Paul S J, Ortolano G A, Haisenleder D J, Stewart J M, Shupnik M A, Marshall J C
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0354.
Mol Endocrinol. 1990 Dec;4(12):1943-55. doi: 10.1210/mend-4-12-1943.
Regulation of gonadotropin gene expression by sex steroids may occur via direct effects on the pituitary and/or indirect effects of steroids mediated through hypothalamic GnRH. We aimed to define the effects of testosterone (T) on alpha, LH beta, and FSH beta mRNA expression in the male rat after blockade of GnRH action on the gonadotrope. A water-soluble GnRH antagonist was administered iv to castrate male rats (increased endogenous GnRH secretion) and to castrate T-replaced rats in which gonadotropin subunit mRNAs had been increased by prior treatment with exogenous GnRH pulses. In castrate male rats, GnRH antagonist resulted in a fall in all three subunit mRNAs. Alpha and LH beta declined at slower rates (half-disappearance after 50 and 65 h, respectively), and neither fell to values present in intact rats over 84 h. In contrast, FSH beta mRNA declined more rapidly, with a half-disappearance after 20 h. In castrate T-replaced rats, alpha mRNA declined at a rate similar to that in castrates (half-disappearance after 50 h). LH beta declined more slowly, and the rate of FSH beta decline was markedly prolonged in the presence of T (half-disappearance time increased from 20 to 50 h). These results suggest that T exerts direct effects on FSH beta transcription or mRNA stability which are independent of GnRH action. To assess these possibilities, a long-acting GnRH antagonist (Detirelix) was administered to castrate male rats, which also received T or sham implants 4 days after castration. FSH beta mRNA levels fell during the 4 days of Detirelix alone, but the addition of T on day 4 resulted in a 2-fold rise in FSH beta mRNA, restoring FSH beta mRNA to levels present in intact rats. Serum FSH closely paralleled FSH beta mRNA concentrations. Alpha mRNA was reduced by 25%, and LH beta mRNA concentrations were unchanged in the presence of T. The rate of alpha mRNA transcription was markedly reduced and that of LH beta tended to fall in T-treated rats, but T had no significant effect on the FSH beta transcription rate. Thus, the action of T to increase concentrations of cytosolic FSH beta mRNA appears to be exerted at a posttranscriptional level, possibly via effects of T on FSH beta mRNA stability. This may represent a mechanism by which T can effect differential regulation of gonadotropin subunit mRNA concentrations.
性类固醇对促性腺激素基因表达的调节可能通过对垂体的直接作用和/或下丘脑促性腺激素释放激素（GnRH）介导的类固醇间接作用来实现。我们旨在确定在阻断GnRH对促性腺激素细胞的作用后，睾酮（T）对雄性大鼠α、促黄体生成素β（LHβ）和促卵泡生成素β（FSHβ）mRNA表达的影响。将一种水溶性GnRH拮抗剂静脉注射给去势雄性大鼠（内源性GnRH分泌增加）以及去势后用外源性GnRH脉冲预处理使促性腺激素亚基mRNA增加的T替代去势大鼠。在去势雄性大鼠中，GnRH拮抗剂导致所有三种亚基mRNA水平下降。α和LHβ下降速度较慢（分别在50和65小时后半衰期消失），且在84小时内均未降至完整大鼠的水平。相比之下，FSHβmRNA下降更快，20小时后半衰期消失。在去势T替代大鼠中，αmRNA下降速度与去势大鼠相似（50小时后半衰期消失）。LHβ下降更慢，且在有T存在时FSHβ下降速度明显延长（半衰期时间从20小时增加到50小时）。这些结果表明，T对FSHβ转录或mRNA稳定性有直接作用，且独立于GnRH作用。为评估这些可能性，给去势雄性大鼠注射长效GnRH拮抗剂（地瑞林），这些大鼠在去势4天后还接受了T或假植入。仅在使用地瑞林的4天内FSHβmRNA水平下降，但在第4天添加T导致FSHβmRNA升高2倍，使FSHβmRNA恢复到完整大鼠的水平。血清FSH与FSHβmRNA浓度密切平行。αmRNA降低了25%，在有T存在时LHβmRNA浓度未改变。在T处理的大鼠中，αmRNA转录速度明显降低，LHβ转录速度趋于下降，但T对FSHβ转录速度无显著影响。因此，T增加细胞溶质FSHβmRNA浓度的作用似乎在转录后水平发挥，可能是通过T对FSHβmRNA稳定性的影响。这可能代表了T对促性腺激素亚基mRNA浓度进行差异调节的一种机制。
