Hormonal Etiology Research Articles

First Case Report of Synchronous Presentation of Tumoriform Psudoangumatous Stromal Hyperplasia (PASH) and Malignant Phyllodes Tumor in One Breast Lesion

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign proliferative mesenchymal lesion with possible hormonal etiology. PASH is mostly identified as an incidental finding in the final histopathology of excised breast specimens. However, another less common presentation of PASH is the tumoriform palpable lesion. Herein, we report an unusual case of tumorous PASH of the breast with a deceiving clinical presentation mimicking invasive mammary carcinoma, and a surprising final histopathological diagnosis. Our report indicates that widening the differential diagnosis of a breast mass, to include rare and uncommon diseases, as well as careful decision making are essential measures to avoid overlooking a serious diagnosis or over treating a simple disease.

Mammary Glands of Women, Female Dogs and Female Rats: Similarities and Differences to Be Considered in Breast Cancer Research

Breast cancer is one of the most common and well-known types of cancer among women worldwide and is the most frequent neoplasm in intact female dogs. Female dogs are considered attractive models or studying spontaneous breast cancer, whereas female rats are currently the most widely used animal models for breast cancer research in the laboratory context. Both female dogs and female rats have contributed to the advancement of scientific knowledge in this field, and, in a “One Health” approach, they have allowed broad understanding of specific biopathological pathways, influence of environmental factors and screening/discovery of candidate therapies. This review aims to clearly showcase the similarities and differences among woman, female dog and female rat concerning to anatomical, physiological and histological features of the mammary gland and breast/mammary cancer epidemiology, in order to better portray breast tumorigenesis, and to ensure appropriate conclusions and extrapolation of results among species. We also discuss the major aspects that stand out in these species. The mammary glands of female dogs and women share structural similarities, especially with respect to the lactiferous ducts and lymphatic drainage. In contrast, female rats have only one lactiferous duct per nipple. A comprehensive comparison between humans and dogs is given a special focus, as these species share several aspects in terms of breast/mammary cancer epidemiology, such as age of onset, hormonal etiology, risk factors, and the clinical course of the disease. Holistically, it is clear that each species has advantages and limitations that researchers must consider during the development of experimental designs and data analysis.

THE ROLE OF ANTHROPOGENIC DERMATOTOXICANTS IN THE FORMATION OF ACNE IN ADOLESCENTS

Abstract. Against the background of the steady pace of urbanization, the negative impact of anthropogenic toxic substances on human health is increasing every year. The most sensitive to the action of ecotoxicants is the child and adolescent organism. Given the acute reaction of the skin to the influence of toxic chemicals, aggravated by humoral changes in the body during puberty, the identification of criteria for the toxic etiology of acne is certainly relevant.
 The aim of the study was to determine the criteria of the predominantly toxicological mechanism of acne formation.
 To assess the effect of anthropogenic dermatotoxicants on the formation of acne, 595 children and various districts of the Moscow region were examined, of which 301 adolescents suffered from acne, and 294 practically healthy children made up the control group. The study used spectrometric, cytogenetic, biochemical and immunological research methods. The content of essential and toxic trace elements in adolescent hair samples was evaluated. A micronuclear test was performed in buccal epithelial cells. The testosterone level and the immunoregulatory index were evaluated.
 The results obtained in the study indicate at least two mechanisms of the formation of acne vulgaris in adolescents. The first is associated with a violation of the regulation of sex hormones, and the second with the dermatotoxicity of anthropogenic ecotoxicants. Adolescents with predominantly intoxicating etiology were characterized by low concentrations of selenium and zinc, high mercury and lead in hair samples, as well as an increase in the number of micronuclei in the buccal epithelium. Adolescents with predominantly hormonal etiology were characterized by an increase in testosterone levels and a decrease in the immunoregulatory index. At the same time, in adolescents with signs of genetic instability determined by the results of a micronucleus test, the clinical course of acne was significantly more severe than in children without pronounced karyopathology. Based on statistical processing of these data, prognostic algorithms were built to differentiate acne in adolescents by etiological factor.
 Thus, anthropogenic chemical toxicants, represented mainly by heavy metal salts, have an aggravating effect on the formation and course of acne in adolescents.

Mendelian randomization analyses identified bioavailable testosterone mediates the effect of sex hormone-binding globulin on prostate cancer.

A better knowledge of the hormonal etiology of prostate cancer is essential for its prevention and treatment. The goal of this study was to provide causal estimates of the connection between sex hormone-binding globulin and prostate cancer and investigate the possible mediating function of other modifiable risk indicators. We used two-step, two-sample multivariable Mendelian randomization using single-nucleotide polymorphisms as instrumental variables for exposure and mediators. Single-nucleotide polymorphisms associated with sex hormone-binding globulin and bioavailable testosterone were screened via a genome-wide association study enrolling European-descent adult male individuals. Summary-level data for prostate cancer (79,148 cases and 61,106 controls) were extracted from the PRACTICAL consortium. The total effect of sex hormone-binding globulin on prostate cancer risk was decomposed into direct and indirect effects through the mediator, bioavailable testosterone. An inverse-variance-weighted method was the primary Mendelian randomization analysis method. Sensitivity analyses were performed via Mendelian randomization-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out test. The directionality that exposure causes the outcome was verified using Mendelian randomization-Steiger test. In the univariable Mendelian randomization analysis, genetically predicted higher sex hormone-binding globulin levels had a causal association with lower prostate cancer risk (odds ratio = 0.944, 95% confidence interval = 0.897-0.993, p = 0.027) and an inverse association with bioavailable testosterone level (odds ratio = 0.945, 95% confidence interval = 0.926-0.965, p = 1.62E-07) without controlling for other factors. Moreover, an increase of one standard deviation (59.5 pmol/L) in genetically predicted bioavailable testosterone level was significantly associated with a 22.0% increase in the overall prostate cancer risk (odds ratio = 1.220, 95% confidence interval = 1.064-1.398, p = 0.004) after adjusting for sex hormone-binding globulin level. The effect size ratio of bioavailable testosterone-mediated sex hormone-binding globulin to prostate cancer was further analyzed to clarify the importance of the mediating effect. Notably, the mediator bioavailable testosterone explained 19.28% (95% confidence interval = 10.76%, 73.78%) of the total effect of sex hormone-binding globulin level on prostate cancer risk. The results support the potentially protective causal effect of genetically predicted higher sex hormone-binding globulin levels against prostate cancer with mediation by the modifiable risk factor, bioavailable testosterone. More research is needed to determine how this possible sex hormone-binding globulin-bioavailable testosterone-prostate cancer link works. Targeting sex hormone-binding globulin and bioavailable testosterone traits may be a valuable strategy for preventing prostate cancer.

Cyclic Thrombocytopenia: A Case Report

Introduction Cyclic thrombocytopenia (CTP) is a rare disorder characterized by episodes of oscillating platelet counts. It is usually associated with another primary hematologic disorder but there are idiopathic cases in the literature. Patients with CTP have similar clinical features and symptoms with idiopathic thrombocytopenic purpura (ITP), so they are often misdiagnosed as ITP and treated accordingly. In general, CTP does not respond to ITP therapies, so it should always be considered when treatments are not effective. It is more common in females. However, in our case report we present a 93-year-old male with CTP who was initially mistaken for ITP. Case description A 93-year-old male patient with a past medical history of hypertension was initially thought to have idiopathic thrombocytopenia (ITP) presenting with mucosal gum bleeding and a petechial rash. He was found to have isolated thrombocytopenia, and no evidence of other cytopenias. He did trials of multiple medications such as corticosteroids and intravenous immunoglobulin (IVIG) with no response. He was not a surgical candidate for splenectomy. He also deferred a bone marrow biopsy, though peripheral blood testing with flow cytometry showed a small monoclonal B cell population. Peripheral blood myeloid sequencing panel showing ASXL1 and EZH2. He was started on Eltrombopag, a thrombopoietin (TPO) agonist with significant lability in the platelet count, from 8,000 per microliter (mcL) to over 1,000,000 per mcL. Romiplostim, another TPO agonist also gave similar results. A diagnosis of cyclic thrombocytopenia was suspected. A Helicobacter pylori antibody was positive, and treated with antibiotics with no improvement in platelet count oscillations. Thyroid function was within normal limits. T-cell gene rearrangement was negative. Thrombopoetin (TPO) levels were checked and these were found to be in discordance with the platelet count, consistent with a CTP diagnosis. He was started on cyclosporine 150 milligrams twice daily with significant improvement in fluctuations of platelet counts. Discussion Cyclic hematopoietic disorders are rare and have regular predictable oscillations of one or more cellular components of the blood. Physiologically, there is a complex interplay between thrombopoietic stimulation and feedback inhibition in order to maintain the circulating platelets within the normal range. An error in any of these steps results in oscillation of the platelet counts (cyclic thrombocytopenia). Many mechanisms are behind the pathophysiology of this disease, such as: autoimmune destruction of platelets, hypoplasia of megakaryocytes, a defect in regulating platelet formation and an infectious or hormonal etiology. There are many reports linking T-lymphocytes proliferation and clonal TCR gene rearrangement to cyclic thrombocytopenia. We noticed in the literature that there can be variable responses to TPO agonists, but often can result in very high platelet counts. Due to its rarity, there are only case reports which show reports of remission after hormone therapy with danazol and immune suppressant therapies, such as cyclosporine. Further studies are needed to determine the mechanism responsible for cycling phenomena and optimal treatments for this disorder. In conclusion, any presumed ITP case that does not respond well to the standard therapy of ITP should be reevaluated for the possibility of cyclic thrombocytopenia.

Could Hormone Levels Impact the Severity of Clitoral Phimosis?

ABSTRACT Introduction Clitoral adhesions (CA) occur when the prepuce adheres to the glans clitoris. CA can be classified as mild, moderate, or severe, based on if more than 75%, 25% to 75%, or less than 25% of the glans clitoris is exposed. Symptoms of CA include pain, difficulty with arousal, and muted or absent orgasm. There is a paucity of information on how hormone levels may contribute to the formation of CA. We hypothesize that patients with lower levels of free and total testosterone, and higher levels of the blood transport protein sex hormone binding globulin (SHBG) could have more severe adhesions. Higher free and total testosterone can yield more oily skin, which may break up or prevent adhesions. Additionally, with higher SHBG, there is less free testosterone available to be used by tissues in the body. Objective To determine if patients with lower free and total testosterone, and higher SHBG have more severe adhesions. Methods Charts of females with CA who underwent the non-surgical lysis procedure at one sexual medicine practice were considered for this study. 24 charts contained information on the severity of phimosis before lysis, total and free testosterone levels, as well as SHBG levels around the time of lysis. The study group consisted of patients with mild (n=9), moderate (n=8), or severe (n=7) CA. Results The average calculated free testosterone among patients with mild, moderate, and severe CA was 0.23ng/dL, 0.35ng/dL, and 0.14ng/dL. The average total testosterone among patients with mild, moderate, and severe CA was 24.79ng/dL, 27.81ng/dL, and 20.26ng/dL. The average SHBG among patients with mild, moderate, and severe CA was 98.69nmol/L, 95.76nmol/L, and 109.40nmol/L. Conclusions We predicted that patients with more severe adhesions would have lower levels of free and total testosterone, as well as higher levels of SHBG, yet this trend did not appear overall in this data among patients with mild, moderate, or severe adhesions. Additional studies with larger sample sizes are needed to explore the potential impact of free and total testosterone, as well as SHBG levels on the development and severity of CA. Studies could also compare levels of these hormones in patients with and without adhesions, or consider patients with recurrence of adhesions. Insight into a hormonal etiology could be important to patients with altered levels of these hormones - for example, patients with medical conditions such as PCOS, patients taking medications such as oral contraceptive pills, and menopausal women on oral estrogen (as increased estrogen raises levels of SHBG) could be at an increased risk for developing CA. Further studies could also consider if the clitoides of transgender males on gender-affirming hormone therapy with testosterone have lower incidences of CA. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout (Raleigh, NC), Absorption Pharmaceuticals

New Developments in Topical Acne Therapy.

Acne vulgaris is a common chronic inflammatory disease with a multifactorial pathogenesis. Although myriad acne treatments are available, current options may not be sufficient because of a lack of efficacy, limited tolerability, or burden of cost to patients. In this review, we highlight recently approved topical acne treatments, as well as those currently in clinical trials. Novel formulations of tretinoin, tazarotene, and minocycline provide modifications of and improvements to existing products. Trifarotene, a novel fourth-generation retinoid, has demonstrated improved tolerability compared with existing topical retinoids. Clascoterone is a novel first-in-class antiandrogen that topically addresses the hormonal etiology of acne. The late-phase clinical trials pipeline consists of agents with bactericidal and anti-sebum mechanisms. Although it is evident that acne treatments continue to evolve, it is important to recognize the need for further comparative studies among new and existing agents to define optimal treatment algorithms that address not only safety and efficacy but also cost-effective care.

Severe tricuspid regurgitation as first manifestation of a primary ovarian carcinoid tumor

A 52-year-old woman presented with a 1 year-history of reduced exercise tolerance and fatigue. Physical examination revealed a grade II/VI systolic murmur at the left sternal border. Transthoracic echocardiography showed thickened tricuspid leaflets with retraction and restricted movement, resulting in a severe tricuspid regurgitation. The characteristic pattern aroused the suspicion of a systemic or hormonal etiology. 24-Hour urine analysis revealed an increased level of 5hydroxyindoleacetic acid and abdominal computed tomography (CT) showed a large tumor in the pelvis; however, without the presence of liver metastasis. During uncomplicated trans-abdominal surgery a large mass in the ovary was removed, and pathology showed a primary ovarian carcinoid tumor. One year after the diagnosis, patient remains clinically stable without signs of right heart failure and an excellent exercise tolerance. This case report shows that isolated tricuspid valve pathology in the absence of left valvular disease may raise the suspicion for an atypical cause of valvular dysfunction, in which carcinoid tumor is included.

Association of Endogenous Pregnenolone, Progesterone, and Related Metabolites with Risk of Endometrial and Ovarian Cancers in Postmenopausal Women: The B∼FIT Cohort.

Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01]. Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the\xa0UK Biobank

BackgroundIntrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.MethodsWe harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980–1998 and 2006–2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).ResultsHysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27–3.09), compared to women aged 50–54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03–2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.ConclusionsThis study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

Pseudoangiomatous Stromal Hyperplasia (PASH) of the Breast: An Uncommon Finding in an Uncommon Patient

Patient: Female, 30-year-oldFinal Diagnosis: Pseudoangiomatous stromal hyperplasia (PASH)Symptoms: Breast massMedication: —Clinical Procedure: LumpectomySpecialty: Obstetrics and GynecologyObjective:Unknown ethiologyBackground:Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon benign breast lesion.Case Report:PASH is reported in a young female in treatment for neurological diseases with multi-drug therapy (clonazepam, valproate and risperidone). Her menstrual cycles are irregular, and she reached menarche very late.Conclusions:The higher PASH prevalence in premenopausal woman (the majority of whom are actively taking oral contraceptive pills), in 24% to 47% of men with gynecomastia and during pregnancy supports a hormonal etiology; the interaction between clonazepam, valproate, risperidone and progesterone could increase the level of progesterone that could stimulate PASH growth.

Clinical status of reproductive aged women with combined pathology of the uterus – leiomyoma and adenomyosis

Clinical assessment of the general status of patients with combined uterine pathology (leiomyoma (LM) and adenomyosis) has a practical importance for determining specific therapeutic tactics. The study of the general condition of reproductive aged women with this pathology allows determining of many factors that can affect the clinical course of disease.Purpose of the study was to investigate the clinical status of reproductive aged women who suffer from combined uterine pathology – LM and adenomyosis.Materials and methods. 120 women of reproductive age were examined. Group IA united 60 patients with combined uterine pathology – asymptomatic LM and nodal, diffuse, diffuse-focal adenomyosis III, IV degrees of severity with active clinical course; group IB united 60 patients with combined uterine pathology - symptomatic LM and diffuse, diffuse focal adenomyosis I, II degrees of severity with inactive clinical course. Examination was carried out in accordance with the orders of the Ministry of Health of Ukraine.Results. A study of the general status of reproductive aged women has revealed many factors that can affect the clinical course of disease. The study of nosological forms of extragenital pathology revealed a wide range of different organs and systems diseases, co-morbidities of mainly chronic course, varying severity in 100% of women. A number of somatic diseases can be both a cause and a consequence of gynecological pathology, especially hormonal etiology. Analysis of the anamnestic data on the transferred gynecological diseases showed 100% frequency of the combined and concomitant pathology of the female genital tract.Conclusions. Completed study involving reproductive aged women with combined uterine pathology (LM and adenomyosis) showed many factors that can affect the clinical course of disease. Obtained data indicate that there are complex metabolic disorders in the women’s body suffering from that combined uterine pathology.

Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women's Health Initiative Observational Study.

Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users. We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype. Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT). These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.

Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study.

Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC-MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68-11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47-8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer.

Other Primary Malignancies Among Women With Adult-Type Ovarian Granulosa Cell Tumors.

The aim of this study was to determine the incidence of new primary malignancies after adult-type granulosa cell tumor (AGCT) and the incidence of AGCT after breast and uterine cancer using nationwide population-based registry data. We used the Finnish Cancer Registry to identify all patients diagnosed with AGCT in 1968 to 2013 (n = 986). The number of subsequent primary malignancies among women with AGCT and the number of AGCTs in women with previous breast or uterine cancer were compared with the expected number of cases and expressed as standardized incidence ratios (SIRs). There were 122 cases of subsequent cancers diagnosed at least 6 months after the primary diagnosis of AGCT (SIR, 1.09; 95% confidence interval [CI], 0.91-1.3). In particular, the observed number of cancers of the soft tissue (SIR, 4.13; 95% CI, 1.33-12.8), thyroid (SIR, 3.42; 95% CI, 1.54-7.62), and leukemia (SIR, 2.67; 95% CI, 0.98-5.82) exceeded the number of expected cases. The SIR for breast cancers after AGCT was 1.26 (95% CI, 0.92-1.73), and the SIR for AGCT after breast cancer was 1.59 (95% CI, 1.04-2.29). The risk for subsequent AGCT was more than 2-fold in breast cancer patients younger than 50 years, and over 15 years after primary diagnosis. There is an increased risk for thyroid and soft tissue cancer as well as leukemia after AGCT, which may be associated with late effects of carcinogenic treatments and possibly shared risk factors. After breast cancer, the risk for AGCT was higher, which may indicate a shared hormonal etiology.

Abstract 2206: A new sensitive, accurate liquid chromatography-tandem mass spectrometry (LC-MS-MS) method to measure circulating estrogens, androgens, and progesterone in postmenopausal and premenopausal women

Abstract Endogenous steroid hormones play a critical role in the etiology of breast cancer. However, the interrelationships among estrogens, androgens, and progesterone in determining risk are not well understood. Relative strengths of associations, independent and joint effects, differential effects for tumor subtypes, and effect modification by lifestyle and genetic profile remain unclear. A major reason is the limited accuracy, specificity, and sensitivity of many steroid hormone assays, especially at the low circulating hormone concentrations characteristic of postmenopausal women. CDC developed a new sensitive, accurate isotope dilution LC-MS/MS method capable of measuring eight important steroid hormones in 200 µL of female serum. The method uses sequential liquid-liquid extractions for isolation of estradiol (E2), estrone (E1), estrone sulfate (E1S), testosterone (TT), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), progesterone (P), and 17-hydroxyprogesterone (17-OHP) without derivatization or hydrolysis. Chromatographic separation of the steroids is carried out using a phenyl-hexyl HPLC column and a gradient of methanol and methanol:water. Scheduled selected reaction monitoring by electrospray ionization in the positive and negative ion modes is applied to quantify the analytes. Two mass transitions, each specific to the fragmentation of the analyte, are monitored for each analyte: quantitation ion (QI) and confirmation ion (CI). The QI to CI ratios are used as criteria to identify possible interferences. The method is able to measure each steroid in nearly all postmenopausal women as well as premenopausal women. Limits of detection in serum-based materials are: E2 1.72 pg/mL, E1 0.13 ng/dL, E1S 2.04 pg/mL, TT 0.57 ng/dL, A 0.82 ng/dL, DHEAS 0.22 µg/dL, P 0.86 ng/dL, and 17-OHP 0.41 ng/dL. Precision, expressed as coefficients of variation and evaluated at three levels for each analyte, ranged from 1.2 to 9.9%. Average bias, a measure of accuracy, ranged from -0.3 to 8.8%. The method is certified through the CDC Hormone Standardization Program for estradiol and testosterone and meets the requirements of the College of American Pathologists Proficiency Testing Program for androgens and progesterone. This new, highly specific and sensitive method demonstrates high accuracy and precision while requiring small amounts of specimens. It can assay up to 140 samples at once. Thus, the method is suitable for large epidemiologic studies investigating the hormonal etiology of breast, endometrial, and ovarian cancer. Citation Format: Lumi Duke, Paul H. Kim, Julianne Cook Botelho, Regina G. Ziegler, Hubert Vesper. A new sensitive, accurate liquid chromatography-tandem mass spectrometry (LC-MS-MS) method to measure circulating estrogens, androgens, and progesterone in postmenopausal and premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2206.

Canine mammary tumors as a model for human disease.

Animal models for examining human breast cancer (HBC) carcinogenesis have been extensively studied and proposed. With the recent advent of immunotherapy, significant attention has been focused on the dog as a model for human cancer. Dogs develop mammary tumors and other cancer types spontaneously with an intact immune system, which exhibit a number of clinical and molecular similarities to HBC. In addition to the spontaneous tumor presentation, the clinical similarities between human and canine mammary tumors (CMT) include the age at onset, hormonal etiology and course of the diseases. Furthermore, factors that affect the disease outcome, including tumor size, stage and lymph node invasion, are similar in HBC and CMT. Similarly, the molecular characteristics of steroid receptor, epidermal growth factor, proliferation marker, metalloproteinase and cyclooxygenase expression, and the mutation of the p53 tumor suppressor gene in CMT, mimic HBC. Furthermore, ductal carcinomas in situ in human and canine mammary glands are particularly similar in their pathological, molecular and visual characteristics. These CMT characteristics and their similarities to HBC indicate that the dog could be an excellent model for the study of human disease. These similarities are discussed in detail in the present review, and are compared with the in vitro and other in vivo animal models available.

The role of pregnancy, perinatal factors and hormones in maternal cancer risk: a review of the evidence

An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence foetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial and possibly pancreatic cancer, whilst the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer, and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal aetiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age-dependent increase in the incidence of most malignancies, is expected to affect the incidence of pregnancy-associated cancer.

Autoimmune diseases and breast cancer risk by tumor hormone-receptor status among elderly women.

The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Little research exists on systemic and organ-specific autoimmune diseases and risk of breast cancer by tumor estrogen receptor (ER)- and progesterone receptor (PR)- status. Here, we evaluate associations between selected systemic and organ-specific autoimmune diseases and breast cancer risk overall and by tumor ER- and PR-status. We used linked Surveillance, Epidemiology and End Results (SEER)-Medicare data, with first female breast cancer cases ages ≥66 years identified by SEER registries (years 1992-2011; N = 209,929). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients who were alive and breast cancer-free. We assessed exposures until 12 months before breast cancer diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional and multinomial logistic regression. We found reduced breast cancer risk among those with rheumatoid arthritis (OR = 0.84; 99.9% CI 0.79-0.89), systemic lupus erythematosus (OR = 0.82; 99.9% CI 0.70-0.97) and pernicious anemia (OR = 0.90; 99.9% CI 0.83-0.97) and increased risk among those with psoriasis (OR = 1.16; 99.9% CI 1.06-1.27). Statistically significant alterations in risk for rheumatoid arthritis were limited to ER-positive (+) breast cancer, whereas those for the other three conditions were further limited to ER+/PR+ breast cancer. However, only differences for rheumatoid arthritis by ER-status were statistically significant (p-heterogeneity = 0.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment.

Criminological approach of aggressive conduct and its hormonal etiology

Hormones are chemicals substances produced by glands, are secreted into the bloodstream and move throughout the body influencing human behavior. Thanks to the study of physiological and pathophysiological mechanisms, identified the behavioral effects of the testosterone hormone, cortisol, norepinephrine and serotonin. Recent studies have also demonstrated the importance of vasopressin, dopamine, insulin, thyroid hormone and nitric oxide. These scientific contributions identified the importance of medical research on the causal explanation of aggressive behavior of the human being, within the integral and multidisciplinary approach of contemporary Criminology.