Endogenous Estrogen Exposure Research Articles

Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women

The cardiovascular consequences of hypoestrogenism in premenopausal women are unclear. Accordingly, the influence of menstrual status and endogenous estrogen (E(2)) exposure on blood pressure (BP), heart rate (HR), and calf blood flow in young (18-35 yr) regularly exercising premenopausal women with exercise-associated menstrual aberrations was investigated. Across consecutive menstrual cycles, daily urinary ovarian steroid levels were analyzed, and the area under the curve was calculated to determine menstrual status and E(2) exposure. BP, HR, blood flow, vascular conductance, and resistance were measured at baseline and following ischemic calf exercise. Exercising subjects consisted of 14 ovulatory (ExOv), 10 short-term (anovulatory and <or=100 days amenorrhea; ST-E(2) Def), and 8 long-term (>100 days amenorrhea; LT-E(2) Def) E(2)-deficient women. Nine sedentary ovulatory subjects (SedOv) were also studied. All groups were similar in age (24.8 +/- 0.7 yr), height (164.8 +/- 1.3 cm), weight (57.9 +/- 0.9 kg), and body mass index (21.3 +/- 0.3 kg/m(2)). E(2)-deficient groups had lower (P < 0.002) E(2) exposure compared with ovulatory groups. Resting systolic BP, HR, blood flow, and vascular conductance were lower (P < 0.05) and vascular resistance higher (P < 0.05) in LT-E(2) Def compared with both ovulatory groups. Peak ischemic blood flow, vascular conductance, and HR were also lower (P < 0.05) and vascular resistance higher (P < 0.05) in LT-E(2) Def compared with all other groups. Our findings show that exercising women with long-term E(2) deficiency have impaired regional blood flow and lower systolic BP and HR compared with exercising and sedentary ovulatory women. These cardiovascular alterations represent markers of altered vascular function and autonomic regulation of which the long-term effects remain unknown.

Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism.

Lifetime estrogen exposure has been related to breast cancer risk, osteoporosis, and cardiovascular disease but data on venous thromboembolism (VTE) risk are limited. Data from a hospital-based case-control study among 608 postmenopausal women (191 with a first episode of idiopathic VTE and 417 age-matched controls) were used to determine whether estrogen exposure, as assessed by age at menopause [classified as early (< or = 45 years), normal (46-54 years) and late menopause (> or = 55 years)] and parity, was associated with the risk of VTE. After adjustment for potential confounding variables, the risk of VTE was increased with each year's delay in the menopause [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, P < 0.0075]. When compared with women with normal menopause used as a reference, the adjusted OR for VTE was 0.59 (95% CI = 0.36-0.97) and 2.53 (95% CI = 1.28-4.99) for women with early menopause and late menopause, respectively (P = 0.001). Adjusted OR for VTE was also higher for women with more than two children when compared with those with less than or equal to two children (1.56, 95% CI = 1.03-2.34, P = 0.03). The lowest risk of VTE was observed in women with early menopause and lower parity (adjusted OR = 0.60, 95% CI = 0.30-1.24), the highest risk was among women with late menopause who have had more than two children (adjusted OR = 3.41, 95% CI = 1.46-9.25). These results show that the longer exposure to endogenous estrogen is associated with an increased VTE risk.

Polymorphisms in CYP1A1 and breast carcinoma risk in a population‐based case–control study of Chinese women

Cytochrome P450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogen, the hormone that plays a critical role in the etiology of breast carcinoma. The authors evaluated common polymorphisms in the CYP1A1 gene in relation to breast carcinoma risk in a large population-based case-control study among Chinese women, the Shanghai Breast Cancer Study. Because the CYP1A1*3 and CYP1A1*4 alleles were not detected in the study population, analyses were performed for CYP1A1*2A (T-->C transition in the 3' noncoding region) and CYP1A1*2C (A-->G transition in exon 7, resulting in a substitution of Val for Ile) in 1134 patients with breast carcinoma and 1227 controls. The frequencies of the variant allele were 38.3% and 38.8% among cases and controls (P = 0.91), respectively, for the CYP1A1*2A polymorphism, and 23.1% and 24.8% (P = 0.26) for the CYP1A1*2C polymorphism. Homozygosity for both variant alleles in these 2 polymorphic sites (CYP1A1*2B) was associated with a borderline significant odds ratio (OR) of 0.71 (95% confidence interval [CI], 0.47-1.06). The reduced risk was more pronounced among postmenopausal women with long duration (> 30 yrs) of menstruation (OR = 0.43; 95% CI, 0.19-0.99) or among women with a low waist-to-hip ratio (OR = 0.52; 95% CI, 0.28-0.94). Results from the current study suggest that homozygosity for the CYP1A1*2A and CYP1A1*2C alleles in the CYP1A1 gene may be associated with a reduced risk for breast carcinoma, particularly among lean women with long-term endogenous estrogen exposure.

Progestins and Recurrence in Breast Cancer Survivors

Progestins and Recurrence in Breast Cancer Survivors

CYP19 (aromatase) haplotypes and endometrial cancer risk

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)(n) repeat polymorphism in intron IV as well as a 3'UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case-control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989-1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning > 123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency > or = 5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13-2.48) to 2.07 (95% CI 1.33-3.23), comparing variant allele carriers to wild-type homozygotes. We observed significant interactions between menopausal status and 2 of the high-risk loci (p = 0.03 and p < 0.01), with > 2-fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high-frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women.

Cytochrome P450 1B1 and Catechol-O-Methyltransferase Genetic Polymorphisms and Breast Cancer Risk in Chinese Women: Results from the Shanghai Breast Cancer Study and a Meta-analysis

Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes and, thus, genetic polymorphisms of these enzymes may affect breast cancer risk. A population-based case-control study was conducted to assess the association of breast cancer risk with CYP1B1 and COMT polymorphisms. A meta-analysis was done to summarize the findings from this and previous studies. Included in this study were 1,135 incident breast cancer cases diagnosed from August 1996 through March 1998 among female residents of Shanghai and 1,235 randomly selected, age frequency-matched controls from the same general population. The common alleles of the CYP1B1 gene were Arg (79.97%) in codon 48, Ala (80.53%) in codon 119, and Leu (86.57%) in codon 432. The Val allele accounted for 72.46% of the total alleles identified in codon 108/158 of the COMT gene. No overall associations of breast cancer risk were found with any of the single nucleotide polymorphisms described above. This finding was supported by a meta-analysis of all previous published studies. No gene-gene interactions were observed between CYP1B1 and COMT genotypes. The associations of breast cancer risk with factors related to endogenous estrogen exposure, such as years of menstruation and body mass index, were not significantly modified by the CYP1B1 and COMT genotypes. We observed, however, that women who carried one copy of the variant allele in CYP1B1 codons 48 or 119 were less likely to have estrogen receptor-positive breast cancer than those who carried two copies of the corresponding wild-type alleles. The results from this study were consistent with those from most previous studies, indicating no major associations of breast cancer risk with CYP1B1 and COMT polymorphisms.

Reproductive period and cognitive function in a representative sample of naturally postmenopausal women aged 60–64 years

Background Greater lifetime estrogen exposure has been postulated to result in better cognition in later life, particularly in the area of verbal memory. In women, the highest levels of endogenous estrogen occur during their reproductive period, between menarche and menopause.Objective To investigate the association between reproductive period and cognition.Methods The sample consisted of 760 naturally postmenopausal women aged 60–64 years (mean age 62.5 ± 1.5 years) participating in the PATH Through Life Study who were randomly drawn from the population of Canberra, Australia. Participants were administered a verbal learning test (immediate recall and 1-minute delay), the Mini-Mental State Examination (MMSE), digit span backwards, the Symbol-Digit Modalities Test and simple and choice reaction time tests.Results There were no significant associations detected between reproductive period and performance on any of the cognitive tests, either before or after controlling for potential confounding variables.Conclusions Reproductive period, a surrogate measure of endogenous estrogen exposure, had no detectable effect on cognitive performance in this sample.

Synergistic Effects of STK15 Gene Polymorphisms and Endogenous Estrogen Exposure in the Risk of Breast Cancer

Abstract STK15 is a member of a family of serine/threonine kinases that act as key regulators of chromosome segregation and cytokinesis. Over expression of the STK15 gene leads to centrosome amplification, chromosomal instability, aneuploidy, and transformation. It has been reported that the 91T → A (Phe → Ile at codon 31) polymorphism in the STK15 gene affects the function of this gene. We hypothesized that this polymorphism may interact with endogenous estrogen exposure in the risk of breast cancer and evaluated this hypothesis in a population-based, case-control study conducted among Chinese women in Shanghai. Genotyping assays were completed for 1,102 incident cases and 1,186 community controls. Participation and blood donation rates were over 90% and 80%, respectively. Elevated risks of breast cancer were found to be associated with the Phe/Ile [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7] and Ile/Ile (OR, 1.2; 95% CI, 0.9-1.6) genotypes at codon 31 of the STK15 gene, although the ORs were not statistically significant. The risk associated with this polymorphism was modified by factors related to endogenous estrogen exposure, such as high body mass index (BMI), high waist-to-hip ratio, long duration of lifetime menstruation, or long duration of menstruation before first live birth. In particular, a statistically significant interaction was found between BMI and the STK15 Phe31Ile polymorphism (P = 0.02) and a positive association with breast cancer risk for the Ile allele was found only among overweight (BMI ≥ 25 kg/m2) women with adjusted ORs (95% CIs) of 3.3 (1.4-7.7) and 4.1 (1.7-9.8) associated with the Phe/Ile and Ile/Ile genotypes (Pfor trend &amp;lt;0.01), respectively. The findings from this study are consistent with the evidence from invitro and in vivo experiments, implicating an etiologic role of the STK15 gene in human breast cancer, and provide evidence for the modifying effects of genetic background on human cancer risk.

Mammographic Density and Estrogen Receptor Status of Breast Cancer

Abstract Background: The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)–positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer. Methods: We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity. Results: Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18). Conclusion: Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.

Transvaginal Ultrasound Measurement of Endometrial Thickness as a Biomarker for Estrogen Exposure

Abstract Objective: In clinical settings, transvaginal ultrasound has been used to evaluate abnormal vaginal bleeding. Because the endometrium responds to estrogens, endometrial thickness may constitute a biomarker of estrogen status in postmenopausal women. This study aimed to validate the transvaginal ultrasonographic measurement of endometrial thickness as an estrogen biomarker in asymptomatic, postmenopausal women by demonstrating an association between endometrial thickness and risk factors known to be associated with estrogen exposure. Method: Endometrial thickness was measured in 1,271 women ages 55 to 74 years who underwent transvaginal ultrasound screening as part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A questionnaire, completed before screening, provided risk factor information, including reproductive and hormone use histories. Results: Endometrial thickness measurements ranged from 1 to 32 mm (median 3.0 mm). The frequencies of thicker endometrium (≥3.0 mm), according to body mass index (BMI) quartile, were 55.2%, 66.1%, 69.7%, and 76.7% (P &amp;lt; 0.0001). The frequencies of thicker endometrium were 57.8%, 58.3%, and 82.6% among never users, ex-users, and current users of hormone replacement therapy (HRT), respectively (P &amp;lt; 0.0001). Other factors associated with thicker endometrium included age, marital status, history of uterine fibroids, years since menopause, and history of hypertension. Statistically significant associations were not seen in analyses limited to current HRT users (n = 461). In multiple variable analysis (R2 = 0.08), current HRT use (P &amp;lt; 0.0001) and higher BMI (P &amp;lt; 0.0001) were independently associated with thicker endometrium. Conclusion: In postmenopausal women, factors reflecting exogenous (current HRT use) and endogenous (BMI) estrogen exposure were associated with increased endometrial thickness as measured during screening transvaginal ultrasound. Practical limitations related to screening transvaginal ultrasound include measurement variability, lack of information regarding type or dose of HRT, and problems of differentiating true endometrial thickening from unrecognized endometrial polyps or fluid accumulations. Constrained by these limitations, these results partially validate a transvaginal ultrasound measurement of endometrial thickness as a potential biomarker related to estrogen status.

Indicators for the total duration of premenopausal endogenous estrogen exposure in relation to BMD.

Previous studies have shown that age at menopause is an important indicator of duration of endogenous estrogen exposure. The present study investigates whether combining more information on reproductive factors is useful in estimating individual total duration of exposure to endogenous estrogens. Bone mineral density (BMD) was used as operational outcome. The study population consisted of 3476 white women living in Eindhoven, The Netherlands, aged 46-57 years, either pre- (n = 2420) or postmenopausal (n = 1056). BMD of the lumbar spine was measured by dual X-ray absorptiometry. Information on reproductive factors was obtained with questionnaires. The number of reproductive years explained 4.8% of the variance in BMD, while age at menopause alone accounted for 3.6%. Duration of lactation or oral contraceptive use did not add to the proportion of variance explained. The effect of reproductive years on BMD was stronger in older women. No significant associations with BMD were found for other reproductive variables. The number of miscarriages in premenopausal women (beta = 0.00760, SE = 0.00357, P = 0.03) explained only 0.16% of the variance in BMD. We conclude that it is not necessary to use more reproductive factors besides age at menopause and menarche in determining total duration of endogenous estrogen exposure.

Sulfotransferase 1A1 ( SULT1A1) polymorphism and breast cancer risk in Chinese women

Background: Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. A major human sulfotransferase, SULT1A1, catalyzes the sulfation of a variety of phenolic and estrogenic compounds. A functional polymorphism of the SULT1A1 gene has been implicated in a decreased activity and thermostability when the wild-type arginine ( Arg) at codon 213 is substituted by a histidine ( His). Methods: We investigated the association between the His allele and the risk breast cancer in 213 cases and 430 matched controls in Chinese women, and the interaction between His allele and endogenous estrogen and dietary mutagens exposure factors were also determined by use of logistic regression analysis. Results: There was no significant difference in genotypes between the cancer patients and control populations. However, the frequency of the His allele in cases (13.6%) were significant higher than that in controls (9.5%), P=0.03. Compared with women carrying the Arg/ Arg genotype, the adjusted odds ratio (OR) of Arg/ His was 1.48 (95% CI=0.59–3.31) and His/ His was 2.28 (95% CI=0.69–9.58), P trend was 0.04. The adjusted OR of Arg/ His + His/ His was 2.60 (95% CI=1.12–6.05). His allele strengthen the effect of endogenous estrogen exposure with interaction index r>1, and weaken the effect of heterocyclic amines and polycyclic aromatic hydrocarbons derived from dietary with interaction index r<1, both were multiplicative interaction model. Conclusions: Our findings suggest that the SULT1A1 His allele was positively associated with the risk of breast cancer in Chinese women. And there was interaction between SULT1A1 polymorphism and related exposure factors.

The effect of hormone therapy on the risk for age-related maculopathy in postmenopausal women.

To evaluate the effect of postmenopausal hormone therapy (HT) as well as the use of oral contraceptives and lifetime endogenous hormone exposure on the risk for age-related maculopathy (ARM) in postmenopausal women. This was a cross-sectional, controlled study. A total of 102 women from 60 to 80 years of age who were receiving HT and 100 controls underwent a detailed clinical funduscopic evaluation and stereoscopic fundus photography for the presence and grading of ARM. All participants completed a standardized questionnaire regarding vascular risk factors, HT, and lifetime exogenous and endogenous estrogen and progesterone exposure. Statistical analysis was performed using Student's t test, chi2 test, and a multivariate logistic regression model. The HT and the non-HT groups did not differ in terms of early (11% v 15%), late (6% v 6%), or wet (2% v 2%) ARM prevalence rates. Women with ARM were significantly older than controls (69 v 66 years; P = 0.001, 95% CI = 0.008 - 0.027) and were more likely to have ischemic heart disease (21% v 9%; OR = 2.86, P = 0.03, 95% CI = 0.020 - 0.360). Lifetime exogenous and endogenous hormone exposures and other cardiovascular risk factors were not significantly different among women with ARM as compared with controls. Postmenopausal HT may not affect the risk for either early or late ARM in women aged 60 to 80 years. The risk for both entities is not necessarily affected by either exogenous or endogenous lifetime hormone exposure. A history of ischemic heart disease may be associated with an increased risk for ARM.

Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women.

In this study, the authors investigated whether combined information on reproductive factors has additive value to the single reproductive factor age at menopause for assessing endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. They conducted a population-based cohort study that included 9,450 postmenopausal women from Nijmegen, the Netherlands, who were aged 35--65 years at enrollment in 1975, with a median follow-up of 20.5 years. A Cox proportional hazards model and Receiver Operating Curves were used to analyze the data. Women aged 52 years or more at menopause had an 18% reduction in cardiovascular mortality (hazard ratio = 0.82, 95% confidence interval (CI): 0.69, 0.98) compared with those aged 44 years or less. Women with more than 18 years of exposure to endogenous estrogen had a statistically significant 20% reduction in cardiovascular mortality (hazard ratio = 0.80, 95 percent CI: 0.67, 0.96) compared with those who had 13 years of exposure or less. The area under the curve of the Receiver Operating Curves for the two models was identical (area under the curve = 0.67, 95 percent CI: 0.66, 0.68). This study shows that age at menopause is related to cardiovascular disease mortality and that a newly developed composite measure of endogenous estrogen exposure does not add to the predictive value of age at menopause for cardiovascular mortality.

Postmenopausal hormone replacement therapy: effects on normal mammary gland in humans and in a mouse postmenopausal model.

Endogenous estrogen exposure has long been implicated in the causation of breast cancer through a mechanism of epithelial cell proliferation. Whether estrogen, progesterone, or both exhibit mitogenic activity and promote carcinogenesis in the human breast has been the subject of considerable debate. The purpose of this review article is to examine the evidence for the effects of hormone replacement therapy in its various forms on the biology of the postmenopausal breast both in humans and in an animal model, and to identify the gaps in knowledge that research will need to address to further understand this complex issue.

Reproductive factors, bone mineral density, and fracture history: the NORA study

Objective: To examine the associations of elements of reproductive history with peripheral bone mineral density (BMD) t scores and fracture history after age 45 years. Methods: Data on risk factors and reproductive history were collected from 47,050 women who had not had hysterectomies. The key variable of interest was the duration of endogenous estrogen exposure (difference between the ages of menarche and menopause). Other variables examined included parity, lactation, oral contraceptive (OC) use, age of mother at birth of first- and last-born children, and postmenopausal (PM) estrogen supplementation. We estimated the separate and collective effects of these variables on BMD and fracture risk using bivariate analyses and regression models adjusted for age, ethnicity, and level of education. Results: Using women with less than 30 years of endogenous estrogen exposure for comparison, t scores increased 0.12, 0.25, 0.41, and 0.53, and the odds ratios for fracture were 0.92, 0.87, 0.76, and 0.76 among women with 30–34, 35–39, 40–44, and 45+ years of endogenous estrogen, respectively. Oral contraceptive use, parity, and PM estrogen use also had significant positive effects on BMD. Conclusion: The study provides evidence that the duration of endogenous estrogen exposure has a beneficial effect on BMD and lowers fracture risk, even after adjusting for BMD.

Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

Urinary oestrogen patterns in long follicular phases

Long menstrual cycles have been associated with reduced risk of breast cancer and increased risk of osteoporosis. These observations have led to assumptions about the endogenous oestrogen exposure of women with long cycles. However, daily oestrogen profiles in long menstrual cycles have not been described. This paper examines daily urinary oestrogen profiles during the follicular phases of 416 conception and non-conception cycles. Women were aged 21-42 years, had no history of infertility and were not under treatment. Twenty-eight cycles were defined as long, with a follicular phase that lasted 24 days or more. Five patterns were observed among these long cycles, the most common being a pattern consistent with delayed emergence of a dominant follicle. Other patterns were a pattern consistent with demise and replacement of a dominant follicle, one consistent with delayed follicular recruitment, one showing a prolonged initial drop in oestrogen and one with an extended oestrogen peak. Average follicular phase oestrogen concentrations were highest in cycles with short follicular phases (7-11 days). Oestrogen concentrations from long follicular phases (24-59 days) did not differ substantially from follicular phases of usual length (12-17 days). The oestrogen profiles in long follicular phases are heterogeneous and not necessarily hypo-oestrogenic.

Promotion of estrogen-induced mammary gland carcinogenesis by androgen in the male Noble rat: probable mediation by steroid receptors.

Both endogenous and exogenous estrogen exposure is associated with an increased breast cancer risk. In some studies, elevated serum testosterone levels have also been linked to an increased breast cancer risk. Estrogen alone or combined with progesterone induces high mammary tumor incidences in various strains of both male and female rats. Mammary gland ductal adenocarcinomas were induced after 17beta-estradiol (E2) and testosterone propionate (TP) treatment in male Noble rats. Tumor incidence was 100% after 8-9 months of treatment. Such neoplasms were not detected after either estrogen or androgen exposure alone within this time period. TP alone caused disruption of mammary gland ducts and proliferation of stromal tissue, while E2 treatment alone induced both ductal epithelial growth and nodular atypical hyperplasia. To study the interaction of these hormones in mammary tumorigenesis, sex hormone receptors were characterized in mammary glands of Noble rats. Estrogen receptor-alpha (ER) was detected in age-matched, untreated mammary gland epithelium; in most early atypical hyperplastic lesions appearing after E2 and E2 + TP treatment and in E2 + TP-induced mammary tumors. Two major ER putative isoforms, 116 and 120 kDa, were detected in E2- and E2 + TP-treated mammary glands, and in the induced tumors. A 54 kDa ER protein was found in untreated and TP-treated mammary glands, and in the induced tumors. Both progesterone receptor-B (PR-B) and PR-A2, as well as androgen receptor-B (AR-B) and AR-A isoforms were markedly elevated in all E2 + TP-induced mammary tumors. However, the levels of both PR and AR were very low in mammary glands of E2- and E2 + TP-treated male rats. Low and moderate levels of AR and PR, respectively, were detected in most atypical hyperplastic lesions induced by E2- and E2 + TP-treated mammary glands. These results suggest that androgens may interact with either AR or PR, and perhaps both receptors, in E2 + TP-induced mammary glands and the induced tumors to effect the reduction in latency period, enhance tumor size, and increase incidence to 100%.

Prolonged lactation and endometrial cancer. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The risk of endometrial cancer is related to oestrogen levels, showing an increased risk with increasing endogenous or exogenous oestrogen stimulation and a reduced risk when oestrogen is opposed by progesterone. During breastfeeding, the reduction of endogenous oestrogen exposure is larger than that of progesterone, suggesting that breastfeeding may possibly reduce the risk of endometrial cancer. The relationship between lactation and endometrial cancer was assessed in data from six countries, including four developing countries, that were collected for a multinational hospital-based case-control study conducted between 1979 and 1988. In all, 136 cases were compared with 933 controls matched on age, hospital, and year of interview. Standardized questionnaires, administered in the local language, ascertained information on the length of time breastfed, age started and stopped breastfeeding, reproductive and contraceptive practices, and other risk factors for endometrial cancer. Conditional logistic regression was used to control for the confounding effects of gravidity and age at menarche. Significant decreasing trends in risk were observed with increasing duration of lactation, and with months of breastfeeding per pregnancy. Risk was lowest in women who had most recently lactated, and the apparent protective effect declined with time since cessation of breastfeeding, so that there was no evidence for a protective effect after age 55 even in women who had breastfed for over 5 years. The long-term lactation that takes place in developing countries probably reduces the risk of endometrial cancer, but this effect may not persist into the ages at which this disease is most common.