Labrie Fernand, Luu-The Van, Labrie Claude, Bélanger Alain, Simard Jacques, Lin Sheng-Xiang, Pelletier Georges
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l'Université Laval) and Laval University, Québec City, Québec G1V 4G2, Canada.
Endocr Rev. 2003 Apr;24(2):152-82. doi: 10.1210/er.2001-0031.
Serum androgens as well as their precursors and metabolites decrease from the age of 30-40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.
女性血清雄激素及其前体和代谢产物从30 - 40岁起开始减少，这表明更年期更符合生理的激素替代疗法应包含一种雄激素类化合物。然而，需要考虑的是，女性体内的大多数雄激素，尤其是在绝经后，是由肾上腺来源的无活性前体脱氢表雄酮（DHEA）和硫酸脱氢表雄酮（DHEA - S）在外周内分泌组织中合成的。在这个被称为内分泌学的内分泌生理学新领域，随着负责将DHEA和DHEA - S在外周靶组织中转化为雄激素和雌激素的大多数酶的克隆和特性研究取得了很大进展，在这些外周靶组织中，局部产生的性类固醇在其合成的同一细胞中发挥作用，而不会大量扩散到循环中，从而严重限制了对活性性类固醇血清水平的解读。外周组织中产生的性类固醇随后在局部被灭活为更易溶于水的化合物，这些化合物扩散到全身循环中，在那里可以被检测到。在一系列动物模型中，已发现雄激素和DHEA可抑制乳腺癌的发生和生长，并刺激骨形成。在临床研究中，已发现DHEA可增加骨矿物质密度并刺激阴道成熟，而不影响子宫内膜，同时改善幸福感和性欲，且无明显副作用。DHEA相对于其他雄激素类化合物的优势在于，在生理剂量下，DHEA仅在具有适当生理酶机制的特定内分泌靶组织中转化为雄激素和/或雌激素，从而将性类固醇的作用限制在那些具有负责其形成的基因组织特异性表达谱的组织中，而使其他组织不受影响，从而将全身性给予雄激素或雌激素时观察到的潜在副作用降至最低。
