Aromatization of androgens is important for skeletal maintenance of aged male rats

A nonsteroidal aromatase inhibitor vorozole (VOR) was administered to aged (12 months old) male Wistar rats and its effect was compared with the effect of androgen deficiency. The rats were either sham-operated (SHAM) or orchidectomized (ORCH) and treated with or without VOR. Thus, four experimental groups were created (SHAM, ORCH, SHAM + VOR, ORCH + VOR). The follow-up period was 4 months. At the end of the experimental period, bone mineral density (BMD) of the first four lumbar vertebrae and right femur was measured ex vivo with dual-energy X-ray absorptiometry, bone formation was evaluated by serum osteocalcin, and bone resorption by urinary excretion of (deoxy)pyridinoline. Orchidectomy increased bone resorption 2- to 3-fold whereas bone formation was only slightly increased. Treatment of intact male rats with VOR also increased bone resorption (+30% increase) whereas bone formation was not increased in this SHAM + VOR group. Their BMD was 7% lower in the femur (P < 0.01) and 6% lower in the lumbar vertebrae (P < 0.01) compared with the SHAM group that had not received VOR. Moreover, this decrease of bone mineral density was not significantly different from the expected decrease of bone density observed in the ORCH groups (6–10%). This was also reflected by a decrease of calcium content of the first four lumbar vertebrae of 15% (P < 0.001) in the SHAM + VOR group and 9–14% (P < 0.05) in the ORCH groups compared with the SHAM group, respectively. These data therefore suggest that inhibition of aromatization of androgens into estrogens increases bone resorption and bone loss similar to that observed after complete removal of androgens. Aromatization of androgens into estrogens may therefore, at least partly, explain the effects of androgens on skeletal maintenance. Received: 13 October 1995 / Accepted: 23 February 1996     

Effect of Chronic Aromatase Inhibition by Δ1 -Testolactone on Pituitary-Gonadal Function in Oligozoospermic Men

Aromatase inhibition by delta 1-testolactone (Teslac, 500 mg twice daily) for 6 months in 9 patients with idiopathic oligozoospermia lowered the levels of serum estradiol (E2) and thereby sex hormone binding globulin (SHBG) (rS = +0.40, p less than 0.025) to values -35 and -25%, respectively, below the pretreatment values (P less than 0.001 and less than 0.005). The E2 decrease was accompanied by a temporary increase (+50%) in the levels of follicle stimulating hormone (FSH), not of luteinizing hormone (LH), and of 17 alpha-hydroxyprogesterone (17 alpha-OHP), but less of testosterone (T) (+30%), which led to a transient rise in the 17 alpha-OHP/T ratio. The T/E2 ratio and "free T" index (T/SHBG) almost doubled until the end of the treatment period. During delta 1-testolactone treatment the mean sperm density gradually rose from 8.1 +/- 1.3 (SEM) before to 21.3 +/- 6.7 X 10(6)/ml after 6 months (P less than 0.01), whereas the total sperm count almost threefold increased (P less than 0.05). Sperm concentrations exceeding 20 X 10(6)/ml were achieved in 4 of the 9 patients. Two of these patients' wives became pregnant. Although the data point to a pivotal role of estrogens in the pathogenesis of the spermatogenic lesion in some patients with idiopathic oligozoospermia, the lack of a beneficial effect of estrogen lowering in others points to a multicausal nature of the disease entity.     

Antitumor effects of a nonsteroidal aromatase inhibitor (CGS 16949A) on 7, 12-dimethylbenz[alpha]anthracene-induced mammary tumors in rats.

The effects of a nonsteroidal aromatase inhibitor, CGS 16949A, on female Sprague-Dawley (SD) rats with 7, 12-dimethylbenz[alpha]anthracene (DMBA)-induced mammary cancers were examined in relation to estrogen receptors (ER). Rat tumor sizes in each treated group were significantly smaller (P less than 0.05) and rat body weights in most treated groups were significantly increased (P less than 0.05) compared to those in the control group (no treatment) at all measurement points during treatment. Rat uterine weights in each treated group decreased significantly compared with those in the control group (P less than 0.05). There was no significant difference between ER-positive and ER-negative groups in tumor size, body weight or uterine weight. At increased doses of CGS 16949A in the experiment, further increases in testosterone levels and further decreases in estradiol levels were shown to occur. The results suggest the mechanisms of CGS 16949A action not to be influenced by the presence or absence of ER, but to be due to its potent aromatase inhibition of the conversion of androgens to estrogens.     

芳香化酶P450在子宫内膜异位症中的表达及意义

目的：探讨芳香化酶P450在子宫内膜异位症发病中的作用。其阳性表达用于诊断子宫内膜异位症可行性。方法：应用免疫组化方法检测正常子宫内膜和子宫内膜异位症的在位及异位内膜芳香化酶P450的表达。结果：芳香化酶P450在正常子宫内膜无表达或弱阳性，在子宫内膜异位症的在位和异位内膜均有强表达，且增殖期高于分泌期表达，敏感度为92％，特异度为95．5％。结论：子宫内膜芳香化酶分泌增加促进子宫内膜异位症的发生，并对其诊断有重要意义。     

芳香化酶抑制剂来曲唑的研究进展

来曲唑是新一代强效的非甾体芳香化酶抑制剂,用于一线治疗晚期乳腺癌,并广泛用作乳腺癌的二线用药．疗效好,不良反应少,耐受性好．值得临床推广应用。本文综述了来曲唑的合成方法以及临床研究进展。     

Alopecia With Endocrine Therapies in Patients With Cancer

Background.

Whereas the frequency of alopecia to cytotoxic chemotherapies has been well described, the incidence of alopecia during endocrine therapies (i.e., anti-estrogens, aromatase inhibitors) has not been investigated. Endocrine agents are widely used in the treatment and prevention of many solid tumors, principally those of the breast and prostate. Adherence to these therapies is suboptimal, in part because of toxicities. We performed a systematic analysis of the literature to ascertain the incidence and risk for alopecia in patients receiving endocrine therapies.

Methods.

An independent search of citations was conducted using the PubMed database for all literature as of February 2013. Phase II–III studies using the terms “tamoxifen,” “toremifene,” “raloxifene,” “anastrozole,” “letrozole,” “exemestane,” “fulvestrant,” “leuprolide,” “flutamide,” “bicalutamide,” “nilutamide,” “fluoxymesterone,” “estradiol,” “octreotide,” “megestrol,” “medroxyprogesterone acetate,” “enzalutamide,” and “abiraterone” were searched.

Results.

Data from 19,430 patients in 35 clinical trials were available for analysis. Of these, 13,415 patients had received endocrine treatments and 6,015 patients served as controls. The incidence of all-grade alopecia ranged from 0% to 25%, with an overall incidence of 4.4% (95% confidence interval: 3.3%–5.9%). The highest incidence of all-grade alopecia was observed in patients treated with tamoxifen in a phase II trial (25.4%); similarly, the overall incidence of grade 2 alopecia by meta-analysis was highest with tamoxifen (6.4%). The overall relative risk of alopecia in comparison with placebo was 12.88 (p < .001), with selective estrogen receptor modulators having the highest risk.

Conclusion.

Alopecia is a common yet underreported adverse event of endocrine-based cancer therapies. Their long-term use heightens the importance of this condition on patients'' quality of life. These findings are critical for pretherapy counseling, the identification of risk factors, and the development of interventions that could enhance adherence and mitigate this psychosocially difficult event.     

Effects of letrozole on proliferation and apoptosis in cultured leiomyoma cells treated with prostaglandin E(2)

OBJECTIVE: The objective was to determine the direct effect of letrozole on the proliferation and apoptosis of cultured leiomyoma cells co-treated with prostaglandin E(2) (PGE(2)). STUDY DESIGN: Leiomyoma cells were obtained from three groups of patients who had undergone hysterectomy due to leiomyoma. Percentages of antiproliferative cells were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis was assessed with sub-G1 cell counts by flow cytometry and Western blot analysis. RESULTS: Combined treatment with 100 microM letrozole and 10 microM PGE(2) for 48 h resulted in a significantly lower viability rate (25.9+/-4.5%) and an increased cell death rate (31.6+/-4.4%) than groups treated with letrozole or PGE(2) alone. However, after adding 10nM estradiol to the combined treatment group, the cell viability rate was restored (75.1+/-7.7%) and the cell death rate was decreased (10.5+/-3.1%). Increased caspase-3 expression was found in the letrozole and PGE(2) combined treatment group, but not in the group in which estradiol was added. CONCLUSION: The present results demonstrate that letrozole inhibits growth and induces apoptosis of leiomyoma cells by blocking the aromatase up-regulated by PGE(2) treatment. These findings support the need for further investigation of aromatase inhibitors as a medical treatment option in leiomyoma.     

绝经后Luminal B型乳腺癌的内分泌治疗

目的 探讨芳香化酶抑制剂和三苯氧胺对绝经后Luminal B型乳腺癌患者的疗效.方法 收集天津市肿瘤医院2002年7月至2005年3月间733例术后接受辅助内分泌治疗的原发性乳腺癌患者资料,肿瘤性质均经手术切除病理组织学证实.患者均为绝经后且ER阳性,其中501例接受三苯氧胺治疗,232例接受芳香化酶抑制剂治疗.采用免疫组化SP法进行ER、PR、HER2检测.随访时间36～90个月,中位随访时间46个月.结果 芳香化酶抑制剂治疗组Luminal B型乳腺癌患者三年无瘤生存率高于三苯氧胺组(90.6% vs.88.6%,P=0.038).三苯氧胺组亚组分析显示:LN+/HER2+患者三年无瘤生存率低于LN+/HER2-患者(88.2% vs 90.4%,P=0.037);HER2+/PR+患者高于HER2+/PR-患者(90.8% vs.89.5%,P=0.032).芳香化酶抑制剂组内LN(+)和LN(-)亚组中,HER2(+)患者与HER2(-)患者的三年无瘤生存率差异均无统计学意义(P>0.05);而HER2+/PR+组高于HER2+/PR-组(91.9% vs.90.5%,P=0.029).芳香化酶抑制剂组潮热、阴道出血、静脉血栓形成的发生率低,肌肉骨骼疼痛、骨折的发生率则高于三苯氧胺组(P<0.05).结论 芳香化酶抑制剂对绝经后Luminal B型患者疗效好于三苯氧胺,此效果不受患者腋窝淋巴结状态的影响,且耐受性和安全性较好.     

乳腺癌内分泌治疗发展与未来

乳腺癌是激素依赖性肿瘤,内分泌药物的选择除了根据患者的年龄、病灶部位、手术到复发的间隔时间以及受体测定等因素外,还要根据不同药物的作用机制以及副反应而定。随着对内分泌治疗药物作用机制的深入研究和大规模临床研究的证实,激素受体阳性乳腺癌的内分泌治疗疗效将不断提高。