Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents
Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents
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DOI：
10.1111/j.2047-2927.2012.00047.x
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发表时间：
2013-03-01
期刊：
影响因子：
4.5
通讯作者：
Swerdloff, Ronald S.
中科院分区：
文献类型：
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作者：
Lue, Yanhe;Wang, Christina;Swerdloff, Ronald S.
合成孕激素如左炔诺孕酮（LNG）在男性避孕临床试验中与睾酮（T）联合使用，以抑制促性腺激素分泌，但孕激素是否对睾丸有额外的直接影响尚不清楚。本研究旨在研究一种有效的孕酮（LNG），单独或与睾酮（T）联合对成年大鼠精子发生的影响，并评估睾丸中孕酮受体（PR）的功能作用。与低剂量LNG处理4周的成年大鼠相比，T和T + LNG处理分别使睾丸精子计数降低至对照水平的64.1%和40.2%。LNG在I-IV和XII-XIV阶段诱导生殖细胞凋亡; T在VII-VIII阶段增加凋亡; LNG + T处理在更广泛的生精上皮阶段诱导更大的生殖细胞凋亡。RT-PCR和Western Blot结果显示，PR在睾丸中存在，并在睾丸激素剥夺诱导的精子发生抑制过程中表达上调。PR基因敲除（PRKO）小鼠的睾丸更大，精子产量更高，支持细胞和间质细胞数量增加。通过GnRH拮抗剂治疗抑制促性腺激素和睾丸内T诱导PR启动子驱动的PRKO小鼠Leydig细胞中LacZ表达。这表明GnRH拮抗剂治疗在诱导生殖细胞凋亡的同时也上调了PR。我们得出结论：（i）LNG + T通过增加生殖细胞凋亡诱导了更大的精子发生抑制，涉及更广泛的生精上皮阶段，而不是单独治疗，（ii）PR的上调与精子发生的抑制有关，（iii）PR基因敲除小鼠的精子产量增加，表明睾丸PR激活事件在睾丸中发挥着生理和药理抑制作用。这些数据支持这一假设，即除了已知的对促性腺激素的抑制作用外，孕激素可能对睾丸有直接的抑制作用。
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.