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.

Timing of natural menopause covaries with timing of birth of a first daughter: evidence for a mother-daughter evolutionary contract?

Age at natural menopause is characterized by significant variability, but the factors responsible for this observed variation are still not well recognized. Humans are cooperative breeders and non-reproducing grandmothers play important roles in raising children. We propose an evolutionary "mother-daughter contract" hypothesis that suggests that the oldest daughter helps her mother to raise younger siblings but, in return, expects her mother to cease her reproduction, shifting energy and time once her daughter's children are born. Data were collected by a questionnaire from 914 Polish postmenopausal women. From among those, 506 women, 44-98 years old, who had at least one child and who went through a natural menopause were included in the analysis. A woman's age at menopause was sensitive to the age at which she had her first daughter. The age of giving birth to the first daughter, even when she was not her first child, positively correlated with the age of the mother's menopause (N=332, p<0.02), while the age of giving birth to a first son did not have a statistically significant effect (N=332, p=0.36). Results of our study suggest that research on the menopausal transition should take into account mother-daughter relationships as potentially important determinants of the timing of menopause.

Higher luteal progesterone is associated with low levels of premenstrual aggressive behavior and fatigue.

Contradictory findings show both positive and negative effect of progesterone on the premenstrual mood changes in women. Here we present the study investigating this relationship on the large sample of premenstrual women. 122 healthy, reproductive age women collected daily morning saliva samples and recorded intensity scores for the mood symptoms: irritability, anger, sadness, tearfulness, insomnia, and fatigue. Saliva samples were assayed for progesterone concentrations and mood intensity scores were used to calculate behavioral indices. Women with low Aggression/Irritability and Fatigue had consistently higher progesterone levels during the luteal phase than women with high Aggression/Irritability and Fatigue. Additionally, Aggression/Irritability and Fatigue correlated negatively with maximal progesterone value during the luteal phase. Our results demonstrated a negative effect of low progesterone level on the premenstrual mood symptoms such as aggressive behavior and fatigue in healthy reproductive age women. This supports a previously proposed model of biphasic action of progesterone metabolites on mood.

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.

Body fat, energy balance and estradiol levels: a study based on hormonal profiles from complete menstrual cycles.

BACKGROUND: Female fecundity is regulated by nutritional status. Although widely cited, this hypothesis is not strongly supported by empirical data from non-obese, healthy women of reproductive age. METHODS: Healthy, reproductive aged women (n = 141) from Southern Poland collected daily morning saliva samples for one complete menstrual cycle. Levels of 17-beta-estradiol were analyzed by radioimmunoassay. Anthropometric measurements, including body fat percentage, were taken randomly with respect to phase of the menstrual cycle. Energy balance was specified based on changes in body fat percentage from the beginning to the end of the observation period. RESULTS: Women with very low and high body fat had significantly lower levels of E2 compared with women with low and average body fat. In women of very low to average body fat, a 10% increase in body fat was associated with a 5-7 pmol/l increase in estradiol levels. The association between fat percentage and E2 was even stronger in women with positive energy balance, who also showed significant differences between body fat groups in estradiol profiles across whole the menstrual cycle. No such relationship was found in women with negative energy balance. CONCLUSIONS: In healthy women, we found a non-linear association between body fat and estradiol levels. Both very low and high body fat was associated with decreased estradiol levels. The relationship between estradiol and body fat was strongly influenced by women's energy balance.

17-beta-estradiol in relation to age at menarche and adult obesity in premenopausal women.

BACKGROUND: We hypothesize that premenopausal endogenous estradiol may be associated with age at menarche and adult overweight and obesity, potentially contributing to breast cancer risk. METHODS: We assessed age at menarche by questionnaire among 204 healthy Norwegian women, aged 25-35 years. Measures of body composition included body mass index (BMI, kg/m(2)), waist circumference (WC, cm), waist-to-hip ratio (WHR) and fat percentage dual energy X-ray absorptiometry, (DEXA). Daily salivary 17-beta-estradiol (E(2)) concentrations were collected throughout one entire menstrual cycle and assessed by radioimmunoassay (RIA). Linear regression analyses and linear mixed models for repeated measures were used and potential confounding factors and effect modifiers were tested. RESULTS: Among women with an early age at menarche (< or =12 years), the overall mean salivary E(2) concentration increased by 3.7 pmol/l (95% confidence interval, 1.8-5.7 pmol/l) with each 9.8 cm (1 SD) increase in WC, which represents a 20.7% change in the mean for the total group. Among the same early maturers, a 1 SD (0.06) change in WHR was directly associated with a 24.0% change in mean E(2) concentration for the total group. CONCLUSIONS: Our findings support the hypothesis that early age at menarche, together with adult overweight and obesity, result in high levels of 17-beta-estradiol throughout the menstrual cycle.

Energetic factors, ovarian steroids and the risk of breast cancer.

In industrial countries, women often have excess metabolic energy due to high food consumption and low physical activity. High lifetime energy availability results in high lifetime levels of ovarian steroid hormones. Oestrogens and progesterone are hypothesized to play a crucial role in the development and prognosis of breast cancer. Epidemiological studies document the importance of physical activity and caloric limitations in reducing breast cancer risk. The risk of breast cancer is much higher in industrial countries than in developing countries, where women are characterized by lower energy intake and higher energy expenditure. It is likely, that the beneficial effects of physical activity and of negative energy balance are mediated by the reduced levels of ovarian steroids. While both weight loss and physical activity may have similar efficacy in suppressing ovarian function and, therefore, in reducing the risk of breast cancer, we suggest that it may be more advantageous for premenstrual women to achieve lifetime reduction in steroid levels by increasing their physical activity, rather than by weight loss due to caloric restriction alone.

Physical work causes suppression of ovarian function in women.

The suppression of reproductive function is known to occur in women engaging in activities that require high energetic expenses, such as sport participation and subsistence work. It is still unclear, however, if reproductive suppression is a response to high levels of energy expenditure, or only to the resulting state of negative energy balance. To our knowledge, this study provides the first evidence that work-related energy expenditure alone, without associated negative energy balance, can lead to the suppression of reproductive function in women. We document suppression of ovarian function expressed as lowered salivary progesterone levels in women from an agricultural community who work hard, but remain in neutral energy balance. We propose two alternative evolutionary explanations (the 'pre-emptive ovarian suppression' hypothesis and the 'constrained down-regulation' hypothesis) for the observed results.