Derkach K V, Romanova I V, Bakhtyukov A A, Morina I Yu, Dar'in D V, Sorokoumov V N, Shpakov A O
Laboratory of Molecular Endocrinology and Neurochemistry, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
Department of Organic Chemistry, St. Petersburg State University, St. Petersburg, Russia.
Bull Exp Biol Med. 2021 May;171(1):81-86. doi: 10.1007/s10517-021-05177-5. Epub 2021 May 29.
Human chorionic gonadotropin that is widely used for improving spermatogenesis. The effect of chorionic gonadotropin is mediated through luteinizing hormone receptor. Treatment with gonadotropin is associated with undesirable effects due to hyperactivation of testosterone production and luteinizing hormone receptor desensitization. A promising alternative could be low-molecular-weight agonists of luteinizing hormone receptors, but their effects on spermatogenesis have not been investigated. Here we analyzed the effect of a thieno[2,3-d]pyrimidines (TP), 4-((3-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno [2,3-d]pyrimidine-4-yl) phenyl)carbamoyl)pyridine 1-oxide (TP22), an allosteric agonist of luteinizing hormone receptors, on the seminiferous tubules and spermatogenic cells in 4- and 18-month-old male rats and in animals with diabetes mellitus. TP22 and gonadotropin were administered in daily doses of 15 mg/kg and 20 U/rat for 5 days. Blood testosterone level, morphology of the seminiferous tubules, and the number of germ cells in them were estimated. Being comparable by the efficiency to gonadotropin, TP22 increased the testosterone level in all the studied groups of rats and restored epithelium thickness in the seminiferous tubules and the number of spermatogonia and pachytenic spermatocytes that are reduced in aging and diabetes, but, unlike gonadotropin, did not suppress the expression of luteinizing hormone receptor. The efficacy of TP22 as a stimulator of testicular spermatogenesis has been demonstrated both under normal conditions and in age-related and diabetes-associated reproductive dysfunctions.
人绒毛膜促性腺激素被广泛用于改善精子发生。绒毛膜促性腺激素的作用是通过促黄体生成素受体介导的。由于睾酮生成的过度激活和促黄体生成素受体脱敏，使用促性腺激素治疗会产生不良影响。一种有前景的替代方法可能是促黄体生成素受体的低分子量激动剂，但它们对精子发生的影响尚未得到研究。在这里，我们分析了噻吩并[2,3-d]嘧啶（TP），4-((3-(5-氨基-6-(叔丁基氨基甲酰基)-2-(甲硫基)噻吩并[2,3-d]嘧啶-4-基)苯基)氨基甲酰基)吡啶1-氧化物（TP22），一种促黄体生成素受体的变构激动剂，对4个月和18个月大的雄性大鼠以及糖尿病动物的生精小管和生精细胞的影响。TP22和促性腺激素以每日剂量15mg/kg和20U/大鼠给药5天。估计血液睾酮水平、生精小管的形态以及其中生殖细胞的数量。TP22在提高睾酮水平方面与促性腺激素效果相当，它能恢复所有研究组大鼠的睾酮水平，恢复生精小管的上皮厚度以及衰老和糖尿病中减少的精原细胞和粗线期精母细胞的数量，但与促性腺激素不同的是，它不会抑制促黄体生成素受体的表达。TP22作为睾丸精子发生刺激剂的功效在正常条件下以及与年龄相关和糖尿病相关的生殖功能障碍中均得到了证实。
