Publications by authors named "Richard Santen"

115 Publications

Approach to Managing a Postmenopausal Patient.

J Clin Endocrinol Metab 2020 12;105(12)

University of California San Diego, School of Medicine, Division of Endocrinology and Metabolism, La Jolla, California.

Case And Principles Of Management: The case of a symptomatic, postmenopausal woman is presented and a full discussion of the approach to her management is discussed. Pertinent guidelines and scientific evidence are emphasized as support for the recommendations.
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http://dx.doi.org/10.1210/clinem/dgaa623DOI Listing
December 2020

WITHDRAWN - Administrative Duplicate Publication: Risks and benefits of hormone replacement therapy before and after a breast cancer diagnosis.

Post Reprod Health 2020 Jul 23:2053369120934026. Epub 2020 Jul 23.

Department of Endocrinology and Metabolism, University of Virginia, VA, USA.

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http://dx.doi.org/10.1177/2053369120934026DOI Listing
July 2020

Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois.

Menopause 2020 06;27(6):614-624

George Washington University, Women's Health and Research Consultants, Washington, DC.

The North American Menopause Society (NAMS) organized the Workshop on Normal Ranges for Estradiol in Postmenopausal Women from September 23 to 24, 2019, in Chicago, Illinois. The aim of the workshop was to review existing analytical methodologies for measuring estradiol in postmenopausal women and to assess existing data and study cohorts of postmenopausal women for their suitability to establish normal postmenopausal ranges. The anticipated outcome of the workshop was to develop recommendations for establishing normal ranges generated with a standardized and certified assay that could be adopted by clinical and research communities. The attendees determined that the term reference range was a better descriptor than normal range for estradiol measurements in postmenopausal women. Twenty-eight speakers presented during the workshop.
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http://dx.doi.org/10.1097/GME.0000000000001556DOI Listing
June 2020

In Memoriam: C. Wayne Bardin, MD (1934 - 2019).

Andrology 2020 Mar;8(2):264-265

University Pierre et Marie Curie, Paris, France.

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http://dx.doi.org/10.1111/andr.12738DOI Listing
March 2020

Underlying Breast Cancer Risk and Menopausal Hormone Therapy.

J Clin Endocrinol Metab 2020 06;105(6)

University of California San Diego, School of Medicine, Division of Endocrinology and Metabolism, La Jolla, California.

The recent Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) publication calculated the attributable risk of breast cancer from use of estrogen alone and estrogen plus a synthetic progestogen for less than 5 to 15 or more years of use. This CGHFB report calculated attributable risk based on their findings of relative risk from pooled data from 58 studies. Notably, neither the CGHFBC nor other previous studies have examined the effect of underlying risk of breast cancer on attributable risk. This omission prompted us to determine the magnitude of the effect of underlying risk on attributable risk in this perspective. Meaningful communication of the potential risk of menopausal hormonal therapy requires providing women with the estimated risk above their existing underlying risk (ie, attributable risk). Therefore, we have estimated attributable risks from the data published by the CGHFBC, taking into account varying degrees of underlying risk. Based on the Endocrine Society Guideline on Menopausal Hormone Therapy (MHT), we divided groups into 3 categories of risk: low (1.5%), intermediate (3.0%), and high (6.0%) underlying risk of breast cancer over 5 years. In women taking estrogen plus a synthetic progestogen for 5 to 9 years, the attributable risks of MHT increased from 12, to 42, to 85 additional women per 1000 in the low-, intermediate-, and high-risk groups, respectively. The attributable risks for estrogen alone were lower but also increased based on underlying risk. Notably, the attributable risks were amplified with duration of MHT use, which increased both relative risk and breast cancer incidence.
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http://dx.doi.org/10.1210/clinem/dgaa073DOI Listing
June 2020

Systemic estradiol levels with low-dose vaginal estrogens.

Menopause 2020 03;27(3):361-370

EndoRheum Consultants, LLC, Malvern, PA.

Objectives: To critically evaluate published systemic estradiol levels during use of low-dose vaginal estrogens considering detection method and estrogen dose; describe challenges with accurately measuring estradiol; and determine the normal estradiol level range in postmenopausal women.

Methods: PubMed was searched for studies reporting systemic estradiol levels with lower-dose vaginal estrogens (≤25 μg estradiol or 0.3 mg conjugated equine estrogens). Estradiol levels at baseline and during treatment, area under the curve, and maximum estradiol concentrations were summarized by dose within assay type. A proposed range of systemic estradiol in normal, untreated, postmenopausal women was estimated by conservatively pooling means and standard deviations from published studies.

Results: Mean basal estradiol levels were 3.1 to 4.9 pg/mL using liquid or gas chromatography/mass spectroscopy (LC or GC/MS/MS) with a range of undetectable to 10.5 pg/mL using radioimmunoassay. Systemic estradiol levels with vaginal estrogens reflected their doses as measured with LC or GC/MS/MS in different studies: 7.1 to 9.1 pg/mL and 16.7 to 22.7 pg/mL with a 25-μg softgel capsule insert and a tablet insert, respectively; 4.6 to 7.4 pg/mL and 6.6 to 14.8 pg/mL with a 10-μg softgel capsule and a tablet insert, respectively; and 3.6 to 3.9 pg/mL with a 4-μg softgel capsule insert. A mean systemic estradiol concentration ranging from undetectable to 10.7 pg/mL is proposed as an estimate for basal estradiol levels in normal, untreated, postmenopausal women. Systemic estradiol absorption may be influenced by the placement of estradiol higher (as with an applicator) versus lower (as without an applicator) in the vagina, as estradiol transport to the uterus would be more likely further away than closer to the introitus.

Conclusion: Serum estradiol concentrations were generally lower when measured with more specific and sensitive assays. Estradiol absorption was dose-dependent, and may be influenced by dose, formulation, and positioning in the vagina. Very low systemic estradiol absorption with low/ultralow-dose vaginal estrogens may potentially decrease any adverse events that may be associated with higher doses of vaginal estrogens used for treating moderate to severe VVA due to less estradiol exposure.
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http://dx.doi.org/10.1097/GME.0000000000001463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050796PMC
March 2020

"Re-booting" after retirement: Novel approach using telemedicine to solve the work-force gap in diabetes management.

Authors:
Richard J Santen

Maturitas 2020 03 7;133:68-69. Epub 2019 Oct 7.

The Endocrine Society, The University of Virginia, Charlottesville, VA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.maturitas.2019.10.001DOI Listing
March 2020

Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells.

Breast Cancer (Auckl) 2019 15;13:1178223419844198. Epub 2019 May 15.

Department of Medicine, Division of Endocrinology & Metabolism, University of Virginia Health Systems, Charlottesville, VA, USA.

Purpose: Postmenopausal women with estrogen receptor-positive breast cancers often respond initially to tamoxifen or aromatase inhibitor therapy. Resistance to these treatments usually develops within 12 to 18 months. Clinical studies have demonstrated that high-dose estrogen can induce regression of these endocrine-resistant tumors. However, side-effects of high-dose estradiol (E) or diethylstilbestrol (DES) limit their usage. Estetrol (E) is the most abundant estrogen during pregnancy and has a long half-life and a low potential for side-effects. Estetrol might then provide benefits similar to DES on tumor regression but with lesser toxicity.

Methods: In this study, we systematically evaluated the effects of E on cell proliferation and apoptosis in wild-type MCF-7 and long-term estrogen-deprived (LTED) MCF-7 cells and compared its effects with E and estriol (E).

Results: Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10 to 10 M. These effects of E are similar to those of E but require much higher doses. Differing from E, E at 10 M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E, acted similarly. No antagonistic effect of E or E against E occurred when they were combined.

Conclusions: The pro-apoptotic effects of E and E on LTED cells and at low doses on MCF-7 cells indicate that these steroids could be used as therapeutic agents for endocrine-resistant or sensitive breast cancer.
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http://dx.doi.org/10.1177/1178223419844198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535901PMC
May 2019

Pituitary as a Source of HCG: Residual Levels After Bilateral Testicular Tumor Removal.

J Investig Med High Impact Case Rep 2019 Jan-Dec;7:2324709619841414

2 Memorial Sloan Kettering Cancer Center, Cornell-Weil School of Medicine, New York, NY, USA.

Context: Challenging clinical scenario in which elevated β-human chorionic gonadotropin (HCG, subsequently termed HCG) levels suggested occult tumor metastases after removal of bilateral testicular cancers and metastases from them and as well as after chemotherapy.

Case Report: A 22-year-old male, post excision of bilateral testicular tumors, who had no imaging or clinical evidence of residual tumor but an elevated HCG raising the question of the presence and location of occult tumor metastases. Clinical Questions. Does luteinizing hormone (LH) cross-react with HCG in current assays? What levels of testosterone and estradiol are necessary to suppress LH and follicle-stimulating hormone (FSH) in a male patient with bilateral orchiectomy, and therefore lacking inhibin? Does the pituitary secrete HCG and under what circumstances?

Assessment: Current HCG assays no longer cross-react with LH as did prior assays, but the presence of heterophile antibodies and other factors such as biotin can still cause false positive HCG levels. In the chronic post-orchiectomy state, the pituitary is relatively resistant to LH and FSH suppression by testosterone. The pituitary secretes HCG in very small amounts unless interruption of negative feedback results in high LH and FSH whereupon HCG levels become elevated. Clinical Conclusion. A GnRH antagonist suppressed both LH and HCG in this patient indicating that the elevated HCG was secreted by the pituitary and not by occult tumor metastases. Further credence for this conclusion resulted from the lack of a progressive increase in HCG levels over a 4-year period of follow-up and from no evidence of metastatic tumors on serial imaging.
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http://dx.doi.org/10.1177/2324709619841414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480980PMC
June 2020

History of Estrogen: Its Purification, Structure, Synthesis, Biologic Actions, and Clinical Implications.

Endocrinology 2019 03;160(3):605-625

Hudson Institute of Medical Research, Clayton, Victoria, Australia.

This mini-review summarizes key points from the Clark Sawin Memorial Lecture on the History of Estrogen delivered at Endo 2018 and focuses on the rationales and motivation leading to various discoveries and their clinical applications. During the classical period of antiquity, incisive clinical observations uncovered important findings; however, extensive anatomical dissections to solidify proof were generally lacking. Initiation of the experimental approach followed later, influenced by Claude Bernard's treatise "An Introduction to the Study of Experimental Medicine." With this approach, investigators began to explore the function of the ovaries and their "internal secretions" and, after intensive investigations for several years, purified various estrogens. Clinical therapies for hot flashes, osteoporosis, and dysmenorrhea were quickly developed and, later, methods of hormonal contraception. Sophisticated biochemical methods revealed the mechanisms of estrogen synthesis through the enzyme aromatase and, after discovery of the estrogen receptors, their specific biologic actions. Molecular techniques facilitated understanding of the specific transcriptional and translational events requiring estrogen. This body of knowledge led to methods to prevent and treat hormone-dependent neoplasms as well as a variety of other estrogen-related conditions. More recently, the role of estrogen in men was uncovered by prismatic examples of estrogen deficiency in male patients and by knockout of the estrogen receptor and aromatase in animals. As studies became more extensive, the effects of estrogen on nearly every organ were described. We conclude that the history of estrogen illustrates the role of intellectual reasoning, motivation, and serendipity in advancing knowledge about this important sex steroid.
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http://dx.doi.org/10.1210/en.2018-00529DOI Listing
March 2019

Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome.

Clin Endocrinol (Oxf) 2019 01 25;90(1):155-161. Epub 2018 Oct 25.

Penn SRP Center and Center for Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.

Objective: The established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. We aimed to assess whether the route of administration of 17β oestradiol (E ) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome.

Methods: Stored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison.

Results: After treatment, least square mean (SE) total E concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E ) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E (149 vs 28 [±49] pmol/L), 2-hydroxy-E (300 vs 76 [±52]), 4-hydroxy-E (450 vs 105 [±113]), 2-hydroxy-E (3094 vs 740 [±684]) and 16α-hydroxy-E (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group.

Conclusions: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens' first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed.
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http://dx.doi.org/10.1111/cen.13869DOI Listing
January 2019

Glucocorticoid Receptor Mutations and Hypersensitivity to Endogenous and Exogenous Glucocorticoids.

J Clin Endocrinol Metab 2018 10;103(10):3630-3639

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.

Background: The glucocorticoid receptor (GR) consists of two alternatively spliced isoforms: GRα, which activates gene transcription, and GRβ, a dominant-negative receptor. Theoretically, inactivating variants of GRβ could result in glucocorticoid hypersensitivity.

Design: A 46-year-old woman presented for evaluation of adrenal insufficiency prompted by low plasma cortisol levels and multiple unexplained symptoms but without clinical evidence of glucocorticoid insufficiency. To explain these findings, extensive clinical, genetic, and molecular studies were performed.

Methods: Standard clinical methods assessed the patient's hypothalamic-pituitary-adrenal axis. Validated molecular techniques were used for receptor sequencing, stable transfections, stimulation of candidate genes, cDNA arrays, Ingenuity Pathway Analysis, volcano analysis, and isolation and analysis of the patient's mononuclear cells.

Results: Clinical studies excluded primary or secondary adrenal insufficiency, established consistently low basal cortisol levels, and demonstrated hypersensitivity to ultra-low-dose dexamethasone. Receptor sequencing identified two variants of GR9β (A3669G and G3134T) as well as the known Bcl1 polymorphism. Reductionist studies using stable osteosarcoma cell lines transfected with the GRβ variants demonstrated glucocorticoid hypersensitivity of transcribed genes on cDNA array analysis. The patient's monocytes responded to hydrocortisone with exaggerated stimulation of the candidate genes GILZ and FKBP5.

Conclusion: Two variants of the dominant-negative GRβ, in conjunction with a common Bcl1 intron variant, resulted in hypersensitivity to endogenous and exogenous glucocorticoids and, as a reflection of severity, low circulating cortisol levels without clinical evidence of glucocorticoid insufficiency. This prismatic case exemplifies the unique effects of variants of a dominant-negative receptor.
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http://dx.doi.org/10.1210/jc.2018-00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179182PMC
October 2018

Effect of a tissue selective estrogen complex on breast cancer: Role of unique properties of conjugated equine estrogen.

Int J Cancer 2018 09 16;143(5):1259-1268. Epub 2018 Apr 16.

Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health Systems, Charlottesville, VA.

The Women's Health Initiative studies reported that the menopausal hormone therapy (MHT) regimen containing conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased, whereas CEE alone reduced breast cancer incidence. These observations suggest the possibility that CEE might exert unique actions on breast and also suggest the need to eliminate the progestogen from MHT regimens. A MHT regimen called a tissue selective estrogen complex (TSEC), containing CEE plus bazedoxifene (BZA), to avoid the need for a progestogen, was developed and FDA approved. Our study addressed two questions regarding this TSEC: (i) whether CEE exert effects on breast cancer which differ from those of estradiol (E ) and (ii) whether BZA antagonize the effects of E and CEE on breast cancer? Two rodent models (NMU and ACI) were used to compare the effect of CEE with E on mammary tumor formation, proliferation and apoptosis. In both the NMU and ACI models, E significantly increased tumor incidence and multiplicity whereas in striking contrast CEE did not, even though the estrogenic effects of CEE and E on uterine weight were identical. Mechanistically E blocked whereas CEE stimulated apoptosis (cleaved caspase-3) in ACI animals and only E stimulated proliferation (Ki67). BZA exerted highly potent anti-estrogenic effects on tumors by completely blocking palpable tumor formation. These data suggest that the CEE/BZA TSEC may be a safer, breast-antagonistic, MHT agent for women and might have potential to prevent breast cancer while relieving menopausal symptoms.
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http://dx.doi.org/10.1002/ijc.31401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377943PMC
September 2018

Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations.

J Clin Endocrinol Metab 2018 05;103(5):1790-1803

Nemours Children's Health System, Jacksonville, Florida.

Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied.

Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty.

Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement.

Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.
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http://dx.doi.org/10.1210/jc.2017-02183DOI Listing
May 2018

The Jewel in the Crown: Specific Aims Section of Investigator-Initiated Grant Proposals.

J Endocr Soc 2017 Sep 17;1(9):1194-1202. Epub 2017 Aug 17.

Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.

The specific aims section of National Institutes of Health and other grants is the most important component, as it summarizes the scientific premise, gap in current knowledge, hypotheses, methods, and expected results of the project proposed. The reviewer usually reads this section first and forms an immediate opinion, usually confirmed on reading the entire grant. This treatise reviews the philosophical background underlying generation of hypotheses, emphasizes the important characteristics of the specific aims section, and offers a point-by-point roadmap for writing. This perspective arose out of a new Endocrine Society initiative in which senior investigators review the specific aims of next-generation members.
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http://dx.doi.org/10.1210/js.2017-00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686640PMC
September 2017

Managing Menopausal Symptoms and Associated Clinical Issues in Breast Cancer Survivors.

J Clin Endocrinol Metab 2017 10;102(10):3647-3661

Department of Medicine, Dentistry and Nursing, University of Glasgow School of Medicine, Glasgow G31 2ER, Scotland.

Objective: Review evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly.

Evidence: Randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies.

Background: Symptoms and clinical problems associated with estrogen depletion-sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis-confront the estimated 9.3 million breast cancer survivors globally.

Recommendations: Following breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind-brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol.

Conclusions: Nonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential.
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http://dx.doi.org/10.1210/jc.2017-01138DOI Listing
October 2017

Use of cardiovascular age for assessing risks and benefits of menopausal hormone therapy.

Authors:
Richard J Santen

Menopause 2017 05;24(5):589-595

Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Virginia Health Sciences System, Charlottesville, VA.

The Women's Health Initiative studies and others have suggested that menopausal hormone therapy may enhance the risk of new cardiovascular (CV) events in older women and diminish the development of coronary atherosclerosis in younger women. The underlying mechanisms to explain these findings are encapsulated in the term "Timing Hypothesis." Extensive pathophysiologic studies have provided mechanistic evidence for the dichotomous effects of estrogen on coronary artery vasculature. Early in the atherosclerotic disease process, estrogen exerts protective effects on the endothelium and retards plaque formation. Late in the process, estrogen causes plaque erosion or rupture with subsequent thrombosis and acute coronary events. Analysis of the Timing Hypothesis in women examined in the Women's Health Initiative primarily used chronologic age to assess divergent effects of estrogen. The complexity of the data underlying coronary pathophysiology has resulted in controversy whether MHT can be used in older women or those with prior CV disease. In a debate of this issue at a recent International Menopause Society meeting, the concept of using CV age rather than chronologic age was discussed as a practical method of resolving this issue and facilitating therapeutic decisions in older women. This "Personal Perspective" will review the concepts underlying CV age, describe how it is determined, provide support for its utility, and propose future studies using this parameter.
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http://dx.doi.org/10.1097/GME.0000000000000847DOI Listing
May 2017

Career Advancement: Meeting the Challenges Confronting the Next Generation of Endocrinologists and Endocrine Researchers.

J Clin Endocrinol Metab 2016 12 3;101(12):4512-4520. Epub 2016 Oct 3.

Division of Endocrinology and Metabolism (R.J.S.), University of Virginia Health Sciences System, Charlottesville, Virginia 22908; Monash Centre for Health Research and Implementation (A.J., M.G.-H., H.T.), School of Public Health and Preventive Medicine, and Department of Medicine (P.R.E.), School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia; Department of Medicine (L.F.), Divisions of Endocrinology, Metabolism, and Diabetes and Bioinformatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Medicine (K.R.V.), Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.

Context: Challenges and opportunities face the next generation (Next-Gen) of endocrine researchers and clinicians, the lifeblood of the field of endocrinology for the future. A symposium jointly sponsored by The Endocrine Society and the Endocrine Society of Australia was convened to discuss approaches to addressing the present and future Next-Gen needs.

Evidence Acquisition: Data collection by literature review, assessment of previously completed questionnaires, commissioning of a new questionnaire, and summarization of symposium discussions were studied.

Evidence Synthesis: Next-Gen endocrine researchers face diminishing grant funding in inflation-adjusted terms. The average age of individuals being awarded their first independent investigator funding has increased to age 45 years. For clinicians, a workforce gap exists between endocrinologists needed and those currently trained. Clinicians in practice are increasingly becoming employees of integrated hospital systems, resulting in greater time spent on nonclinical issues. Workforce data and published reviews identify challenges specifically related to early career women in endocrinology. Strategies to Address Issues: Recommendations encompassed the areas of grant support for research, mentoring, education, templates for career development, specific programs for Next-Gen members by senior colleagues as outlined in the text, networking, team science, and life/work integration. Endocrine societies focusing on Next-Gen members provide a powerful mechanism to support these critical areas.

Conclusions: A concerted effort to empower, train, and support the next generation of clinical endocrinologists and endocrine researchers is necessary to ensure the viability and vibrancy of our discipline and to optimize our contributions to improving health outcomes. Collaborative engagement of endocrine societies globally will be necessary to support our next generation moving forward.
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http://dx.doi.org/10.1210/jc.2016-3016DOI Listing
December 2016

Progression of Metabolic Syndrome Severity During the Menopausal Transition.

J Am Heart Assoc 2016 08 3;5(8). Epub 2016 Aug 3.

Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia, Charlottesville, VA

Background: After menopause, women exhibit a higher prevalence of the metabolic syndrome (MetS) and higher risk of cardiovascular disease. However, the timing of changes in MetS severity over the menopausal transition and whether these changes differ by racial/ethnic group remain unclear.

Methods And Results: We assessed data from 1470 women from the Atherosclerosis Risk in Communities cohort who experienced transition in menopausal status over 10 years (visits 1-4). We used linear mixed models to evaluate changes by menopausal status (premenopause, perimenopause, and postmenopause) in a MetS severity Z-score and in the individual MetS components. While there were gradual increases in MetS severity over time across menopause stages, black women in particular exhibited more rapid progression in MetS severity during the premenopausal and perimenopausal periods than during the postmenopausal period. In the postmenopausal period (compared with prior periods), white women exhibited unfavorable decreases in high-density lipoprotein, while black women exhibited favorable alterations in the rate of change for waist circumference, triglycerides, high-density lipoprotein, and glucose, contributing to the slowed progression of MetS severity. These changes were all observed after adjusting for hormone replacement treatment.

Conclusions: During menopausal transition, women exhibited rapid increases in MetS severity during the premenopausal and perimenopausal periods, with black women having significant reductions in this increase in severity during the postmenopausal period. These data suggest that the higher prevalence of MetS in postmenopausal women may be caused more by changes during the menopausal transition than by postmenopause. These findings may thus have implications regarding the timing of cardiovascular risk relative to menopause.
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http://dx.doi.org/10.1161/JAHA.116.003609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015287PMC
August 2016

Undetectable Urine Calcium in a Gastric Bypass Patient.

Clin Chem 2016 08;62(8):1161

Department of Pathology and.

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http://dx.doi.org/10.1373/clinchem.2015.251868DOI Listing
August 2016

Preclinical breast effects of a tissue selective estrogen complex (TSEC) including conjugated estrogen with bazedoxifene.

J Steroid Biochem Mol Biol 2017 06 9;170:61-64. Epub 2016 May 9.

Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1416, USA.

The first tissue-selective estrogen complex (TSEC), consisting of a combination of a conjugated equine estrogen (CEE) and bazedoxifene (BZA), has been approved for treatment of the menopause in the USA and European Union. We have postulated that this TSEC might block the estrogenic effects of CEE on breast tissue and thereby prevent breast cancer growth. This manuscript, representing a presentation at a Festschrift honoring Evan Simpson, reviews our published data BZA blocked the in vitro effects of both estradiol and CEE on cell growth and gene expression in MCF-7 cells. BZA completely blocked CEE- or E-stimulated ductal and terminal end bud growth of immature murine mammary glands and the growth of experimental breast cancers. These findings provide a rationale for future clinical studies to determine whether this TSEC prevents the growth of occult breast cancer in women.
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http://dx.doi.org/10.1016/j.jsbmb.2016.05.008DOI Listing
June 2017

An introduction to the Endocrine Society Clinical Practice Guideline on treatment of symptoms of the menopause.

Post Reprod Health 2016 Mar;22(1):6-8

University of Virginia Health System, Division of Endocrinology and Metabolism, Charlottesville, VA, USA.

Treatment of symptoms of menopause remains a challenge for many health care practitioners. In an effort to facilitate this process, the Endocrine Society convened an international Task Force of menopause experts to review the relevant clinical evidence and formulate practical recommendations for relieving the most common menopausal symptoms. The result is a comprehensive evidence-based guideline, which emphasizes an individualized approach to alleviate bothersome vasomotor symptoms and those related to postmenopausal changes of the vagina and urinary tract. Therapies including estrogen, either alone or in combination with progestogen or bazedoxifene, tibolone, antidepressants, gabapentin, as well as complementary approaches are discussed. In this commentary, the chairs of the Task Force highlight the organization and content of the guideline and the processes involved in its development.
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http://dx.doi.org/10.1177/2053369115626029DOI Listing
March 2016

Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline.

J Clin Endocrinol Metab 2015 Nov 7;100(11):3975-4011. Epub 2015 Oct 7.

University of California, San Diego, Endocrine/Metabolism (C.A.S.), La Jolla, California 92093; Monash University, School of Public Health and Preventive Medicine (S.R.D.), Melbourne 03004, Australia; Université Paris Descartes, Hôpitaux Universitaires Port Royal-Cochin Unit de Gynécologie Endocrnienne (A.G.), Paris 75014, France; University of Glasgow School of Medicine (M.A.L.), Glasgow G31 2ER, Scotland; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; University of Virginia, Obstetrics and Gynecology (J.V.P.), Charlottesville, Virginia 22908; and University of Virginia Health System (R.J.S.), Charlottesville, Virginia 22903.

Objective: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause.

Participants: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society.

Evidence: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials.

Consensus Process: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft.

Conclusions: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures.
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http://dx.doi.org/10.1210/jc.2015-2236DOI Listing
November 2015

Celebrating 75 years of oestradiol.

J Mol Endocrinol 2015 Dec 5;55(3):T1-20. Epub 2015 Oct 5.

Hudson Institute of Medical ResearchClayton, Victoria 3168, AustraliaDivision of Endocrinology and MetabolismDepartment of Medicine, University of Virginia Health Sciences System, Charlottesville, Virginia 22908-1416, USA.

Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists.
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http://dx.doi.org/10.1530/JME-15-0128DOI Listing
December 2015

Response to the Letter by Labrie et al.

J Clin Endocrinol Metab 2015 Sep;100(9):L88

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http://dx.doi.org/10.1210/jc.2015-2980DOI Listing
September 2015

Estrogens and Their Genotoxic Metabolites Are Increased in Obese Prepubertal Girls.

J Clin Endocrinol Metab 2015 Jun 9;100(6):2322-8. Epub 2015 Apr 9.

Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.

Context: Estrogen levels and their metabolites are higher in obese vs lean postmenopausal women, and obesity increases breast cancer risk. Quinone derivatives of 4-hydroxylated estrogen metabolites, independently of the estrogen receptor, cause depurination and impaired DNA repair (genotoxic). 16α-Hydroxy (16α-OH)-estrone (E1), eg, promotes tumor proliferation and 2-methoxy-estradiol (E2) may be chemoprotective. Childhood obesity increases breast cancer death risk in women, but levels of estrogen derivatives had not been previously studied in young children.

Objective: The objective of the study was to investigate whether total and genotoxic estrogens are increased in prepubertal obese girls compared with lean controls.

Design: Stored sera from 12 lean and 23 obese prepubertal girls (Tanner stage I breast and pubic hair) studied previously were assayed for E1, E2, and their multiple metabolites (12 steroids total) using highly sensitive liquid chromatography and tandem mass spectrometry.

Results: E2 concentrations were significantly higher in obese [3.45 (0.5, 4.65) pg/ml (median [quartile 1, quartile 3])] vs lean girls [0.5 (0.5, 2.37), P = .04], 57% of values upper quartile or greater (quartile 3) of controls. Concentrations of 16α-OH-E1 were higher in obese [7.17 (0.5, 9.64) pg/mL] vs lean girls [0.5 (0.5, 1.72, P = .007)], 65% of values quartile 3 or greater of controls. 2-Methoxy-E2 concentrations were lower in the obese group (P = .012). 16α-OH-E1 concentrations were positively correlated with body mass index, percentage fat mass, and IL-6 concentrations (P < .001).

Conclusions: E2 and genotoxic metabolites were higher in obese vs lean prepubertal girls. These data suggest that obesity is associated with an increased extraglandular estrogen production and metabolism before the onset of puberty in girls. Long-term epidemiological studies are needed to assess any potential increase in breast cancer risk.
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http://dx.doi.org/10.1210/jc.2015-1495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454805PMC
June 2015

Adenosine monophosphate activated protein kinase (AMPK), a mediator of estradiol-induced apoptosis in long-term estrogen deprived breast cancer cells.

Apoptosis 2015 Jun;20(6):821-30

Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, P. O. Box 801416, Charlottesville, VA, 22908, USA.

Estrogens stimulate growth of hormone-dependent breast cancer but paradoxically induce tumor regress under certain circumstances. We have shown that long-term estrogen deprivation (LTED) enhances the sensitivity of hormone dependent breast cancer cells to estradiol (E2) so that physiological concentrations of estradiol induce apoptosis in these cells. E2-induced apoptosis involve both intrinsic and extrinsic pathways but precise mechanisms remain unclear. We found that exposure of LTED MCF-7 cells to E2 activated AMP activated protein kinase (AMPK). In contrast, E2 inhibited AMPK activation in wild type MCF-7 cells where E2 prevents apoptosis. As a result of AMPK activation, the transcriptional activity of FoxO3, a downstream factor of AMPK, was up-regulated in E2 treatment of LTED. Increased activity of FoxO3 was demonstrated by up-regulation of three FoxO3 target genes, Bim, Fas ligand (FasL), and Gadd45α. Among them, Bim and FasL mediate intrinsic and extrinsic apoptosis respectively and Gadd45α causes cell cycle arrest at the G2/M phase. To further confirm the role of AMPK in apoptosis, we used AMPK activator AICAR in wild type MCF-7 cells and examined apoptosis, proliferation and expression of Bim, FasL, and Gadd45α. The effects of AICAR on these parameters recapitulated those observed in E2-treated LTED cells. Activation of AMPK by AICAR also increased expression of Bax in MCF-7 cells and its localization to mitochondria, which is a required process for apoptosis. These results reveal that AMPK is an important factor mediating E2-induced apoptosis in LTED cells, which is implicative of therapeutic potential for relapsing breast cancer after hormone therapy.
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http://dx.doi.org/10.1007/s10495-015-1111-7DOI Listing
June 2015

Workshop on measuring estrogen exposure and metabolism: Summary of the presentations.

Steroids 2015 Jul 30;99(Pt A):1-7. Epub 2014 Dec 30.

Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States.

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http://dx.doi.org/10.1016/j.steroids.2014.12.012DOI Listing
July 2015