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史上自然选择的作用。改变卵巢类固醇生产与生态或能量条件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。该研究项目将研究人类孕酮受体基因（PROGINS）的生理学显著性，高频率遗传变异是否影响子宫功能。PROGINS由处于完全连锁不平衡的三个遗传标记组成。三个标记之一，外显子4中的单核苷酸非同义替换，导致所得蛋白质中的缬氨酸至亮氨酸氨基酸替换。这种氨基酸取代可能是PROGINS编码的孕酮受体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，将其确定为生殖障碍和癌症的风险因素。在本项目中，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、月经出血长度和月经失血量）间接评估子宫功能，更直接的方法是通过超声测量子宫内膜厚度。 由于PROGINS变异体可能导致对孕酮的反应性降低，而孕酮通常会抵消雌激素对子宫的增殖作用，因此预计PROGINS变异体个体的月经出血持续时间更长，失血量更大，周期长度改变，黄体中期子宫内膜更厚。在极端情况下，这些表型可能对当代人群的生育能力产生负面影响，但在过去卵巢激素水平可能较低时，对孕酮的反应性降低可能是选择性有利的。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，导致子宫功能的变化。将通过使用适度多元回归技术研究加性和倍增效应。所有研究都将在欧洲血统的正常健康女性样本中进行，该种族群体具有PROGINS变体携带者的最高报告频率（37%）。妇女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，但潜在的遗传变异对正常生殖功能的影响尚不清楚。该项目产生的数据将有助于解释遗传变异和基因型-环境相互作用的作用的模型，这些作用有助于正常女性复杂的生殖表型。这种人类生物学的方法阐明了非病理性人类变异的范围，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.