Walter B. Severs

Oral Contraceptive Use as a Risk Factor for Premenopausal Breast Cancer: A Meta-analysis

OBJECTIVE To perform a meta-analysis of case-control studies that addressed whether prior oral contraceptive (OC) use is associated with premenopausal breast cancer. METHODS We searched the MEDLINE and PubMed databases and bibliography reviews to identify case-control studies of OCs and premenopausal breast cancer published in or after 1980. Search terms used included breast neoplasms, oral contraceptives, contraceptive agents, and case-control studies. Studies reported in all languages were included. Thirty-four studies were identified that met inclusion criteria. Two reviewers extracted data from original research articles or additional data provided by study authors. We used the DerSimonian-Laird method to compute pooled odds ratios (ORs) and confidence intervals (CIs) and the Mantel-Haenszel test to assess association between OC use and cancer. RESULTS Use of OCs was associated with an increased risk of premenopausal breast cancer in general (OR, 1.19; 95% CI, 1.09-1.29) and across various patterns of OC use. Among studies that provided data on nulliparous and parous women separately, OC use was associated with breast cancer risk in both parous (OR, 1.29; 95% CI, 1.20-1.40) and nulliparous (OR, 1.24; 95% CI, 0.92-1.67) women. Longer duration of use did not substantially alter risk in nulliparous women (OR, 1.29; 95% CI, 0.85-1.96). Among parous women, the association was stronger when OCs were used before first full-term pregnancy (FFTP) (OR, 1.44; 95% CI, 1.28-1.62) than after FFTP (OR, 1.15; 95% CI, 1.06-1.26). The association between OC use and breast cancer risk was greatest for parous women who used OCs 4 or more years before FFTP (OR, 1.52; 95% CI, 1.26-1.82). CONCLUSION Use of OCs is associated with an increased risk of premenopausal breast cancer, especially with use before FFTP in parous women.

Induced abortion as an independent risk factor for breast cancer: a comprehensive review and meta-analysis.

STUDY OBJECTIVE: To ascertain, from the published reports to date, whether or not a significantly increased risk of breast cancer is specifically attributable to a history of induced abortion, independent of spontaneous abortion and age at first full term pregnancy (or first live birth); to establish the relative magnitude of such risk increase as may be found, and to ascertain and quantify such risk increases as may pertain to particular subpopulations of women exposed to induced abortion; in particular, nulliparous women and parous women exposed before compared with after the first full term pregnancy. INCLUDED STUDIES: The meta-analysis includes all 28 published reports which include specific data on induced abortion and breast cancer incidence. Since some study data are presented in more than one report, the 28 reports were determined to constitute 23 independent studies. Overall induced abortion odds ratios and odds ratios for the different subpopulations were calculated using an average weighted according to the inverse of the variance. An overall unweighted average was also computed for comparison. No quality criteria were imposed, but a narrative review of all included studies is presented for the readers use in assessing the quality of individual studies. EXCLUDED STUDIES: All 33 published reports including data on abortion and breast cancer incidence but either pertaining only to spontaneous abortion or to abortion without specification as to whether it was induced or spontaneous. These studies are listed for the readers information. RESULTS: The overall odds ratio (for any induced abortion exposure; n = 21 studies) was 1.3 (95% confidence interval of 1.2, 1.4). For comparison, the unweighted overall odds ratio was 1.4 (1.3,1.6). The odds ratio for nulliparous women was 1.3 (1.0,1.6), that for abortion before the first term pregnancy in parous women was 1.5 (1.2,1.8), and that for abortion after the first term pregnancy was 1.3 (1.1,1.5). CONCLUSIONS: The results support the inclusion of induced abortion among significant independent risk factors for breast cancer, regardless of parity or timing of abortion relative to the first term pregnancy. Although the increase in risk was relatively low, the high incidence of both breast cancer and induced abortion suggest a substantial impact of thousands of excess cases per year currently, and a potentially much greater impact in the next century, as the first cohort of women exposed to legal induced abortion continues to age.

Angiotensin II immunohistochemistry of the rat brain.

Immunoreactive angiotensin II (AII) in rat brain is identified histochemically by the unlabelled antibody-enzyme method. Addition of protease inhibitors, phenylmethyl sulfonyl fluoride (PMSF) and ethylenediamine tetra-acetic acid (EDTA), to subzero (-10 degrees C) fixation with propylene glycol and formaldehyde provides reproducible preservation of immunoreactive AII. Synaptic boutons within the brainstem and cerebellum contain immunoreactive AII. The deep cerebellar nuclei have the richest density of AII positive synapses. Other nonneuronal cells such as pinealocytes, pituicytes, and 3rd ventricular tanycytes contain immunoreactive AII. This dual AII localization suggests that both neurons and blood vessels may be involved in the transport of AII to sensitive sites within the rat brain.

The role of angiotensin in thirst

Abstract A relatively large literature has described the motivated drinking behavior produced by angiotensin, which occurs even in normally hydrated animals. Many investigations have attempted to relate angiotensin to a “regulatory” thirst drive, i.e., drinking in response to an osmotic or volume stimulus. A review of this literature is difficult because there are unclarities in various aspects of regulatory thirst. Therefore, this review is divided into two sections. The first section briefly discusses the nature and location of receptors and anatomic sites for osmotic and volume thirst and some methodological considerations. The second section describes angiotensin thirst and its potential significance.

On the central hypertensive effect of angiotensin II.

Abstract It was the purpose of this study to investigate further the mechanism by which angiotensin II produces central hypertensive effects. When administered into the perfused lateral ventricle of the cat, the peptide consistently produced neural presser effects which were essentially abolished by lesions at high midbrain levels. Presser activity was apparently not generated by bulbar efferent or afferent mechanisms, as topical application of the peptide at the termination of the cerebral aqueduct during perfusion produced little or no change in femoral blood pressure when compared with the intraventricular responses in the same animals. Similar pressor activity was observed in perfused dog lateral ventricle experiments but was not detected in experiments in which only subarachnoid structures of the dog brain were perfused.

Localization of angiotensin in rat brain.

cytes, posterior pituicytes, third ventricular tanycytes, and some cells within the spinal trigeminal tract. Preincubating the All antiserum with excess angiotensin I and antidiuretic hormone did not affect this distribution while pre-incubation with All abolished it. Cross-reactivity of All antiserum with angiotensin I, dog renin substrate, and synthetic renin substrate, tetradecapeptide was less than 1%. However, the antiserum showed 70% cross reactivity with angiotensin III (Al!!); therefore this immunohistochemical map could also correlate with the presence of Al!!. This morphology of the All/All! localization in the rat brain when correlated to the known patterns of All/All! receptors within brain suggests angiotensin may be transported to sensitive brain sites by both neurons and vascular channels.

Angiotensin and thirst: Studies with a converting enzyme inhibitor and a receptor antagonist

Abstract Although exogenous angiotensin is recognized as a potent dipsogen, the participation of endogenous angiotensin in thirst has not been well established. To investigate this question, we produced thirst in rats by relative cellular dehydration (hypertonic NaCl injection), or hypovolemia (hyperoncotic polyethylene glycol injection). An angiotensin receptor antagonists (sar(1)-ala(8)- angiotensin II, P-113), or a converting enzyme inhibitor (SQ, 20, 881, SQ) given to thirsty rats by intracerebroventricular (IVT) or peripheral routes. P-113 infused i.v. (10 μg/kg/min) or injected IVT (10 μg) did not alter the drinking response to either thirst stimulus. The latter treatment reduced the drinking response to 50 ng of IVT angiotensin II (p

Influence of Adrenergic Blocking Drugs on Central Angiotensin Effects

The central effects of angiotensin in unanes thetized rats were studied before and after administration of adrenergic blocking drugs. Intraventricular injections of prevented angiotensin-induced drinking, sympathetic stimulation, and vasopressin release. Administration Phentolamine of various β-adrenergic blocking drugs, either intraarterially or intraventricularly, did not alter central angiotensin activity in a manner which could be correlated with β-adrenergic blockade. Local anesthetics inhibited central angiotensin pressor and drinking effects. Centrally administered phentolamine or tetracaine appear to be useful tools for further studies of the actions of angiotensin on the central nervous system.

Urethane Anesthesia in Rats

Anesthesia in rats produced by urethane administered intraperitoneally caused (1) peritoneal fluid accumulation; (2) inability to undergo a renal response to NaCl or water loading, and (3) pronounced

Developing renal innervation in the spontaneously hypertensive rat: evidence for a role of the sympathetic nervous system in renal damage

The spontaneously hypertensive rat (SHR) exhibits increased renal sympathetic nerve activity and neurotransmitter levels compared with the control Wistar-Kyoto rat (WKY). These renal nerve abnormalities have been implicated as the cause of hypertension in the SHR. The aims of the present study were to characterize the ontogeny of renal sympathetic innervation in SHR in order to determine any functional implications. Glyoxylic acid histofluorescent and radio-enzymatic norepinephrine assays demonstrated an accelerated development of renal innervation in newborn and 1-, 2-, 3- and 6-week-old SHR compared with WKY. Sympathetic nervous system function was blocked in developing male SHR by treating pups from days 0 to 14 with: (1) guanethidine, (2) combined alpha- and beta-receptor antagonists (prazosin and timolol), or (3) vehicle (5% sucrose). Blood pressure (mean), renal function (plasma creatinine) and histologic renal damage were assessed at 42 weeks of age. Although the blood pressure of the drug-treated rats remained elevated, renal damage was reduced and renal function was improved compared with control (sucrose-treated) SHR. The data demonstrate that the SHR kidney develops a precocious sympathetic innervation and that inhibition of the development of sympathetic function ameliorates renal damage independently of systemic hypertension.