Department of Experimental Medicine, University La Sapienza, Via A. Scarpa 16, 00160 Rome, Italy.
Section of Histology and Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Via A. Scarpa 16, 00160 Rome, Italy.
Int J Mol Sci. 2023 Mar 27;24(7):6296. doi: 10.3390/ijms24076296.
Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers-myo-Inositol and D-Chiro-Inositol-have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association-according to the physiological ratio of 40:1-patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.
多囊卵巢综合征（PCOS）是女性最常见的内分泌疾病，除了慢性无排卵/月经稀少和卵巢囊肿外，高雄激素血症在很大一部分患者中起着关键作用。肌醇异构体-肌醇和 D-手性肌醇-最近在治疗许多 PCOS 症状方面具有药理作用，同时恢复卵巢生育能力。然而，一些令人失望的临床结果促使人们重新考虑它们的特定生物学功能。令人惊讶的是，D-手性肌醇刺激雄激素合成并减少卵巢雌激素途径；相反，肌醇激活 FSH 反应和芳香酶活性，最终减轻卵巢高雄激素血症。然而，当两种异构体按生理比例 40:1 联合使用时-患者可以受益于肌醇增强的 FSH 和雌激素反应性，同时利用 D-手性肌醇主要表现出的胰岛素增敏作用。我们不需要假设胰岛素抵抗来解释 PCOS 的发病机制，因为胰岛素敏感性很可能是 PCOS 卵巢的共同特征。事实上，即使在生理胰岛素刺激下，PCOS 卵巢合成的 D-手性肌醇也比对照的卵泡膜细胞中测量到的多四倍。卵巢内增加的 D-手性肌醇不利于维持甾体生成控制，这种失败很容易解释为什么基于高 D-手性肌醇的治疗策略被认为效果不佳。从这个角度来看，有两个因素成为 PCOS 的主要决定因素：高雄激素血症和芳香酶表达减少。因此，PCOS 不能再仅仅因为雄激素合成增加而被认为是一种疾病，而不考虑芳香酶和 FSH 受体的同时下调。此外，这些发现表明，肌醇异构体可能仅对那些以高雄激素血症为特征的 PCOS 表型具有特异性作用。
