Urine tests for Down's syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome. SEARCH METHODS: We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles. SELECTION CRITERIA: Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. DATA COLLECTION AND ANALYSIS: We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses. MAIN RESULTS: We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies).In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR). AUTHORS' CONCLUSIONS: Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available.

Urinary estrogen metabolites and gastric cancer risk among postmenopausal women.

BACKGROUND: The overall incidence of gastric cancer in women is half that in men for most global populations. Sex hormone pathways may be involved in carcinogenesis and estrogens have been postulated to protect women against gastric cancer. AIM: To evaluate associations of gastric cancer with estrogen metabolites in postmenopausal women. METHODS AND RESULTS: We performed an analysis of 233 gastric cancer cases and 281 age-matched controls from three prospective cohorts and two case-control studies of early-stage gastric cancer, mainly conducted in high-risk Asian populations. Fifteen estrogen-parent (estrone and estradiol) and -metabolite analytes (2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestrone-3-methyl ether, 4-hydroxyestrone; 4-methoxyestrone, 4-methoxyestradiol, 2-methoxyestrone, 2-methoxyestradiol, estriol, 16α-hydroxyestrone, 16-ketoestradiol, 16-epiestriol, and 17-epiestriol) were measured in spot urines using liquid chromatography-tandem mass spectrometry. Odds ratios for association with each marker were estimated by logistic regression. Heterogeneity was assessed by Cochran's Q test. Study-specific odds ratios were pooled by fixed-effects meta-analysis. Urinary levels of estrogen-related molecules were not associated with gastric cancer (adjusted odds ratios ranged from 0.87 to 1.27; p-values >.05), with low between-study heterogeneity (p-values >.1) for all but two metabolites (2-hydroxyestrone-3-methyl ether and 2-methoxyestradiol). CONCLUSION: To date, this is the first comprehensive assessment of endogenous estrogens with gastric cancer risk in women. Estrogens do not appear to have an etiologic role in gastric cancer risk among postmenopausal women. Given the complex network of sex steroid hormones and their extreme variation over the lifespan, further evaluation of this hypothesis is warranted.

Stability of chimpanzee (Pan troglodytes) urinary reproductive hormones during long-term preservation on filter paper.

Urine contains multiple water-soluble hormones, which are valuable non-invasive biomarkers for the monitoring of reproductive status and health. An effective method for drying urine on filter paper was previously developed to preserve wildlife urine samples where electrical equipment was not available for this; however, the stability of samples preserved in this way remains to be verified. Here, we developed and validated a method to elute multiple water-soluble reproductive hormones from filter paper that had been stored for an extended period of time. Aliquots of urine from chimpanzees were adsorbed on filter papers, air dried and stored for 1 year at room temperature. Estrone-3-conjugate (E1C), pregnanediol-3-glucuronide (PdG), estriol-3-glucuronide (E3G), and chorionic gonadotropin (CG) were eluted into deionized water from the filter papers and measured using enzyme immunoassays (EIAs). The mean recoveries of E1C, PdG, and creatinine from filter papers stored for 1 year were 69.5%, 128.7%, and 83.8%, respectively. The profiles of E1C and PdG from preserved filter papers significantly correlated with those derived from a direct analysis of the frozen urine of menstruating chimpanzees. We detected E3G and CG from 1-year-old filter papers for urine collected during early pregnancy, but the recovery of E3G was low and CG profiles did not correlate with those of the original frozen urine samples. The method proposed here for the elution and measurement of reproductive hormones in urine preserved for a long period of time on filter paper provides a practical and simple way to monitor the reproductive status of chimpanzees. We propose that this method can also be utilized in field studies of other wild nonhuman primates.

Trimester-specific, gender-specific, and low-dose effects associated with non-monotonic relationships of bisphenol A on estrone, 17ß-estradiol and estriol.

BACKGROUND: Bisphenol A (BPA) may cause some adverse effects on human health by mimicking estrogen activities. In vitro andanimalstudies have observed the non-monotonic associations between BPA and natural estrogens, but the evidence in human study is lacking, particularly at multiple points in time during pregnancy. OBJECTIVE: We aimed to examine the relationships between BPA and estrogens in the three trimesters among Chinese pregnant women and their gender variations. METHODS: This study included 851 participants from a birth cohort conducted in Wuhan, China between 2014 and 2015. We measured concentrations of BPA and three estrogens (estrone (E1), 17ß-estradiol (E2) and estriol (E3)) in urine samples collected in the three trimesters of pregnancy (mean for each visit: 13.0, 23.6, and 35.9 weeks' gestation). We calculated the estimated daily intakes using urinary BPA concentrations and compared them with the tolerable intake value to assess potential health risks. We used multivariate linear regression models stratified by trimester and gender to explore trimester-specific and gender-specific associations of BPA with E1, E2, and E3. RESULTS: We found the decreased levels of estrogens (ß < 0, P < 0.05) in the upper BPA quartiles over three trimesters, except for the elevated levels of E3 (ß = 0.20, 95% CI: 0.02, 0.38) in the highest BPA quartile in the 2nd trimester. There were significant non-linear associations (overall associations P < 0.05, non-linear associations P < 0.05) between BPA and E3 in the three trimesters. In the gender-stratified analysis, we observed significant negative relationships (ß < 0, P < 0.05) between BPA and E2 among mothers carrying male fetuses in the 1st trimester and significant associations between BPA and E3 among mothers carrying female fetuses in the 2nd trimester. However, we found no significant relationship between BPA and E2 among mothers carrying female fetuses over three trimesters. CONCLUSIONS: Our findings support experimental evidence of non-monotonic relationships between BPA and three major estrogens, even at low doses of BPA. Mothers delivering male fetuses may be more sensitive to E2 at early pregnancy, and those delivering female fetuses may be more susceptive to E3 at mid-pregnancy.

Low urinary estrogen glucuronides in women at risk for familial breast cancer.

Daily (12-hour) urine collections taken throughout the menstrual cycle were obtained from 30 young women who by genetic analysis were at risk for familial breast cancer, and from 30 control women carefully matched for age, height, and reproductive history. Steroids in the urine were extracted by glucuronidase hydrolysis, and the primary glucocorticoid, androgen, and estrogen hormones and their metabolites were measured by radioimmunoassay. Highly significant differences were observed only in the case of estrone and estradiol, with the high-risk subjects exhibiting lower values that the controls. This endocrine abnormality in young women at risk for breast cancer may be a potential discriminant for identifying women at risk for the disease in the population at large.

Analysis of nonderivatized steroids by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using C70 fullerene as matrix.

Neutral steroid hormones are currently analyzed by gas or liquid chromatography/mass spectrometry based methods. Most of the steroid compounds, however, lack volatility and do not contain polar groups, which results in inadequate chromatographic behavior and low ionization efficiency. Derivatization of the steroids to form more volatile, thermostable, and charged products solves this difficulty, but the derivatization of compounds with unknown chemical moieties is not an easy task. In this study, a rapid, high-throughput, sensitive matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method is described using C(70) fullerene as a matrix compound. The application of the method is demonstrated for five general sex steroids and for synthetic steroid compounds in both negative and positive ionization modes.

Maternal urine and serum steroid measurements to identify steroid sulfatase deficiency (STSD) in second trimester pregnancies.

OBJECTIVE: To document the performance of second trimester maternal urine and serum steroid measurements for detecting fetal steroid sulfatase deficiency (STSD). METHODS: We studied detection rate and false positive rate (DR, FPR) of analytes in maternal urine [combinations of 16alpha-OH-dehydroepiandrosterone sulfate (16alpha-OH-DHEAS), 11beta-hydroxyandrosterone, total estriol] and serum [combinations of 16alpha-OH-DHEAS, 11beta-hydroxyandrosterone, total estriol, unconjugated estriol (uE3)]. Samples were obtained from pregnancies which were screen positive for Smith-Lemli-Opitz syndrome (SLOS). RESULTS: Among 1 079 301 pregnancies, 3083 (0.29%) were screen positive for SLOS. Urine and/or serum samples were available from 917 viable pregnancies with known gender. We assigned likelihood ratios (LRs) to steroid measurements from male fetuses with known STSD and unaffected female fetuses. An LR > or = 100 was present in urine from 84 of 86 STSD pregnancies (98% DR, 95% CI 92-99), along with 0 of 198 pregnancies with normal female fetuses (0.0% FPR, CI 0-1.9). LRs were > or = 100 in 4 of 129 female fetuses with major abnormalities (3% FPR). In maternal serum, steroid measurements performed less effectively, achieving a 71% DR for STSD at a 1.6% FPR. CONCLUSION: Maternal urine steroid measurements are effective for detecting STSD, including those with point mutations and those with full deletions.

Hypertrophic osteoarthropathy: estrogens, prostaglandinE2, prostaglandin A2, and the inflammatory reflex.

It has been claimed that hyperestrogenism occurs in hypertrophic osteoarthropathy (HOA), but not in simple clubbing. However, one of our patients had simple clubbing and hyperestrogenism. We therefore measured estrogens, androgens, sex hormone-binding globulin (SHBG), and gonadotropins in five patients with HOA and in 18 patients with simple clubbing. Of the patients with HOA, 80% had a high urinary estriol concentration. In their serum, 80% had high estrone, 0% high estradiol, and 40% high SHBG. Of the patients with simple clubbing, 89% had a high urinary estriol concentration. In their serum, 76% had high estrone, 6% high estradiol, and 31% high SHBG. In all patients, urinary estriol concentration correlated positively with the degree of clubbing. Serum concentration of androstenedione, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was mostly normal, but androstenedione concentration correlated positively with the degree of clubbing. Spider angiomas were present in 74%, palmar erythema in 39%, and gynecomastia in 9%. Urinary creatinine concentration was low in 48% and correlated positively with the degree of clubbing. We reject the claim that hyperestrogenism occurs in HOA, but not in simple clubbing. Hyperestrogenism occurs both in HOA and in simple clubbing. Our results also support earlier reports that clubbing and HOA are associated with spider angiomas, palmar erythema, gynecomastia, adrenal cortical hyperfunction, muscle atrophy, and water retention. These results led to a new hypothesis on the pathogenesis of HOA, involving estrogens, prostaglandin E2, prostaglandin A2, and the inflammatory reflex.

Urinary excretion of sex steroid hormone metabolites after consumption of cow milk: a randomized crossover intervention trial.

Background: Current cow milk production practices introduce considerable levels of pregnancy hormones into the milk. Humans are exposed to these hormones when cow milk is consumed, and this may explain the observed association between cow milk consumption and several hormone-sensitive cancers. Objectives: The aim of the study was to evaluate whether cow milk consumption is associated with an increase in urinary excretion of sex steroid hormones and their metabolites in humans. Methods: We conducted a randomized crossover intervention feeding experiment. A total of 109 postmenopausal women consumed 1 L of semiskimmed milk (1.5% fat) per day for 4 d and 1 L of whole milk (3.5% fat) per day for 4 d, intersected by 4-d wash-out periods. Sex steroid hormone levels were measured in 24-h urine samples collected at the end of each intervention and wash-out period. Results: Estrogens, androgens, and progesterone were detected in the examined milk samples used for our intervention. Although a very high proportion of the estrogens were conjugated, only small proportions of the androgens and progesterone were conjugated. Milk consumption resulted in a significant increase in urinary estrone (E1) excretion, whereas estradiol (E2), estriol (E3), and 16ketoE2 excretion only increased after semiskimmed milk consumption. Urinary pregnanediol glucuronide excretion was not significantly affected. Conclusion: Cow milk consumption increases urinary excretion of E1 in humans. Ingestion of semiskimmed milk appears also to raise E2, E3, and 16ketoE2 excretion, but future studies need to confirm these associations. This trial was registered at https://www.drks.de as DRKS00003377.

Hydrophilic interaction liquid chromatography-tandem mass spectrometry determination of estrogen conjugates in human urine.

We report a hydrophilic interaction liquid chromatography (HILIC) separation with tandem mass spectrometry (MS) detection method for analysis of seven urinary estrogen conjugates. HILIC separation employing a mobile phase with high organic solvent content resulted in enhanced electrospray ionization efficiency and MS sensitivity compared with reversed-phase (RP) LC-MS methods. Solid-phase extraction (SPE) was used to further improve the limit of detection and to eliminate interferences for the analysis of urine samples. No hydrolysis or derivatization was required in the sample pretreatment. This SPE/HILIC-MS/MS method provided limits of quantification (LOQs at S/N = 10) for the seven conjugates ranging from 2 to 1000 pg/mL with only 1 mL of urine sample, representing an improvement of 1 order of magnitude over the RPLC tandem MS methods previously reported. This method provided a linear dynamic range of 3 orders of magnitude, recovery of 92-109%, intraday accuracy of 84-109%, intraday precision of 1-14%, interday accuracy of 80-111%, and interday precision of 1-22%. We have successfully applied this technique to determine the seven estrogen conjugates in urine samples of a pregnant woman and found unique concentration changes of six estrogen conjugates at different stages of pregnancy while the concentration of estriol-3-glucuronide (E3-3G) remained constant. We further studied the profiles of individual estrogen conjugates in breast cancer patients before and after treatment and found patient-dependent effects of aromatase inhibitor treatment on estrogen phase-II metabolism, which have not been reported previously. This study demonstrates the potential clinical application of the HILIC-MS/MS technique for sensitive monitoring of the changes of urinary estrogen conjugates in a clinical setting.

Determining estrogens using surface-assisted laser desorption/ionization mass spectrometry with silver nanoparticles as the matrix.

We describe the application of silver nanoparticles (Ag NPs) as matrices for the determination of three estrogens using surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). Because Ag NPs have extremely high absorption coefficients (1.2 x 10(8) M(-1) cm(-1)) at 337 nm, they are effective SALDI matrices when using a nitrogen laser. Three tested estrogens--estrone (E1), estradiol (E2), and estriol (E3)--adsorb weakly onto the surfaces of the Ag NPs, through van der Waals forces. After centrifugation, the concentrated analytes adsorbed on the Ag NPs were subjected directly to SALDI-MS analyses, with the limits of detection for E1, E2, and E3 being 2.23, 0.23, and 2.11 microM, respectively. The shot-to-shot and batch-to-batch variations for the three analytes were less than 9% and 13%, respectively. We validated the practicality of this present approach through the quantitation of E2 in human urine. Using this approach, we determined the concentration of E2 in a sample of a pregnant woman's urine to be 0.16+/-0.05 microM (n=10).

Studies on phenolic steroids in human subjects. 8. Metabolism of estriol-16 alpha-glucosiduronate.

6,7-(3)H-Estriol-16alpha-glucosiduronate-(14)C was administered to eight women (nine studies) by several routes: both injection and infusion (300 min) into the cubital vein, injection into the portal vein system, ingestion and instillation into the duodenum, jejunum, and ileum. Urine, collected from 0-2, 2-4, 4-8, 8-12, and 12-24 hr, was analyzed by countercurrent distribution for its content of radioactive 3- and 16-glucosiduronate (E(3)-3Gl,E(3)-16Gl) and sulfoglucosiduronate (E(3)-3S,16Gl) of estriol as well as for (3)H/(14)C ratio of each conjugate. After peripheral injection 50-60% of the injected E(3)-16Gl was excreted unchanged along with about 5% as E(3)-3S,16Gl with an unchanged (3)H/(14)C ratio, indicating direct sulfation of the injected E(3)-16Gl. During a 300 min infusion, urinary excretion closely resembled that following injection. But 2-4 hr after the end of the infusion excretion of E(3)-3S, 16Gl stopped, excretion of E(3)-3Gl (17%/24 hr) with an elevated (3)H/(14)C ratio started, and excretion of E(3)-16Gl continued (70%/24 hr), but with a rapidly increasing (3)H/(14)C ratio. This indicated sequestration in a sluggishly metabolizing compartment where two processes occurred: (a) extensive hydrolysis of E(3)-16Gl followed by reconjugation at either C3 or C16 with unlabeled uridine diphosphate glucuronic acid (UDPGA), thereby increasing the (3)H/(14)C ratio; and (b) transconjugation from C16 to C3, thereby producing E(3)-3Gl with finite (3)H/(14)C ratios. Instillation into various segments of the small intestine produced results qualitatively similar to those after intravenous infusion, whereas ingestion and intraportal injection resembled peripheral intravenous injection. Therefore, we have postulated the possibility of an enteric circulation (in addition to an enterohepatic circulation) in which the steroid or its conjugates are transported into the small intestine in the succus entericus, modified, and then reabsorbed and excreted in the urine-a process which requires several hours.

Studies on phenolic steroids in human subjects. IX. Role of the intestine in the conjugation of estriol.

In order to compare the enteric circulation of estriol-16alpha-glucosiduronate (see preceding paper) with that of estriol (E(3)), labeled estriol was administered to six women by several routes: both injection and infusion (300 min) into the cubital vein, injection into the portal vein system, ingestion and instillation into the jejunum and ileum. Urine, collected from 0-2, 2-4, 4-8, 8-12, and 12-24 hr, was analyzed by countercurrent distribution for its content of radioactive 3- and 16-glucosiduronate (E(3)-3Gl,E(3)-16Gl) and sulfoglucosiduronate (E(3)-3S,16Gl) of estriol. After peripheral injection of E(3), E(3)-16Gl was excreted rapidly and E(3)-3S,16Gl at a slower and more constant rate. E(3)-3Gl was barely detectable after infusion. After injection of E(3) into the portal vein, the excretion of E(3)-3S,16Gl was greater and quicker than after peripheral injection. Even in a subject with a complete bile fistula, the urinary excretion of E(3)-3S,16Gl was essentially unchanged. Ingestion also produced the same result. Only after instillation into the ileum was a large and rapid excretion of E(3)-3Gl obtained, whereas the excretion of E(3)-3S,16Gl, and E(3)-16Gl were depressed. These results together with those of the preceding paper suggest that E(3) does not readily appear in the small intestine except via a hepatoenteric circulation that produces very little E(3)-3Gl. When present in the distal segment of the small intestine, however, absorption, conjugation, and elimination proceed readily.

Estrogen metabolites and systolic blood pressure in a population-based sample of postmenopausal women.

CONTEXT: Lower systolic blood pressure (SBP) and lower rates of coronary heart disease among premenopausal women compared with similarly aged men and postmenopausal women suggest that female sex hormones may confer cardiovascular protection. 2-Hydroxyestradiol, a product of 17beta-estradiol oxidative metabolism, inhibits the proliferation of vascular smooth muscle cells in vitro. The other major product of 17beta-estradiol oxidative metabolism, 16alpha-hydroxyestradiol, does not demonstrate similar inhibitory effects. Concentrations of 2-hydroxyestrone (2-OHE) and 16alpha-hydroxyestrone (16-OHE) in urine reflect the relative activity of the 2- and 16alpha-hydroxylation pathways of 17beta-estradiol. OBJECTIVE: The objective of this study was to determine the relationship between SBP and the ratio of 2-OHE to 16-OHE in urine. DESIGN AND PARTICIPANTS: This was a cross-sectional study of 80 postmenopausal women living in Cook County, Illinois. SETTING: This study was performed in an academic clinical laboratory. MAIN OUTCOME MEASURE: The main outcome measure was SBP. RESULTS: Women taking hormone replacement therapy had higher levels of urinary 2-OHE and 16-OHE, but their mean 2:16-OHE ratio and SBP did not differ from that of women not taking hormone replacement therapy. In a multivariate regression model that controlled for age, body mass index, race/ethnicity, and antihypertensive medication use, a sd increase in the 2:16-OHE ratio was associated with a 6.7-mm Hg decrease (P < 0.05) in SBP. CONCLUSIONS: The ratio of urinary 2-OHE to 16-OHE is a significant predictor of SBP among postmenopausal women and may reflect the effects of 2-hydroxyestradiol, a potent inhibitor of vascular smooth muscle cell proliferation.

Elevated urine estrogen and pregnanediol levels in daughters of breast cancer patients.

Urine levels of three major estrogens and of pregnanediol were measured for 76 nulliparous daughters of breast cancer patients and for 115 control women of similar age and parity. Concentrations of estrone and estradiol tended to be higher in the daughters of breast cancer patients than in the controls; total estrogens were elevated in both phases than in the controls; total estrogens were elevated in both phases of the menstrual cycle and significantly so in the luteal phase. There was little difference between the daughters and the controls in estriol ratios--the ratios of the concentration of estriol to the sum of the concentrations of estrone and estradiol. Pregnanediol levels were higher in the daughters than in the controls.

Urinary excretion of estrone, estradiol, and estriol in postmenopausal women with primary breast cancer.

The daily excretion of estrone, estradiol, and estriol was determined for 22 normal women and 35 women with primary breast cancer. The excretion of the hormones (measured in microgram/24 hr) in the breast cancer group was elevated and showed a statistical significance of P less than 0.001. The same wide difference between the 2 groups was also noted when excretion was expressed in terms of the body area of the individuals and when women of similar ages were compared.

Relationship between steroid excretion patterns and breast cancer incidence in Israeli women of various origins.

A nationwide study of the steroid excretion patterns in postmenopausal Israeli migrant women demonstrated differences between high- and low-risk groups for breast cancer in the following variables: age at first parturition, number of pregnancies, number of live births, height, and weight. The direction of the differnces was in line with those observed for breast cancer patients. The groups also differed in the exretion of estriol, 17-ketosteroids, and allotetrahydrocortisol. Multiple regression analysis revealed that the exretion of estriol was significantly lower in population groups in whom breast cancer incidence was high. Possibly this trend--which has also been observed in adolescent and premenopausal women--reflected environmental influences on peripheral estrogen metabolism.

Estrogen profiles in young women: effect of maternal history of breast cancer.

To examine the hypothesis that familial breast cancer risk is related to estrogen metabolism, we analyzed urines of daughters of breast cancer patients and their matched controls for estrone (E1), estradiol (E2), and estriol (E3). From this, we computed estriol proportions (E3/E1 + E2 + E3). "Patient-daughters" and the matched controls showed no differences in estriol proportions. Our results failed to support the hypothesis that high-risk women (those with a family history of breast cancer) have relatively lower estriol proportions, and we concluded that whatever family history contributes to breast cancer risk, that risk is not likely to be transmitted by the estrogen profile.

PIP: A study designed to test the hypothesis that daughters of breast cancer patients would have "less favorable" estriol proportions than would a group of otherwise similar controls is reported. Urinary estrogen profiles of 46 daughters born to 45 women who later developed breast cancer and of 46 controls were examined. Computed estriol proportions (estriol/estrone plus estradiol plus estriol) revealed no differences in "patient-daughters" and the matched controls. It is concluded that whatever family history contributes to breast cancer risk, that risk is not likely transmitted by the estrogen profile.

Socioeconomic status, urine estrogens, and breast cancer risk.

Urine estrogens were measured in 46 women students, ages 15-18, at a middle-class high school in Athens and in 40 women of the same age residing at one of three orphanages in the same city. The lower socioeconomic status (SES) of the latter group was documented by their lower mean height (by 5.2 cm) and weight (by 5.3 kg) relative to the high school students. Both in follicular and luteal phases of the menstrual cycle, the women with lower SES had 50% higher estriol ratios (ratio of the concentration of estriol to the sum of the concentrations of estrone and estradiol). In luteal specimens the concentration of all three major estrogens was higher in the group with low SES than in the women in the other group, but the concentration of estriol was most increased. There was also an indication of less frequent anovular cycles among the women with low SES. These findings are consistent with hypotheses linking either the estriol ratio or the frequency of anovular cycles to breast cancer risk.

PIP: Urine estrogen levels were measured in 46 women students, ages 15-18, at a middle-class high school in Athens, Greece and in 40 women of the same age residing at 1 of 3 orphanages in the same city. The lower (SES) socioeconomic status of the latter group was documented by their lower mean height (by 5.2 cm) and weight (by 5.3 kg) relative to the high school students. Both in follicular and luteal phases of the menstrual cycle, the women with lower SES had 50% higher estriol ratios (ratio of the concentration of estriol to the sum of the concentrations of estrogens and estradiol). In luteal specimens, the concentration of all 3 major estrogens was higher in the group with low SES than in the women in the other group, but the concentration of estriol was most increased. There was also an indication of less frequent anovulan cycles among the women with low SES. These findings are consistent with hypotheses linking either the estriol ratio or the frequency of anovular cycles to breast cancer risk.

Estrogen profiles of premenopausal women with breast cancer.

Population surveys have demonstrated an inverse relationship between breast cancer incidence rates and the urine "estriol ratio," the concentration of estriol relative to the sum of the concentrations of estrone and estradiol. In this study, the urine estriol ratio was evaluated in premenopausal breast cancer patients and control women from Boston and San Francisco. Although at least 2 years had passed since last use of oral contraceptives, women with a history or oral contraceptive use for 19 months or longer excreted estrogen in low concentrations compared to nonusers and so were excluded. Among the remaining 73 cases and 55 controls, the cases had lower estriol ratios and higher estrone and estradiol levels than did controls. However, these differences, which averaged about 10%, were not statistically significant. Thus the hypothesis that a low estriol ratio is a cause of breast cancer is given only minimal support. Among women in their 40's, the excretion of estrogens is subject to many influences and is difficult to study. The many determinants of estrogen excretion, including age and oral contraceptive use, should be accommodated in the design of future studies of the estriol ratio.