Postmenopausal Control Subjects Research Articles

Serum Klotho levels in primary hyperparathyroidism patients before and after parathyroidectomy.

To investigate Klotho level and its association with biochemical indices of primary hyperparathyroidism (PHPT). Fifty PHPT patients and fifty-two age- and body mass index-(BMI) matched healthy control subjects were recruited. In addition, twenty-five PHPT patients underwent parathyroidectomy (PTX) and had 4-month follow-up visits. Intact parathyroid hormone (iPTH), 25-hydroxyvitamin D [25(OH)D], calcium, albumin, corrected calcium, and Klotho levels were determined. There was no significant difference in age and BMI between PHPT subjects and controls (p > 0.05). PHPT patients had Klotho levels (15.4 ± 1.2 ng/mL) about 23% higher compared with those of the controls (11.9 ± 0.8 ng/mL), but this difference was not significant (p = 0.063). However, postmenopausal PHPT patients had 45% higher Klotho levels (17.6 ± 1.5 ng/ml) compared with postmenopausal controls (12.1 ± 0.9 ng/mL, p = 0.008). For postmenopausal subjects, Klotho levels had positive correlation with levels of iPTH (r = 0.25, p = 0.026) and corrected calcium (r = 0.34, p = 0.003), but negative correlation with 25(OH)D (r = -0.23, p = 0.042). After PTX, levels of iPTH and corrected calcium decreased and 25(OH)D levels increased to normal range (p < 0.001). However, there was no significant change in Klotho levels after a 4-month follow-up. Serum Klotho levels are higher in postmenopausal PHPT patients than in healthy postmenopausal control subjects. The etiology of elevated Klotho level and its clinical significance requires further investigation.

Antioxidant Status of Breast, Cervical and Ovarian Cancer Patients at Various Menopausal Stages in Lagos State, Nigeria

Cancer is a collection of diseases which involves the abnormal growth of cells with the potential to invade or spread to other parts of the body. The aim of this study is to access the antioxidant status of women with female predominant cancer (breast, cervical and ovarian) in relationship with their menopausal stages. Blood samples were collected from 180 freshly diagnosed female patients of breast, cervical and ovarian cancer at Lagos State University Teaching Hospital, Idi- Araba, Mushin, Lagos and Lagos State University Teaching Hospital Ikeja, Lagos and 60 relatively healthy subjects at different menopausal stages. Serum catalase (CAT), Superoxide dismutase (SOD) activites, Reduced Glutathione (GSH), Vitamin C and E concentrations were evaluated in subject’s blood sample using standard established methods. The results obtained were subjected to statistical analysis (p&lt;0.05). However, the results of the female cancer patients at each menopausal stage were compared to premenopausal, menopausal and postmenopausal control groups, while the results obtained from the menopausal and postmenopausal control subjects were compared to the premenopausal control subjects. There was significant decrease (p&lt;0.05) in the activities of CAT, SOD and in the concentrations of GSH, Vitamins C and E in all the menopausal stages when compared to the control groups. However, MDA concentrations showed significant increase (p&lt;0.05) in all the menopausal stages in comparison to the corresponding control groups. These findings suggest that cancer patients might be at risk from oxidative cell damage. Therefore, further research is required in this field with a view of improving the management of cancers predominant in females.

MicroRNAs 182 and 375 Sera Expression as Prognostic Biochemical Markers in Breast Cancer

IntroductionBreast cancer (BC) is the most common malignancy among women; supporting the need for identification of novel prognostic biomarkers, circulating microRNAs (miRNAs) could serve as such in various cancers. The aim of this study was to explore the association between miRNAs 182 and 375 with BC stages and its receptors, based on their expression using real time PCR. Materials and MethodsDetailed medical history was taken and blood samples were withdrawn from 80 female subjects divided over the studied groups. Patients ranged in age from 24 to 80 years and were classified as follows: group I included 10 noncancerous postmenopausal control subjects; group II included 32 postmenopausal patients with BC; group III included 10 noncancerous premenopausal control subjects; group IV included 24 premenopausal patients with BC; and group V included 6 patients with benign breast tumors. ResultsmiRNA 182 expression was significantly higher in group II, group IV, and group V (3.36 ± 0.14, 2.52 ± 0.34, and 4.93 ± 0.3,9 respectively); miRNA 375 expression was significantly higher in group II, group IV, and group V (4.41 ± 0.40, 3.12 ± 0.35, and 11.28 ± 2.37, respectively) (P < .05). Both miRNAs were significantly associated with each other and with receptors used for the prognosis of BC even after multiple regression analysis. ConclusionAccordingly, miRNAs 182 and 375 could be potential noninvasive markers used for the follow up of BC patients.

Associations between polymorphisms of HLA-B gene and postmenopausal osteoporosis in Chinese Han population.

Osteoporosis is a systemic skeletal disease, which is more prevalent in postmenopausal women. Osteoporosis likely develops beginning with genetic risk. This study explored the relationships between polymorphisms of HLA-B gene and postmenopausal osteoporosis in a Chinese Han population. Polymerase chain reaction sequence-based typing (PCR-SBT) method was used for DNA typing at HLA-B locus in 70 patients with postmenopausal osteoporosis and 73 healthy controls in female Han population of Shaanxi Province, situated in north-western China. We found that 40 HLA-B alleles in postmenopausal osteoporosis patients and control subjects, respectively. Furthermore, the frequency of HLA-B* 3501 allele was significantly higher in postmenopausal osteoporosis patients than in the control group (P = 0.033), and the relative risk was 7.632 (95% CI: 0.927-62.850). Our results suggest that HLA-B* 3501 was likely an important risk factor for postmenopausal osteoporosis. As different populations have different HLA polymorphisms, further investigation of the relationship of various HLA genes and osteoporosis with larger sample size is still necessary in the future.

Variations in the PDCD6 Gene Are Associated with Increased Uterine Leiomyoma Risk in the Chinese

Programmed cell death 6 (PDCD6) participates in T cell receptor, Fas, and glucocorticoid-induced programmed cell death. To test the relationship between PDCD6 polymorphisms and uterine leiomyomas (UL) risk, we investigated the association of two SNPs (rs4957014 and rs3756712) in PDCD6 with UL risk in a case-control study of 295 unrelated premenopausal UL patients and 436 healthy postmenopausal control subjects in a population of China. Genotypes of the two SNPs were determined with the use of PCR-restriction fragment length polymorphism assay. Significantly increased UL risks were found to be associated with the T allele of rs4957014 and the T allele of rs3756712 (p=0.016, odds ratio [OR]=1.325, 95% confidence intervals [CI]=1.053-1.668 for rs4957014; p<0.0001, OR=1.898, 95% CI=1.457-2.474 for rs3756712, respectively). Increased UL risks were associated with them in different genetic models. The present study provided evidence that rs4957014 and rs3756712 are associated with UL risk, the results indicated that genetic polymorphisms in PDCD6 may contribute to the development of UL.

Sclerostin and DKK1 in Primary Hyperparathyroidism

Bone formation is influenced by the Wnt pathway through effects on osteoblast functionality, and these actions are opposed by two antagonists: sclerostin and Dickkopf-1 (DKK1). Decreased levels of serum sclerostin were found after treatment with the PTH analogue teriparatide and in patients with primary hyperparathyroidism (PHPT), while treatment with teriparatide of postmenopausal osteoporosis is associated with increases in serum DKK1. We studied mineral metabolism and Wnt pathway in 21 postmenopausal women affected by PHPT and in 42 age-matched healthy women. Mean serum calcium and PTH were significantly higher and serum phosphates significantly lower in the PHPT group compared with the control group. Serum 25-OH-vitamin D (25OHD) was lower in PHPT patients and 1,25 dihydroxy-vitamin D [1,25(OH)2D] was significantly higher. Patients with PHPT had significantly higher levels of bone alkaline phosphatase (BAP) and of serum C-terminal telopeptides of type I collagene (sCTX). Serum sclerostin in PHPT was significantly lower (-26 %) and serum DKK1 significantly higher (+57 %) than in healthy control subjects. Serum PTH was positively correlated with 1,25OH2D (p < 0.001), BAP (p = 0.036), sCTX (p = 0.003), and DKK1 (p = 0.007) and negatively with 25OHD (p = 0.002) and sclerostin (p = 0.02). In PHPT patients, serum sclerostin was negatively correlated with BAP (p = 0.038) and sCTX (p = 0.07). Patients with PHPT have significantly lower sclerostin and higher DKK1 levels compared with healthy postmenopausal control subjects. Further studies are warranted in order to verify whether the balance between these two opposite effects on Wnt function might help explain the variable bone involvement among patients with PHPT.

Association of T869C gene polymorphism of transforming growth factor-β1 with low protein levels and anthropometric indices in osteopenia/osteoporosis postmenopausal Thai women

Osteoporosis is the most common metabolic bone disease; it is an important health problem among postmenopausal women. We evaluated the association of three polymorphisms, T869C, C-509T and G915C, of the TGF-β1 gene with bone mineral density (BMD) serum TGF-β1 levels in 278 postmenopausal female osteopenia/osteoporosis subjects and 95 postmenopausal female control subjects. Serum TGF-β1 levels were significantly lower in osteopenia/osteoporosis subjects than in control subjects. Serum TGF-β1 levels of the CT+CC (T869C) genotype group were significantly lower in osteopenia/osteoporosis subjects than in control subjects (11.3 vs 15.8 ng/mL). There was a significant difference in the CT+CC (T869C) genotype frequencies between the osteopenia/osteoporosis and control subjects (74.18 vs 60.22%; OR = 1.90, 95%CI = 1.16-3.12). In the age group of more than 50 years, subjects with the TC+CC genotype of T869C polymorphism had significantly increased risk of osteopenic/ osteoporotic bones at L1 (OR = 2.36, 95%CI = 1.37-4.07), L2 (OR = 1.71, 95%CI = 1.01-2.90), L3 (OR = 2.21, 95%CI = 1.23-3.98), L4 (OR = 1.74, 95%CI = 1.00-3.03) and the femoral neck (OR = 1.80, 95%CI = 1.04-3.12). The CT+CC genotype of the T869C polymorphism of the TGF-β1 gene was found to be associated with lower serum TGF-β1 in osteopenia/osteoporosis subjects and increased risk of osteopenic and osteoporotic fracture at L1-4, femoral neck and total hip in postmenopausal Thai women. Logistic regression analysis showed that T869C polymorphism is a significant risk factor for osteopenia/ osteoporosis. We concluded that T869C polymorphism of the TGF-β1 gene has an impact on decreased serum TGF-β1 levels and influences susceptibility to osteopenia/osteoporosis in Thai women.

Abstract 912: Soy isoflavone intake, MDM2 gene polymorphism and breast cancer risk among Chinese women in Singapore

Abstract Epidemiologic studies among populations that consume moderate to high amount of soy have shown that soy isoflavones may reduce breast cancer risk, and the chemopreventive effects are postulated to be related to the anti-estrogenic properties of soy isoflavones. Recently, experimental studies have revealed that dietary isoflavones may also down-regulate the expression of the MDM2 oncogene, and the inhibition of the expression of the MDM2 oncoprotein has in turn been associated with antitumor activities in breast cancer models. Furthermore, a polymorphism in the promoter region of MDM2 SNP309 (T&amp;gt;G change at nucleotide 309 in the first intron; rs2279744) leads to increased expression of the oncogene and has been associated with earlier onset of breast cancer. We have previously shown that postmenopausal women with a higher than median intake of soy have a reduced risk of breast cancer compared with those with a lower intake. If down-regulation of the MDM2 oncogene is one of the mechanistic pathways for the chemopreventive effects of soy isoflavones in breast cancer, we postulate that the protective effect of soy isoflavones on breast cancer will be stronger in those possessing the high-activity MDM2 genotype. To confirm this hypothesis, we conducted a nested case-control study among 281 incident, postmenopausal breast cancer cases and 462 postmenopausal control subjects within the Singapore Chinese Health Study Cohort. Overall, there was no significant association between MDM2 gene polymorphism and breast cancer risk. Postmenopausal women who had a higher than median intake of soy had a reduced risk of breast cancer [odds ratio (OR), 0.76; 95% confidence interval (CI), 0.56-1.03]. This inverse association was principally noted among women homozygous for the high activity MDM2 allele (GG genotype). There was a statistically significant, roughly 50% reduction in breast cancer risk between above versus below median level of soy consumption in this subgroup of women (OR, 0.52; 95% confidence interval, 0.28-0.98). On the other hand, a much weaker, and statistically nonsignificant association was noted among women possessing the lower-activity MDM2 genotypes (OR, 0.86, 95% CI, 0.59-1.24). Our findings suggest that the ability of soy isoflavones to down-regulate the MDM2 oncoprotein may be one etiologic mechanism through which the intake of soy is associated with breast cancer protection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 912.

In Asian-American Women, Westernization Influences Estrogen Metabolism, but Not Total Endogenous Estrogen Production.

Abstract Background: Historically, breast cancer incidence rates were 4-7 times higher in the United States than in China and Japan. When Asian women migrate to the U.S., their risk rises over several generations and approaches that in U.S. Whites. Endogenous estrogen has been postulated to explain these international differences. Methods: In a population-based case-control study in Chinese, Japanese, and Filipino women living in San Francisco-Oakland, CA; Los Angeles, CA; or Oahu, HI, we documented a six-fold gradient in breast cancer risk with Westernization. Using 12-h, overnight urines from 263 premenopausal mid-luteal and 168 postmenopausal control subjects, we investigated associations of estrogens and estrogen metabolites (EM) with Westernization, particularly birthplace in the East or West. Fifteen EM were measured concurrently by liquid chromatography-tandem mass spectrometry with high accuracy, precision, and sensitivity. Log-transformed EM measures, adjusted for age and ethnicity, were compared by robust linear regression. Results: Total urinary EM (pmol/mg creatinine) was not associated with birthplace in premenopausal or postmenopausal women. When the three estrogen hydroxylation pathways were expressed as percent of total EM, the relative difference by birthplace, West compared to East, was 15% lower for 2-pathway EM (p=0.009), 7% lower for 4-pathway EM (p=0.37), and 10% higher for 16-pathway EM (p=0.008). Similar results were observed for individual EM in each pathway, premenopausal and postmenopausal women, and the three ethnicities. In both menopausal groups, 2-pathway EM concentration decreased steadily with increasing risk across six categories of Westernization. Conclusions: Our results do not indicate that total estrogen production explains the increased breast cancer risk in Western societies. However, estrogen metabolism patterns, especially reduced 2-hydroxylation, may contribute to the elevated risk; and underlying mechanisms merit further exploration. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3063.

Two-year Longitudinal Changes in Forearm Cortical Bone Geometry in Postmenopausal Women with Mild Primary Hyperparathyroidism without Parathyroidectomy

Several studies suggest that mild PTH excess does not have any deteriorative effects on bone mineral density (BMD) in several-year-longitudinal studies of patients with mild primary hyperparathyroidism (pHPT) without parathyroidectomy (PTX). However, it remains unknown about the change in bone geometry in pHPT patients without PTX. We examined the longitudinal effects of mild PTH excess on cortical bone geometry in postmenopausal patients with mild pHPT without PTX by using peripheral quantitative computed tomography (pQCT), and we compared them with normal and hypoparathyroidism women. Nine postmenopausal female patients who were diagnosed as pHPT, six postmenopausal female patients with hypoparathyroidism (3 idiopathic and 3 postoperative), and thirty postmenopausal control subjects participated in this study. Radial volumetric (v) BMD and several bone geometry parameters were measured by pQCT at basal line and after 2 years. Cortical vBMD was significantly lower in pHPT group. Moreover, total area and periosteal circumferences were significantly higher in pHPT group. Total and cortical vBMD were significantly decreased after 2 years in control group. However, they were stable in pHPT group after 2-year follow-up. As for bone geometry, cortical thickness and area were also stable in pHPT group during 2-year follow-up, although they were significantly reduced in control group and hypoparathyroidism group. In conclusion, the present longitudinal study revealed that there were no significant changes in radial vBMD and cortical bone geometry in postmenopausal women with mild pHPT, whereas age-related thinning of cortical bone as well as decrease of vBMD were observed in the control and patients with hypoparathyroidism.

Retinal Hemorrhages in Anastrozole Users

To determine whether women using anastrozole (an aromatase inhibitor, which suppresses estrogen synthesis) are likely to have retinal hemorrhages. Fundus photographs were obtained for a study comparing effects on vision and the eye of anastrozole (1 mg/d) and tamoxifen (20 mg/d) for women receiving adjuvant endocrine therapy for early-stage breast cancer. Photographs (2 eyes per subject) were evaluated for hemorrhages by an ophthalmologist masked from identifying subject information. The presence of hemorrhages was assessed for 35 anastrozole users, 38 amenorrheic tamoxifen users, and 53 amenorrheic (peri- or postmenopausal) control subjects not using any endocrine medication. The age range was 43 to 69 years; only subjects reporting normal vision and healthy eyes were recruited. Photographs from 36 tamoxifen users from a previous study also were assessed. Views of the fundus extended appreciably beyond the posterior pole for all tamoxifen and anastrozole users, and for 38 of the control subjects. Photographic assessments were compared with medical history and blood pressure data, and optical coherence tomography was used for quantifying aspects of foveal shape that might be affected by vitreoretinal traction. Four anastrozole users and no contemporaneous tamoxifen users but one previously tested tamoxifen user had retinal hemorrhages, in each case within the posterior pole. Two anastrozole users had a flame hemorrhage (in the retinal nerve fiber layer), and two had a blot hemorrhage (deeper in the retina). No control subjects were observed to have hemorrhages. Anastrozole use appears to be associated with an increased prevalence of retinal hemorrhages. The hemorrhages may mark systemic vascular compromise resulting from estrogen depletion, and/or they may be consequences of vitreoretinal traction resulting from estrogen depletion. They may also depend on the use of medications for controlling common anastrozole-induced side effects. Prospective studies need to be conducted with larger numbers of subjects.

Elevated serum M-CSF level predicts reduced survival in metastatic breast cancer patients

10591 Background: Macrophage colony stimulating factor (M-CSF) and its receptor (CSF-1R, the c-fms oncogene protein product) have been reported to be expressed in a variety of cancers, including breast cancer. The M-CSF produced by breast cancer cells and surrounding stromal cells increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation. In this study we evaluated the predictive and prognostic potential of circulating M-CSF in metastatic breast cancer patients treated with hormone therapy. Methods: Using an M-CSF ELISA (R&amp;D Systems, Minneapolis, MN), M-CSF concentration was determined in pretreatment sera from 204 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial of fadrozole vs. megace, and also in sera from 25 post-menopausal control female subjects. Results: The serum M-CSF level from the 25 healthy post-menopausal female control subjects had a mean ± SD of 835.6 ± 276.1 pg/ml (range 319.0 - 1,465.8 pg/ml). The upper limit of normal was defined as the 95th percentile of the serum M-CSF level from the female control group (1277 pg/ml). Pretreatment serum M-CSF levels from the metastatic breast cancer patients ranged from 82.2 - 3,019.8 pg/ml, and were found elevated above the upper limit of normal in 15 of 204 patients (7.35 %). Patients with elevated pretreatment serum M- CSF did not have a significantly different objective response rate, clinical benefit rate, or time to progression to hormone therapy; but these patients did have significantly reduced overall survival (median survival 10.0 months) compared to patients with normal serum M-CSF levels (median survival 24.3 months)(p = 0.007). In multivariate analysis with serum HER-2/neu included as a covariate, elevated serum M-CSF level remained a significant independent variable for reduced survival (p= 0.032). Conclusions: Pretreatment serum M-CSF levels were elevated in 7 % of metastatic breast cancer patients compared to healthy female control subjects, and these patients had significantly reduced overall survival. Serum M-CSF deserves further study to determine its predictive and prognostic biomarker potential in breast cancer patients. No significant financial relationships to disclose.

Body composition and vertebral fracture risk in female patients treated with glucocorticoid

Glucocorticoid (GC) causes bone loss and an increase in bone fragility. However, fracture risk was found to be only partly explained by bone mineral density in GC-treated patients (GC patients). Although GC causes a change in the distribution of fat in the body, the relationship between body composition and fracture risk in GC patients remains unknown. The present study examined the relationship between the presence or absence of vertebral fractures and various indices, including body composition, in 92 premenopausal GC patients, 122 postmenopausal GC patients and 122 postmenopausal age-matched control subjects. Dual-energy X-ray absorptiometry was employed to analyze body composition. Percentage lean body mass (LBM), % fat and % trunk fat were not significantly different between postmenopausal GC patients and the control women. When groups with and without vertebral fractures were compared, % LBM and % fat were significantly higher and lower in groups with vertebral fractures, respectively, in postmenopausal GC patients, but not in the postmenopausal control women, although % trunk fat was not significantly different between groups with and without vertebral fractures. Femoral neck BMD was negatively correlated with % LBM and positively correlated with % fat. In premenopausal GC patients, % trunk fat was significantly higher in the fracture group, although % LBM and % fat were not significantly different between groups with and without vertebral fractures. The present study revealed that body composition is related to vertebral fracture risk in GC-treated patients. Lower % fat can be included in the determination of vertebral fractures in postmenopausal GC-treated patients. The influence of body composition on vertebral fracture risk may be different between the pre- and postmenopausal state in GC patients.

The color appearance of stimuli detected via short-wavelength-sensitive cones for breast cancer survivors using tamoxifen

This study compared color appearance data for two populations of middle-aged women: (1) women using the selective estrogen receptor modulator tamoxifen as adjuvant therapy following successful treatment for early-stage breast cancer, and (2) healthy amenorrheic (peri- or post-menopausal) control subjects not using any hormonally acting medications. A 3-alternative forced-response paradigm (with “blue”, “lavender”, or “white” as the allowable responses) was used for assessing the perceived color of 440-nm foveal test stimuli superimposed on a larger 3.6 log td 580-nm background. In contrast to the control subjects, the majority of tamoxifen users described the test stimuli as “white”, whether at threshold or slightly suprathreshold. Threshold-sensitivity measurements themselves appeared less effective for distinguishing between subject groups. The results show that a simple color-naming procedure can reveal alterations of foveal short-wavelength-sensitive cone-mediated visual function that are common among tamoxifen users.

Premenopausal advantages in postprandial lipid metabolism are lost in women with type 2 diabetes.

Women with type 2 diabetes appear to lose the protection against cardiovascular disease afforded by estrogens. We examined the effects of menopausal status on postprandial clearance of dietary fat in healthy and diabetic women. Fasting subjects (premenopausal and postmenopausal control subjects, premenopausal and postmenopausal diabetic women, all n = 8) were given a meal containing the stable isotope 1,1,1-(13)C-tripalmitin, with blood and breath sampled for 6 and 24 h, respectively, in the postprandial period. Lower levels of (13)C-palmitic acid ((13)C-PA) in the triglyceride fraction implies more efficient chylomicron clearance, lower levels of (13)C-PA in the nonesterified fatty acid (NEFA) fraction implies improved dietary NEFA entrapment, and higher levels of (13)CO(2) in the breath denote more efficient of oxidation of dietary-derived lipid. In diabetic women, there were no differences between the pre- and postmenopausal groups for any of these parameters. In contrast, premenopausal control subjects, compared with postmenopausal control subjects, had lower (13)C-PA in the triglyceride fraction area under the curve (AUC) (premenopausal median [range] 25.2 [12.1-49.4 mmol/l] per 6 h, postmenopausal 48.5 [15.5-77.2 mmol/l] per 6 h; P < 0.01) and higher (13)CO(2) levels in the breath AUC (premenopausal 22.5 [18.0-31.5%] of administered dose, postmenopausal 17.2 [11.2-31.5%] of administered dose; P < 0.01) with no difference between groups in levels of (13)C-PA in the NEFA fraction AUC. The premenopausal advantage in clearance of dietary lipid is not seen in premenopausal diabetic women. This is likely to promote an atherogenic lipoprotein profile and may contribute to the loss of cardiovascular disease protection seen in diabetic women.

Effect of family history, obesity and exercise on breast cancer risk among postmenopausal women.

We examined effects of obesity and lifetime exercise patterns on postmenopausal breast cancer risk according to family history in a large population-based case control study conducted in Los Angeles County, California, because we hypothesized that both factors would affect risk through similar mechanistic pathways, and that their effects would be stronger among women with a family history. We studied 1883 postmenopausal breast cancer case subjects and 1628 postmenopausal control subjects ranging in age from 55-72 years. Cases were diagnosed with incident breast cancer in the late 1980s and 1990s. Controls were individually matched to case subjects on age, ethnic origin and neighborhood. In-person interviews determined known breast cancer risk factors including: height, weight, lifetime exercise, and family history of breast and other cancers. Breast cancer risk was raised among women who had at least 1 first-degree relative with breast cancer (odds ratio [OR] = 1.68; 95% confidence interval [CI] = 1.36-2.08). Risk increased with increasing levels of body-mass index (wt-kg/ht-m(2)) (p-trend = 0.005). Breast cancer risk was reduced among women who maintained, on average, 17.6 metabolic equivalent of energy expenditure (MET)-hr of activity/week from menarche onward (OR = 0.66; 95% CI = 0.48-0.90). Body-mass index, adjusted for lifetime exercise, was strongly associated with breast cancer risk among women with a positive family history of breast cancer (p-trend < 0.0001), but only weakly associated among women with no family history (p-trend = 0.08; homogeneity of trends p = 0.0005). In contrast, the risk reduction associated with exercise activity, adjusting for body-mass index, was limited to women without a family history of breast cancer (p-trend = 0.001; homogeneity of trends p = 0.005). Body-mass index and exercise activity, both modifiable risk factors for breast cancer, seem to have differential effects depending on a woman's family history of breast cancer, and may impact risk through different biological mechanisms.

Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin

Background: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman’s risk of developing breast cancer in a population-based, case‐control study. Methods: Case subjects included those with incident breast cancers diagnosed over 4 1 ⁄ 2 years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55‐72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. Results: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR 5 = 1.10; 95% confidence interval [CI] = 1.02‐1.18). Risk was substantially higher for CHRT use (OR5 = 1.24; 95% CI = 1.07‐1.45) than for ERT use (OR 5 = 1.06; 95% CI = 0.97‐1.15). Risk estimates were higher for SEPRT (OR 5 = 1.38; 95% CI = 1.13‐1.68) than for CCRT (OR5 = 1.09; 95% CI = 0.88‐1.35), but this difference was not statistically significant. Conclusions: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk‐ benefit equation for HRT in women using CHRT. [J Natl Cancer Inst 2000; 92:328‐32]

Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.

Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.

Desaturation function does not decline after menopause in human females.

Aging appears to decrease delta6-desaturase activity in males, but in females it is uncertain. delta6- and delta5-desaturase functions were investigated in pre- and post-menopausal women who were normoglycemic or had type 2 diabetes (2 x 2 factorial, n = 37). Subjects were compared for indicators of diabetic control, estrogen levels, fatty acid profiles and indices of delta6- and delta5-desaturase activity. Diet intakes that were compared to determine whether results were a function of dietary factors known to influence desaturase activity revealed no differences (P>0.05). Post-menopausal women with type 2 diabetes had more 18:2 n6 in serum phospholipids (P<0.05) than did the pre- and post-menopausal control subjects. Fatty acid ratios of 18:3 n6/18:2 n6 indicated greater delta6-desaturase activity for women with type 2 diabetes, but differences were not found between pre- and post-menopausal groups. Significant correlation (P < 0.05) indicates an association between diabetic status and desaturase function, but function did not appear to be affected by menopausal status. In contrast to reports using male subjects, we found no evidence that desaturase function decreased in aging females, as reported for males, or increased as hypothesized in this study.

Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women.

In animal studies, prolactin has been found to be important for mammary epithelial development and its administration has been shown consistently to increase the rate of mammary tumor formation. Previous epidemiologic studies of prolactin and breast cancer risk in postmenopausal women have been limited in size, and the results have been inconsistent. We conducted a nested case-control study within the prospective Nurses' Health Study cohort to better determine the relationship between plasma prolactin levels and postmenopausal breast cancer risk. Blood samples were collected from cohort members during the period from 1989 through 1990. Prolactin levels were measured by use of a microparticle enzyme immunoassay. Included in this analysis were 306 postmenopausal women who were diagnosed with breast cancer after blood donation but before June 1994. One or two postmenopausal control subjects were matched per case subject on the basis of age, postmenopausal hormone use, and time of day and month of blood collection; the study included a total of 448 control subjects. In conditional logistic regression analyses, a significant positive association was observed between plasma level of prolactin and postmenopausal breast cancer risk (highest versus lowest quartile, multivariate relative risk = 2.03; 95% confidence interval = 1.24-3.31; two-sided P for trend = .01). The relationship was independent of plasma sex steroid hormone levels and was similar after excluding case subjects diagnosed in the first 2 years after blood collection. These prospective data suggest that higher plasma prolactin levels are associated with an increased risk of breast cancer in postmenopausal women.