Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown. METHODS: We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol. RESULTS: We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17ß-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype. CONCLUSION: Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.

Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival.

Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose-response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.

Ovarian hormones and reproductive risk factors for breast cancer in premenopausal women: the Norwegian EBBA-I study.

BACKGROUND: Ovarian hormones, parity and length of 'menarche-to-first birth' time interval are known risk factors for breast cancer, yet the associations between 17ß-estradiol, progesterone and these reproductive factors remain unclear. METHODS: A total of 204 women (25-35 years) who participated in the Norwegian EBBA-I study collected daily saliva samples for one complete menstrual cycle, and filled in a reproductive history questionnaire. Anthropometry was measured and saliva samples were analyzed for ovarian hormones. Associations between parity, the interval and ovarian hormones, and effects of hormone-related lifestyle factors were studied in linear regression models. RESULTS: Mean age was 30.7 years, and age of menarche 13.1 years. Parous women had on average 1.9 births, and age at first birth was 24.5 years. No association was observed between parity and ovarian steroids. In nulliparous women, higher waist circumference (≥ 77.75 cm) and longer oral contraceptive (OC) use (≥ 3 years) were associated with higher levels of 17ß-estradiol. Short (<10 years) versus long (>13.5 years) 'menarche-to-first birth' interval was associated with higher overall mean (P(trend) = 0.029), 47% higher maximum peak and 30% higher mid-cycle levels of 17ß-estradiol. We observed a 2.6% decrease in overall mean salivary 17ß-estradiol with each 1-year increase in the interval. CONCLUSIONS: Nulliparous women may be more susceptible to lifestyle factors, abdominal overweight and past OC use, influencing metabolic and hormonal profiles and thus breast cancer risk. Short time between 'menarche-to-first birth' is linked to higher ovarian hormone levels among regularly cycling women, suggesting that timing of first birth is related to fecundity.

[Patients with cluster headache in a neurological department]. / Pasienter med clusterhodepine ved en nevrologisk avdeling.

BACKGROUND: Cluster headache is a devastating disorder which needs intensive drug treatment in the cluster periods. MATERIAL AND METHODS: All patients hospitalised for cluster headache (n = 37) at the Department of Neurology, Haukeland University Hospital 1988-1998 were studied. Data were retrieved from patient files and all patients were asked to fill in a postal questionnaire, which were returned by 27 (73%). RESULTS: Median age was 47 years, range 22-78 years. 28 patients were male. Ten of the patients had chronic cluster headache, all men. 20 out of 27 patients who answered the questionnaire used sumatriptan for acute attacks, 15 of them as subcutaneous injection. 17 patients had tried oxygen inhalation during an attack. Ten of the patients had tried prednisone as prophylactic treatment during a cluster, half of them with effect. Only two patients had tried verapamil and four had tried lithium. None of the patients had ever used valproate as drug prophylaxis. 18 of the patients smoked more than five cigarettes per day. INTERPRETATION: The treatment of cluster headache patients is at present suboptimal, both regarding symptomatic and prophylactic drugs.