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Oukseub Lee1, David Ivancic1, Robert T Chatterton Jr2, Alfred W Rademaker3, Seema A Khan11Department of Surgery, 2Department of Obstetrics/Gynecology, 3Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USAPurpose: Oral tamoxifen, a triphenylethylene (TPE), is useful for breast cancer prevention, but its adverse effects limit acceptance by women. Tamoxifen efficacy is related to its major metabolites 4-hydroxytamoxifen (4-OHT) and N-desmethyl-4-hydroxytamoxifen (endoxifen [ENX]). Transdermal delivery of these to the breast may avert the toxicity of oral tamoxifen while maintaining efficacy. We evaluated the relative efficiency of skin permeation of 4-OHT and ENX in vitro, and tested oleic acid (OA) as a permeation-enhancer.Methods: 4-OHT, ENX, and estradiol (E2) (0.2 mg/mL of 0.5 µCi 3H/mg) were dissolved in 60% ethanol-phosphate buffer, ±OA (0.1%–5%). Permeation through EpiDermTM (Matek Corp, Ashland, MA) and split-thickness human skin was calculated based on the amount of the agents recovered from the receiver fluid and skin using liquid scintillation counting over 24 hours.Results: In the EpiDerm model, the absorption of 4-OHT and ENX was 10%–11%; total penetration (TP) was 26%–29% at 24 hours and was decreased by OA. In normal human skin, the absorption of 4-OHT and ENX was 0.3%; TP was 2%–4% at 24 hours. The addition of 1% OA improved the permeation of ENX significantly more than that of 4-OHT (P < 0.004); further titration of OA at 0.25%–0.5% further improved the permeation of ENX to a level similar to that of estradiol.Conclusion: The addition of OA to ENX results in a favorable rapid delivery equivalent to that of estradiol, a widely used transdermal hormone. The transdermal delivery of ENX to the breast should be further developed in preclinical and clinical studies.Keywords: endoxifen, breast cancer prevention, human skin, transdermal, oleic acid

Background: Formation of single strand breaks in DNA is a constant process, estimated to occur 10,000 times per day in each cell, either from endogenous biosynthetic errors or from interference by endogenous or exogenous agents. Base excision repair in some cases may be impaired or may be exceeded by the rate of DNA damage, leading to cancer. Nick translation of with labeled nucleotides can be used as a quantitative indicator of SSBs. Methods: Healthy women were recruited through the Love-Avon Army of Women and breast clinics of Northwestern and John Hopkins Universities. Digital or digitized mammograms were evaluated for percent density using Cumulus software. The medians (ranges) were age 51 (36 to 60); BMI 28.2 (18.7 to 51.3); life-time Gail estimate 12.5 (5.6 to 28.3); % breast density 16.5 (2.4 to 52.5); Masood score 13 (0 to 18). Breast tissue was obtained by random fine needle aspiration (rFNA). Specimens were rinsed into ice-cold phosphate buffered saline and were stored at -80°C. Thawed samples were centrifuged at 2200 g for 60 min. A kit from Norgen Inc., was used to separate DNA, RNA, and protein from the pellet. The lipids were extracted with ethyl acetate-hexane (3:2) from the supernatant fluid, and triglycerides were precipitated from cold 90% methanol, leaving a purified lipid fraction containing the steroids. Steroids were then fractionated by HPLC on a C18 column, and estradiol was analyzed by a radioimmunoassay. Blood was obtained at the same time as the rFNA samples and was frozen prior to analysis. An aliquot containing 200 ng of DNA (260/280 ratio 1.3 to 2.3) was taken for the nick translation assay. Incorporation of free nucleotides at SSBs with dCTP labeled with³H was catalyzed by Polymerase I from E. coli. A quality control preparation prepared from calf thymus DNA and a reagent blank without DNA was included with each set of 6 samples. Incorporation of³HdCTP was linear with dose of DNA and reached a maximal at 30 min. Separation of free from incorporated³H-dCTP was accomplished by gel chromatography on an 80 x 15 mm column. The concordance of interassay values was 0.96. Results: Incorporation of nucleotides into DNA ranged from 0.03 to 8.59 pmol/μg, median 0.63 pmol/μg DNA. The association with other factors associated with breast cancer is shown in the Table. A significant correlation, was found with % breast density, life-time risk by the Gail model, but not serum estradiol concentrations. Conclusions: Assessment of SSBs by the nick translation procedure may be a useful indicator of breast cancer risk. Future studies will relate this method with actual risk as assessed by analysis of pre-diagnosis specimens with subsequent occurrence of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Earlier studies have shown that 1-2mg of 4-hydroxytamoxifen (4-OHT) gel applied to the breast skin reduced cell proliferation in estrogen receptor (ER) positive invasive cancers to a similar degree as oral tamoxifen (TAM), with significantly lower plasma levels. We now report results of a Phase IIB pre-surgical window trial of women with DCIS, designed to obtain pilot data in early lesions. Our ultimate goal is to develop transdermal 4-OHT as an alternative to oral TAM for women at high risk for breast cancer and those with DCIS. The study was closed early because the manufacturer discontinued the drug supply, but remains blinded until all biomarker analysis is complete. Here we report the plasma and breast adipose tissue concentration of TAM metabolites from the topical 4-OHT gel group (4 mg) in comparison with the oral TAM group (20mg). Methods: Women with DCIS were enrolled, and randomized to 4-OHT gel (4mg/day, 2mg per breast, E: Z isomers = 1:1,) or to oral (Z) TAM (20mg/day) for 4-10 weeks before surgery. Blood was collected on the day of surgery, and breast adipose tissue was collected at surgery. There were a total of 22 patients with matched blood and breast adipose tissue. The concentration of TAM metabolites in plasma and breast tissue was determined with liquid chromatography/tandem mass spectrometry. We assumed that the subjects with detectable N-desmethyl TAM (NDT) in plasma belong to the oral TAM group because NDT is not a product of 4-OHT metabolism. Under this assumption, 13 subjects were categorized into oral TAM group, and 9 subjects into the topical 4-OHT group. Wilcoxon rank-sum test was used for statistical analysis. Results: The results are shown in the table. The concentration is presented as mean ± SD; the lowest quantitation limit (LQL) was 1 ng/mL for plasma, and 3 ng/g for tissue. TAM and its metabolites were found in the plasma of the presumed oral TAM group, with high levels of TAM and NDT. In the presumed 4-OHT gel group, only (Z) 4-OHT was found in the plasma although both (E) and (Z) forms were applied. The mean plasma level of 4-OHT in the gel group was 70% lower than the mean of 4-OHT in the oral TAM group (p = 0.004). In breast tissue, similar amounts of (E) and (Z) forms of 4-OHT were found in the 4-OHT gel group, with the (Z) 4-OHT level being equivalent to that in the oral TAM group (p = 0.48). Endoxifen was only found in the oral TAM group. We saw no evidence of further metabolic transformation of 4-OHT in the breast following topical administration. Conclusions: With 4 mg of 4-OHT gel daily applied to the breasts of DCIS patients, the mean plasma level of 4-OHT was significantly lower and the mean breast tissue level of 4-OHT was similar to that in women taking oral TAM 20 mg daily, thus confirming the results from previous studies. We are still evaluating efficacy of topical 4-OHT in terms of reduction of cell proliferation (Ki67). [ABSTRACT FROM AUTHOR]

Abstract Background Studies have shown associations of diabetes and endogenous hormones with exposure to a wide variety of organochlorines. We have previously reported positive associations of polychlorinated biphenyls (PCBs) and inverse associations of selected steroid hormones with diabetes in postmenopausal women previously employed in a capacitor manufacturing plant. Methods This paper examines associations of PCBs with diabetes and endogenous hormones in 63 men previously employed at the same plant who in 1996 underwent surveys of their exposure and medical history and collection of bloods and urine for measurements of PCBs, lipids, liver function, hematologic markers and endogenous hormones. Results PCB exposure was positively associated with diabetes and age and inversely associated with thyroid stimulating hormone and triiodothyronine-uptake. History of diabetes was significantly related to total PCBs and all PCB functional groupings, but not to quarters worked and job score, after control for potential confounders. None of the exposures were related to insulin resistance (HOMA-IR) in non-diabetic men. Conclusions Associations of PCBs with specific endogenous hormones differ in some respects from previous findings in postmenopausal women employed at the capacitor plant. Results from this study, however, do confirm previous reports relating PCB exposure to diabetes and suggest that these associations are not mediated by measured endogenous hormones.

Background: The expression of many genes is known to be regulated by ambient hormone levels. In a preliminary study of random fine-needle aspirate (rFNA) samples from benign breast tissue, we found several genes that were highly correlated with the serum levels of progesterone (P4) and estradiol (E2). We now present data to further validate these genes as markers of menstrual cycle phase (MCP) and menopausal status (MPS) in benign breast tissue which may allow retrospective classification of archived breast samples with respect to MCP and MPS at the time of sampling. Methods: 240 rFNA samples from healthy women with recorded hormonal data at the time of sampling were analyzed. We divided these subjects by menstrual cycle phase (MCP) and menopausal status (MPS): 41 early follicular: (low circulating E2 and P4); 48 mid-cycle (high E2 and low P4); 31 luteal (moderate E2 and high P4). 120 post-menopausal (low E2 and low P4). 100 ng of RNA from rFNA samples of the breast was reverse transcribed. Amplicons of interest were linearly amplified to 14 cycles for 35 genes related to hormone responsiveness. qPCR reactions were carried out using the TaqMan OpenArray (Applied Biosystems). For each gene of interest, expression levels were normalized to the average expression of GAPDH. Gene expression difference between groups were conducted using the Mann-Whitney Test. P-values from gene expression difference were adjusted via the Benjamini-Hochberg (1995) approach. Results: The mean value of TNFSF11 expression level was 13.19 fold higher in luteal phase subjects than in post-menopausal subjects (p = 0.0003) where there was also the biggest difference of serum P4 level between groups. The expression of DIO2 and MYBPC1 was also significantly higher in luteal phase group than in the post-menopausal group (p = 0.005, p = 0.02, respectively). These 3 genes also demonstrated a higher expression pattern in luteal phase than mid-cycle and follicular phase but analysis is still ongoing. All comparisons between these groups will be presented at the meeting. Conclusion: The expression levels of TNFSF11, DIO2 and MYBPC1 vary with MCP and MPS. These hormone-responsive genes are candidate MCP classifiers which could be applied to archived breast samples to assess whether biomarkers of breast cancer risk are stable across the menstrual cycle, since MCP and MPS variation is likely an important source of biological noise in studies of archived breast biopsy material. [ABSTRACT FROM AUTHOR]

Background: Risk biomarkers that are specific to ER subtypes of breast cancer would help developing distinct prevention strategies. The contralateral unaffected breast of women with unilateral breast is a good model for defining subtype specific risk as women with ER- primary tumor are at high risk for subsequent ER- tumor in contralateral breast. Methods: We performed random fine needle aspiration of unaffected breast of cases. RNA samples from 30 subjects (15 ER+ and 15 ER-) were used for Ilumina expression array analysis. Findings were validated by qRT-PCR using independent sample set consisted of 36 subjects (12 ER+, 12 ER-, and 12 standard risk healthy controls). Results: Gene array studies identified 18 genes with significant higher expression in ER- case samples, 8 of which were associated with lipid metabolism. This pattern was confirmed by qRT -PCR in the same samples and in the 24 cases of validation set. When compared to the healthy controls, significant over-expression of 4 genes (DHRS2, HMGCS2, HPGD, ACSL3) was observed in ER- cases, with significant lower expression of UGT2B11 and APOD in ER+ cases, and decreased expression of UGT2B7 in both subtypes. Conclusion: Differential expression of lipid metabolism genes my be involved in the risk for subtypes of breast cancer, which might be potential biomarkers of ER specific breast cancer risk. [ABSTRACT FROM AUTHOR]

Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A and MCF-12A cells, and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility, and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC., (© 2022. The Author(s).)

Background: The ovarian hormones estrogen and progesterone (EP) are implicated in breast cancer causation. A specific consequence of progesterone exposure is the expansion of the mammary stem cell (MSC) and luminal progenitor (LP) compartments. We hypothesized that this effect, and its molecular facilitators, could be abrogated by progesterone receptor (PR) antagonists administered in a mouse model., Methods: Ovariectomized FVB mice were randomized to 14 days of treatment: sham, EP, EP + telapristone (EP + TPA), EP + mifepristone (EP + MFP). Mice were then sacrificed, mammary glands harvested, and mammary epithelial cell lineages separated by flow cytometry using cell surface markers. RNA from each lineage was sequenced and differential gene expression was analyzed using DESeq. Quantitative PCR was performed to confirm the candidate genes discovered in RNA seq. ANOVA with Tukey post hoc analysis was performed to compare relative expression. Alternative splicing events were examined using the rMATs multivariate analysis tool., Results: Significant increases in the MSC and luminal mature (LM) cell fractions were observed following EP treatment compared to control (p < 0.01 and p < 0.05, respectively), whereas the LP fraction was significantly reduced (p < 0.05). These hormone-induced effects were reversed upon exposure to TPA and MFP (p < 0.01 for both). Gene Ontology analysis of RNA-sequencing data showed EP-induced enrichment of several pathways, with the largest effect on Wnt signaling in MSC, significantly repressed by PR inhibitors. In LP cells, significant induction of Wnt4 and Rankl, and Wnt pathway intermediates Lrp2 and Axin2 (confirmed by qRTPCR) were reversed by TPA and MFP (p < 0.0001). Downstream signaling intermediates of these pathways (Lrp5, Mmp7) showed similar effects. Expression of markers of epithelial-mesenchymal transition (Cdh1, Cdh3) and the induction of EMT regulators (Zeb1, Zeb2, Gli3, Snai1, and Ptch2) were significantly responsive to progesterone. EP treatment was associated with large-scale alternative splicing events, with an enrichment of motifs associated with Srsf, Esrp, and Rbfox families. Exon skipping was observed in Cdh1, Enah, and Brd4., Conclusions: PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention., (© 2021. The Author(s).)

Neurons release neurotransmitters such as glutamate to communicate with each other and to coordinate brain functioning. As increased glutamate release is indicative of neuronal maturation and activity, a system that can measure glutamate levels over time within the same tissue and/or culture system is highly advantageous for neurodevelopmental investigation. To address such challenges, we develop for the first time a convenient method to realize functionalized borosilicate glass capillaries with nanostructured texture as an electrochemical biosensor to detect glutamate release from cerebral organoids generated from human embryonic stem cells (hESC) that mimic various brain regions. The biosensor shows a clear catalytic activity toward the oxidation of glutamate with a sensitivity of 93 ± 9.5 nA·µM -1 ·cm -2 . It was found that the enzyme-modified microelectrodes can detect glutamate in a wide linear range from 5 µM to 0.5 mM with a limit of detection (LOD) down to 5.6 ± 0.2 µM. Measurements were performed within the organoids at different time points and consistent results were obtained. This data demonstrates the reliability of the biosensor as well as its usefulness in measuring glutamate levels across time within the same culture system., Competing Interests: The authors declare no conflict of interest.

Objective: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy., Design: We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints., Results: At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention., Conclusions: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice., Trial Number: NCT00468910., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: The human breast comprise several ductal systems, or lobes, which contain a small amount of fluid containing cells, hormones, proteins and metabolites. The complex physiology of these ducts is likely a contributing factor to the development of breast cancer, especially given that the vast majority of breast cancers begin in a single lobular unit., Methods: We examined the levels of total protein, progesterone, estradiol, estrone sulfate, dehydroepiandrosterone sulfate, and macrophages in ductal fluid samples obtained from 3 ducts each in 78 women, sampled twice over a 6 month period. Samples were processed for both cytological and molecular analysis. Intraclass correlation coefficients and mixed models were utilized to identify significant data., Results: We found that the levels of these ductal fluid components were generally uncorrelated among ducts within a single breast and over time, suggesting that each lobe within the breast has a distinct physiology. However, we also found that estradiol was more correlated in women who were nulliparous or produced nipple aspirate fluid., Conclusions: Our results provide evidence that the microenvironment of any given lobular unit is unique to that individual unit, findings that may provide clues about the initiation and development of ductal carcinomas.

Context: Fetal growth restriction (FGR) due to placental dysfunction impacts short- and long-term neonatal outcomes. Abnormal umbilical artery Doppler velocimetry indicating elevated fetoplacental vascular resistance has been associated with fetal morbidity and mortality. Estrogen receptors are regulators of vasomotor tone, and fetoplacental endothelium expresses estrogen receptor-β (ESR2) as its sole estrogen receptor., Objective: Our objective was to elucidate the mechanism whereby ESR2 regulates placental villous endothelial cell prostanoid biosynthesis., Design and Participants: We conducted immunohistochemical analysis of human placental specimens and studies of primary fetoplacental endothelial cells isolated from subjects with uncomplicated pregnancies., Main Outcome Measures: We evaluated in vivo levels of ESR2 and cyclooxygenase-2 (PTGS2) in villous endothelial cells from fetuses with or without FGR and/or abnormal umbilical artery Doppler indices and in vitro effects of ESR2 on prostanoid biosynthetic gene expression., Results: ESR2 and PTGS2 expression were significantly higher within subjects with FGR with abnormal umbilical artery Doppler indices in comparison with controls (P < 0.01). ESR2 knockdown led to decreased cyclooxygenase-1 (PTGS1), PTGS2, prostaglandin F synthase (AKR1C3), and increased prostacyclin synthase (PTGIS), with opposing results found after ESR2 overexpression (P < 0.05). ESR2 mediates prostaglandin H2 substrate availability and, in the setting of differential regulation of AKR1C3 and PTGIS, altered the balance between vasodilatory and vasoconstricting prostanoid production., Conclusions: Higher ESR2 expression in the placental vasculature of FGR subjects with abnormal blood flow is associated with an endothelial cell phenotype that preferentially produces vasoconstrictive prostanoids. Endothelial ESR2 appears to be a master regulator of prostanoid biosynthesis and contributes to high-resistance fetoplacental blood flow, thereby increasing morbidity and mortality associated with FGR.

There is an increasing body of literature showing associations of organochlorine exposure with risk of diabetes and insulin resistance. Some studies suggest that associations differ by gender and that diabetes risk, in turn, may be affected by endogenous steroid hormones. This report examines the relationships of serum PCBs and endogenous hormones with history of diabetes in a cohort of persons previously employed at a capacitor manufacturing plant. A total of 118 women were post-menopausal with complete data, of whom 93 were not using steroid hormones in 1996, at the time of examination, which included a survey of exposure and medical history, height, weight and collection of blood and urine for measurements of lipids, liver function, hematologic markers and endogenous hormones. This analysis examines relationships of serum polychlorinated biphenyls (PCBs), work exposure and endogenous hormones with self-reported history of diabetes after control for potential confounders. All PCB exposure groups were significantly related to history of diabetes, but not to insulin resistance as measured by the homeostatic model assessment of insulin resistance (HOMA-IR) in non-diabetics. Diabetes was also independently and inversely associated with follicle stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS) and triiodothyronine (T3) uptake. HOMA-IR was positively associated with body mass index (BMI) and C-reactive protein (CRP) and inversely associated with sex hormone binding globulin (SHBG) and T3 uptake after control for PCB exposure. Possible biologic mechanisms are discussed. This study confirms previous reports relating PCB exposure to diabetes and suggests possible hormonal pathways deserving further exploration., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Persistent pollutants, such as polychlorinated biphenyls (PCBs), affect endocrine function. Human exposure to polybrominated diphenyl ethers (PBDEs), which are similar in structure to PCBs, has increased recently, but health effects have not been well studied., Objectives: Our goal in this study was to determine whether PBDE body burdens are related to thyroid and steroid hormone levels, thyroid antibodies, and thyroid disease in a cohort of frequent and infrequent adult male sport fish consumers., Methods: We tested serum from 405 adult males for PBDE congeners, PCB congeners, testosterone, sex-hormone-binding globulin (SHBG), SHBG-bound testosterone, thyroglobulin antibodies, and the thyroid hormones thyroxine (T(4)), triiodothyronine (T(3)), thyroid-stimulating hormone (TSH), and T(4)-binding globulin (TBG). We collected data on demographics, fish consumption, medical diseases, and medication use., Results: The median sum of PBDEs was 38 ng/g lipid. In 308 men without thyroid disease or diabetes, PBDEs were positively related to measures of T(4) and reverse T(3) and inversely related to total T(3) and TSH. PBDEs were positively related to the percentage of T(4) bound to albumin, and inversely related to the percentage of T(4) bound to TBG. Associations of BDE congeners with hormones varied. BDE-47 was positively associated with testosterone levels. Participants with PBDEs over the 95th percentile were more likely to have thyroglobulin antibodies, although high PBDE exposure was not associated with thyroid disease. PBDE effects were independent of PCB exposure and sport fish consumption., Conclusions: PBDE exposure, at levels comparable with those of the general U.S. population, was associated with increased thyroglobulin antibodies and increased T(4) in adult males.

This study investigated the relationships of steroid and thyroid hormones with total noncoplanar polychlorinated biphenyls (PCBs), total toxic equivalents (TEQs) from dioxins-like organochlorines, and dichlorodiphenyl dichloroethene (DDE) in 56 male frequent and infrequent Great Lakes sport caught fish consumers. Significant negative associations were found for triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), and sex hormone binding globulin (SHBG)-bound testosterone with PCBs, for TSH with total TEQs, and for estrone sulfate with DDE, adjusting for age, body mass index, and medication use. Follicle-stimulating hormone, luteinizing hormone, free testosterone, and SHBG were not significantly associated with organochlorines. Models that accounted for exposure to both PCBs and TEQs predicted T4, estrone sulfate, and SHBG-bound testosterone better than models that included either PCBs or TEQs alone, with the lowest hormone levels occurring in the participants with both higher PCB levels and lower TEQ levels. These data suggest that exposure to PCBs, dioxin-like organochlorines, and DDE, alone and potentially in combination, may be associated with effects on the endocrine system in adult males. Further studies should help delineate specific exposure effects and effects of exposures to other common environmental contaminants alone and in combination with PCBs.

Despite evidence supporting the involvement of the IGF system in the development of breast and other cancers, the major determinants of interindividual variability in circulatory IGF-I levels are not well understood. Previous research has pointed to important genetic influences as well as dietary effects through marked calorie or protein restriction. We conducted a randomized trial to determine the effects of 2 dietary patterns on serum IGF-1, IGFBP1 and IGFBP3 in free-living premenopausal women: phase 1, an isocaloric low-fat, high-fiber (LFHF) vs. usual diet, and phase 2, a soy supplement either with or without isoflavones (soy+IF vs. soy-IF). Participants completed 12 menstrual cycles on phase 1 and then were randomly assigned to a soy supplement for 3 cycles while maintaining the phase 1 diet. Before and after each phase, 154 women provided serum. We found no difference in the change in IGF-I, BP1 or BP3 in the LFHF group compared to the usual diet group. In phase 2, there were no differences in any IGF protein between the soy+IF and the soy-IF groups or any evidence of interaction between isoflavone exposure and the background diet. However, there was a small but statistically significant decrease (2.3%) in BP3 and an increase in the IGF-I:BP3 molar ratio among all 153 subjects following either soy supplement. These changes were correlated with changes in intake of calcium, total vegetable protein and soy. The results are compatible with previous data suggesting that increases in dietary calcium, protein and soy, in particular, could increase circulating levels of bioavailable IGF-I., (Copyright 2005 Wiley-Liss, Inc.)

Previous studies have suggested that exposure to polychlorinated biphenyls (PCBs) may alter thyroid function, but data on effects of PCB exposure on other endogenous hormones has been lacking. The current study is ancillary to a larger investigation of the effects of Great Lakes fish consumption on PCBs and reproductive function. In the current study we examine associations of PCBs, 1,1-bis (4-chlorophenyl)-2,2-dichloroethene (DDE), and fish consumption with thyroid and steroid hormones in 178 men and PCBs, DDE, and fish consumption with thyroid hormones in 51 women from the original study. Serum PCB level and consumption of Great Lakes fish are associated with significantly lower levels of thyroxine (T(4)) and free thyroxine index (FTI) in women and with significantly lower levels of T(4) in men. Fish consumption, but not PCB level, is significantly and inversely associated with triiodothyronine (T(3)) in men. Results for thyroid-stimulating hormone (TSH) are inconsistent. Among men, there are significant inverse associations of both PCB and fish consumption with sex hormone-binding globulin (SHBG)-bound testosterone, but no association with SHBG or free testosterone. There are no significant overall associations of PCB, DDE, or fish consumption with estrone sulfate, follicle-stimulating hormone, luteinizing hormone, or dehydroepiandrosterone sulfate. The results of this study are consistent with previous studies showing effects of fish consumption and PCB exposure on thyroid hormones and suggest that PCBs may also decrease steroid binding to SHBG. Elucidation of specific mechanisms must await future investigations.

This secondary data analysis examined if time of initiation of milk expression and pumping frequency influenced milk weight weeks 2-5 postpartum. Of the 39 subjects in the convenience sample, 20 were in the early initiating (EI) group, (n = 12 high frequency [HF], n = 8 low frequency [LF]), and 19 were in the late intiating (LI) group, (n = 7 HF, n = 12 LF). The EI group initiated pumping < or = 48 hours after birth; the HF group pumped a minimum of 6.25 times daily. A two-way analysis of variance indicated that milk weight was significantly higher in the HF as compared to the LF group. While there was no significant difference in milk weight between the EI and LI groups, there was a significant interaction between frequency and initiation. Milk weight for the LF/EI group appeared to be positively influenced by the initiation of mechanical expression soon after birth.