Amargant Farners, Magalhaes Carol, Pritchard Michele T, Duncan Francesca E
Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA.
Geroscience. 2024 Sep 16. doi: 10.1007/s11357-024-01322-w.
The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here, we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells treated with a pro-fibrotic or a pro-inflammatory stimulus. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression. We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6 weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.
女性生殖系统是人类最早出现衰老的系统之一，会导致不孕和内分泌紊乱。衰老的卵巢呈现出一种纤维炎症环境，对配子的数量和质量以及排卵产生负面影响。在此，我们测试了全身性给予抗炎药物（依那西普）或抗纤维化药物（吡非尼酮）是否能减轻小鼠的卵巢衰老。我们首先评估了这些药物在经促纤维化或促炎刺激处理的原代卵巢基质细胞中降低纤维炎症基因表达的能力。虽然依那西普并未阻断卵巢基质细胞中肿瘤坏死因子（Tnf）的表达，但吡非尼酮显著降低了Ⅰ型胶原蛋白α1（Col1a1）的表达。然后我们在体内测试了吡非尼酮，该药物通过微型渗透泵进行全身性给药，持续6周。吡非尼酮减轻了卵巢纤维化随年龄增长的增加，且不影响整体健康参数。在接受吡非尼酮治疗的小鼠中，卵巢功能得到改善，表现为卵泡和黄体数量增加、抗苗勒管激素（AMH）水平升高以及动情周期改善。转录组分析显示，吡非尼酮治疗在8.5月龄时导致生殖功能相关基因上调，在12月龄时导致炎症基因下调。这些发现表明，减少卵巢纤维炎症微环境可改善卵巢功能，从而支持将调节卵巢环境作为延长生殖寿命的一种治疗途径。
