Labrie Fernand, Bélanger Alain, Pelletier Georges, Martel Céline, Archer David F, Utian Wulf H
1Laval University, Quebec City, Canada 2Endoceutics Inc, Quebec City, Canada 3CONRAD Clinical Research Center, Norfolk, VA 4Case Western Reserve University, Cleveland, OH.
Menopause. 2017 Jun;24(6):702-712. doi: 10.1097/GME.0000000000000808.
To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of intracrinology, whereby each cell of each peripheral tissue makes a small and appropriate amount of estrogens and androgens from the inactive precursor dehydroepiandrosterone (DHEA), DHEA being mainly of adrenal origin. Because only the inactivated sex steroids are released in the blood, influence in the other tissues is avoided.
Molecular biology has been used for the identification/characterization of the steroid-forming and steroid-inactivating enzymes, whereas steroids have been measured by mass spectrometry-based assays validated according to the US Food and Drug Administration guidelines.
Evolution over 500 million years has engineered the expression of about 30 steroid-forming enzymes specific for each peripheral tissue. These tissue-specific enzymes transform DHEA into the appropriate small amounts of estrogens and androgens for a strictly intracellular and local action. Humans, contrary to species below primates, also possess intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, which inactivate the estrogens and androgens at their local site of formation, thus preventing the release of a biologically significant amount of estradiol (E2) and testosterone in the circulation. Since DHEA becomes the unique source of sex steroids after menopause, serum E2 and testosterone are thus maintained at low biologically inactive concentrations with no activity outside the cells of origin. DHEA secretion, unfortunately, starts decreasing at about the age of 30 at various rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when the concentration of serum DHEA decreases. Considering this mechanism is unique to the human, it seems logical to replace DHEA locally in women suffering from vulvovaginal atrophy (genitourinary syndrome of menopause). The clinical data obtained using a small dose of intravaginal DHEA (prasterone) confirm the mechanisms of intracrinology mentioned above which avoid biologically significant changes in serum E2 and testosterone.
The symptoms and signs of vulvovaginal atrophy (genitourinary syndrome of menopause) can be successfully treated by the intravaginal administration of DHEA without safety concerns. This strategy exclusively replaces in the vagina the missing cell-specific intracellular estrogens and androgens. This approach avoids systemic exposure and the potential risks of estrogen exposure for the tissues other than the vagina.
阐述经典内分泌学与内分泌自分泌学之间的显著差异。经典内分泌学通过血液循环将激素输送到身体的所有组织，而内分泌自分泌学是指身体每个外周组织的每个细胞从无活性前体脱氢表雄酮（DHEA）合成少量适量的雌激素和雄激素，DHEA主要来源于肾上腺。由于只有失活的性类固醇释放到血液中，因此可避免对其他组织产生影响。
利用分子生物学技术鉴定/表征类固醇生成酶和类固醇失活酶，而类固醇则通过根据美国食品药品监督管理局指南验证的基于质谱的分析方法进行测定。
5亿多年的进化过程促使每个外周组织表达约30种特异性类固醇生成酶。这些组织特异性酶将DHEA转化为适量的少量雌激素和雄激素，用于严格的细胞内局部作用。与灵长类以下的物种不同，人类还拥有细胞内类固醇失活酶，尤其是葡萄糖醛酸转移酶和硫酸转移酶，它们在雌激素和雄激素的生成部位使其失活，从而防止大量具有生物学活性的雌二醇（E2）和睾酮释放入循环系统。由于绝经后DHEA成为性类固醇的唯一来源，血清E2和睾酮因此维持在低生物学无活性浓度，在其产生细胞之外无活性。不幸的是，DHEA分泌在30岁左右开始以不同速度下降，不同女性下降速度各异。此外，当血清DHEA浓度降低时，没有反馈机制来增加DHEA分泌。鉴于此机制是人类特有的，对于患有外阴阴道萎缩（绝经后泌尿生殖综合征）的女性，局部补充DHEA似乎是合理的。使用小剂量阴道内DHEA（普拉睾酮）获得的临床数据证实了上述内分泌自分泌学机制，即避免血清E2和睾酮出现具有生物学意义的变化。
阴道内给予DHEA可成功治疗外阴阴道萎缩（绝经后泌尿生殖综合征）的症状和体征，且无安全问题。该策略仅在阴道内补充缺失的细胞特异性细胞内雌激素和雄激素。这种方法避免了全身暴露以及除阴道外其他组织雌激素暴露的潜在风险。
