Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA 90509, USA.
Andrology. 2013 Mar;1(2):308-17. doi: 10.1111/j.2047-2927.2012.00047.x.
Synthetic progestins such as levonorgestrel (LNG) are used in combination with testosterone (T) in male contraceptive clinical trials to suppress gonadotropins secretion, but whether progestins have additional direct effects on the testis are not known. This study aimed to examine the effect of a potent progestin, (LNG), alone or in combination with testosterone (T) on spermatogenesis in adult rats, and to evaluate the functional role of the progesterone receptors (PRs) in the testis. In comparison with a low dose of LNG treatment in adult rats for 4 weeks, T and T + LNG treatment decreased testicular sperm count to 64.1 and 40.2% of control levels respectively. LNG induced germ cell apoptosis at stages I-IV and XII-XIV; T increased apoptosis at stages VII-VIII; LNG + T treatment induced greater germ cell apoptosis at a wider range of seminiferous epithelial stages. RT-PCR and Western Blots showed that PR was present in testes and up-regulated during suppression of spermatogenesis induced by testicular hormonal deprivation. PR knockout (PRKO) mice had larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells. Suppression of gonadotropin and intratesticular T by GnRH-antagonist treatment induced PR promoter driven LacZ expression in Leydig cells of PRKO mice. This suggests that GnRH-antagonist treatment while inducing germ cell apoptosis also up-regulates PR. We conclude that (i) LNG + T induced greater suppression of spermatogenesis through increase in germ cell apoptosis involving a wider range of seminiferous epithelial stages than either treatment alone, (ii) up-regulation of PR was associated with inhibition of spermatogenesis, (iii) PR knockout mice showed increased sperm production suggesting that testicular PR activated events play a physiological and pharmacological inhibitory role in the testis. These data support the hypothesis that in addition to its known suppressive effects on gonadotropins, progestins may have direct inhibitory actions on the testis.
合成孕激素如左炔诺孕酮（LNG）与睾酮（T）联合用于男性避孕临床试验中，以抑制促性腺激素的分泌，但孕激素是否对睾丸有额外的直接作用尚不清楚。本研究旨在研究一种强效孕激素（LNG）单独或与睾酮（T）联合应用对成年大鼠生精的影响，并评估孕激素受体（PR）在睾丸中的功能作用。与成年大鼠低剂量 LNG 处理 4 周相比，T 和 T+LNG 处理使睾丸精子计数分别下降至对照水平的 64.1%和 40.2%。LNG 诱导 I-IV 期和 XII-XIV 期精母细胞凋亡；T 增加 VII-VIII 期凋亡；LNG+T 处理诱导更广泛的生精上皮阶段的精母细胞凋亡。RT-PCR 和 Western Blot 显示 PR 存在于睾丸中，并在睾丸激素剥夺诱导的生精抑制中上调。PR 敲除（PRKO）小鼠的睾丸较大，精子生成较多，支持细胞和间质细胞数量增加。促性腺激素释放激素拮抗剂治疗抑制促性腺激素和睾丸内 T 诱导 PRKO 小鼠间质细胞中 PR 启动子驱动的 LacZ 表达。这表明 GnRH 拮抗剂治疗在诱导精母细胞凋亡的同时，还上调 PR。我们得出结论：（i）LNG+T 通过增加涉及更广泛的生精上皮阶段的精母细胞凋亡，比单独治疗更能抑制生精作用；（ii）PR 的上调与生精抑制有关；（iii）PRKO 小鼠精子生成增加，表明睾丸 PR 激活的事件在睾丸中发挥生理和药理学抑制作用。这些数据支持以下假设：除了已知对促性腺激素的抑制作用外，孕激素可能对睾丸有直接抑制作用。
