phase length, luteal phase length, length of menstrual bleeding and menstrual blood loss), and more directly, by measuring endometrial thickness via ultrasound. Because the PROGINS variant may cause less responsiveness to progesterone which normally counters the proliferative effects of estrogen on the uterus it is anticipated that individuals with the PROGINS variant will have a longer duration of menstrual bleeding, greater volume of blood loss, altered cycle length, and thicker endometria at the mid-luteal phase. At the extreme these phenotypes may have a negative impact on fertility in contemporary populations but a diminished responsiveness to progesterone may have been selectively advantageous in the past when ovarian hormone levels were likely lower. The current project will also investigate whether PROGINS interacts with life history and energetic variables to cause variation in uterine function. Both additive and multiplicative effects will be studied through the use of a moderated multiple regression technique. All studies will be conducted in a sample of normal, healthy women of European descent, the ethnic group that has the highest reported frequency of carriers (37%) of the PROGINS variant. The causes of fertility differences among women are multifactoral. Lifestyle, diet, activity levels, access to health care, and biological variables such as age or parity, clearly impact the likelihood of successful pregnancy but the influence of underlying genetic variation on normal reproductive function is less well understood. Data generated from this project will contribute to models that explain the role of genetic variation and genotype-environment interactions that contribute to complex reproductive phenotypes in normal women. This approach to human biology illuminates the range of non-pathological human variation and will provide a context in which to study health and disease.