Zhejiang Provincial Key Laboratory of Anesthesiology, Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Front Endocrinol (Lausanne). 2021 Nov 12;12:765251. doi: 10.3389/fendo.2021.765251. eCollection 2021.
Midazolam is a neurological drug with diverse functions, including sedation, hypnosis, decreased anxiety, anterograde amnesia, brain-mediated muscle relaxation, and anticonvulsant activity. Since it is frequently used in children and adolescents for extended periods of time, there is a risk that it may affect their pubertal development. Here, we report a potential effect of the drug on the development of Leydig cells (LCs), the testosterone (T)-producing cells in the testis.
Stem LCs (SLCs), isolated from adult rat testes by a magnetic-activated cell sorting technique, were induced to differentiate into LCs for 3 weeks. Midazolam (0.1-30 μM) was added to the culture medium, and the effects on LC development were assayed.
Midazolam has dose-dependent effects on SLC differentiation. At low concentrations (0.1-5 μM), the drug can mildly increase SLC differentiation (increased T production), while at higher concentrations (15-30 μM), it inhibits LC development (decreased T production). T increases at lower levels may be due to upregulations of scavenger receptor class b Member 1 (SCARB1) and cytochrome P450 17A1 (CYP17A1), while T reductions at higher levels of midazolam could be due to changes in multiple steroidogenic proteins. The uneven changes in steroidogenic pathway proteins, especially reductions in CYP17A1 at high midazolam levels, also result in an accumulation of progesterone. In addition to changes in T, increases in progesterone could have additional impacts on male reproduction. The loss in steroidogenic proteins at high midazolam levels may be mediated in part by the inactivation of protein kinase B/cAMP response element-binding protein (AKT/CREB) signaling pathway.
Midazolam has the potential to affect adult Leydig cell (ALC) development at concentrations comparable with the blood serum levels in human patients. Further studies are needed to test the effects on human cells.
咪达唑仑是一种具有多种功能的神经药物，包括镇静、催眠、降低焦虑、顺行性遗忘、脑介导的肌肉松弛和抗惊厥活性。由于它在儿童和青少年中经常被长时间使用，因此存在影响他们青春期发育的风险。在这里，我们报告了该药物对睾丸中产生睾酮（T）的睾丸间质细胞（LC）发育的潜在影响。
通过磁激活细胞分选技术从成年大鼠睾丸中分离出干细胞 LC（SLC），并将其诱导分化为 LC 3 周。将咪达唑仑（0.1-30 μM）添加到培养基中，检测其对 LC 发育的影响。
咪达唑仑对 SLC 分化具有剂量依赖性影响。在低浓度（0.1-5 μM）下，该药物可轻度增加 SLC 分化（增加 T 产生），而在较高浓度（15-30 μM）下，它抑制 LC 发育（减少 T 产生）。较低水平的 T 增加可能是由于清道夫受体 B 类成员 1（SCARB1）和细胞色素 P450 17A1（CYP17A1）的上调，而较高水平的咪达唑仑导致 T 减少可能是由于多种类固醇生成蛋白的变化。类固醇生成途径蛋白的不均匀变化，特别是高咪达唑仑水平下 CYP17A1 的减少，也导致孕酮的积累。除了 T 的变化外，孕酮的增加也可能对男性生殖产生额外的影响。高咪达唑仑水平下类固醇生成蛋白的丢失可能部分是通过蛋白激酶 B/cAMP 反应元件结合蛋白（AKT/CREB）信号通路的失活介导的。
咪达唑仑在与人类患者血清水平相当的浓度下有可能影响成人睾丸间质细胞（ALC）的发育。需要进一步的研究来测试对人类细胞的影响。
