Menstrual and reproductive characteristics and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities study

We pooled multiethnic data from four population-based studies and examined associations of menstrual and reproductive characteristics with breast cancer (BC) risk by tumor hormone receptor (HR) status [defined by estrogen receptor (ER) and progesterone receptor (PR)]. We estimated odds ratios and 95% confidence intervals using multivariable logistic regression, stratified by age (<50, ≥50 years) and ethnicity, for 5,186 HR+ (ER+ or PR+) cases, 1,365 HR− (ER− and PR−) cases and 7,480 controls. For HR+ BC, later menarche and earlier menopause were associated with lower risk in non-Hispanic whites (NHWs) and Hispanics, and higher parity and longer breast-feeding were associated with lower risk in Hispanics and Asian Americans, and suggestively in NHWs. Positive associations with later first full-term pregnancy (FTP), longer interval between menarche and first FTP and shorter time since last FTP were limited to younger Hispanics and Asian Americans. Except for nulliparity, reproductive characteristics were not associated with risk in African Americans. For HR− BC, lower risk was associated with later menarche, except in African Americans and older Asian Americans and with longer breast-feeding in Hispanics and Asian Americans only. In younger African Americans, HR− BC risk associated with higher parity (≥3 vs. 1 FTP) was increased fourfold in women who never breast-fed, but not in those with a breast-feeding history, suggesting that breast-feeding may mitigate the adverse effect of higher parity in younger African American women. Further work needs to evaluate why menstrual and reproductive risk factors vary in importance according to age and ethnicity.     

Time-dependent effects of ovarian steroids on tyrosine hydroxylase activity in the limbic forebrain of female rats

Summary In this work, we have studied the time-course of the effects of pharmacological administration of ovarian steroids on tyrosine hydroxylase (TH) activity in the limbic forebrain of ovariectomized rats. Administration of estradiol produced a late decrease in TH activity. This effect was found 24 hours after the last steroid injection, disappearing at 32 hours. It was antagonized by progesterone, since a single injection of this steroid to estradiol-pretreated rats reversed to control values the estradiol-induced decrease. Nevertheless, the administration of progesterone after estradiol treatment caused a short-time decrease in the limbic activity of TH, which was observed 4 hours after the last steroid injection, disappearing subsequently. On the other hand, the administration of progesterone alone produced a biphasic effect, with a reduction at 24 hours, followed by an increase at 32 hours. These effects were only observed in the animals non-treated with estradiol, disappearing with a previous treatment with estrogens. Hence, it can be concluded that both ovarian steroids may affect the limbic TH activity. Thus, estradiol produced a late inhibitory effect on the activity of this enzyme, which was antagonized by progesterone. Administration of the last one to estradiol-treated rats produced a short-time inhibitory effect, whereas its administration to non-treated rats produced a late biphasic effect (inhibition followed by stimulation), which was not observed in estradiol-treated rats.     

雌、孕激素受体和C-erbB-2在原发胆囊癌中的表达及意义

目的　探讨雌、孕激素受体 (ER、PgR)和C erbB 2癌基因蛋白产物在原发胆囊癌发生、发展中的作用及相互关系 ,研究它们的表达与肿瘤的病理类型、分级 ,临床分期及预后的关系 ,并为该病的临床诊治提供参考依据。方法　应用免疫组织化学法 ,检测 3 5例原发胆囊癌 ,2 0例慢性胆囊炎组织中ER、PgR和C erbB 2癌基因蛋白的表达水平。结果　在原发胆囊癌中ER、PgR和C erbB 2阳性表达率分别为 60 %、4 5 .7%和 65 .7%。ER的阳性表达与浸润及淋巴结转移密切相关 (P <0 .0 5 )。C erbB 2过度表达与胆囊癌淋巴结转移有关 (P <0 .0 5 )。ER或PgR阳性患者的累计生存率明显低于阴性者。结论　ER、PgR及C erbB 2在原发胆囊癌中的表达率显著高于其在胆囊良性病变中的表达率。ER或PgR阳性者积累生存率显著低于ER或PgR阴性者。ER可能有希望成为反映胆囊癌恶性程度和预后的一项生物学指标     

Loss of heterozygosity alterations associated with progesterone therapy in endometrial hyperplasia and adenocarcinoma

Loss of heterozygosity (LOH) was analyzed in four patients with endometrial hyperplasia (EH) with atypia (two patients) and without atypia (two patients) and in five patients with endometrial adenocarcinoma (EAC) to clarify the clinicopathologic relationship between genetic alterations and hormone therapy. Each patient was initially administered high-dose medroxyprogesterone acetate (MPA) as a uterine-sparing treatment. The five microsatellite markers used to analyze LOH were at chromosomal loci 8p22.1, 8p21, 8p21.3, 8p22, and 8p22. DNA was extracted from paraffin-embedded sections before, during, and after MPA therapy using laser capture microdissection. As a result, LOH was more frequently detected after MPA therapy (overall ratios were 16, 17, and 29% before, during, and after MPA therapy, respectively). LOH is more easily detected in EH loci than in EAC loci before MPA. For EAC, initial LOH detection on chromosome 8 may be related to an incomplete response to MPA, but negative LOH does not guarantee a favorable treatment outcome. For EH or atypical endometrial hyperplasia, it is unknown whether LOH alteration associated with MPA therapy is related to atypia of the disease.     

Nociceptin (Orphanin FQ) abolishes gestational and ovarian sex steroid-induced antinociception and induces hyperalgesia

Nociceptin (Orphanin FQ) is a newly discovered endogenous heptadecapeptide substrate for the opioid-receptor-like 1 receptor, a G protein coupled receptor that bears striking amino acid sequence homology to opiate receptors. In rats, intrathecal (i.t.) administration of nociceptin is without effect on basal thresholds for responsiveness to electric foot shock. However, during either late gestation or its hormonal simulation, when nociceptive thresholds are elevated by approximately 70%, i.t. nociceptin substantially attenuates jump thresholds in a dose-dependent fashion. This hypoalgesic effect of nociceptin is not limited to attenuating the gestational or sex steroid-induced increment in pain thresholds. Following the highest i.t. dose of nociceptin employed (20 nmol), the gestational or sex steroid-induced increment in jump thresholds is not only abolished but a significant hyperalgesia is observed. These results underscore the importance of the hormonal milieu to nociceptin hypoalgesic sensitivity. The potential contribution of spinal nociceptive pathways that utilize nociceptin to the etiology of extraordinary painful pregnancy and labor should not be ignored.     

Estrogen receptor alpha pathway is involved in the regulation of Calbindin-D9k in the uterus of immature rats.

It has been demonstrated in our previous studies that Calbindin-D9k (CaBP-9k) is a potent biomarker for screening estrogen-like chemicals in the rat model. Although treatments with 17beta-estradiol (E2) and endocrine disrupting compounds resulted in the up-regulation of uterine CaBP-9k, the mechanism of CaBP-9k induction by these compounds through two subtypes of estrogen receptors (ERalpha and ERbeta) is unclear. Thus, in the present study, immature rats were treated with propyl pyrazole triol (PPT, an ERalpha-selective ligand), diarylpropionitrile (DPN, an ERbeta-selective ligand), E2, or dimethyl sulfoxide (DMSO, a vehicle control) for three days in order to clarify which subtype of ER is involved in the uterine CaBP-9k induction. Following injection with these ER ligands, uterine CaBP-9k expression was analyzed by Northern blot and immunoblot assays. Uterine CaBP-9k expression is mainly mediated by PPT in a dose- and time-dependent manner in immature rats, whereas no significant alteration of the uterine CaBP-9k gene was observed after DPN treatment. In addition, an estrogenicity of PPT in inducing CaBP-9k expression was completely blocked by the anti-estrogen ICI 182,780, implying that uterine CaBP-9k is solely induced by ERalpha. A single treatment with PPT rapidly increased the protein levels of ERalpha and PR, an E2-mediated gene, in these tissues. Taken together, these results indicate that uterine CaBP-9k is induced by E2 and endocrine disrupting chemicals via the ERalpha pathway, but not ERbeta, in the uterus of immature rats.     

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.     

前列腺癌组织中性激素受体表达的分析

目的:定性分析雄激素受体(AR)、雌激素受体(ER)、孕激素受体(PR)在良性前列腺增生(BPH)和前列腺癌(PCa)组织中的阳性表达,为激素治疗PCa和预后判断提供一定的依据。方法:采用免疫组化DAKO Envision二步法,分析30例BPH与32例PCa标本中AR、ER、PR的阳性表达情况。结果:AR、ER、PR阳性数BPH组分别为22、10、6例;PCa组分别为18、14、2例,两组差异无显著性。随访30例PCa患者术后的生存期表明:AR表达阳性者平均生存时间为6.41年,AR阴性者为4.28年,两者差异有统计学意义(P<0.05)。结论:BPH和PCa患者在性激素受体表达上的差异无显著意义;PCa患者中AR表达阳性者平均生存时间长于AR阴性者,后者的预后较差,对AR阴性者行激素治疗效果不确定。     

Effect of estradiol and progesterone on muscle weight and acetylcholine receptors in “myasthenic” rats

Summary Clinical evidence suggests that endocrinal factors are involved in fluctuations of the symptoms of women with myasthenia gravis. We studied the effect of estradiol and progesterone in an animal model for myasthenia gravis in rats. Although it was found that the mass of muscles was dependent on sex, and in female rats affected by estradiol, the number of acetylcholine receptors in these muscles was independent of sex and hormone administration. Sex hormones failed to influence the severity of muscle weakness in myasthenic rats.