In vivo Regulation of Prolactin Gene Expression in the Male Rat: Role of Sex Steroids and Dopamine

The influence of sex steroids and the dopaminergic system on the in vivo modulation of prolactin (PRL) mRNA levels was investigated by quantitative in situ hybridization in the male rat anterior pituitary gland. In situ hybridization was performed using a [³⁵S]-labeled cDNA probe encoding PRL. Orchiectomy performed 14 days earlier did not modify PRL mRNA levels. In orchiectomized rats treatment with the dopaminergic agonist bromocriptine for 14 days decreased PRL mRNA levels by 30%, while in intact animals the same treatment did not induce any changes in PRL mRNA levels. Administration of the dopamine D₂ receptor antagonist haloperidol in both intact and orchiectomized rats induced a 4-fold increase in mRNA levels. Administration of dihydrotestosterone to orchiectomized animals which had been treated or not with haloperidol or bromocriptine did not modify PRL mRNA levels. In orchiectomized animals administration of 17ß-estradiol (0.25 μg twice daily) for 14 days caused a 4-fold increase in amounts of PRL mRNA. Administration of bromocriptine to 17ß-estradiol-treated animals induced a 15% decrease of PRL mRNA levels compared to those obtained by 17ß-estradiol administered alone. The concomitant administration of 17ß-estradiol and haloperidol resulted in a 50% increase in PRL mRNA levels compared to those measured in animals treated with haloperidol alone. The present results clearly demonstrate that in vivo estrogen as well as dopamine-mediated mechanisms play a regulatory role in PRL mRNA levels in the male rat.     

溃疡病男性患者血浆睾丸酮和雌二醇浓度的变化

本文对20例溃疡病男性患者和20名男性健康者进行了血浆睾丸酮和雌二醇则定。两者相比,溃疡病男性患者血浆睾丸酮水平虽较健康者为高,但经统计学处理,无显著差异(t:1.616 P>0.05);而血浆雌二醇水平,溃疡病男性患者低于健康者,经统计学处理,有显著差异(t:2.53 P<0.05)。     

雌二醇对去势沙鼠脑缺血再灌注损伤后脑组织中NO和NOS的影响

目的　观察雌二醇对去势沙鼠脑缺血再灌注脑损伤的保护作用。方法　去势雌性沙鼠 30只 ,随机分为假手术组、缺血再灌注组和雌二醇干预组。采用夹闭双侧颈总动脉法复制沙鼠脑缺血再灌注模型 ,缺血 7min再灌注 12h ,取脑组织测定脑组织中一氧化氮 (NO)含量、一氧化氮合酶 (NOS)活力的变化 ,并取脑组织观察海马CA1区神经细胞的病理改变。结果　缺血再灌注组脑组织中NO含量明显增高 ,NOS活力明显降低 ,与假手术组比较有显著差异 (P <0 . 0 1) ;雌二醇干预组脑组织中NO水平明显降低 ,NOS活力有所增高 ,与缺血再灌注组比较有显著差异 (P <0 . 0 1) ;缺血再灌注组脑组织海马CA1区神经细胞损伤明显 ,脑组织水肿明显 ;雌二醇干预组神经细胞损伤明显减轻。结论　预防性应用雌二醇能明显减轻缺血再灌注所造成的神经细胞损伤 ,对脑缺血再灌注损伤有保护作用。     

女性银屑病患者血清性激素浓度测定

对20例女性、非妊娠期、生育年龄的寻常型、进行期银屑病患者检测了雌二醇(E_2)、孕酮(P)和睾酮(T)的血清浓度。结果为:卵泡期E_2平均值为84±61.6pg/ml,黄体期E_2平均值为164.9±115pg/ml,均显著高于正常平均值(P值分别为<0.001,<0.005);黄体期P平均值为2.67±4.62ng/ml,显著低于正常平均值(P<0.005);T平均值在正常范围,提示银屑病可能与血清E_2和P浓度有关。     

Prodrugs for Improved Oral β-Estradiol Bioavailability

Prodrugs of -estradiol (1) were prepared with the objective of improving its oral bioavailability. -Estradiol-3-acetylsalicylate (2), -estradiol-3-salicylate (3), and -estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.     

Transdermal Dual-Controlled Delivery of Contraceptive Drugs: Formulation Development,in Vitro and in Vivo Evaluations,and Clinical Performance

Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17-estradiol (E₂), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E₂ from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia–Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45°C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm²). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.     

Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta

We previously demonstrated the therapeutic effects of ethinyl estradiol (EE), an orally active estrogen and a component of birth control pills, in encephalitogenic autoimmune encephalomyelitis (EAE). In this study, we report the effectiveness of EE in treating collagen-induced arthritis (CIA) induced with bovine type II collagen (bCII) in DBA/1LacJ mice, a CIA susceptible strain. Both low and high doses of EE notably suppressed clinical and histological signs of CIA in a dose-dependent manner compared to vehicle-treated controls. Oral treatment with EE decreased proliferation and secretion of pro-inflammatory factors, TNF-alpha IFN-gamma, MCP-1 and IL-6 by bCII peptide-specific T cells, production of bCII-specific IgG2a antibodies, and mRNA for cytokines, chemokines and chemokine receptors in joint tissue. This is the first report demonstrating effective treatment of joint inflammation and clinical signs of CIA with orally administered ethinyl estradiol, thus supporting its possible clinical use for treating rheumatoid arthritis in humans.     

Sex differences in estradiol-induced progestin receptor immunoreactivity in the guinea pig preoptic area and hypothalamus

Progesterone exerts on the central nervous system a number of effects, some of which are estrogen dependent mostly in the preoptic area and the mediobasal hypothalamus. In these regions, an immunocytochemical study was used to evaluate differences in progesterone receptor (PR) immunoreactivity between the male and the female guinea pig in response to 10 μg/day estradiol benzoate (EB) for 5 consecutive days. Compared to EB-treated females, EB-treated males showed a slightly lower number of PR-immunoreactive cells in the preoptic area whereas PR-immunoreactivity appeared in more cells in the anterior part of the ventrolateral nucleus. The numbers of PR-immunoreactive cells in the arcuate nucleus did not differ significantly between males and females. These results show that regionally localized sex differences exist in the induced PR system after 5 days exposure to EB.     

Effect of estradiol on mouse uterine epithelial cell transepithelial resistance (TER)

PROBLEM: The effects of estradiol on epithelial cell function in the uterus may either be direct or indirect through the paracrine effects of underlying stromal cells. The aim of this study was to test whether estradiol-17beta (E(2)) acts directly to regulate uterine epithelial cell monolayer integrity. METHODS OF STUDY: Mouse uterine epithelial cells were isolated and grown on cell culture inserts to form confluent, polarized monolayers, as indicated by the development of high transepithelial resistance (TER). RESULTS: When polarized epithelial cells were treated with E(2), TER was significantly decreased within 24 hr of exposure. Epithelial cells remained hormonally responsive in culture for at least 10 days. In contrast to estradiol, incubation with progesterone, cortisol, aldosterone, and DHT had no effect on uterine epithelial cell TER. The ability of E(2) to decrease TER was inhibited following co-incubation with ICI 182,780, a pure estrogen receptor antagonist. To further investigate the mechanism involved in estradiol-induced decreases in TER, we tested the effect of TAPI-0, an inhibitor of matrix metalloproteinases. Our findings indicate that TAPI-0 reversed the inhibitory effect of E(2) on TER. CONCLUSIONS: These studies demonstrate that epithelial monolayer integrity is directly influenced by E(2) and ER mediated. Further, it suggests that the mechanism through which estradiol decreases TER is mediated by matrix metalloproteinases.     

雌激素替代治疗大鼠海马结构PKC阳性细胞的变化

目的 :观察雌性大鼠行去势后以及雌激素替代治疗海马结构蛋白激酶C ( proteinkinaseC ,PKC)阳性细胞的变化 ,通过该模型研究绝经期后女性情绪烦躁、记忆下降等神经精神症状的分子机制。方法 :将大鼠分为对照组、去势 3个月组和去势后雌激素替代治疗 3个月组 ,用免疫组织化学方法检测海马结构PKC阳性细胞的变化。结果 :PKC阳性细胞主要分布于下托和齿状回的颗粒层 ,其中齿状回内的阳性细胞较下托的多。去势 3个月组与对照组相比 ,齿状回内的PKC阳性细胞没有显著性减少 (P >0 .0 5 ) ,下托PKC阳性细胞显著减少 (P <0 .0 5 ) ;雌激素治疗组与对照组相比 ,下托细胞数量有所减少 ,但无显著性差异 (P >0 .0 5 )。结论 :海马结构下托PKC阳性细胞的减少可能在绝经后女性情绪烦躁、记忆下降等症状中起重要的作用。