正常动情周期和性腺摘除大鼠外周性激素对下丘脑的影响
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摘要
背景和目的：性激素(sex hormone)可以分为雌激素(estrogen)、雄激素(androgen)和孕激素(progestogen)三大类,而以前两者为外周最主要性激素。它们主要由性腺合成和分泌。雌性大鼠的卵巢和雄性大鼠的睾丸分别是体内分泌性激素的外周主要器官。下丘脑作为神经内分泌系统的控制中枢,可以通过调控下丘脑—垂体—性腺(hypothalamo-pituitary-gonad, HPG)轴来调节外周性激素的分泌。作为甾体激素,外周合成的性激素又能透过血脑屏障(blood-brain-barrier, BBB)进入大脑,反馈调节HPG轴的活性。同时,性激素已被证实可以由大脑自身合成。因此,脑内性激素水平受到中枢和外周两方面因素影响。关于脑内尤其是下丘脑性激素水平是否和外周性激素水平变化相一致,目前还没有相关报道。此外,已有研究表明,HPG轴和下丘脑—垂体—肾上腺(hypothalamo-pituitary-adrenal, HPA)轴间存在着紧密的联系,性激素水平可以影响HPA轴的活性,进而参与应激反应乃至众多神经、精神疾病的性别差异机制。但是,生理和病理条件下外周性激素水平波动是否以及如何影响下丘脑性激素水平、HPA轴活性,和其他相关神经肽活性的影响的机制以及性激素在应激性别差异中的作用仍有待阐明。本实验旨在探讨正常动情周期内或性腺切除后大鼠外周性激素水平改变对下丘脑性激素水平、HPA轴以及相关激素受体和神经肽基因水平的影响,以及这种影响是否存在性别差异。
实验方法：通过阴道涂片观察而确定雌性SD大鼠(体重220-250g)至少3轮以上规则动情周期后,随机将大鼠分为动情前期组(P)、动情期组(E)、动情间期组(D),每组数量为12只；另取30只雌性SD大鼠(体重220-250g)和20只雄性SD大鼠(体重290-320g)随机分为假手术组(sham)和性腺摘除组。在10%水合氯醛麻醉状态下打开腹腔,sham组仅切除卵巢(雌性大鼠)或睾丸(雄性大鼠)旁部分脂肪,性腺摘除组分别进行卵巢切除(ovariectomy, OVX)和睾丸摘除(castration, CAS).术后恢复1周后,sham组雌性大鼠通过确定3轮以上规则动情周期而选取动情前期作为实验对象。各组大鼠于上午9：00至11：00之间断头,留取躯干血血浆、分离下丘脑。放射免疫分析法检测各组血浆和下丘脑雌二醇(estradiol, E2)、睾酮(testosterone, T)的水平以及血浆促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH)的水平；酶联免疫法测定血浆皮质酮(coricosterone, CORT)含量；实时定量PCR检测下丘脑雌激素受体(estrogen receptor-a、-β, ER-a、-β).雄激素受体(androgen receptor, AR).芳香化酶(aromatase)、盐皮质激素受体(mineralcorticoid receptor, MR).糖皮质激素受体(glucocorticoid receptor, GR)、CRH.血管加压素(Vasopressin, AVP).催产素(oxytocin, OXT) mRNA表达。
结果：1.在正常动情周期内,血浆E2、T的水平在动情前期明显高于动情期(p<0.0001、p<0.0001)、动情间期(p<0.0001、p<0.0001)。血浆中CRH和CORT在各实验组之间没有显著差异(p>0.05)。下丘脑E2和T水平在动情周期各阶段没有明显变化(p>0.05),且与血浆E2和T的水平无显著相关性(p>0.05)。除了动情前期aromatase-mRNA表达较动情期相比有增高趋势外(p=0.06),其余所测下丘脑相关受体及神经肽的基因表达在动情周期之间无显著变化(p>0.05)。2.卵巢切除后,与假手术组相比,OVX组血浆中E2、T的水平明显降低(p<0.0001、p<0.01)；下丘脑内E2水平有增加趋势(p=0.055)而T水平变化不明显(p>0.05)；外周与下丘脑的性激素水平未发现显著相关性(p>0.05)。血浆CORT水平则显著降低(p<0.01)。此外,ER-α-mRNA表达在OVX后明显增高(p<0.01); aromatase-CRH-、OVX-mRNA表达明显减低(分别为p<0.01、p<0.01、p<0.05)；其余所测下丘脑相关受体及神经肽的基因表达在OVX无显著变化(p>0.05)。3.睾丸摘除后,与假手术组相比,CAS组血浆中T的水平明显降低(p<0.01),而下丘脑内T水平也显著降低(p<0.05),两者呈显著正相关(r=0.774,p=0.014)；血浆CORT水平显著增高(p<0.05)。此外,下丘脑内仅发现aromatase-mRNA表达明显减低(p<0.001)；其余所测下丘脑相关受体及神经肽的基因表达在CAS后无显著变化(p>0.05)。4.雌性和雄性大鼠对于HPA轴和下丘脑相关神经肽的调节存在性别差异。在正常状态下,雌鼠血浆CORT水平高于雄鼠(p<0.0001)。当性腺摘除后,雌鼠CORT水平降低,而雄鼠则显著升高,此时雌鼠和雄鼠CORT水平相当。雌鼠性腺摘除后伴随着下丘脑神经肽基因水平的降低,雄鼠在性腺摘除后神经肽基因水平没有改变。
结论：生理状态下大鼠外周性激素水平在动情周期内的显著波动对于下丘脑内稳态平衡没有明显影响。外周持久而显著的性激素水平改变,例如性腺摘除导致外周性激素水平持久而显著的减低可显著影响下丘脑的内稳态平衡,下丘脑性激素水平、相关受体及神经肽基因水平均发生明显改变。外周性激素改变对于HPA轴及下丘脑相关神经肽的影响存在性别差异。
Background and Objective:Sex hormones are a kind of steroid mainly synthesized by sexual gonads. The major sex hormones in body are estrogens and androgen. The ovary in a female and the testis in a male are the most important organs where secrete sex hormones are produced. The hypothalamus is the centre of neuroendocrine system, which regulates the secretion of sex hormones through the hypothalamo-pituitary-gonad (HPG) axis. It is clear that sex hormones are also produced in the brain. Since sex hormones are small hydrophobic steroids that can diffusion through the blood-brain barrier (BBB) freely, the contents of sex hormones in the brain are, at least partly, determined by both sex steroids derived from the peripheral and those produced de novo in the brain. The question how the peripheral sex hormone levels contribute to the levels of sex hormones in the brain, however, remains so far as unclear. In addition, it is well known that there is a close interaction between the HPG and the hypothalamo-pituitary-adrenal (HPA) axis that is the key system involved in the stress response of body. Changes of sex hormones can influence the activity of the HPA-axis, participating in the mechanism of sex differences in the stress responses and a lot of neuropsychiatric disorders. However, so far it is lack of study on the effect of the fluctuating sex hormones in the periphery on the activity of the HPA axis, thus on the vulnerability to the neuropsychiatric disorders. The present study thus aimed to investigate the influence of changes in circulating sex hormones during normal estrous cycle or after gonadectomy upon the hypothalamic sex hormone levels, the activity of the HPA axis, and the transcriptional levels of relevant hormone receptors and neuropeptides in the hypothalamus, and whether there are sex differences.
Methods:The estrous cycle stages of female Sprague-Dawley (SD) rats (weigh 220-250g) were monitored by daily vaginal smears. After at least three consecutive regular cycles, rats were sacrificed in proestrus, estrus and diestrus stage respectively, with 12 rats each stage(=group). Another 30 female SD rats (weigh 220-250g) and 20 male SD rats (weigh 290-320g) were recruited and divided at random into sham-operated and gonadectomy groups, respectively. Under 10% chloral hydrate anesthesia, the rats in sham groups were only treated with excising a part of the fat tissue next to the ovary or testis, while the rats in ovariectomy (OVX) or in castration (CAS) group, the ovaries or the testes were removed respectively under the same operation condition. After one week of recovery, female rats of the sham-operation-group were monitored for three consecutive regular cycles then sacrificed in the proestrus stage, the same period as the OVX, CAS and the sham-operation male groups were sacrificed. Animals were decapitated between 9:00-11:00hr. Trunk blood and hypothalamus were collected. Estradiol (E2) and testosterone (T) levels in plasma, the hypothalamus, and CRH levels in plasma were determined by radioimmunoassay. Coricosterone (CORT) levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA). Expression levels of estrogen receptor-a (ER-a)-, ER-β, androgen receptor (AR)-, aromatase-, mineralcorticoid receptor (MR)-, glucocorticoid receptor (GR)-, CRH-, Vasopressin (AVP)-and oxytocin (OXT)-mRNA in the hypothalamus were tested by means of real-time quantitative PCR (QPCR).
Results:1. During estrus cycle, E2 and T levels in plasma were dramatically higher in proestrus than in estrus (p<0.0001、p<0.0001) or diestrus (p<0.0001、p<0.0001). No significant changes were found in plasma CORT and CRH (p>0.05). E2 and T levels in the hypothalamus did not show significant changes (p>0.05). There were on significant correlations between plasma-and hypothalamus-sex hormone levels (p>0.05). The mRNA levels of the receptors and neuropeptides detected in the the present study did not show any significant changes (p>0.05) in hypothalamus, except for the expression of aromatase-mRNA showed a trend for increase in the proestrus compared with the estrus stage (p=0.06).2. After OVX, E2 and T levels in plasma significantly declined (p<0.0001, p<0.01),while there was a trend for increase of E2 in the hypothalamic (p=0.055). The hypothalamic T levels did not change significantly in the OVX group compared with the sham-operation group. In addition, the expression of ER-a-mRNA significantly increased (p<0.01), while aromatase-, CRH-and OXT-mRNA significantly decreased (p<0.01, p<0.01, p<0.05 respectively) in hypothalamus of OVX females compared to sham-operation group. Other relevant receptors and neuropeptides detected in the hypothalamus showed no significant changes (p>0.05).3. After castration, T levels in plasma and hypothalamus were both significantly decreased compared to the sham-operation group (p<0.01, p<0.05), and they showed a significant positive correlation in between (r=0.774, p=0.014). In addition, CORT level in plasma increased in CAS group (p<0.05). The receptors and neuropeptides detected did not show significant changes in hypothalamus except that the aromatase-mRNA expression was dramatically decreased in the CAS group (p<0.001).4. Females had a higher CORT level in plasma than males in sham-operation groups (p<0.0001). After gonadectomy, CORT level was down-regulated in female OVX rats but increased in male CAS subjects, while the CORT levels in OVX females showed no significant differences from the CAS males. In addition, OVX female rats showed decreased levels of neuropeptides(CRH and OXT) in the hypothalamus while CAS male rats did not show any significant changes in these neuropeptides, compared with the sham-operation control subjects.
Conclusion:The significant fluctuation of circulating sex hormone levels during the estrus cycle does not remarkably affect the homeostasis in the hypothalamus, in the sense of the levels of sex hormones, and HPA activity. The long-lasting dramatic changes of sex hormone levels in the periphery by for instance gonadectomy may break down such homeostasis leading to significant changes in levels of sex hormones, transcriptional levels of relevant receptors and neuropeptides in the hypothalamus. There is a sex difference in the influence of changed peripheral sex hormones on the HPA axis and related neuropeptides in the hypothalamus.
实验方法：通过阴道涂片观察而确定雌性SD大鼠(体重220-250g)至少3轮以上规则动情周期后,随机将大鼠分为动情前期组(P)、动情期组(E)、动情间期组(D),每组数量为12只；另取30只雌性SD大鼠(体重220-250g)和20只雄性SD大鼠(体重290-320g)随机分为假手术组(sham)和性腺摘除组。在10%水合氯醛麻醉状态下打开腹腔,sham组仅切除卵巢(雌性大鼠)或睾丸(雄性大鼠)旁部分脂肪,性腺摘除组分别进行卵巢切除(ovariectomy, OVX)和睾丸摘除(castration, CAS).术后恢复1周后,sham组雌性大鼠通过确定3轮以上规则动情周期而选取动情前期作为实验对象。各组大鼠于上午9：00至11：00之间断头,留取躯干血血浆、分离下丘脑。放射免疫分析法检测各组血浆和下丘脑雌二醇(estradiol, E2)、睾酮(testosterone, T)的水平以及血浆促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH)的水平；酶联免疫法测定血浆皮质酮(coricosterone, CORT)含量；实时定量PCR检测下丘脑雌激素受体(estrogen receptor-a、-β, ER-a、-β).雄激素受体(androgen receptor, AR).芳香化酶(aromatase)、盐皮质激素受体(mineralcorticoid receptor, MR).糖皮质激素受体(glucocorticoid receptor, GR)、CRH.血管加压素(Vasopressin, AVP).催产素(oxytocin, OXT) mRNA表达。
结果：1.在正常动情周期内,血浆E2、T的水平在动情前期明显高于动情期(p<0.0001、p<0.0001)、动情间期(p<0.0001、p<0.0001)。血浆中CRH和CORT在各实验组之间没有显著差异(p>0.05)。下丘脑E2和T水平在动情周期各阶段没有明显变化(p>0.05),且与血浆E2和T的水平无显著相关性(p>0.05)。除了动情前期aromatase-mRNA表达较动情期相比有增高趋势外(p=0.06),其余所测下丘脑相关受体及神经肽的基因表达在动情周期之间无显著变化(p>0.05)。2.卵巢切除后,与假手术组相比,OVX组血浆中E2、T的水平明显降低(p<0.0001、p<0.01)；下丘脑内E2水平有增加趋势(p=0.055)而T水平变化不明显(p>0.05)；外周与下丘脑的性激素水平未发现显著相关性(p>0.05)。血浆CORT水平则显著降低(p<0.01)。此外,ER-α-mRNA表达在OVX后明显增高(p<0.01); aromatase-CRH-、OVX-mRNA表达明显减低(分别为p<0.01、p<0.01、p<0.05)；其余所测下丘脑相关受体及神经肽的基因表达在OVX无显著变化(p>0.05)。3.睾丸摘除后,与假手术组相比,CAS组血浆中T的水平明显降低(p<0.01),而下丘脑内T水平也显著降低(p<0.05),两者呈显著正相关(r=0.774,p=0.014)；血浆CORT水平显著增高(p<0.05)。此外,下丘脑内仅发现aromatase-mRNA表达明显减低(p<0.001)；其余所测下丘脑相关受体及神经肽的基因表达在CAS后无显著变化(p>0.05)。4.雌性和雄性大鼠对于HPA轴和下丘脑相关神经肽的调节存在性别差异。在正常状态下,雌鼠血浆CORT水平高于雄鼠(p<0.0001)。当性腺摘除后,雌鼠CORT水平降低,而雄鼠则显著升高,此时雌鼠和雄鼠CORT水平相当。雌鼠性腺摘除后伴随着下丘脑神经肽基因水平的降低,雄鼠在性腺摘除后神经肽基因水平没有改变。
结论：生理状态下大鼠外周性激素水平在动情周期内的显著波动对于下丘脑内稳态平衡没有明显影响。外周持久而显著的性激素水平改变,例如性腺摘除导致外周性激素水平持久而显著的减低可显著影响下丘脑的内稳态平衡,下丘脑性激素水平、相关受体及神经肽基因水平均发生明显改变。外周性激素改变对于HPA轴及下丘脑相关神经肽的影响存在性别差异。
Background and Objective:Sex hormones are a kind of steroid mainly synthesized by sexual gonads. The major sex hormones in body are estrogens and androgen. The ovary in a female and the testis in a male are the most important organs where secrete sex hormones are produced. The hypothalamus is the centre of neuroendocrine system, which regulates the secretion of sex hormones through the hypothalamo-pituitary-gonad (HPG) axis. It is clear that sex hormones are also produced in the brain. Since sex hormones are small hydrophobic steroids that can diffusion through the blood-brain barrier (BBB) freely, the contents of sex hormones in the brain are, at least partly, determined by both sex steroids derived from the peripheral and those produced de novo in the brain. The question how the peripheral sex hormone levels contribute to the levels of sex hormones in the brain, however, remains so far as unclear. In addition, it is well known that there is a close interaction between the HPG and the hypothalamo-pituitary-adrenal (HPA) axis that is the key system involved in the stress response of body. Changes of sex hormones can influence the activity of the HPA-axis, participating in the mechanism of sex differences in the stress responses and a lot of neuropsychiatric disorders. However, so far it is lack of study on the effect of the fluctuating sex hormones in the periphery on the activity of the HPA axis, thus on the vulnerability to the neuropsychiatric disorders. The present study thus aimed to investigate the influence of changes in circulating sex hormones during normal estrous cycle or after gonadectomy upon the hypothalamic sex hormone levels, the activity of the HPA axis, and the transcriptional levels of relevant hormone receptors and neuropeptides in the hypothalamus, and whether there are sex differences.
Methods:The estrous cycle stages of female Sprague-Dawley (SD) rats (weigh 220-250g) were monitored by daily vaginal smears. After at least three consecutive regular cycles, rats were sacrificed in proestrus, estrus and diestrus stage respectively, with 12 rats each stage(=group). Another 30 female SD rats (weigh 220-250g) and 20 male SD rats (weigh 290-320g) were recruited and divided at random into sham-operated and gonadectomy groups, respectively. Under 10% chloral hydrate anesthesia, the rats in sham groups were only treated with excising a part of the fat tissue next to the ovary or testis, while the rats in ovariectomy (OVX) or in castration (CAS) group, the ovaries or the testes were removed respectively under the same operation condition. After one week of recovery, female rats of the sham-operation-group were monitored for three consecutive regular cycles then sacrificed in the proestrus stage, the same period as the OVX, CAS and the sham-operation male groups were sacrificed. Animals were decapitated between 9:00-11:00hr. Trunk blood and hypothalamus were collected. Estradiol (E2) and testosterone (T) levels in plasma, the hypothalamus, and CRH levels in plasma were determined by radioimmunoassay. Coricosterone (CORT) levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA). Expression levels of estrogen receptor-a (ER-a)-, ER-β, androgen receptor (AR)-, aromatase-, mineralcorticoid receptor (MR)-, glucocorticoid receptor (GR)-, CRH-, Vasopressin (AVP)-and oxytocin (OXT)-mRNA in the hypothalamus were tested by means of real-time quantitative PCR (QPCR).
Results:1. During estrus cycle, E2 and T levels in plasma were dramatically higher in proestrus than in estrus (p<0.0001、p<0.0001) or diestrus (p<0.0001、p<0.0001). No significant changes were found in plasma CORT and CRH (p>0.05). E2 and T levels in the hypothalamus did not show significant changes (p>0.05). There were on significant correlations between plasma-and hypothalamus-sex hormone levels (p>0.05). The mRNA levels of the receptors and neuropeptides detected in the the present study did not show any significant changes (p>0.05) in hypothalamus, except for the expression of aromatase-mRNA showed a trend for increase in the proestrus compared with the estrus stage (p=0.06).2. After OVX, E2 and T levels in plasma significantly declined (p<0.0001, p<0.01),while there was a trend for increase of E2 in the hypothalamic (p=0.055). The hypothalamic T levels did not change significantly in the OVX group compared with the sham-operation group. In addition, the expression of ER-a-mRNA significantly increased (p<0.01), while aromatase-, CRH-and OXT-mRNA significantly decreased (p<0.01, p<0.01, p<0.05 respectively) in hypothalamus of OVX females compared to sham-operation group. Other relevant receptors and neuropeptides detected in the hypothalamus showed no significant changes (p>0.05).3. After castration, T levels in plasma and hypothalamus were both significantly decreased compared to the sham-operation group (p<0.01, p<0.05), and they showed a significant positive correlation in between (r=0.774, p=0.014). In addition, CORT level in plasma increased in CAS group (p<0.05). The receptors and neuropeptides detected did not show significant changes in hypothalamus except that the aromatase-mRNA expression was dramatically decreased in the CAS group (p<0.001).4. Females had a higher CORT level in plasma than males in sham-operation groups (p<0.0001). After gonadectomy, CORT level was down-regulated in female OVX rats but increased in male CAS subjects, while the CORT levels in OVX females showed no significant differences from the CAS males. In addition, OVX female rats showed decreased levels of neuropeptides(CRH and OXT) in the hypothalamus while CAS male rats did not show any significant changes in these neuropeptides, compared with the sham-operation control subjects.
Conclusion:The significant fluctuation of circulating sex hormone levels during the estrus cycle does not remarkably affect the homeostasis in the hypothalamus, in the sense of the levels of sex hormones, and HPA activity. The long-lasting dramatic changes of sex hormone levels in the periphery by for instance gonadectomy may break down such homeostasis leading to significant changes in levels of sex hormones, transcriptional levels of relevant receptors and neuropeptides in the hypothalamus. There is a sex difference in the influence of changed peripheral sex hormones on the HPA axis and related neuropeptides in the hypothalamus.
引文
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14. Graham, E.A. and M. Glasser, Relationship of pregnanediol level to cognitive behavior and mood. Psychosom Med,1985.47(1):p.26-34.
15. Fink, G., et al., Estrogen control of central neurotransmission:effect on mood, mental state, and memory. Cell Mol Neurobiol,1996.16(3):p.325-44.
16. Targum, S.D., K.P. Caputo, and S.K. Ball, Menstrual cycle phase and psychiatric admissions. J Affect Disord,1991.22(1-2):p.49-53.
17. Rubinow, D.R. and P.J. Schmidt, Gonadal steroid regulation of mood:the lessons of premenstrual syndrome. Front Neuroendocrinol,2006.27(2):p. 210-6.
18. Diamond, M.I., et al., Transcription factor interactions:selectors of positive or negative regulation from a single DNA element. Science,1990.249(4974):p. 1266-72.
19. Do Rego, J.L., et al., Neurosteroid biosynthesis:enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol,2009.30(3):p.259-301.
20. Mellon, S.H. and H. Vaudry, Biosynthesis of neurosteroids and regulation of their synthesis. Int Rev Neurobiol,2001.46:p.33-78.
21. Stoffel-Wagner, B., Neurosteroid metabolism in the human brain. Eur J Endocrinol,2001.145(6):p.669-79.
22. Miller, W.L., Molecular biology of steroid hormone synthesis. Endocr Rev,1988. 9(3):p.295-318.
23. Compagnone, N.A. and S.H. Mellon, Neurosteroids:biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol,2000.21(1):p.1-56.
24. Baulieu, E.E., Neurosteroids:a novel function of the brain. Psychoneuroendocrinology,1998.23(8):p.963-87.
25. Shaikh, A.A., Estrone and estradiol levels in the ovarian venous blood from rats during the estrous cycle and pregnancy. Biol Reprod,1971.5(3):p.297-307.
26. Brown-Grant, K., D. Exley, and F. Naftolin, Peripheral plasma oestradiol and luteinizing hormone concentrations during the oestrous cycle of the rat. J Endocrinol,1970.48(2):p.295-6.
27. Isgor, C., et al., Correlation of estrogen beta-receptor messenger RNA with endogenous levels of plasma estradiol and progesterone in the female rat hypothalamus, the bed nucleus of stria terminalis and the medial amygdala. Brain Res Mol Brain Res,2002.106(1-2):p.30-41.
28. Cameron, V.A., et al., Adrenomedullin expression in rat uterus is correlated with plasma estradiol. Am J Physiol Endocrinol Metab,2002.282(1):p. E139-46.
29. Viau, V. and M.J. Meaney, Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology,1991. 129(5):p.2503-11.
30. Kau, M.M., et al., Effects of estradiol on aldosterone secretion in ovariectomized rats. J Cell Biochem,1999.73(1):p.137-44.
31. Lo, M.J., L.L. Chang, and P.S. Wang, Effects of estradiol on corticosterone secretion in ovariectomized rats. J Cell Biochem,2000.77(4):p.560-8.
32. Reznikov, A.G., N.D. Nosenko, and L.V. Tarasenko, Early postnatal effects of prenatal exposure to glucocorticoids on testosterone metabolism and biogenic monoamines in discrete neuroendocrine regions of the rat brain. Comp Biochem Physiol C Toxicol Pharmacol,2004.138(2):p.169-75.
33. Kian Tee, M., et al., Estradiol and selective estrogen receptor modulators differentially regulate target-genes with estrogen receptors alpha and beta. Mol Biol Cell,2004.15(3):p.1262-72.
34. Ogawa, S., et al., Roles of estrogen receptor-alpha gene expression in reproduction-related behaviors in female mice. Endocrinology,1998.139(12):p. 5070-81.
35. Weiser, M.J., C.D. Foradori, and R.J. Handa, Estrogen receptor beta in the brain: from form to function. Brain Res Rev,2008.57(2):p.309-20.
36. Solomon, M.B. and J.P. Herman, Sex differences in psychopathology:of gonads, adrenals and mental illness. Physiol Behav,2009.97(2):p.250-8.
37. Roselli, C.E., W.E. Ellinwood, and J.A. Resko, Regulation of brain aromatase activity in rats. Endocrinology,1984.114(1):p.192-200.
38. Dupon, C. and M.H. Kim, Peripheral plasma levels of testosterone, androstenedione, and oestradiol during the rat oestrous cycle. J Endocrinol, 1973.59(3):p.653-4.
39. Shughrue, P.J., C.D. Bushnell, and D.M. Dorsa, Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle:a comparison with ovariectomized females and intact males. Endocrinology,1992.131(1):p.381-8.
40. Yuan, H., et al., Distribution of occupied and unoccupied estrogen receptors in the rat brain:effects of physiological gonadal steroid exposure. Endocrinology, 1995.136(1):p.96-105.
41. Lephart, E.D., et al., Inverse relationship between ovarian aromatase cytochrome P450 and 5 alpha-reductase enzyme activities and mRNA levels during the estrous cycle in the rat. J Steroid Biochem Mol Biol,1992.42(5):p. 439-47.
42. Lund, T.D., et al., Androgen inhibits, while oestrogen enhances, restraint-induced activation of neuropeptide neurones in the paraventricular nucleus of the hypothalamus. J Neuroendocrinol,2004.16(3):p.272-8.
43. McCormick, C.M., et al., Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats. Stress,2002.5(4):p.235-47.
44. Kant, G.J., et al., Comparison of stress response in male and female rats: pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone. Psychoneuroendocrinology,1983.8(4):p.421-8.
45. Burgess, L.H. and R.J. Handa, Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology,1992.131(3):p. 1261-9.
46. Viau, V. and M.J. Meaney, The inhibitory effect of testosterone on hypothalamic-pituitary-adrenal responses to stress is mediated by the medial preoptic area. J Neurosci,1996.16(5):p.1866-76.
47. Lesniewska, B., et al., Sex differences in adrenocortical structure and function. ⅩⅩⅦ. The effect of ether stress on ACTH and corticosterone in intact, gonadectomized, and testosterone- or estradiol-replaced rats. Res Exp Med (Berl),1990.190(2):p.95-103.
48. Bao, A.M., et al., A direct androgenic involvement in the expression of human corticotropin-releasing hormone. Mol Psychiatry,2006.11(6):p.567-76.
49. Chen, X. and J. Herbert, The effect of long-term castration on the neuronal and physiological responses to acute or repeated restraint stress:interactions with opioids and prostaglandins. J Neuroendocrinol,1995.7(2):p.137-44.
50. Bao, A.M., et al., Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression. Horm Behav,2004. 45(2):p.93-102.
51. Bohler, H.C., Jr., et al., Corticotropin releasing hormone mRNA is elevated on the afternoon of proestrus in the parvocellular paraventricular nuclei of the female rat. Brain Res Mol Brain Res,1990.8(3):p.259-62.
52. Forsling, M.L. and K. Peysner, Pituitary and plasma vasopressin concentrations and fluid balance throughout the oestrous cycle of the rat. J Endocrinol,1988. 117(3):p.397-402.
53. Ho, M.L. and J.N. Lee, Ovarian and circulating levels of oxytocin and arginine vasopressin during the estrous cycle in the rat. Acta Endocrinol (Copenh),1992. 126(6):p.530-4.
54. Crofton, J.T., et al., Vasopressin release in male and female rats:effects of gonadectomy and treatment with gonadal steroid hormones. Endocrinology, 1985.117(3):p.1195-200.
55. Tamma, R., et al., Oxytocin is an anabolic bone hormone. Proc Natl Acad Sci U S A,2009.106(17):p.7149-54.
56. Handa, R.J., et al., Hormonal regulation of androgen receptor messenger RNA in the medial preoptic area of the male rat. Brain Res Mol Brain Res,1996. 39(1-2):p.57-67.
57. McCormick, C.M., et al., Neonatal sex hormones have'organizational'effects on the hypothalamic-pituitary-adrenal axis of male rats. Brain Res Dev Brain Res, 1998.105(2):p.295-307.
1. Solomon, M.B. and J.P. Herman, Sex differences in psychopathology:of gonads, adrenals and mental illness. Physiol Behav,2009.97(2):p.250-8.
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