Labrie F, Luu-The V, Labrie C, Simard J
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), Quebec, G1V 4G2, Canada.
Front Neuroendocrinol. 2001 Jul;22(3):185-212. doi: 10.1006/frne.2001.0216.
A new understanding of the endocrinology of menopause is that women, at menopause, are not only lacking estrogens resulting from cessation of ovarian activity but have also been progressively deprived for a few years of androgens and some estrogens originating from adrenal DHEA and androstenedione (4-dione). In fact, serum DHEA decreases by about 60% between the maximal levels seen at 30 years of age to the age of menopause. This decreased secretion of DHEA and DHEA-S by the adrenals is responsible for a parallel decrease in androgen and estrogen formation in peripheral tissues by the steroidogenic enzymes specifically expressed in each cell type in individual target tissues. This new field of endocrinology, called intracrinology, describes the local synthesis of androgens and estrogens made locally in each cell of each peripheral tissue from the adrenal precursors DHEA and 4-dione. These androgens and estrogens exert their action in the same cells where their synthesis takes place and they are released from these target cells only after being inactivated. To further understand the effect of DHEA in women, DHEA has been administered in postmenopausal women for 12 months. Such treatment resulted in increased bone formation and higher bone mineral density accompanied by elevated levels of osteocalcin, a marker of bone formation. Vaginal maturation was stimulated, while no effect was observed on the endometrium. Preclinical studies, on the other hand, have shown that, due to its predominant conversion into androgens, DHEA prevents the development and inhibits the growth of dimethylbenz(a)anthracene-induced mammary carcinoma in the rat, a model of breast cancer. DHEA also inhibits the growth of human breast cancer ZR-75-1 xenografts in nude mice. The inhibitory effect of DHEA on breast cancer is due to an androgenic effect of testosterone and dihydrotestosterone made locally from DHEA. When used as replacement therapy, DHEA is free of the potential risk of breast and uterine cancer, while it stimulates bone formation and vaginal maturation and decreases insulin resistance. The combination of DHEA with a fourth generation SERM, such as EM-652 (SCH 57068), a compound having pure and potent antiestrogenic activity in the mammary gland and endometrium, could provide major benefits for women at menopause (inhibition of bone loss and serum cholesterol levels) with the associated major advantages of preventing breast and uterine cancer. A widely used application of intracrinology is the treatment of prostate cancer where the testicles are blocked by an LHRH agonist while the androgens made locally in the prostate from DHEA are blocked by a pure antiandrogen. Such treatment, called combined androgen blockade, has led to the first demonstration of a prolongation of life in prostate cancer.
对更年期内分泌学的一种新认识是，处于更年期的女性不仅因卵巢活动停止而缺乏雌激素，而且在过去几年中还逐渐缺乏源自肾上腺脱氢表雄酮（DHEA）和雄烯二酮（4-二酮）的雄激素和一些雌激素。事实上，血清DHEA在30岁时达到的最高水平至更年期时会下降约60%。肾上腺DHEA和硫酸脱氢表雄酮（DHEA-S）分泌的减少导致各个靶组织中每种细胞类型特异性表达的类固醇生成酶在外周组织中雄激素和雌激素生成的平行减少。这个内分泌学的新领域，称为细胞内内分泌学，描述了外周组织中每个细胞从肾上腺前体DHEA和4-二酮在局部合成雄激素和雌激素的过程。这些雄激素和雌激素在其合成发生的相同细胞中发挥作用，并且仅在失活后才从这些靶细胞中释放出来。为了进一步了解DHEA对女性的影响，已对绝经后女性给予DHEA 12个月。这种治疗导致骨形成增加和骨矿物质密度升高，同时骨钙素水平升高，骨钙素是骨形成的标志物。阴道成熟受到刺激，而对子宫内膜未观察到影响。另一方面，临床前研究表明，由于DHEA主要转化为雄激素，它可以预防二甲基苯并(a)蒽诱导的大鼠乳腺癌的发生并抑制其生长，这是一种乳腺癌模型。DHEA还抑制裸鼠中人乳腺癌ZR-75-1异种移植物的生长。DHEA对乳腺癌的抑制作用归因于由DHEA在局部生成的睾酮和二氢睾酮的雄激素作用。当用作替代疗法时，DHEA没有乳腺癌和子宫癌的潜在风险，同时它刺激骨形成和阴道成熟并降低胰岛素抵抗。DHEA与第四代选择性雌激素受体调节剂（SERM），如EM-652（SCH 57068）联合使用，EM-652是一种在乳腺和子宫内膜中具有纯而有效的抗雌激素活性的化合物，可为更年期女性带来主要益处（抑制骨质流失和血清胆固醇水平），同时具有预防乳腺癌和子宫癌的主要优势。细胞内内分泌学的一个广泛应用是前列腺癌的治疗，其中睾丸被促黄体生成素释放激素（LHRH）激动剂阻断，而前列腺中由DHEA在局部生成的雄激素被纯抗雄激素阻断。这种治疗方法称为联合雄激素阻断，已首次证明可延长前列腺癌患者的生命。
