Oakley Amy E, Steiner Robert A, Chavkin Charles, Clifton Donald K, Ferrara Laura K, Reed Susan D
1Department of Physiology and Biophysics, University of Washington, Seattle, WA 2Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 3Department of Pharmacology, University of Washington, Seattle, WA.
Menopause. 2015 Dec;22(12):1328-34. doi: 10.1097/GME.0000000000000476.
The etiology of postmenopausal hot flashes is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing kisspeptin, neurokinin B and dynorphin-called KNDy neurons-are located adjacent to the thermoregulatory center. KNDy neurons regulate pulsatile secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Dynorphin may inhibit this system by binding κ opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation.
A double-blind, cross-over, placebo-controlled pilot study evaluated the effects of a κ agonist. Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate to severe hot flashes (aged 48-60 y) were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all three interventions: placebo, standard-dose pentazocine/naloxone (50/0.5 mg), or low-dose pentazocine/naloxone (25/0.25 mg). In an inpatient research setting, each participant received the three interventions, in randomized order, on three separate days. On each day, an intravenous catheter was inserted for LH blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded.
The mean (SEM) hot flash frequency 2 to 7 hours after therapy initiation was lower than that for placebo (standard-dose κ agonist, 4.75 [0.67] hot flashes per 5 h; low-dose κ agonist, 4.50 [0.57] hot flashes per 5 h; placebo, 5.94 [0.78] hot flashes per 5 h; P = 0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some--but not all--women.
This pilot study suggests that κ agonists may affect menopausal vasomotor symptoms.
绝经后潮热的病因尚不清楚，这使得开发和靶向理想疗法变得困难。一组产生 kisspeptin、神经激肽 B 和强啡肽的下丘脑雌激素敏感神经元网络（称为 KNDy 神经元）位于体温调节中心附近。KNDy 神经元调节促性腺激素释放激素（GnRH）和促黄体生成素（LH）的脉冲式分泌。强啡肽可能通过与 KNDy 神经元附近的κ阿片受体结合来抑制该系统。我们假设通过操纵 KNDy 神经元可减少潮热。
一项双盲、交叉、安慰剂对照的试点研究评估了一种κ激动剂的效果。潮热频率是主要结局指标。12 名患有中度至重度潮热的健康绝经后女性（年龄 48 - 60 岁）被随机分组。8 名有足够基线潮热次数可供统计分析的女性完成了所有三种干预：安慰剂、标准剂量喷他佐辛/纳洛酮（50/0.5mg）或低剂量喷他佐辛/纳洛酮（25/0.25mg）。在住院研究环境中，每位参与者在三个不同的日子里按随机顺序接受这三种干预。每天插入一根静脉导管用于采集 LH 血样，并放置皮肤电导和动态心电图监测仪。记录主观潮热频率和严重程度。
治疗开始后 2 至 7 小时的平均（SEM）潮热频率低于安慰剂组（标准剂量κ激动剂，每 5 小时 4.75[0.67]次潮热；低剂量κ激动剂，每 5 小时 4.50[0.57]次潮热；安慰剂，每 5 小时 5.94[0.78]次潮热；P = 0.025）。潮热强度在各干预组之间没有差异。在部分（但不是全部）女性中，LH 脉冲式分泌与客观潮热情况相符。
这项试点研究表明κ激动剂可能会影响绝经后血管舒缩症状。
