- 學位論文
雄性賀爾蒙之於多囊性卵巢症候群的代謝功能，臨床形態的表現與其排卵功能的影響之研究
Hyperandrogenism in Relation to Metabolic Disorder, Ovarian Morphology and Ovulatory Dysfunction in Women with Polycystic Ovary Syndrome
摘要
多囊性卵巢囊腫症候群是育齡期女性最常見的一種內分泌疾病，盛行率約為5-10% 。 2003年於荷蘭鹿特丹舉辦的會議上所修訂過的最新診斷標準，為患者應至少符合下列三項條件中的兩項，包括:慢性無排卵、外觀或是生化學上高雄性賀爾蒙的表現以及骨盆腔超音波上可看到多囊性卵巢的型態。雖然如此，對於如此的診斷標準仍然存在很多的爭議。基本上，雄性激素偏高的表現還是被認為是多囊性卵巢囊腫症候群的核心表現型。由於不同的飲食習慣、遺傳背景以及環境因素等影響，多囊性卵巢症候群的婦女其胰島素抗阻的表現如肥胖及代謝症候群的盛行率，在不同種族的多囊性卵巢症候群會有很大的差異。亞洲婦女過去都被認為較西方人種為較少肥胖與高雄性賀爾蒙的表現，然而研究卻顯示亞洲多囊性卵巢症候群的婦女，其雄性素過高、胰島素抗阻及多囊性卵巢的表現其實近似於西方多囊性卵巢症候群的婦女的表現。而且根據過去的研究報告也證實，雖然亞裔民族包括華人、日本人等對於多囊性卵巢囊腫症候群婦女的高雄性激素的臨床表現如多毛、青春痘與雄性禿的表現與西方人種不盡相同，但是對於可測得之體內的男性賀爾蒙 (testosterone) 值，則不論是在哪個人種都是差不多的。然而，針對亞洲婦女尤其是台灣婦女的多囊性卵巢症候群的研究，卻是寥寥可數。因此在本研究中我們會特別對於雄性賀爾蒙之於多囊性卵巢囊腫症候群病患的代謝功能，臨床形態的表現與其排卵功能的影響予以研究。 多囊性卵巢症候群，顧名思義就是其卵巢會有比正常卵巢多二至三倍的濾泡數目，然而這些卵泡會在早期就停止成長，濾泡的選擇與持續成長會在初期就中斷而進入濾泡成長休止的狀態。近來的研究特別強調雄性賀爾蒙在初期濾泡成長所扮演的重要角色。國外的研究報告顯示，在體外培養的小鼠濾泡研究發現雄性賀爾蒙會刺激濾泡的成長。此外，雄性賀爾蒙也可以刺激顆粒細胞與隨峭細胞的增生與抑制細胞凋亡的發生。而同時高胰島素血症也會刺激卵巢濾泡數目與卵巢體積的增加。然而，這樣的結論卻還是有爭議的，原因是還有其他的研究並沒有看到這樣的現象。 我們認為在這個干擾排卵的議題上，抗穆勒氏賀爾蒙扮演著一個很重要的角色。抗穆勒氏賀爾蒙主要是由卵巢的顆粒細胞產生，會抑制人類原始濾泡成長的啟蒙以及會防止主要濾泡的多種選擇，避免單一週期卵巢自發性的排超過兩顆以上的卵子，因此又可以稱為濾泡選擇的看門人。若是抗穆勒氏賀爾蒙激素作用的調控發生問題就會影響排卵功能。過去一些研究證實多囊性卵巢症候群的婦女其卵巢內的抗穆勒氏賀爾蒙激素濃度較正常婦女的卵巢含量為高，且大部分的多囊性卵巢症候群的婦女同時具有肥胖與胰岛素抗性的問題。此外有研究報告顯示，减重在有多囊性卵巢囊腫症候群的肥胖婦女可以改進其自發排卵的功能。然而，肥胖是否會影響或是干擾抗穆勒氏賀爾蒙激素的作用及對多囊的卵巢形態學上的影響，則至目前為止並沒有好的報告。在我們的研究中，我們發現除抗穆勒氏賀爾蒙激素之外，多囊性卵巢囊腫症候群的婦女其體內典型的高雄性素血症和胰島素阻抗性均會影響其卵巢的形態和大小。 另外，對於多囊性卵巢症候群與心血管疾病發生的關係，一直是有爭議的，主要是過去Wild等人曾提出多囊性卵巢症候群與心血管疾病之間的相關性，在經過校正了肥胖的因素後就變得不顯著。而代謝症候群是一群集合發生心血管疾病的風險因子，其中包括有肥胖、高血脂症、高血糖與高血壓等表現。它會增加五倍未來罹患第二型糖尿病的機會，與二至三倍未來發生心血管疾病的機會。最近的研究指出，在已開發及開發中國家，發生代謝症候群盛行率增加的現象，已經成為一項重要的公共健康問題。雖然對於多囊性卵巢症候群的婦女，未來是否會增加其罹患心血管疾病的結論依然沒有共識，然而有許多與心血管疾病相關的危險因子如:肥胖、胰島素抗阻、高血脂症與代謝症候群卻還是可以在多囊性卵巢症候群的婦女中被廣泛的觀察到。另外，在多囊性卵巢症候群的婦女中可發現到的高血壓、血管延展功能不良與內皮細胞受損是獨立於肥胖與胰島素抗阻而存在，因此，可以合理推論多囊性卵巢症候群的婦女，其所增加的心血管疾病的風險的代謝異常，應該與其高雄性賀爾蒙的狀態有關。 性腺賀爾蒙鍵結球蛋白是雄性賀爾蒙的攜帶蛋白質，當他的濃度越低，代表血液中游離態的雄性賀爾蒙越高。在我們的研究中，我們發現當多囊性卵巢症候群的婦女，其體內的性腺賀爾蒙鍵結球蛋白含量越低時，其同時發生代謝症候群的機會會越高。此外，性腺賀爾蒙鍵結球蛋白在血液中的值是與其血液中的高密度膽固醇成正相關。在我們的研究中，我們也發現當多囊性卵巢症候群的婦女其體內血液中游離態的雄性賀爾蒙越高時，其可測得的血壓包括收縮壓與輸舒張壓都會顯著較高。而且血壓與雄性賀爾蒙之間的關係，在校正了年齡、肥胖、胰島素抗阻、高血脂症等等可能的干擾因素之後，還是顯著存在。 胰島素抗阻越高向來被認為會增加體內慢性的發炎現象。而慢性的低度發炎反應，如血液中C反應蛋白的上升被認為可用來預測未來罹患心血管疾病的風險。多囊性卵巢症候群的婦女其血清中的C反應蛋白的含量與正常沒有多囊性卵巢症候群的婦女體內可測得的含量為高。在一些研究中我們也可以發現，若要達到相同程度對於慢性低度發炎反應的改善，相對於同樣程度肥胖的非多囊性卵巢症候群的正常婦女，罹患多囊性卵巢症候群的婦女須要減去更多的體重才能達到相同程度的C反應蛋白的含量的下降幅度。過去的研究一直不能解釋為何多囊性卵巢症候群的婦女其體內卵泡抑制素的含量較正常婦女為高。我們的研究發現，多囊性卵巢症候群的婦女的高卵泡抑制素基因含量應該與其體內的高C反應蛋白的含量有關。 由我們的研究成果可以發現多囊性卵巢症候群的臨床特徵中最顯著的就是其雄性荷爾蒙濃度偏高的表現，不論是生化值亦或是臨床表現皆是。在我們所建立的多囊性卵巢症候群的動物模式中，我們發現不同的雄性賀爾蒙會造成不同的生化值，代謝功能與排卵功能的變化。可分別代表臨床上不同表現型的多囊性卵巢症候群。DHT (dihydrotestosterone) 會造成大鼠的肥胖與生化代謝值上的異常，包括血脂肪、胰島素、與肝功能上的變化，並且會使得卵巢自發性排卵的週期減少，與我們先前在臨床研究上所觀察到的多囊性卵巢症候群的表現相符合。至於DHEA (dehydroepiandrosterone)的投予，雖然並不會造成大鼠的肥胖現象，但是也是會造成血脂肪與肝功能等生化代謝值上的異常表現，則可能又是另一種型態的多囊性卵巢症候群的表現。
並列摘要
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age with a probable prevalence of 5% to 10%. PCOS is characterized by chronic anovulation, menstrual irregularities, evidence of hyperandrogenism (either clinical, manifested as hirsutism, acne, male pattern balding, or biochemical, manifested by elevated serum adrenal and/or ovarian androgen concentration). Fifty percent of all patients with PCOS are overweight or obese, and the presence of obesity affects the clinical manifestations of PCOS. The underlying pathogenic mechanisms appear to involve insulin resistance and hyperinsulinemia, the magnitude of which is greater in obese than in non-obese women with PCOS. Basically, the hyperandrogenism was considered as a core manifestation for women with PCOS. However, because of the effects of different dietary culture, genetic background and environment factors, there has been a very big difference of the phenotypic expression of insulin resistance and the prevalence of metabolic syndrome in women with PCOS among the different ethnicities. Previous studies already showed that although the Asian women have less severity of phenotypic hyperandrogenism and obesity than the Caucasian women, while the degree of insulin resistance, hyperandrogenemia, and polycystic ovary were comparable between Asian and Caucasian women. However, studies concerning the Asian women with PCOS, with special emophasis on Taiwanese women are rare. Therefore, in the present study, we may focus to work on the issues of hyperandrogenism on the metabolic dysfunction, phenotypic expression and ovulatory dysfunction for women with PCOS. Since the Rotterdam consensus meeting in 2003, the ultrasound criteria of increased ovarian volume (>10 ml) and/or the presence of 12 or more follicles (2-9 mm in size) in at least a single ovary has become one of the triad definitive criteria for the diagnosis of the polycystic ovary syndrome (PCOS). However, this criteria for the definition of PCOS is still a controversy, owing to the fact that the significance of the polycystic ovary morphology and the characteristic endocrine syndrome for women with PCOS is still conflicting. Insulin-sensitizing agents and/or weight loss have been demonstrated to improve the recovery of spontaneous ovulation in obese women with PCOS. Whether or not the obesity or insulin resistance contributes to the polycystic ovary morphology and function of ovulation has not been reported. Anti-Mullerian hormone, as a gate-kepper to prevent the multiple selection of dominant follicle in natural cycle was also considered as an important to regulate the regulation in women with PCOS. In our study, we found that not only, anti-Mullerian hormone, the hyperandrogenism and insulin resistance may lead to the polycystic ovary morphology in women with PCOS. Furthermore, the relationship between PCOS and cardiovascular disease is always controversial. Wild et al. proposed that the association between PCOS and CVD might disappear after consider the confounding effect of obesity. Metabolic syndrome was well-known to increase the future risk of diabetes and cardiocascular disease. Dyslipidemia and hypertension which are parts of metabolic syndrome were reported to have high prevalence in women with PCOS. Previous reports focused on the obesity and insulin resistance of women with PCOS. Here, we aim to investigate the roles of hyperandrogenemia in association with the metabolic abnormalities in women with PCOS. In our study, we found that the low sex-hormone binding globulin in women with PCOS which might aggravate the hyperandrogenemia was associated with low HDL-C levels and the occurrence of metabolic syndrome. In addition, the hyperandrogenism in women with PCOS was independently and significantly correlated to both systolic and diastolic blood pressure after further adjustment for the age, obesity, insulin resistance and dyslipidemia. Previous studies already provide a a lot of evidence to show that the insulin resistance may lead to chronic low-grade inflammation in human beings. In addition, the increased level of C-reactive protein was currently considered to be a biomarker to predict the risk of future cardiovascular disease. There were also several reports that level of CRP was significantly higher in women with PCOS than those without PCOS. Two previous studies reported that the follistatin level was specifically higher in women with PCOS than control subjects. In our studies, we found that the high follistatin level in women with PCOS might be a reflection of their chronic low grade inflammatory status. From our study results, we found the most evident characteristic for women with PCOS was the hyperandrogenism, no matter in biochemical or clinical aspects. We found different origins of androgen may lead to different phenotypic expressions of biochemistry, metabolism and ovulatory function that might even represent the different clinical phenotypic expression of women with PCOS. Rat that treated with dihydrotestosterone may lead to obesity, insulin resistane, dyslipidemia, abnormal liver function tests and decreased spontanerous ovulatory cycles that mimic the obese women with PCOS. However, rats that treated with dehydroepiandrostenedione, on the contrary, may not lead to the obesity but still lead to the dyslipidemia and abnormal liver function tests. This might represent another clinical subgroup of women with PCOS. Conclusivly, in this project, our investigation in women with PCOS was found: 1. The characteristic hyperandrogenism in women with PCOS was related to the dyslipidemia, insulin resistance, metabolic syndrome and cardiovascular disease. 2. The characteristic hyperandrogenism in women with PCOS has also impact for hypertension in women with PCOS. 3. Not only the characteristic hyperandrogenemia, but also the insulin resistance and anti-mullerian hormone were related to the polycystic ovary morphology and the anovulation for women with PCOS. Besides, the anovulation in women with PCOS might through the dysregulation of anti-mullerian hormone by insulin resistance. 4. Follistatin as representation for the low-grade inflammation was related to the insulin resistance in women with PCOS. 5. From hyperandrogenic rat models, we found the different origins of androgen might lead to different metabolic phenotypes as clinical presented in women with PCOS.