Tissue Hormone Levels Research Articles

Prolonged exposure to NaAsO2 induces thyroid dysfunction and inflammatory injury in Sprague‒Dawley rats, involvement of NLRP3 inflammasome‒mediated pyroptosis.

Arsenic, a well-known hazardous toxicant, has been found in recent years to act as an environmental endocrine disruptor that accumulates in various endocrine organs, impeding the normal physiological functions of these organs and altering hormone secretion levels. Moreover, some research has demonstrated a correlation between arsenic exposure and thyroid functions, suggesting that arsenic has a toxicological effect on the thyroid gland. However, the specific type of thyroid gland damage caused by arsenic exposure and its potential molecular mechanism remain poorly understood. In this study, the toxic effects of sodium arsenite (NaAsO2) exposure at different doses (0, 2.5, 5.0 and 10.0mg/kg bw) and over different durations (12, 24 and 36 weeks) on thyroid tissue and thyroid hormone levels in Sprague‒Dawley (SD) rats were investigated, and the specific mechanisms underlying the effects were also explored. Our results showed that NaAsO2 exposure can cause accumulation of this element in the thyroid tissue of rats. More importantly, chronic exposure to NaAsO2 significantly upregulated the expression of NLRP3 inflammasome-related proteins in thyroid tissue, leading to pyroptosis of thyroid cells and subsequent development of thyroid dysfunction, inflammatory injury, epithelial-mesenchymal transition (EMT), and even fibrotic changes in the thyroid glands of SD rats. These findings increase our understanding of the toxic effects of arsenic exposure on the thyroid gland and its functions.

Therapeutic potential of the linalool against cadmium-induced testicular tissue damage

Cadmium (Cd) is a heavy metal that has harmful effects and is one of the contaminants found in the environment. Cd exposure causes important pathophysiological processes, such as reproductive toxicity. Linalool (Lnl) is a monoterpene, a component of essential oils known to be produced synthetically. Additionally, Lnl has many important beneficial effects, such as anti-inflammatory and antioxidant effects. The objective of this study is to determine whether Lnl has a healing impact in opposition to testicular tissue damage due to Cd exposure. In the study, 28 male rats were divided at random into four equal groups (n = 7). No treatment was applied to the control group. CdCl2 was applied intraperitoneally to the Cd group at a dose of 3 mg/kg for the first 7 days of the trial. For the Cd + Lnl group, 3 mg/kg CdCl2 was applied intraperitoneally for the first 7 days of the trial, and 100 mg/kg/day Lnl was applied. Upon completion of all applications, the rats were sacrificed and blood samples and testicular tissue were taken. Cd exposure caused histopathological changes, oxidative stress, inflammation, and an increase in apoptotic cells in testicular tissue. However, Cd altered endocrine hormones in the hypothalamic-pituitary-gonad axis. However, Lnl application against Cd exposure was able to regulate the negativity caused by Cd in both testicular tissue and endocrine hormone levels. In conclusion, Lnl may be a potential therapeutic strategy against Cd-induced reproductive toxicity. We believe that Lnl has a high potential for further studies to determine its detailed mechanisms of action and cellular signaling pathways.

Synergistic effect of silicon and arbuscular mycorrhizal fungi reduces cadmium accumulation by regulating hormonal transduction and lignin accumulation in maize

Cadmium (Cd) stress causes serious damage to plants, inducing various physiological and biochemical disruptions that lead to reduced plant biomass and compromised growth. The study investigated the combined effects of silicon (Si) and arbuscular mycorrhizal fungi (AMF) on mitigating Cd stress in plants, revealing promising results in enhancing plant tolerance to Cd toxicity. Under Cd stress, plant biomass was significantly reduced (−33% and −30% shoot and root dry weights) as compared to control. However, Si and AMF application ameliorated this effect, leading to increased shoot and root dry weights (+47% and +39%). Furthermore, Si and AMF demonstrated their potential in reducing the relative Cd content (−43% and −36% in shoot and root) in plants and positively influencing plant colonization (+648%), providing eco-friendly and sustainable strategies to combat Cd toxicity in contaminated soils. Additionally, the combined treatment in the Cd-stressed conditions resulted in notable increases in saccharide compounds and hormone levels in both leaf and root tissues, further enhancing the plant's resilience to Cd-induced stress. Si and AMF also played a vital role in positively regulating key lignin biosynthesis genes and altering lignin-related metabolites, shedding light on their potential to fortify plants against Cd stress. These findings underscore the significance of Si and AMF as promising tools in addressing Cd toxicity and enhancing plant performance in Cd-contaminated environments.

The phytochemical curcumin inhibits steroid sulfatase activity in rat liver tissue and NIH-3T3 mouse fibroblast cells

Curcumin is a phytochemical derived from the spice turmeric that is reported to have therapeutic effects. We are studying the enzyme steroid sulfatase (STS), which removes the sulfate group from inactive steroid hormones in peripheral tissues and we were interested in the effect of curcumin on STS activity due to its structural composition (polyphenolic). We sought to determine if curcumin affects STS activity in two model systems, rat liver and NIH-3T3 mouse fibroblast cells. STS assays were performed on tissue extracts of rat liver, and on NIH-3T3 microsomes and cells, with and without curcumin. Male and female rat liver extracts contained substantial amounts of STS activity, with males averaging higher (4–11 %) levels. Estradiol inhibited STS activity in livers of both sexes at 20 and 10 µM. Curcumin acted as a competitive inhibitor of STS activity in rat liver extracts, with a Ki of 19.8 µM in males and 9.3 µM in females. Curcumin also inhibited STS activity in NIH-3T3 microsomes at both 20 µM and 10 µM, and in whole NIH-3T3 cells at 20 µM. These data are the first to demonstrate STS inhibition by curcumin. Inhibition of STS results in lower active steroid hormone (estrogens and androgens) levels in tissues, possibly altering modulation of immune responses by these steroids.

The nonshivering thermogenesis of brown adipose tissue and fat mobilization of striped hamsters exposed to cycles of cold and warm temperatures

The adaptive adjustments in the capacity for metabolic thermogenesis are critical for the survival in many small mammals that are acclimated to cold winter conditions. In this study the striped hamsters (Cricetulus barabensis) were subjected to repeated cycles of cold (5°C) and warm (23°C) temperatures. Resting metabolic rate (RMR), nonshivering thermogenesis (NST) and energy intake, as well as the expression of uncoupling protein 1 (UCP1) of brown adipose tissue (BAT) and serum thyroid hormone levels were measured. Both RMR and NST were significantly increased in striped hamsters subjected to repeated cycles of short-term cold (5°C, 72 h) – warm (23°C, 4 days) temperatures compared to that of the hamsters consistently kept at 23°C. In these cycled hamsters, BAT UCP1 expression was significantly upregulated, whereas serum T3 and T4 concentration did not change significantly. Moreover, gross energy intake was considerably increased during both cold exposure and warm phases, whereas fat deposition was significantly decreased in these cycled hamsters compared to those consistently kept at 23°C. This indicates that small mammals may both increase energy intake and mobilize fat depots to cope with frequent cold exposure. Thyroid hormone may be not involved in the BAT UCP1-mediated thermogenesis and fat mobilization.

Effects of cholesterol and Lactobacillus acidophilus on testicular function.

ObjectiveIn this study, the effects of Lactobacillus acidophilus on testosterone (TES), follicle-stimulating hormone (FSH), luteinizing hormone (LH), androgen-binding protein (ABP), factor-associated apoptosis (FAS), and total cholesterol (TC), as well as histopathological changes, were investigated in male rats fed a high-cholesterol diet. MethodsThe study included three groups. The control (C) group was fed standard-diet for 8 weeks. The hypercholesterolemia (HC) group was fed a 2% cholesterol-diet for 8 weeks. The therapeutic group (HCL) was fed a 2% cholesterol-diet for 8 weeks and administered L. acidophilus for the last 4 weeks. FSH, TES, and FAS levels in testicular tissue were determined using an enzyme-linked immunosorbent assay (ELISA), while another sample was examined histopathologically. LH and ABP levels were determined using ELISA, and serum TC levels were assessed via an autoanalyzer. ResultsIn the HC group, the TC levels were significantly higher and the LH levels were lower (p<0.05) than in the C group. The ABP levels were lower (p>0.05). In the HCL group, the LH and ABP levels were higher (p>0.05) and the TC level significantly lower (p<0.05) than in the HC group. The TES and FSH levels were lower, and the FAS levels were higher, in the HC than in the C group (p<0.05). In the HCL group, levels of all three resembled control levels. Histologically, in the testicular tissue of the HC group, the cells in the tubular wall exhibited atrophy, vacuolization, and reduced wall structure integrity. However, in the HCL group, these deteriorations were largely reversed.Conclusion Supplementary dietary administration of an L. acidophilus to hypercholesterolemic male rats positively impacted testicular tissue and male fertility hormone levels.

SUN-669 The G209R Mutant Mouse as a Model for Human PCSK1 Polyendocrinopathy

A striking number of SNPs and rare mutations have been identified in PCSK1, the gene that codes for the enzyme proprotein convertase 1/3 (PC1/3) which proteolytically activates prohormones within the secretory pathway. All infants bearing two copies of catalytically inactivating mutations, including G209R, exhibit severe neonatal malabsorption requiring parenteral nutrition for months and subsequently develop additional endocrinopathies, often including diabetes and obesity. In order to create a mouse model to explore the underlying mechanism of the malabsorption phenomenon and the endocrinopathies, a G209R point mutation was introduced into exon 6 of mouse Pcsk1 using CRISPR-Cas9 genome editing. Fifty-six live pups were collected at postnatal days one or two; however, most homozygous G209R mutant pups succumbed by day 2, and surviving pups were severely dwarfed. In homozygous, but not heterozygous pups, blood glucose levels were significantly lower with elevated plasma insulin-like immunoreactivity and accumulation of unprocessed proinsulin in G209R pancreas compared to the wild type pups from the same litters. The POMC product α-MSH (produced by PC2 from PC1/3-generated ACTH) has been strongly implicated in obesity mechanisms. We found pituitary POMC processing to ACTH was also affected by the G209R mutation in combined anterior and intermediate pituitary lobes. ACTH was markedly reduced in homozygote pituitary, with significant accumulation of POMC. Using Western blotting, we observed a significant reduction in PC1/3 protein in homozygote brains, while PC2 protein levels remained unaffected. Most likely due to the continued presence of PC2, pituitary and brain levels of α-MSH were not impaired, suggesting that α-MSH itself is not involved in the phenotype. Prior studies have shown that G209R PC1/3 is not efficiently trafficked out of the ER; further studies will examine the contribution of misfolded G209R PC1/3 to possible cellular ER stress, as well as determine peptide hormone levels in brain and peripheral tissues.

Dietary soybean oil, canola oil and partially-hydrogenated soybean oil affect testicular tissue and steroid hormone levels differently in the miniature pig

The present study was conducted to examine the influence of dietary canola oil (CAN) and partially-hydrogenated soybean oil (HSO) compared to soybean oil (SOY, control) on the morphology and function of testes using miniature pigs as the test subject. Male miniature pigs were fed a diet containing 10%SOY, 9%CAN+1%SOY, or 9%HSO+1%SOY for 18 months. The scheduled autopsies revealed no abnormalities in histopathological examination of the major organs, except the testes. Atrophy of the seminiferous tubules and hyperplasia in the Leydig cells were found in the SOY and CAN groups. DNA microarray analysis indicated downregulation in the CAN and the HSO groups of genes encoding for gonadotropins in the pituitary gland and of enzymes and proteins involved in steroid hormone metabolism in the testes, compared to the SOY group. Plasma levels of sex hormones in the CAN and HSO groups tended to be higher and testosterone and dihydrotestosteorne in the HSO group were significantly higher than in the SOY group. These results demonstrate that testes are morphologically and functionally affected by the dietary oils, while the plasma steroid hormone levels do not necessarily reflect the gene expression, probably owing to feedback regulation via the gonadal hormones in the hypothalamus-pituitary-gonadal axis.

Toxic effects of triptolide on adrenal steroidogenesis in H295R cells and female rats.

Triptolide (TP), a major active ingredient of Tripterygium wilfordii, exerts potent immunosuppressive effects in the treatment of rheumatoid arthritis but is not widely used in clinical practice due to its multiorgan toxicity, particularly hepatotoxicity, nephrotoxicity, and reproductive toxicity. An LC-MS/MS approach was employed to explore the endocrine-disrupting effects of TP. The endocrine-disrupting effects of various concentrations (0-100 nM) of TP for 48 hour were firstly investigated using an in vitro model (H295R cell line). It was found that TP did not decrease cell viability. The transcriptional levels of steroidogenic enzymes in H295R cells were assessed by quantificational real-time polymerase chain reaction. The possible adrenal and endocrine effects of oral administration of TP (0, 50, and 500 μg/kg) for 28 days on both normal and collagen-induced arthritis (CIA) rats were also explored. The serum and adrenal tissue hormone levels (corticosterone and progesterone) and adrenal histopathology were analyzed, with the results that TP significantly decreased the level of cortisol in H295R cells and the level of plasma corticosterone in both normal and CIA rats. Histological alterations in adrenal cortex were observed at the dose of 500 μg/kg. Exposure to TP for 48 hour had an obvious inhibitory effect on the messenger RNA transcript levels of HSD3B2, CYP21A2, CYP17A1, and CYP11B1, which is essential for the synthesis of corticosteroids. In a word, TP leads to the disorder of corticosteroid synthesis and secretion, and corticosteroid may be a potential biomarker for the treatment of multiorgan toxicity of TP.

Role of adiponectin in ovarian follicular development and ovarian reserve.

Adiponectin levels are associated with anti-Müllerian hormone (AMH) and kisspeptin levels in non-ovarian tissues. The objective of the present study was to investigate the association between adiponectin and the genes important for ovarian follicular development and ovarian reserve, specifically AMH and kisspeptin, and their corresponding receptors. In the first experiment, the mRNA levels of anti-Müllerian hormone (amh) and its receptor (Amhr2), as well as those of kisspeptin (Kiss1) and its receptor (Kiss1r), were quantified by reverse transcription-polymerase chain reaction analysis in the ovaries of two groups of mice [adiponectin-knockout (KO) vs. control] that underwent oophorectomy. The second experiment measured follicular phase serum AMH and follicular fluid adiponectin levels in 25 women who underwent controlled ovarian hyperstimulation for in vitro fertilization. Compared with the control mice, adiponectin-KO mice had 6.5 times lower Kiss1 mRNA levels (P=0.009) and a tendency for lower ovarian Kiss1r mRNA expression levels (P=0.06). However, adiponectin-KO mice had significantly higher Amhr2 mRNA levels (P=0.01). In all women participants, there was a positive correlation between serum AMH and follicular fluid adiponectin concentrations (r=0.54, P=0.006). The findings of the present study indicate that adiponectin may play a role in ovarian physiology through its impact on genes crucial for ovarian follicular development and ovarian reserve, such as kisspeptin and AMH. Understanding the role of adiponectin in ovarian function may improve our knowledge of the pathophysiology underlying ovulatory dysfunction in obese women, who usually have low adiponectin levels, and overcome reproductive barriers.

Hormonal profiling of the Fusarium mangiferae infected mango buds in relation to mango malformation

Mango malformation is a serious threat to mango cultivation in various countries and causes 30–80% of fruit yield losses annually. It is now well established that Fusarium mangiferae induces the symptoms of mango malformation disease. Fusarium mangiferae is phylogenetically closely related to Fusarium fujikuroi. However, visible symptoms of floral malformation caused by F. mangiferae and bakanae disease of rice caused by F. fujikuroi are distinctly opposite. In bakanae disease, infected seedlings exhibit abnormal elongation, whereas in mango malformation, length of the primary axis and secondary branches of the panicle are reduced, which is characterized by appreciably reduced internodes that give them a witches’ broom-like appearance. These morphological differences may be attributed to a differentially altered hormonal balance by the respective pathogenic organism. Artificial inoculation of meristems with F. mangifera under phytotron conditions produced malformed inflorescence. In our in vitro studies, the number of macro and micro conidia of F. mangiferae increased with increase in the concentration of GA3 suggesting that GA is needed for causing infection. The current study investigated the endogenous hormone levels in healthy and malformed tissues at different bud development stages. Our results demonstrate that significantly low GA and high auxin levels in mango buds infected with F. mangiferae lead to development of malformed panicles.

Role of testosterone synthesized by skin melanocytes in preventing malignant transformation of nevi.

e21066 Background: Melanocytes are involved into the synthesis and metabolism of steroid hormones in the skin. Cutaneous melanoma in 75% of cases occurs in congenital or acquired pigmented nevi. There are no studies comparing local hormonogenesis in nevi and melanomas. The purpose of the study was a comparative analysis of hormone levels in tissues of dysplastic nevi and cutaneous melanoma (pТ1-2N0M0). Methods: Levels of prolactin (PRL), progesterone (P4), total and free testosterone (T and fT), estrone (E1) and estriol (E3) and sex steroid-binding globulin (SSBG) were studied by ELISA in 17 samples of рТ1-2N0M0 melanoma and in 23 samples of dysplastic nevi. Intact tissues (n = 15) obtained from non-cancer patients during surgical treatment was used as the control. Results: Levels of T in nevi, compared to intact tissues, were 1.4 times higher, fT – 8.7 times higher, while SSBG content was 1.9 times lower; E3 was 1.6 times higher, PRL – 1.4 times lower, and levels of E1 in nevi were similar to the values in intact tissues. рТ1-2N0M0 melanomas, compared to intact tissues, demonstrated local androgen imbalance: T levels were decreased by 1.8 times, while fT exceeded the norm by 1.8 times, and SSBG – by 6 times. E1 content increased by 1.6 times, E3 decreased by 2.8 times. The E1/E3 ratio in nevi was reduced by 1.6 times, while in melanoma it was increased by 4.4 times. The T/E1 ratio in nevi was increased by 1.4 times, and in melanoma it was decreased by 2.8 times. Levels of PRL and P4 in melanomas, nevi and in intact tissues did not differ significantly. Conclusions: Melanoma was characterized by hyperestrogenia due to increased levels of E1 and low E3 concentrations which caused malignant transformation of melanocytes. Most likely, in melanoma spent SVT estrone synthesis, as evidenced by increase in the E1 / E3 and decrease T / E1.Apparently, fT in melanoma is used for estrogen synthesis, as indicated by the E1/E3 increase and decrease in the T/E1 ratio. Increased E1 synthesis can contribute to the realization of estrogen genotoxic effects. These mechanisms are absent in tissues of nevi. Hyperandrogenism in nevi probably prevents malignant transformation due to low aromatase activity.

Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients

BackgroundPostmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients.MethodsFormalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS.ResultsCLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone:androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03–0.59). A similar pattern was observed with estradiol:testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04–0.72).ConclusionsCLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens:androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings.

Association Between Serum Levels of Testosterone and Estradiol With Meibomian Gland Assessments in Postmenopausal Women

PurposeThe aims of this analysis were to determine if there is an association between serum levels of testosterone and estradiol with meibomian gland (MG) morphology and lipid layer thickness.MethodsThe data used for this analysis were collected from postmenopausal women with and without dry eye disease. Meibography was used to assess MG dropout on the central two-thirds of the eyelid and biomicroscopy was used for assessing MG expressibility and meibum quality. Venous blood samples were drawn for serum hormone level analysis. The Kruskal-Wallis test and Spearman correlations were used for statistical analysis.ResultsOne hundred ninety-eight postmenopausal women with an average age of 61.2 (±9.1) years were included in this analysis. Testosterone levels showed significant differences between MG dropout grades 1 and 4 (P = 0.002) and grades 2 and 4 (P = 0.01), whereas estradiol levels were different based on MG dropout (P = 0.53). No significant correlations were found between testosterone (r = 0.10, P = 0.17) or estradiol (r = 0.05, P = 0.45) and lipid layer thickness.ConclusionsTestosterone levels were increased with MG dropout, which was significant between the mild and severe dropout groups, whereas no significant differences were found with estradiol and any MG assessment. Although the literature suggests an association of serum hormone levels and pathogenesis of dry eye disease in postmenopausal women, analysis of active sex steroid precursors and local tissue hormone levels may prove more useful.

Adolescent Idiopathic Scoliosis: An in Depth Analysis and Historical Review

Adolescent idiopathic Scoliosis (AIS) is a common disorder of children about which there is a vast amount of research available for review. This manuscript aims to discuss significant classic and modern literature regarding this spinal deformity. An organized review of topics including the definition, epidemiology, etiology, physiology, diagnosis, and management of adolescent idiopathic scoliosis has been included herein. In this review, it is first explained that AIS now falls under the definition of late-onset idiopathic scoliosis. Epidemiologic discussion then reveals the relatively high prevalence of this disorder in children and lists the variations seen in prevalence by gender. Etiologic review explores the multifactorial nature of AIS and describes various conditions implicated in AIS pathogenesis including abnormalities in connective tissue structure, neuro-osseous development, platelet chemistry and hormone levels. The discussion of physiology explains the three dimensional structure of the AIS deformity and reviews long term complications such as back pain and compromised self-image. The section covering diagnostic methods highlights the physical exam for AIS and details important radiographic measurements including the Cobb angle, clavicle angle, and sagittal balance. Finally, the review of management emphasizes the importance of individualized therapy for AIS and discusses techniques involved in the non-operative and operative treatment of this spinal deformity.

Role of the short isoform of the progesterone receptor in breast cancer cell invasiveness at estrogen and progesterone levels in the pre- and post-menopausal ranges.

Overexpression of the progesterone receptor (PR) isoform A (PR-A) is a negative prognosticator for estrogen receptor (ER)-positive breast cancer but in vitro studies have implicated PR-B in progestin-induced invasiveness. As estrogen is known to suppress invasiveness and tumor progression and as the in vitro studies were conducted in models that either lacked ER or excluded estrogen, we examined the role of PR isoforms in the context of estrogen signaling. Estrogen (< 0.01nM) strongly suppressed invasiveness in various ER+ model cell lines. At low (< 1nM) concentrations, progestins completely abrogated inhibition of invasiveness by estrogen. It was only in a higher (5 nM - 50 nM) concentration range that progestins induced invasiveness in the absence of estrogen. The ability of low dose progestins to rescue invasiveness from estrogen regulation was exclusively mediated by PR-A, whereas PR-B mediated the estrogen-independent component of progestin-induced invasiveness. Overexpression of PR-A lowered the progestin concentration needed to completely rescue invasiveness. Among estrogen-regulated genes, progestin/PR-A counter-regulated a distinctive subset, including breast tumor progression genes (e.g., HES1, PRKCH, ELF5, TM4SF1), leading to invasiveness. In this manner, at relatively low hormone concentrations (corresponding to follicular stage and post-menopausal breast tissue or plasma levels), progesterone influences breast cancer cell invasiveness by rescuing it from estrogen regulation via PR-A, whereas at higher concentrations the hormone also induces invasiveness independent of estrogen signaling, through PR-B. The findings point to a direct functional link between PR-A and progression of luminal breast cancer in the context of the entire range of pre- and post-menopausal plasma and breast tissue hormone levels.

Abstract 1870: Associations among tissue vitamin D metabolites and breast cancer risk factors in women undergoing reduction mammoplasty

Abstract Background: Vitamin D, the precursor to the potent steroid hormone calcitriol (1,25(OH)2D), is mainly obtained through sunlight exposure, diet and supplements. Some basic science and preclinical studies indicate that vitamin D promotes differentiation and apoptosis; inhibits the proliferation and inflammation and therefore decreases the risk of developing cancer. However, most of these studies were done in cell culture and epidemiology studies utilized blood vitamin D assays. This study validates methods for measuring 25(OH)D and 1,25(OH)2D in breast tissues and investigates the relationship between tissue vitamin D, plasma vitamin D and breast cancer risk factors. Methods: To validate the assay, 44 tissue samples from 11 women with no history of breast cancer undergoing reduction mammoplasty were used to investigate the levels of vitamin D across the breast by enzyme immunoassay. Tissue and plasma 25(OH)D and 1,25(OH)2D levels were then determined in 176 subjects who have available epidemiological profiles and among whom we previously determined breast hormone and receptor levels. Correlations between tissue vitamin D metabolites with blood vitamin D metabolites, participants’ characteristics (e.g., age, race and BMI), and other hormone and receptor levels were analyzed using Pearson's correlation coefficient. Non-normally distributed continuous variables were logarithmic transformed. Partial correlation coefficients were also used to examine associations while adjusting for participant characteristics. Results: The average coefficient of variation of 25(OH)D and 1,25(OH)2D among 4 breast sections were 14.81% and 19.13%, respectively. For the entire study set, tissue 25(OH)D levels ranged between 53.24-209.36 nmol/Kg and tissue 1,25(OH)2D range was 2.48-41.91 pmol/Kg. We observed positive correlations between tissue and plasma levels of 25(OH)D (r = 0.55, p&amp;lt;0.0001) and 1,25(OH)2D (r = 0.58, p&amp;lt;0.0001). Tissue 25(OH)D and 1,25(OH)2D levels were also well correlated (r = 0.59, p&amp;lt;0.0001). After adjustment for BMI and age, tissue 1,25(OH)2D was positively correlated with plasma adiponectin to leptin ratio (r = 0.18, p = 0.047), and inversely correlated with tissue IGF to IGFBP3 ratio (r = -0.30, p = 0.025). None of these associations were found when comparing these factors with plasma level vitamin D metabolites. Conclusions: Our data indicate that although plasma and tissue vitamin D metabolites strongly correlate with each other, studying the target organ, namely the breast, provides greater insight into mechanistic carcinogenic relationships and how hormone levels in tissues modulate the microenvironment of the normal breast that may be related to breast cancer risk. Citation Format: Renny S. Lan, Adana A. Llanos, Theodore M. Brasky, Catalin Marian, Ramona G. Dumitrescu, Bhaskar V. S. Kallakury, Kepher H. Makambi, Jo L. Freudenheim, Peter G. Shields. Associations among tissue vitamin D metabolites and breast cancer risk factors in women undergoing reduction mammoplasty. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1870. doi:10.1158/1538-7445.AM2015-1870

Abstract 2767: Investigation of the relationship between crown-like structures and adipose tissue hormone levels among postmenopausal women with breast cancer

Abstract Introduction: Increased levels of circulating estrogens are associated with elevated risks of postmenopausal breast cancer. Previously, we showed that levels of sex steroid hormones in breast adipose tissue are positively correlated with circulating hormones. Further evaluation of hormone levels in breast tissues may help to explain the relationship between estrogens and breast cancer risk. Specifically, data suggest that focal breast lesions consisting of macrophages encircling dying adipocytes, referred to as “crown-like structures (CLS)”, are associated with increased aromatase activity, which could increase conversion of androgens to estrogens locally in the breast. Therefore, we assessed whether the presence of CLS affects the correlations between blood and breast adipose tissue hormone levels. Methods: Participants included 84 postmenopausal women with invasive breast cancer in the Polish Breast Cancer Study, a population based case-control study conducted from 2000 to 2003. We previously reported sex steroid hormone levels in cancer-free breast adipose tissue removed as part of breast excisions performed for cancer. Here, using immunohistochemical stains, we evaluated the number of CD68 positive macrophages and the presence of full CLS (i.e., complete adipocyte encirclement) in benign breast tissue sections prepared from surgical pathology specimens containing breast cancer. The relationship between the number of CD68 positive macrophages per unit area of fat and hormone levels was examined using Spearman rank correlations (rs). We assessed potential effect modification of the association between blood and tissue hormone levels by presence or absence of CLS by including an interaction term in linear regression models. Results: The number of CD68 positive macrophages per unit area of fat was not significantly correlated with levels of estrone, estradiol, androstenedione or testosterone measured in blood (rs = 0.001, -0.04, -0.07, and -0.09, respectively; p&amp;gt;0.05) or breast adipose tissue (rs = -0.15, 0.06, -0.06, and -0.08, respectively; p&amp;gt;0.05). Correlations between serum and adipose tissue hormones did not statistically significantly differ between women with CLS (n = 30) compared to those without CLS (n = 54). CLS were found more frequently in breast adipose tissue from overweight (i.e., women with a body mass index (BMI) between 25 and 29.9) (43%) and obese women (BMI &amp;gt;30) (30%) versus normal weight women, with (BMI between 18.5 and 24.9), (27%); (p = 0.04, χ2 test). The number of CD68 positive macrophages per unit area of fat was not significantly related to BMI (p = 0.31). Conclusion: Among postmenopausal women with invasive breast cancer, the presence of CLS was more common among overweight and obese women, but CLS did not influence the correlation between circulating and breast adipose tissue sex steroid hormone levels. Citation Format: Maeve Mullooly, Hannah P. Yang, Roni T. Falk, Sarah Nyante, Renata Cora, Ruth M. Pfeiffer, Derek C. Radisky, Daniel W. Visscher, Lynn C. Hartmann, Amy C. Degnim, Frank Z. Stanczyk, Jonine F. Figueroa, Montserrat Garcia-Closas, Jolanta Lissowska, Melissa T. Troester, Louise A. Brinton, Mark E. Sherman, Gretchen L. Gierach. Investigation of the relationship between crown-like structures and adipose tissue hormone levels among postmenopausal women with breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2767. doi:10.1158/1538-7445.AM2015-2767

A Question for Women's Health: Chemicals in Feminine Hygiene Products and Personal Lubricants

Vaginal research got a desperately needed boost at the National Institutes of Health (NIH) in 1992. That’s when Penny Hitchcock took over the Sexually Transmitted Diseases Branch at the National Institute of Allergy and Infectious Diseases and Nancy Alexander became chief of the Contraceptive Development Branch in the NIH Center for Population Research—posts previously held by men. “Those two got together and discovered NIH had no programs for vaginal research,” says Richard Cone, a Johns Hopkins biophysics professor. Cone had begun developing vaginal contraceptives that would protect against sexually transmitted infections (STIs) in 1980, and until then, struggled to get funding. Mucous membranes in the vagina and vulva rapidly absorb chemicals without metabolizing them. But until recently scant research existed on how chemicals in feminine hygiene products and personal lubricants may affect women’s health. Hitchcock and Alexander soon initiated research programs on vaginal physiology, immunology, and microbicides, eventually funding Cone’s work. These new programs led to groundbreaking discoveries in animals and humans that certain chemicals—including glycerin (glycerol), a common base for personal lubricants—can damage or irritate vaginal1 and rectal2 epithelial cells, potentially increasing the transmission of STIs such as herpes and human immunodeficiency virus. When it comes to reproductive health, research on contraceptives and STIs continues to garner interest worldwide. But a related area—chemical exposures from feminine hygiene products and personal lubricants—has received much less attention. In the United States alone, women spend well over $2 billion per year on feminine hygiene products,3 including tampons, pads, feminine washes, sprays, powders, and personal wipes. But until recently, scant research existed on how chemicals in these products may affect women’s health. As scattered findings emerge, several scientists and interest groups are calling for more research to fill in the gaps.4,5 A recent report by the nonprofit Women’s Voices for the Earth (WVE) points out that feminine hygiene products may use ingredients that are known or suspected endocrine-disrupting chemicals (EDCs), carcinogens, or allergens. And while nearly all women use tampons and sanitary pads, black and Latina women use douches, wipes, powders, and deodorizers more often than women of other races, putting them at greater risk of potential chemical exposures.4 “It’s a little bit edgy. People have been shocked, saying things like ‘I’ve never really thought about [the vagina] being an important internal link to your body,’” says Alexandra Scranton, director of science and research for WVE. “Although it is well known that the vaginal ecosystem is more sensitive and more absorbent than typical skin, there is surprisingly little research out there on feminine care products.” Surveys conducted in the 1990s–2000s gave a sense not only of how commonly some products are used but also how widely use can vary across racial/ethnic groups.

Editorial: The Birth of Endocrine Pathology

During the last 50 years, phenomenal progress was achieved in the better understanding of a large number of diseases including those of the endocrine glands. Previously unknown hormones were discovered; new methods were developed to measure hormone levels in blood, body fluids, and tissues; and new information emerged relating to the functions of hormones and their regulation. Research focused on animal experiments moved from observational to interventional as the ability to engineer animal models developed. With progress towards personalized care, the investigation of primary human samples became the basis for targeted therapies and precision medicine; newly introduced imaging methods and substantial advances in surgical techniques assumed fundamental importance. The role of pathology increases as novel therapies require more advanced and precise understanding of human diseases. The need for subspecialization and multidisciplinary care teams has led to greater demand for publications that can integrate knowledge in specific areas of medicine. We foresaw a need more than 25 years ago when endocrine pathology was as yet an unrecognized discipline. There were many journals that published papers on clinical endocrinology and therapeutic approaches in endocrine diseases; there were pathology journals that were interested in disease pathogenesis and some that focused on the pathology of tumors of several organs. However, there was no journal focusing on the pathology of diseases of the endocrine glands. Indeed, much of endocrine pathology was lost in the realm of other pathology interests: pituitary pathology was the territory of neuropathologists, thyroid and parathyroid diseases were handled by head-and-neck pathologists, adrenals and the gonads were examined by genitourinary pathologists, and the large number of neuroendocrine pathologies of the gastroenteropancreatic system fell under the auspices of gastrointestinal pathologists. The commonality of hormone function and regulation, the structural essence of endocrine cells, and the systemic impact of endocrine disorders led us to propose the need for an overarching approach; the drive to work with endocrinologists, endocrine surgeons, and endocrine oncologists was the impetus for our work. We decided to challenge the existing order, to define a new discipline, and to create a new journal: Endocrine Pathology. The first issue was published in March 1990. As the two founding editors, we were honored to have as successors Drs. Ricardo V. Lloyd, Arthur S. Tischler, Virginia A. Livolsi, and Anne Marie McNicol who have continued to bring our dream to reality. Their efforts have created a journal that is recognized and respected internationally. The impact factor of the journal continues to rise as the scope and quality of the publications increase. We are grateful to the excellent editorial board, the reviewers, the publishing companies, and all the authors who have chosen to publish their work in Endocrine Pathology. We are optimistic that the journal will continue to be successful and will inspire readers to pursue deeper insights into the pathology of endocrine diseases. William Osler said: “Everywhere the old order changes, and happy they who can change with it.” John F. Kennedy said: “Change is the law of life. And those who look only to the past or present are certain to miss the future.” We are constantly aware of the need for change and the importance of providing our discipline with the tools to ensure its sustainability. We hope that the legacy of this journal and of the discipline of endocrine pathology will be one of insight, foresight, and excellence. For indeed, as Alan Kay said, “the best way to predict the future is to invent it.” K. Kovacs (*) Department of Laboratory Medicine, Divsion of Pathology, St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B1W8, Canada e-mail: kovacsk@smh.ca