Laboratory of Neuroendocrinology, GIGA Neurosciences, University of Liège, Liège, Belgium.
Department of Obstetrics and Gynecology, University of Liège, Liège, Belgium.
J Neuroendocrinol. 2023 Oct;35(10):e13341. doi: 10.1111/jne.13341. Epub 2023 Oct 8.
The activation of male sexual behavior depends on brain estrogen synthesis. Estrogens act through nuclear and membrane receptors producing effects within hours/days or seconds/minutes, respectively. In mice, estrogen receptor alpha (ERα) is the main estrogen receptor (ER) controlling the activation of male sexual behavior. Although neuroestrogens rapidly modulate mouse sexual behavior, it is not known whether these effects involve membrane ERα (mERα). This study combines two complementary approaches to address this question. C451A-ERα mice carry an ERα that cannot signal at the membrane, while estetrol (E4) is a natural estrogen acting as an agonist on nuclear ERα but as an antagonist on membrane ERα. In wild-type males, E4 decreased the number of mounts and intromissions after 10 min. In C451A-ERα males, E4 also altered sexual performance but after 30 min. E4 did not affect time spent near the female in both wild-type and C451A-ERα mice. However, regardless of genotype, the aromatase inhibitor 1,4,6-Androstatriene-3,17-dione (ATD) decreased both sexual performance and the time spent near the female after 10 and 30 min, confirming the key role of aromatization in the rapid control of sexual behavior and motivation. In conclusion, the shift in timing at which the effect of E4 is observed in mice lacking mERα suggests a role for mERα in the regulation of rapid effects of neuroestrogens on sexual performance, thus providing the first demonstration that E4 acts as an antagonist of a mER in the brain. The persisting effect of ATD on behavior in C451A-ERα mice also suggests the implication of another ER.
雄性性行为的激活依赖于大脑中的雌激素合成。雌激素通过核受体和膜受体发挥作用，分别在数小时/天或数秒/分钟内产生作用。在小鼠中，雌激素受体α（ERα）是控制雄性性行为激活的主要雌激素受体（ER）。尽管神经雌激素能迅速调节小鼠的性行为，但尚不清楚这些作用是否涉及膜 ERα（mERα）。本研究结合了两种互补的方法来解决这个问题。C451A-ERα 小鼠携带一种不能在膜上发出信号的 ERα，而雌三醇（E4）是一种天然的雌激素，作为核 ERα 的激动剂，但作为膜 ERα 的拮抗剂。在野生型雄性小鼠中，E4 在 10 分钟后减少了交配和插入的次数。在 C451A-ERα 雄性小鼠中，E4 也改变了性行为表现，但需要 30 分钟。E4 对野生型和 C451A-ERα 小鼠靠近雌性的时间没有影响。然而，无论基因型如何，芳香化酶抑制剂 1,4,6-雄甾三烯-3,17-二酮（ATD）都在 10 分钟和 30 分钟后降低了性行为表现和靠近雌性的时间，这证实了芳香化作用在快速控制性行为和动机方面的关键作用。总之，在缺乏 mERα 的小鼠中观察到 E4 作用的时间变化表明 mERα 在调节神经雌激素对性行为的快速作用中起作用，从而首次证明 E4 作为脑内 mER 的拮抗剂发挥作用。ATD 在 C451A-ERα 小鼠行为上的持续作用也表明另一种 ER 的参与。
