COCAINE AND FEMALE REPRODUCTIVE DYSFUNCTION

可卡因与女性生殖功能障碍

• 批准号: 3212676
• 负责人: THOMAS S KING
• 金额: $ 8.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-30 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3212676
• 关键词: cocaine; drug adverse effect; female reproductive system disorder; follicle stimulating hormone; gonadotropin releasing factor; gonadotropins; hormone regulation /control mechanism; hypothalamus; laboratory rat; luteinizing hormone; menstrual cycle; neurotransmitter receptor; neurotransmitters; ovary; ovulation; pituitary gland; tissue /cell culture

Cocaine has become a major drug of abuse in our society. Unfortunately, very little is known about the possible deleterious effects of this drug on reproductive functions. On the other hand, cocaine is known to inhibit aminergic neurotransmitter reuptake in the brain and thus alter the activities of these neurotransmitter systems. Because several of these aminergic systems play central roles in regulating cyclic reproductive functions, it is reasonable to postulate that cocaine would disrupt those functions. This is supported by clinical case studies documenting the association of chronic cocaine abuse with reproductive dysfunction in humans, including disruption of normal menstrual cyclicity and decreased libido. Our preliminary studies demonstrate that cocaine administration does disrupt estrous cyclicity and normal rates of ovulation in rats. Additionally, our preliminary in vitro studies demonstrate that both GnRH and aminergic release from the hypothalami of cocaine-treated rats is significantly altered. These observations have led to the central hypothesis of this proposal that cocaine induces female reproductive dysfunction by interrupting pulsatile GnRH release from the hypothalamus. The proposed studies will extend and confirm our preliminary findings that cocaine disrupts estrous cyclicity and ovulation rates in the rat. These studies will include dose-response effects of cocaine on estrous cyclicity and normal rates of ovulation as well as examination of the effects of acute cocaine exposure given at different estrous cycle stages on circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and ovulation rates. In vivo perfusion studies will allow us to selectively examine the effects of cocaine on hypothalamic functions integral to the regulation of cyclic reproduction, ie., the effects of cocaine on the peak frequency and amplitude of stimulated aminergic and GnRH release in vitro. We also recognize that cocaine's disruptive reproductive effects may result from an interaction at one or more levels of the hypothalamo-pituitary- ovarian axis. We will therefore examine the ability of GnRH replacement to restore estrous cyclicity and normal ovulation rates in cocaine treated female rats. We will examine the effects of cocaine on in vitro GnRH-stimulated pituitary LH (and FSH) secretion. Finally, we will examine the effects of cocaine on exogenous hormone-induced ovulation in sexually immature female rats. Thus, the proposed studies will define cocaine's effects on the hypothalamus, pituitary and ovary and thus elucidate the disruptive effects of this drug on cyclic reproductive function. Such information will be of tremendous value for the clinical management of cyclic reproductive dysfunction, including endocrine-related psychiatric disorders, related to cocaine abuse.

可卡因已成为我们社会中主要的滥用药物。很遗憾， 人们对这种药物可能产生的有害影响知之甚少 生殖功能。另一方面，已知可卡因可以抑制 大脑中胺能神经递质的重新摄取，从而改变 这些神经递质系统的活动。因为其中几个 胺能系统在调节循环生殖中发挥核心作用 功能，可以合理地假设可卡因会破坏这些功能 功能。这得到了记录的临床案例研究的支持 慢性可卡因滥用与生殖功能障碍的关系 人类，包括正常月经周期的破坏和减少 性欲。我们的初步研究表明可卡因管理 确实会破坏大鼠的动情周期和正常排卵率。 此外，我们的初步体外研究表明，GnRH 可卡因治疗大鼠的下丘脑释放的胺能是 显着改变。这些观察结果导致中央 该提案的假设是可卡因会诱导女性生殖 通过中断下丘脑的脉冲式 GnRH 释放来治疗功能障碍。 拟议的研究将扩展并证实我们的初步发现： 可卡因会扰乱大鼠的动情周期和排卵率。这些 研究将包括可卡因对动情周期的剂量反应效应 和正常排卵率以及检查的影响 在不同动情周期阶段给予急性可卡因暴露 循环黄体生成素 (LH) 和卵泡刺激素 (FSH) 和排卵率。体内灌注研究将使我们能够选择性地 检查可卡因对下丘脑功能的影响 循环繁殖的调节，即可卡因对峰值的影响 体外刺激胺能和 GnRH 释放的频率和幅度。 我们还认识到可卡因的破坏性生殖影响可能会导致 来自下丘脑-垂体的一个或多个水平的相互作用 卵巢轴。因此，我们将检查 GnRH 替代的能力 恢复可卡因治疗的动情周期和正常排卵率 雌性老鼠。我们将检查可卡因对体外的影响 GnRH 刺激垂体 LH（和 FSH）分泌。最后，我们将检查 可卡因对外源性激素诱导排卵的影响 未成熟的雌性大鼠。因此，拟议的研究将定义可卡因 对下丘脑、垂体和卵巢的影响，从而阐明 该药物对周期性生殖功能的破坏作用。这样的 信息对于临床管理具有巨大价值 周期性生殖功能障碍，包括内分泌相关的精神疾病 与可卡因滥用有关的疾病。