Garcia A, Schiff M, Marshall J C
J Clin Invest. 1984 Sep;74(3):920-8. doi: 10.1172/JCI111510.
The pattern of the gonadotropin-releasing hormone (GnRH) stimulus is critically important in the regulation of pituitary gonadotropin secretion and continuous infusions down-regulate secretion while intermittent pulses maintain luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsiveness. We examined the effects of pulsatile GnRH administration on pituitary GnRH receptors (GnRH-R) and gonadotropin secretion in the presence of physiological concentrations of testosterone (T) to elucidate the mechanisms and sites of action of GnRH and T on the pituitary gonadotroph. Castrate male rats received one, two, or four testosterone (T) implants (serum T concentrations of 1.1, 2.4, and 5.2 ng/ml, respectively) to suppress endogenous GnRH secretion. Subsequently, intracarotid pulse injections of GnRH (5-250 ng/pulse) or saline in controls were given every 30 min for 48 h, after which gonadotropin responses and pituitary GnRH-R were measured. In control rats, the T implants prevented the rise in GnRH-R that was seen in castrates (empty implant--600 fmol/mg protein) and maintained receptors at the level that was present in intact animals (300 fmol/mg). Pulsatile GnRH administration increased GnRH-R in castrate T-implanted rats, but the response was dependent on the serum T concentration. With one T implant, increasing GnRH doses per pulse stimulated GnRH-R in a linear manner and the maximum receptor concentration (703 +/- 99 fmol/mg) was seen after the 250 ng GnRH dose. In the presence of two T implants, GnRH-R was maximal (705 +/- 45 fmol/mg) after the 25-ng dose and higher doses did not increase receptors above control values. With four T implants, GnRH doses of 5 ng induced a maximum response, 17-50 ng/pulse did not increase GnRH-R, but receptors were again increased by the 250-ng dose (633 +/- 86 fmol/mg). After 48 h of pulsatile GnRH administration there was no correlation between the number of GnRH-R and LH responses to GnRH. In rats with one or two T implants, LH responses were absent after all but the 250-ng doses. In contrast, LH responsiveness was not impaired in the presence of four implants. Thus, low dose GnRH pulses down-regulate LH secretion by an action at a post GnRH-R site, and this effect is regulated by testosterone. The results show that GnRH, given in a pulsatile manner, regulates its own receptor, and physiological increases in serum T produce a 50-fold increase in the sensitivity of GnRH-R stimulation by GnRH.
促性腺激素释放激素（GnRH）刺激模式在垂体促性腺激素分泌调节中至关重要，持续输注会下调分泌，而间歇性脉冲则维持黄体生成素（LH）和卵泡刺激素（FSH）的反应性。我们研究了在生理浓度睾酮（T）存在的情况下，脉冲式给予GnRH对垂体GnRH受体（GnRH-R）和促性腺激素分泌的影响，以阐明GnRH和T对垂体促性腺细胞的作用机制和作用位点。去势雄性大鼠接受1个、2个或4个睾酮（T）植入物（血清T浓度分别为1.1、2.4和5.2 ng/ml）以抑制内源性GnRH分泌。随后，对照组进行颈内动脉脉冲注射GnRH（5 - 250 ng/脉冲）或生理盐水，每30分钟注射一次，共48小时，之后测量促性腺激素反应和垂体GnRH-R。在对照大鼠中，T植入物阻止了去势大鼠中出现的GnRH-R升高（空植入物组为600 fmol/mg蛋白），并将受体维持在完整动物中的水平（300 fmol/mg）。脉冲式给予GnRH可增加去势T植入大鼠的GnRH-R，但反应取决于血清T浓度。对于1个T植入物，每个脉冲增加GnRH剂量以线性方式刺激GnRH-R，在250 ng GnRH剂量后出现最大受体浓度（703±99 fmol/mg）。在有2个T植入物的情况下，25 ng剂量后GnRH-R达到最大值（705±45 fmol/mg），更高剂量不会使受体增加到对照值以上。对于4个T植入物，5 ng的GnRH剂量诱导最大反应，17 - 50 ng/脉冲不会增加GnRH-R，但250 ng剂量再次增加了受体（633±86 fmol/mg）。脉冲式给予GnRH 48小时后，GnRH-R数量与对GnRH的LH反应之间无相关性。在有1个或2个T植入物的大鼠中，除250 ng剂量外，所有剂量后均无LH反应。相反，在有4个植入物的情况下，LH反应未受损。因此，低剂量GnRH脉冲通过在GnRH-R后位点的作用下调LH分泌，且这种作用受睾酮调节。结果表明，以脉冲方式给予的GnRH调节其自身受体，血清T的生理性增加使GnRH刺激GnRH-R的敏感性提高50倍。
