Frungieri Mónica B, Gonzalez-Calvar Silvia I, Parborell Fernanda, Albrecht Martin, Mayerhofer Artur, Calandra Ricardo S
Instituto de Biología y Medicina Experimental (M.B.F., S.I.G.-C., F.P., R.S.C.), Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina.
Endocrinology. 2006 Sep;147(9):4476-85. doi: 10.1210/en.2006-0090. Epub 2006 Jun 1.
We have previously found that cyclooxygenase-2 (COX-2), a key enzyme in the biosynthesis of prostaglandins (PGs), is present in the testicular interstitial cells of infertile men, whereas it is absent in human testes with no evident morphological changes or abnormalities. To find an animal model for further investigating COX-2 and its role in testicular steroidogenesis, we screened testes from adult species ranging from mice to monkeys. By using immunohistochemical assays, we found COX-2 expression only in Leydig cells of the reproductively active (peripubertal, pubertal, and adult) seasonal breeder Syrian hamster. COX-2 expression in hamster Leydig cells was confirmed by RT-PCR. In contrast, COX-1 expression was not detected in hamster testes. Because COX-2 expression implies PG synthesis, we investigated the effect of various PGs on testosterone production and found that PGF2 alpha stood out because it significantly reduced human chorionic gonadotropin-stimulated testosterone release from isolated hamster Leydig cells in a dose-dependent manner. This mechanism involves a decreased expression of testicular steroidogenic acute regulatory protein and 17beta-hydroxysteroid dehydrogenase. Testicular concentration and content of PGF2 alpha in reproductively active hamsters as well as production of PGF2 alpha from isolated hamster Leydig cells were also determined. Moreover, PGF2 alpha receptors were localized in Leydig cells of hamsters and testicular biopsies from patients with Sertoli cell only and germ arrest syndromes. Thus, in this study, we described a COX-2-initiated pathway that via PGF2 alpha production, PGF2 alpha receptors, steroidogenic acute regulatory protein, and 17beta-hydroxysteroid dehydrogenase represents a physiological local inhibitory system of human chorionic gonadotropin-stimulated testosterone production in the Syrian hamster testes.
我们之前发现，环氧化酶-2（COX-2）是前列腺素（PGs）生物合成中的关键酶，存在于不育男性的睾丸间质细胞中，而在无明显形态变化或异常的人类睾丸中则不存在。为了找到一个动物模型来进一步研究COX-2及其在睾丸类固醇生成中的作用，我们筛选了从小鼠到猴子等成年物种的睾丸。通过免疫组化分析，我们发现COX-2仅在具有生殖活性（青春期前、青春期和成年期）的季节性繁殖叙利亚仓鼠的睾丸间质细胞中表达。通过RT-PCR证实了COX-2在仓鼠睾丸间质细胞中的表达。相比之下，在仓鼠睾丸中未检测到COX-1的表达。由于COX-2的表达意味着PG的合成，我们研究了各种PG对睾酮产生的影响，发现前列腺素F2α（PGF2α）尤为突出，因为它以剂量依赖的方式显著降低了人绒毛膜促性腺激素刺激的分离仓鼠睾丸间质细胞睾酮释放。这一机制涉及睾丸类固醇生成急性调节蛋白和17β-羟基类固醇脱氢酶的表达降低。还测定了具有生殖活性的仓鼠睾丸中PGF2α的浓度和含量，以及分离的仓鼠睾丸间质细胞中PGF2α的产生。此外，PGF2α受体定位于仓鼠的睾丸间质细胞以及仅患有支持细胞和生精阻滞综合征患者的睾丸活检组织中。因此，在本研究中，我们描述了一条由COX-2启动的途径，该途径通过PGF2α的产生、PGF2α受体、类固醇生成急性调节蛋白和17β-羟基类固醇脱氢酶，代表了叙利亚仓鼠睾丸中人类绒毛膜促性腺激素刺激的睾酮产生的生理局部抑制系统。
