Department of Reproductive Biomedicine, National Institute of Health and Family Welfare, Munirka, New Delhi-110067, India.
Contraception. 2012 Aug;86(2):163-71. doi: 10.1016/j.contraception.2011.11.020. Epub 2012 Jan 20.
We had shown that dienogest (DNG) + testosterone undecanoate (TU) induced complete sperm suppression in rats when administered together every 45 days. On the other hand, individual drugs given alone in a similar fashion failed to achieve the same result.
The present study was therefore undertaken to determine the reason for such a differential sperm suppression and to correlate it with the expression of steroidogenic enzyme genes in the rat testis.
Administration of DNG (40 mg/kg body weight [bw]) + TU (25 mg/kg bw) every 45 days for a duration of 90 days induced spermatogenic arrest, leading to a significant reduction in testicular weight and number of precursor germ cells. Flow cytometric analysis further confirmed the same result, leading to a significant shift in the distribution of haploid cells. Measurement of testosterone (serum and intratesticular) was significantly low. Complete sperm suppression coincided with significant down-regulation in the expression of upstream steroidogenic enzyme genes represented serially by cytochrome P450 side-chain cleavage, P450 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein (StAR) in the testis. On the other hand, rats administered with either DNG or TU alone demonstrated incomplete sperm suppression in which the expression of all the above genes remained characteristically nonuniform.
Taken together, the above findings corroborate the fact that regulation of expression of three of the upstream steroidogenic enzymes genes and the StAR protein in rat testis is crucial in leading to complete sperm suppression as observed with DNG+TU treatment.
我们曾表明，当每 45 天联合给予地诺孕素（DNG）和十一酸睾酮（TU）时，它们会导致大鼠的精子完全被抑制。另一方面，以类似方式单独给予这两种药物均无法达到相同的效果。
因此，本研究旨在确定导致这种精子抑制差异的原因，并将其与大鼠睾丸中类固醇生成酶基因的表达相关联。
连续 90 天，每 45 天给予 DNG（40mg/kg 体重）+TU（25mg/kg bw）可导致生精停滞，导致睾丸重量和前体细胞数量显著减少。流式细胞术分析进一步证实了这一结果，导致单倍体细胞分布发生显著变化。血清和睾丸内睾酮的测量均显著降低。完全的精子抑制与上游类固醇生成酶基因的表达显著下调相一致，这些基因依次由细胞色素 P450 侧链裂解酶、P450 17α-羟化酶、3β-羟甾脱氢酶和类固醇急性调节蛋白（StAR）代表。另一方面，单独给予 DNG 或 TU 的大鼠表现出不完全的精子抑制，其中所有上述基因的表达仍然表现出特征性的不均匀。
综上所述，这些发现证实了这样一个事实，即调节大鼠睾丸中三个上游类固醇生成酶基因和 StAR 蛋白的表达对于导致 DNG+TU 治疗中观察到的完全精子抑制至关重要。
