Winters S J, Pohl C R, Adedoyin A, Marshall G R
Department of Medicine, University of Pittsburgh, Pennsylvania 15213, USA.
Biol Reprod. 1996 Dec;55(6):1377-82. doi: 10.1095/biolreprod55.6.1377.
To begin to examine inhibin as a male contraceptive, recombinant human (rh) inhibin-A was administered for 3 days via osmotic minipumps to male rats. Doses of inhibin of 0-150 mg/kg per day did not produce a concentration-dependent suppression of FSH secretion or pituitary FSH beta mRNA levels in adult rats. Treatment of immature rats at a dose of 145 micrograms/kg per day, which was without effect in adults, reduced plasma FSH levels by 49% (p < 0.01), and FSH beta mRNA levels to 47 +/- 11% of control (p < 0.01). Inhibin also decreased levels of LH beta mRNA (63 +/- 8% of control; p < 0.01), alpha-subunit mRNA (86 +/- 10% of control; p < 0.05), and GnRH-receptor mRNA (77 +/- 17% of control; p <0.01) in immature rats. Rh inhibin-A was more effective in immature than in adult animals; plasma inhibin levels were increased (p = 0.03) by rh inhibin-A treatment only in immature rats. Pharmacokinetic studies revealed that the weight-adjusted clearance was greater (p < 0.01), and the elimination half-life of rh inhibin A was shorter (p < 0.01) in adult than in juvenile rats. These data indicate that partial suppression of FSH beta mRNA inhibin is associated with a decline in GnRH receptor gene expression, suggesting that the notion that inhibin can act as a male contraceptive through selective and complete inhibition of FSH production, without effect on LH and Leydig cell function, may be mistaken. In addition, increased inhibin clearance appears to contribute to the fall in plasma inhibin levels with maturation in the male rat.
为了开始研究抑制素作为男性避孕药的作用，通过渗透微型泵给雄性大鼠连续3天注射重组人（rh）抑制素-A。每天0 - 150mg/kg的抑制素剂量并未对成年大鼠的促卵泡激素（FSH）分泌或垂体FSHβ mRNA水平产生浓度依赖性抑制。以每天145μg/kg的剂量对未成年大鼠进行治疗（该剂量对成年大鼠无效），可使血浆FSH水平降低49%（p < 0.01），FSHβ mRNA水平降至对照组的47±11%（p < 0.01）。抑制素还可降低未成年大鼠中促黄体生成素β（LHβ） mRNA水平（降至对照组的63±8%；p < 0.01）、α亚基mRNA水平（降至对照组的86±10%；p < 0.05）以及促性腺激素释放激素（GnRH）受体mRNA水平（降至对照组的77±17%；p < 0.01）。rh抑制素-A对未成年动物的作用比对成年动物更有效；仅在未成年大鼠中，rh抑制素-A治疗可使血浆抑制素水平升高（p = 0.03）。药代动力学研究表明，成年大鼠的体重校正清除率更高（p < 0.01），rh抑制素A的消除半衰期比幼年大鼠更短（p < 0.01）。这些数据表明，FSHβ mRNA抑制素的部分抑制与GnRH受体基因表达的下降有关，这表明抑制素可通过选择性和完全抑制FSH产生来作为男性避孕药，而不影响LH和睾丸间质细胞功能的观点可能是错误的。此外，抑制素清除率的增加似乎导致雄性大鼠随着成熟血浆抑制素水平下降。
