Jones Sherri Lee, Ismail Nafissa, Pfaus James G
Douglas Mental Health University Institute, Perry Pavilion, 6875 LaSalle Blvd., Verdun, QC, H4H 1R3, Canada; Department of Psychiatry, McGill University, Montreal, QC, Canada; Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, 7141 Sherbrooke West, Montreal, QC, H4B 1R6 Canada.
Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, 7141 Sherbrooke West, Montreal, QC, H4B 1R6 Canada.
Psychoneuroendocrinology. 2017 May;79:122-133. doi: 10.1016/j.psyneuen.2017.02.018. Epub 2017 Feb 17.
In the United States and Canada, there are no approved treatments for hypoactive sexual desire disorder in postmenopausal women. Testosterone improves female sexual desire in naturally- and surgically-menopausal women maintained on estrogen replacement therapy, and long-term safety data from randomized placebo-controlled clinical trials has yielded promising results. However, the mechanisms associated with its efficacy are not known, and could be addressed using preclinical rodent models; yet there is no systematic evaluation of the effects of estradiol and testosterone on female rat sexual behavior. The aim of these studies was to assess whether testosterone propionate (TP) facilitates sexual behaviors, particularly appetitive sexual behaviors, in Long-Evans and Wistar ovariectomized (OVX) rats primed with estradiol benzoate (EB). In Experiment 1, Long-Evans OVX rats were treated with Oil (O), 10μg EB+O, O+200μg TP, 10μg EB+500μg progesterone (P), or 10μg EB+200μg TP. In Experiment 2a, Wistar OVX rats were treated with varying doses of EB (2.5, 5, or 10μg) 48h prior, and TP (0, 200, or 400μg) 4h prior to testing in a Latin-Square design. A subset of animals was used in Experiment 2b and treated sequentially with EB (0, 2.5, 5, or 10μg) followed by TP (0, 200, or 400μg, in a Latin-Square design) 48h prior to sexual behavior testing. All tests occurred in the bilevel pacing chamber. Frequencies of female appetitive (hops/darts, solicitations, level changes) and consummatory (lordosis quotient and magnitude) sexual behaviors as well as the number of defensive behaviors towards males were scored. Number of mounts, intromissions and ejaculations from males were also scored. In EB-primed OVX Long-Evans rats, 200μg TP administered 4h prior to testing facilitated hops/darts and lordosis ratings beyond EB alone, and to levels equivalent to EB+P. In contrast, that regimen was not successful in EB-primed OVX Wistar rats. When EB and TP were co-administered 48h prior to testing, 10μg EB+200μg TP significantly increased hops/darts and level changes beyond that observed by 10μg EB alone. In summary, the administration of EB and TP to OVX Long-Evans and Wistar rats facilitates appetitive measures of sexual behavior. Strain differences exist that likely reflect underlying differences in sensitivities to EB, and the EB-primed OVX Long-Evans rat may be useful for studying mechanisms of TP-facilitation of desire due to higher baseline sexual inhibition.
在美国和加拿大，绝经后女性性欲减退障碍尚无获批的治疗方法。睾酮可改善接受雌激素替代疗法的自然绝经和手术绝经女性的性欲，随机安慰剂对照临床试验的长期安全性数据已产生了有前景的结果。然而，其疗效相关机制尚不清楚，可使用临床前啮齿动物模型进行研究；但目前尚无关于雌二醇和睾酮对雌性大鼠性行为影响的系统评估。这些研究的目的是评估丙酸睾酮（TP）是否能促进经苯甲酸雌二醇（EB）预处理的Long-Evans和Wistar去卵巢（OVX）大鼠的性行为，特别是性唤起行为。在实验1中，给Long-Evans OVX大鼠分别注射油剂（O）、10μg EB+O、O+200μg TP、10μg EB+500μg孕酮（P）或10μg EB+200μg TP。在实验2a中，Wistar OVX大鼠在测试前48小时接受不同剂量的EB（2.5、5或10μg），并在测试前4小时接受TP（0、200或400μg），采用拉丁方设计。实验2b使用了一部分动物，在性行为测试前48小时依次给予EB（0、2.5、5或10μg），随后给予TP（0、200或40μg，采用拉丁方设计）。所有测试均在双层起搏室进行。对雌性性唤起（跳跃/ dart、求偶、体位变化）和性行为完成（脊柱前凸商数和幅度）的频率以及对雄性的防御行为数量进行评分。同时记录雄性的爬跨、插入和射精次数。在经EB预处理的OVX Long-Evans大鼠中，测试前4小时给予200μg TP可促进跳跃/ dart和脊柱前凸评分，超过单独使用EB的水平，且达到与EB+P相当的水平。相比之下，该方案在经EB预处理的OVX Wistar大鼠中未成功。在测试前48小时联合给予EB和TP时，10μg EB+200μg TP显著增加了跳跃/ dart和体位变化，超过单独使用10μg EB时观察到的水平。总之，给OVX Long-Evans和Wistar大鼠给予EB和TP可促进性行为的性唤起指标。存在品系差异，这可能反映了对EB敏感性的潜在差异，且经EB预处理的OVX Long-Evans大鼠可能有助于研究TP促进性欲的机制，因为其基线性抑制较高。
