Thyssen S M, Becú-Villalobos D, Lacau-Mengido I M, Libertun C
Laboratory of Neuroendocrinology, Institute of Biology and Experimental Medicine-CONICET, Buenos Aires, Argentina.
Proc Soc Exp Biol Med. 1997 Jun;215(2):192-7. doi: 10.3181/00379727-215-44128.
Polyamines play an essential role in tissue growth and differentiation, in body weight increment, in brain organization, and in the molecular mechanisms of hormonal action, intracellular signaling, and cell-to-cell communication. In a previous study, inhibition of their synthesis by alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, during development in female rats, was followed by prolonged high follicle-stimulating hormone (FSH) serum level and a delayed puberty onset. Those changes were relatively independent of body mass and did not impair posterior fertility. The present work studies the mechanisms and site of action of polyamine participation in FSH secretion during development. DFMO was injected in female rats between Days 1 and 9 on alternate days. At 10 days of age, hypothalami from control and DFMO rats were perifused in vitro, and basal and potassium-induced gonadotropin-releasing hormone (GnRH) release were measured. The response to membrane depolarization was altered in DFMO hypothalami. Increased GnRH release in response to a low K+ concentration was evidenced. Adenohypophyses of the same treated prepubertal rats were perifused in vitro and the response to GnRH pulses was checked. In DFMO-treated rats, higher FSH release was observed, with no changes in LH or PRL secretion. Finally, pituitary GnRH receptor number in adenohypophyseal membranes from treated and control groups was quantified. A significant reduction in specific binding was evident in hypophyses from DFMO-treated rats when compared with binding in the control group. In summary, DFMO treatment in a critical developmental period in the female rat impacts the immature GnRH neuronal network and immature gonadotropes. A delay in maturation is evidenced by a higher sensitivity to secretagogs in both pituitary glands and hypothalamic explants. These events could explain the prolonged high FSH serum levels and delayed puberty onset seen in this experimental model.
多胺在组织生长与分化、体重增加、大脑组织发育以及激素作用、细胞内信号传导和细胞间通讯的分子机制中发挥着重要作用。在先前的一项研究中，在雌性大鼠发育期间，用鸟氨酸脱羧酶的特异性不可逆抑制剂α-二氟甲基鸟氨酸（DFMO）抑制其合成后，血清促卵泡激素（FSH）水平长期居高不下，青春期 onset 延迟。这些变化相对独立于体重，且不影响后期生育能力。本研究探讨多胺在发育过程中参与 FSH 分泌的作用机制和作用部位。在第 1 天至第 9 天期间，每隔一天给雌性大鼠注射 DFMO。在 10 日龄时，对对照大鼠和 DFMO 处理大鼠的下丘脑进行体外灌流，测量基础和钾诱导的促性腺激素释放激素（GnRH）释放。DFMO 处理的下丘脑对膜去极化的反应发生了改变。有证据表明，低 K+浓度会导致 GnRH 释放增加。对相同处理的青春期前大鼠的腺垂体进行体外灌流，并检测其对 GnRH 脉冲的反应。在 DFMO 处理的大鼠中，观察到 FSH 释放增加，而 LH 或 PRL 分泌没有变化。最后，对处理组和对照组腺垂体膜中的垂体 GnRH 受体数量进行了定量。与对照组相比，DFMO 处理大鼠的垂体中特异性结合明显减少。总之，在雌性大鼠关键发育时期进行 DFMO 处理会影响未成熟的 GnRH 神经元网络和未成熟的促性腺激素细胞。垂体和下丘脑外植体对促分泌素的敏感性更高，这证明了成熟延迟。这些事件可以解释在这个实验模型中观察到的 FSH 血清水平长期居高不下和青春期 onset 延迟的现象。
