Naturally-occurring estradiol-17beta-fatty acid esters, but not estradiol-17beta, preferentially induce mammary tumorigenesis in female rats: implications for an important role in human breast cancer

Because mammary glands are surrounded by adipose tissues, we hypothesize that the ultra-lipophilic endogenous estrogen-17beta-fatty acid esters may have preferential hormonal and carcinogenic effects in mammary tissues compared to other target organs (such as the uterus and pituitary). This hypothesis is tested in the present study. We found that all 46 rats implanted with an estradiol-17beta pellet developed large pituitary tumors (average weight=251+/-103 mg) and had to be terminated early, but only 48% of them developed mammary tumors. In addition, approximately one-fourth of them developed a huge uterus. In the 26 animals implanted with a mixture containing estradiol-17beta-stearate and estradiol-17beta-palmitate (two representative estradiol-17beta-fatty acid esters) or in the 29 animals implanted with estradiol-17beta-stearate alone (in the same molar dose as estradiol-17beta), 73% and 79%, respectively, of them developed mammary tumors, whereas only 3 or 2 animals, respectively, had to be terminated early due to the presence of a large pituitary tumor. Both tumorous and normal mammary tissues contained much higher levels of estrogen esterase than other tissues, which catalyzes the releases of bioactive estrogens from their fatty acid esters. In conclusion, while estradiol-17beta is much stronger in inducing pituitary tumor (100% incidence) than mammary tumor, estradiol-17beta-fatty acid esters have a higher efficacy than estradiol-17beta in inducing mammary tumor and yet it only has little ability to induce uterine out-growth and pituitary tumorigenesis. This study establishes the endogenous estrogen-17beta-fatty acid esters as preferential inducers of mammary tumorigenesis.     

骨形态发生蛋白-7(BMP-7)促进小鼠子宫内膜蜕膜化研究

目的:探讨骨形态发生蛋白-7(bone morphogenetic protein 7,BMP-7)在子宫内膜蜕膜化过程中的作用。方法:①采用RT-PCR和免疫组织化学技术分别观察BMP-7的mRNA和蛋白在妊娠第5～8日小鼠子宫中的表达情况;②原代培养小鼠子宫基质细胞,用孕酮(P4)、E2和cAMP诱导蜕膜化的同时分别加入1ng/ml、10ng/ml、100ng/mlBMP-7重组腺病毒,Westernblotting检测催乳素(PRL)的表达。结果:①BMP-7mRNA在妊娠第5～8日小鼠子宫着床位点的表达高于着床旁组织(P<0.01),且在着床点的表达随着妊娠天数的增加逐渐增强(P<0.05)。BMP-7蛋白在妊娠第5日、第6日分别表达于植入胚胎周围的基质细胞和初级蜕膜带,第7日、第8日时主要表达于次级蜕膜带以及植入位点系膜侧基质细胞。②在小鼠子宫基质细胞的蜕膜化过程中,BMP-7重组腺病毒组的催乳素蛋白表达均显著增加(P<0.01),其中10ng/ml组增加最明显(P<0.01)。结论:BMP-7蛋白具有促进小鼠子宫内膜蜕膜化的效应。     

A new key neurohormone controlling reproduction,gonadotropin-inhibitory hormone (GnIH): Biosynthesis,mode of action and functional significance

Identification of novel neurohormones that play important roles in the regulation of pituitary function is essential for the progress of neurobiology. The decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion. Gonadal sex steroids and inhibin inhibit gonadotropin secretion via feedback from the gonads, but a neuropeptide inhibitor of gonadotropin secretion was, until recently, unknown in vertebrates. In 2000, a novel hypothalamic dodecapeptide that inhibits gonadotropin release was identified in quail and termed gonadotropin-inhibitory hormone (GnIH). This was the first demonstration of a hypothalamic neuropeptide inhibiting gonadotropin release in any vertebrate. GnIH acts on the pituitary and GnRH neurons in the hypothalamus via a novel G protein-coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. GnIH neurons express the melatonin receptor and melatonin stimulates the expression of GnIH. Because GnIH exists and functions in several avian species, GnIH is considered to be a new key neurohormone controlling avian reproduction. From a broader perspective, subsequently the presence of GnIH homologous peptides has been demonstrated in other vertebrates. Mammalian GnIH homologous peptides also act to inhibit reproduction by decreasing gonadotropin release in several mammalian species. Thus, the discovery of GnIH has opened the door to a new research field in reproductive neurobiology. This review summarizes the advances made in our understanding of the biosynthesis, mode of action and functional significance of GnIH, a newly discovered key neurohormone, and its homologous peptides.     

局麻和全麻对病人血清NO.PRL水平影响的初步探讨

目的探讨局麻和全身麻醉对手术病人血清一氧化氮（NO）和垂体泌乳素（PRL）水平的影响。方法根据不同的麻醉方法对64例卵巢癌患者手术病人分为硬膜外麻醉组（A组）和静吸复合全麻组（B组）,每组32例。在麻醉诱导前,手术切皮和手术开始后1h抽取静脉血3ml,分别测定血清NO和PRL浓度。结果A组血清NO、PRL含量在切皮和术中1h与术前比较有显著性差异（p〈0.05）。B组血清NO、PRL含量无显著性差异（p〉0.05）,在切皮和手术中1h,B组NO、PRL含量比A组含量降低（p〈0.05）。结论静吸复合麻醉能明显降低PRL浓度和NO的生成。     

The anxiolytic effects of somatostatin following intra-septal and intra-amygdalar microinfusions are reversed by the selective sst2 antagonist PRL2903

Somatostatin (SST) is a polypeptide with two biological isoforms (SST14, and SST28), and five SST receptor subtypes (sst1-5). Together, they mediate a number of neural and hormonal functions. Recently, we found that intracerebroventricular (ICV), intra-amygdalar, and intra-septal microinfusions of SST14, SST28, and a selective sst2 receptor agonist L-779976 all produced anxiolytic-like effects in the elevated plus-maze, a widely used animal model of anxiety. The receptor specificity of these anxiolytic-like effects, however, has not been conclusively established.Accordingly, the anxiolytic effects of SST in the elevated plus-maze were assessed following intra-septal or intra-amygalar microinfusions of 1) SST (1.5 μg per hemisphere), 2) the highly selective sst2 receptor antagonist PRL2903 (1.5 μg per hemisphere), or 3) the combination of SST and PRL2903 (each 1.5 μg per hemisphere). Antagonism of the anxiolytic effects of SST in the plus-maze by PRL2903 should result in open-arm exploration that is equivalent to that of 4) vehicle-injected control rats.Both intra-septal and intra-amygdalar microinfusions of SST produced anxiolytic effects in the elevated plus-maze, consistent with results found previously after ICV microinfusions (see [Engin et al., 2008], [Engin and Treit, 2009] and [Yeung et al., 2011]). More importantly, infusion of PRL2903 completely reversed the anxiolytic effects of SST in both the amygdala and the septum. These results show that somatostatin's anxiolytic effects are mediated by sst2 receptors contained in the amygdala and septum of the rat brain.     

产宝口服液对产后缺乳大鼠催乳作用的实验研究

目的 研究产宝口服液对产后缺乳大鼠的乳腺组织、血清催乳素(PRL)、多巴胺(DA)水平的影响及催乳机制。方法 采用溴隐亭建立SD大鼠的缺乳模型；检测血液中PRL和DA水平。乳腺组织作组织形态学观察和评价。结果 与对照组比较，产宝Ⅲ号口服液使大鼠的红细胞数、血红蛋白量及PRL显著增高，而DA显著降低；大鼠乳腺组织活动期乳腺细胞增多。结论产宝Ⅲ号口服液具有促进大鼠泌乳的作用，其机制可能是促进PRL分泌而抑制DA的分泌。     

Impairment of pituitary and gonadal functions in alloxan-induced diabetic male rats

The inhibitory effect of treatment with a potent LHRH agonist on testicular gonadotropin-receptor levels was compared in intact and diabetic rats. Basal and LHRH-induced pituitary gonadotropin secretion as well as the testicular steroidogenic response to oLH were assessed. A single injection of alloxan (65 mg/kg) led, after 6 weeks, to a 40% decrease of testicular LH- and prolactin-receptor levels. Treatment for 2 weeks with [D-Ala6,des-Gly-NH 1/2 0] LHRH ethylamide (100 ng every second day) led to a 70% reduction of LH-receptor levels accompanied by decreased testicular weight, a similar inhibition being found in intact and diabetic animals. Seminal vesicle and ventral prostate weight were markedly reduced in diabetic animals, a further decrease being obtained after treatment with the LHRH agonist. The loss of accessory sex-organ weight in alloxan-diabetic rats was accompanied by a reduction in the basal testicular content of pregnenolone, progesterone, 17-OH-progesterone, androstenedione, testosterone and dihydrotestosterone whereas the steroid response to oLH was within normal limits. We next examined the possible changes of LH and FSH secretion which could be responsible for the reduced testicular function in diabetic animals. Basal plasma-LH levels were 30% reduced in rats 6 weeks after treatment with alloxan while basal plasma-FSH levels remained unchanged. When the pituitary gonadotropin response to LHRH was measured in chronically cannulated freely-moving intact and diabetic rats, an approx. 50% inhibition of the LH and FSH responses to LHRH was observed in diabetic animals.     

The ontogeny of pineal and serum melatonin in male rats at mid-light and mid-dark

Summary Flunarizine (FLU) treatment has proved effective for migraine but there have been reports—though controversial—of depression and/or extrapyramidal signs and symptoms in cases of chronic therapy. It has been suggested that FLU may interfere with the activity of central dopaminergic systems.In this study, prolactin (PRL) secretion was chosen as a parameter for functional exploration of central dopaminergic systems in normal and migraineous women before and after FLU treatment.Five healthy women were given FLU (20 mg) and placebo per os, each for one day. A significance increase of serum PRL levels was found after FLU administration, but not after placebo.Ten women with common migraine underwent TRH stimulation test (200 g i.v.) before and after a 30-day FLU therapy (10 mg per os). Basal PRL levels were not modified by the treatment, but TRH stimulated PRL values were significantly enhanced after a 30-day FLU therapy.These results seem to confirm the hypothesis that FLU interferes with central dopaminergic activity.