Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland.
Int J Mol Sci. 2022 Apr 27;23(9):4815. doi: 10.3390/ijms23094815.
Hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) is an enzyme that converts estrone to estradiol, while adenomyosis is an estrogen-dependent disease with poorly understood pathophysiology. In the present study, we show that mice universally over-expressing human estrogen biosynthetic enzyme (HSD17B1TG mice) present with adenomyosis phenotype, characterized by histological and molecular evaluation. The first adenomyotic changes with endometrial glands partially or fully infiltrated into the myometrium appeared at the age of 5.5 months in HSD17B1TG females and became more prominent with increasing age. Preceding the phenotype, increased myometrial smooth muscle actin positivity and increased amount of glandular myofibroblast cells were observed in HSD17B1TG uteri. This was accompanied by transcriptomic upregulation of inflammatory and estrogen signaling pathways. Further, the genes upregulated in the HSD17B1TG uterus were enriched with genes previously observed to be induced in the human adenomyotic uterus, including several genes of the NFKB pathway. A 6-week-long HSD17B1 inhibitor treatment reduced the occurrence of the adenomyotic changes by 5-fold, whereas no effect was observed in the vehicle-treated HSD17B1TG mice, suggesting that estrogen is the main upstream regulator of adenomyosis-induced uterine signaling pathways. HSD17B1 is considered as a promising drug target to inhibit estrogen-dependent growth of endometrial disorders. The present data indicate that HSD17B1 over-expression in TG mice results in adenomyotic changes reversed by HSD17B1 inhibitor treatment and HSD17B1 is, thus, a potential novel drug target for adenomyosis.
羟甾体 17β 脱氢酶 1 型（HSD17B1）是一种将雌酮转化为雌二醇的酶，而子宫腺肌病是一种雌激素依赖性疾病，其病理生理学尚未完全阐明。在本研究中，我们表明普遍过表达人雌激素生物合成酶的小鼠（HSD17B1TG 小鼠）表现出子宫腺肌病表型，通过组织学和分子评估进行特征描述。在 5.5 月龄时，HSD17B1TG 雌性小鼠开始出现第一个具有部分或完全浸润到子宫肌层的子宫内膜腺体的子宫腺肌病样改变，并且随着年龄的增长而变得更加明显。在表型出现之前，HSD17B1TG 子宫中的子宫平滑肌肌动蛋白阳性增加和腺体平滑肌成纤维细胞数量增加。这伴随着炎症和雌激素信号通路的转录组上调。此外，HSD17B1TG 子宫中上调的基因与在人类子宫腺肌病子宫中观察到的诱导基因富集，包括 NFKB 途径的几个基因。为期 6 周的 HSD17B1 抑制剂治疗使腺肌病样改变的发生减少了 5 倍，而在未接受治疗的 HSD17B1TG 小鼠中未观察到这种效果，这表明雌激素是诱导子宫信号通路中腺肌病发生的主要上游调节剂。HSD17B1 被认为是抑制雌激素依赖性子宫内膜疾病生长的有前途的药物靶标。本研究数据表明，HSD17B1TG 小鼠中的 HSD17B1 过表达导致腺肌病样改变，HSD17B1 抑制剂治疗可逆转这些改变，因此 HSD17B1 是子宫腺肌病的一个潜在新的药物靶标。
