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

人类女性生殖功能的变化可能反映了我们进化历史中自然选择的作用。生态或能量条件改变卵巢类固醇产生的能力是众所周知的，但潜在的遗传变异也可能影响生殖表型的研究较少。这项研究项目将检验人类孕激素受体基因(PROGINS)的一个具有生理意义的高频遗传变异是否会影响子宫功能。PROGINS由三个完全连锁的遗传标记组成--不平衡。三个标记之一，外显子4的单核苷酸非同源替换，导致所产生的蛋白质中的缬氨酸到亮氨酸氨基酸的替换。这种氨基酸替代可能是PROGINS编码的孕酮受体导致对孕酮反应减弱的原因。许多流行病学研究也表明PROGINS的表型影响，这些研究确定它是生殖障碍和癌症的危险因素。在这个项目中，子宫功能将通过研究月经周期特征(总月经周期长度、卵泡期长度、黄体期长度、月经出血和月经失血的长度)间接评估，更直接的是，通过超声测量子宫内膜厚度。由于PROGINS变异型可能导致对孕酮的反应性降低，这通常会抵消雌激素对子宫的增殖效应，因此预计PROGINS变异型个体将有更长的月经出血持续时间，更多的失血量，周期长度改变，黄体中期子宫内膜增厚。在极端情况下，这些表型可能会对当代人群的生育力产生负面影响，但在过去卵巢激素水平可能较低的时候，对黄体酮的反应减弱可能是有选择性的有利因素。目前的项目还将调查PROGINS是否与生活史和能量变量相互作用，从而导致子宫功能的变化。加性效应和乘性效应都将通过使用温和的多元回归技术进行研究。所有研究都将在正常、健康的欧洲血统女性样本中进行，欧洲血统是报告的PROGINS变种携带者频率最高的民族(37%)。造成女性生育率差异的原因是多方面的。生活方式、饮食、活动水平、获得医疗保健的机会以及年龄或产次等生物变量显然会影响成功怀孕的可能性，但潜在的基因变异对正常生殖功能的影响则不太清楚。该项目产生的数据将有助于建立模型，解释导致正常女性复杂生殖表型的遗传变异和基因-环境相互作用的作用。这种人类生物学的方法阐明了人类非病理性变异的范围，并将提供一个研究健康和疾病的背景。

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.