Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-14. [PMID: 21467283 PMCID: PMC3656722 DOI: 10.1001/jama.2011.382] [Citation(s) in RCA: 368] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]

For:	LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-14. [PMID: 21467283 PMCID: PMC3656722 DOI: 10.1001/jama.2011.382] [Citation(s) in RCA: 368] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]

Number

Cited by Other Article(s)

Haque A, Zaman V, Drasites KP, Matzelle D, Sawant S, Vertegel A, Varma A, Banik NL. Induction of Neural Differentiation and Protection by a Novel Slow-Release Nanoparticle Estrogen Construct in a Rat Model of Spinal Cord Injury. Neurochem Res 2024;50:41. [PMID: 39613948 PMCID: PMC11607007 DOI: 10.1007/s11064-024-04289-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 12/01/2024]

Xiang X, Palasuberniam P, Pare R. Exploring the Feasibility of Estrogen Replacement Therapy as a Treatment for Perimenopausal Depression: A Comprehensive Literature Review. MEDICINA (KAUNAS, LITHUANIA) 2024;60:1076. [PMID: 39064505 PMCID: PMC11279181 DOI: 10.3390/medicina60071076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/27/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024]

Kos Z, Nielsen TO, Laenkholm AV. Breast Cancer Histopathology in the Age of Molecular Oncology. Cold Spring Harb Perspect Med 2024;14:a041647. [PMID: 38151327 PMCID: PMC11146312 DOI: 10.1101/cshperspect.a041647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]

Manson JE, Crandall CJ, Rossouw JE, Chlebowski RT, Anderson GL, Stefanick ML, Aragaki AK, Cauley JA, Wells GL, LaCroix AZ, Thomson CA, Neuhouser ML, Van Horn L, Kooperberg C, Howard BV, Tinker LF, Wactawski-Wende J, Shumaker SA, Prentice RL. The Women's Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA 2024;331:1748-1760. [PMID: 38691368 DOI: 10.1001/jama.2024.6542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]

Abstract

Importance

Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.

Observations

The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.

Conclusions and Relevance

For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

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Affiliation(s)

JoAnn E Manson Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Carolyn J Crandall Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles
Jacques E Rossouw National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
Rowan T Chlebowski Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
Garnet L Anderson Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
Marcia L Stefanick Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, California
Aaron K Aragaki Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
Jane A Cauley Department of Epidemiology, University of Pittsburgh School of Public Health\|Epidemiology, Pittsburgh, Pennsylvania
Gretchen L Wells Department of Medicine, University of Alabama, Birmingham
Andrea Z LaCroix Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, California
Cynthia A Thomson Department of Health Promotion Science, University of Arizona, Tucson
Marian L Neuhouser Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
Linda Van Horn Department of Preventive Medicine, Northwestern University, Chicago, Illinois
Charles Kooperberg Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
Barbara V Howard MedStar Health Research Institute and Department of Medicine, Georgetown University School of Medicine, Washington, DC
Lesley F Tinker Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
Jean Wactawski-Wende Department of Epidemiology and Environmental Health, University at Buffalo-SUNY, Buffalo, New York
Sally A Shumaker Department of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Ross L Prentice Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington

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Hanna M, Wabnitz A, Grewal P. Sex and stroke risk factors: A review of differences and impact. J Stroke Cerebrovasc Dis 2024;33:107624. [PMID: 38316283 DOI: 10.1016/j.jstrokecerebrovasdis.2024.107624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 12/24/2023] [Accepted: 02/02/2024] [Indexed: 02/07/2024] Open

Chaikittisilpa S, Orprayoon N, Vallibhakara O, Vallibhakara SAO, Tanmahasamut P, Somboonporn W, Rattanachaiyanont M, Techatraisak K, Jaisamrarn U. Summary of the 2023 Thai Menopause Society Clinical Practice Guideline on Menopausal Hormone Therapy. J Menopausal Med 2024;30:24-36. [PMID: 38714491 PMCID: PMC11103073 DOI: 10.6118/jmm.24006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 04/01/2024] [Indexed: 05/10/2024] Open

Oh MR, Park JH, Park SK, Park SH. Efficacy of plant-derived dietary supplements in improving overall menopausal symptoms in women: An updated systematic review and meta-analysis. Phytother Res 2024;38:1294-1309. [PMID: 38189863 DOI: 10.1002/ptr.8112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/06/2023] [Accepted: 12/16/2023] [Indexed: 01/09/2024]

Abstract

This updated systematic review and meta-analysis aims to confirm the effectiveness of plant-based supplements in improving overall menopausal symptoms and vasomotor symptoms. A systematic review of the literature was conducted by searching the PubMed/MEDLINE, Web of Science, EMBASE, and CENTRAL databases up to June 2022. Randomized placebo-controlled clinical trials that evaluated the effects of dietary supplements on menopausal symptoms were included. Outcome measures included daily hot flash frequency, Kupperman's index, Menopause Rating Scale, and Greene Climacteric Scale. Pooled data were analyzed using a fixed-effects model and expressed as a weighted mean difference with a 95% confidence interval for continuous outcomes. For qualitative assessment, 67 studies were selected. For quantitative assessment, 54 reports were obtained from 61 studies. The study participants were peri- or postmenopausal women aged 38-85, most of whom experienced hot flashes as a menopausal symptom. The investigational products included 28 soy-derived, 6 red clover-derived, and 28 other plant-derived supplements. Qualitative assessment revealed that approximately 76% of the studies were generally of fair or good quality, whereas 24% were of low quality. Meta-analysis results indicated significant improvements in all questionnaire scores, including hot flash frequency, in the dietary supplement group compared with the placebo group. Comprehensive evaluation using different questionnaire tools showed that the various plant-derived dietary supplements can significantly alleviate menopausal symptoms. However, further rigorous studies are needed to determine the association of plant-derived dietary supplements with menopausal health because of the general suboptimal quality and heterogeneous nature of current evidence.

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Farkas K, Stanek A, Zbinden S, Borea B, Ciurica S, Moore V, Maguire P, Abola MTB, Alajar EB, Marcoccia A, Erer D, Casanegra AI, Sharebiani H, Sprynger M, Kavousi M, Catalano M. Vascular Diseases in Women: Do Women Suffer from Them Differently? J Clin Med 2024;13:1108. [PMID: 38398419 PMCID: PMC10889109 DOI: 10.3390/jcm13041108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open

Affiliation(s)

Katalin Farkas Department of Angiology, Szent Imre University Teaching Hospital, Tétényi út 12-16, 1115 Budapest, Hungary VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.)
Agata Stanek VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Internal Medicine, Angiology and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 Street, 41-902 Bytom, Poland
Stephanie Zbinden VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Angiology, Zurich University Hospital, Ramistrasse 100, 8091 Zurich, Switzerland
Barbara Borea VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Angiology and Haemostasis, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland
Simina Ciurica VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Cardiology, Marie Curie Civil Hospital, CHU Charleroi, Chaussée de Bruxelles 140, 6042 Lodelinsart, Belgium
Vanessa Moore European Institute of Women’s Health, Ashgrove House, Kill Avenue, Dún Laoghaire, A96 N9K0 Dublin, Ireland; (V.M.); (P.M.)
Peggy Maguire European Institute of Women’s Health, Ashgrove House, Kill Avenue, Dún Laoghaire, A96 N9K0 Dublin, Ireland; (V.M.); (P.M.)
Maria Teresa B. Abola VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Clinical Research Department, Education, Training and Research Services, Philippine Heart Center, University of the Philippines College of Medicine, 547 Pedro Gil Street, Manila 1000, Metro Manila, Philippines
Elaine B. Alajar Manila Doctors Hospital, 667 United Nations Ave, Ermita, Manila 1000, Metro Manila, Philippines;
Antonella Marcoccia VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Angiology and Autoimmunity Medical Unit, Rare Diseases Reference Center for Systemic Sclerosis, Sandro Pertini Hospital, 00157 Rome, Italy
Dilek Erer VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Gazi University Hospital, Mevlana Blv. No:29, Yenimahalle, Ankara 06560, Turkey
Ana I. Casanegra Gonda Vascular Center, Department of Cardiovascular Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55901, USA;
Hiva Sharebiani VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Support Association of Patients of Buerger’s Disease, Buerger’s Disease NGO, Mashhad 9183785195, Iran
Muriel Sprynger VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Cardiology, University Hospital of Liège, Hospital Boulevard, 4000 Liege, Belgium
Maryam Kavousi VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
Mariella Catalano VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy; (A.S.); (S.Z.); (B.B.); (S.C.); (M.T.B.A.); (A.M.); (D.E.); (H.S.); (M.S.); (M.K.); (M.C.) Department of Biomedical and Clinical Science, Inter-University Research Center on Vascular Disease, University of Milan, GB Grassi 74, 20157 Milan, Italy

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Nudy M, Buerger J, Dreibelbis S, Jiang X, Hodis HN, Schnatz PF. Menopausal hormone therapy and coronary heart disease: the roller-coaster history. Climacteric 2024;27:81-88. [PMID: 38054425 DOI: 10.1080/13697137.2023.2282690] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/31/2023] [Indexed: 12/07/2023]

Rani J, Swati S, Meeta M, Singh SH, Tanvir T, Madan A. Postmenopausal Osteoporosis: Menopause Hormone Therapy and Selective Estrogen Receptor Modulators. Indian J Orthop 2023;57:105-114. [PMID: 38107817 PMCID: PMC10721581 DOI: 10.1007/s43465-023-01071-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 12/19/2023]

Abstract

Introduction

Osteoporosis is a debilitating silent disease with a huge socio-economic impact. Prevention strategies and early detection of osteoporosis need to be carried out in every health care unit to substantially reduce the fracture rates. Indian studies have indicated a knowledge gap on diagnosis and management of osteoporosis amongst medical professionals and consumers.

Areas Covered

This article reviews the evidences available on searches from PubMed and The National Library of Medicine, author's opinions based on clinical experience. There is a need for escalating the efforts to bridge the knowledge gap regarding various aspects of osteoporosis amongst professionals and consumers. Three indications for postmenopausal hormone therapy (HT), which have constantly withstood the test of time, are symptom relief, urogenital atrophy, and bone health. This article specifically focuses on management of postmenopausal osteoporosis by HT alone or in combinations.

Expert Opinion

Early menopause is within 10 years of menopause and late menopause is considered beyond 10 years of menopause. HT is a cost-effective therapy in the early post menopause especially in symptomatic women at risk for osteoporosis unless contraindicated. HT prevents all osteoporotic fractures even in low-risk population. All HT preparations including low dose and non-oral routes of estrogen are effective for bone health. The bone protective effect lasts while on HT. Extended use of HT in women after 10 years of menopause with reduced bone mass is an option after detailed counselling of the risk benefit analysis compared with the other available therapies for osteoporosis. The primary therapy to prevent bone loss in women with premature menopause and secondary amenorrhea is HT. HT work up and annual follow-up is essential before prescribing HT.

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Shete N, Calabrese J, Tonetti DA. Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches. Cancers (Basel) 2023;15:3647. [PMID: 37509308 PMCID: PMC10377916 DOI: 10.3390/cancers15143647] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/10/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open

Crandall CJ, Mehta JM, Manson JE. Management of Menopausal Symptoms: A Review. JAMA 2023;329:405-420. [PMID: 36749328 DOI: 10.1001/jama.2022.24140] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]

Abstract

IMPORTANCE

Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]).

OBSERVATIONS

Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene.

CONCLUSIONS AND RELEVANCE

During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

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Suba Z. Rosetta Stone for Cancer Cure: Comparison of the Anticancer Capacity of Endogenous Estrogens, Synthetic Estrogens and Antiestrogens. Oncol Rev 2023;17:10708. [PMID: 37152665 PMCID: PMC10154579 DOI: 10.3389/or.2023.10708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open

Abstract

This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient's survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.

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Mangione CM, Barry MJ, Nicholson WK, Cabana M, Caughey AB, Chelmow D, Coker TR, Davis EM, Donahue KE, Jaén CR, Kubik M, Li L, Ogedegbe G, Pbert L, Ruiz JM, Stevermer J, Wong JB. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: US Preventive Services Task Force Recommendation Statement. JAMA 2022;328:1740-1746. [PMID: 36318127 DOI: 10.1001/jama.2022.18625] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]

Abstract

IMPORTANCE

Menopause is defined as the cessation of a person's menstrual cycle. It is defined retrospectively, 12 months after the final menstrual period. Perimenopause, or the menopausal transition, is the few-year time period preceding a person's final menstrual period and is characterized by increasing menstrual cycle length variability and periods of amenorrhea, and often symptoms such as vasomotor dysfunction. The prevalence and incidence of most chronic diseases (eg, cardiovascular disease, cancer, osteoporosis, and fracture) increase with age, and US persons who reach menopause are expected on average to live more than another 30 years.

OBJECTIVE

To update its 2017 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of systemic (ie, oral or transdermal) hormone therapy for the prevention of chronic conditions in postmenopausal persons and whether outcomes vary by age or by timing of intervention after menopause.

POPULATION

Asymptomatic postmenopausal persons who are considering hormone therapy for the primary prevention of chronic medical conditions.

EVIDENCE ASSESSMENT

The USPSTF concludes with moderate certainty that the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons with an intact uterus has no net benefit. The USPSTF concludes with moderate certainty that the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy has no net benefit.

RECOMMENDATION

The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons. (D recommendation) The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy. (D recommendation).

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Gartlehner G, Patel SV, Reddy S, Rains C, Schwimmer M, Kahwati L. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2022;328:1747-1765. [PMID: 36318128 DOI: 10.1001/jama.2022.18324] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]

Abstract

IMPORTANCE

It is uncertain whether hormone therapy should be used for the primary prevention of chronic conditions such as heart disease, osteoporosis, or some types of cancers.

OBJECTIVE

To update evidence for the US Preventive Services Task Force on the benefits and harms of hormone therapy in reducing risks for chronic conditions.

DATA SOURCES

PubMed/MEDLINE, Cochrane Library, EMBASE, and trial registries from January 1, 2016, through October 12, 2021; surveillance through July 2022.

STUDY SELECTION

English-language randomized clinical trials and prospective cohort studies of fair or good quality.

DATA EXTRACTION AND SYNTHESIS

Dual review of abstracts, full-text articles, and study quality; meta-analyses when at least 3 similar studies were available.

MAIN OUTCOMES AND MEASURES

Morbidity and mortality related to chronic conditions; health-related quality of life.

RESULTS

Twenty trials (N = 39 145) and 3 cohort studies (N = 1 155 410) were included. Participants using estrogen only compared with placebo had significantly lower risks for diabetes over 7.1 years (1050 vs 903 cases; 134 fewer [95% CI, 18-237]) and fractures over 7.2 years (1024 vs 1413 cases; 388 fewer [95% CI, 277-489]) per 10 000 persons. Risks per 10 000 persons were statistically significantly increased for gallbladder disease over 7.1 years (1113 vs 737 cases; 377 more [95% CI, 234-540]), stroke over 7.2 years (318 vs 239 cases; 79 more [95% CI, 15-159]), venous thromboembolism over 7.2 years (258 vs 181 cases; 77 more [95% CI, 19-153]), and urinary incontinence over 1 year (2331 vs 1446 cases; 885 more [95% CI, 659-1135]). Participants using estrogen plus progestin compared with placebo experienced significantly lower risks, per 10 000 persons, for colorectal cancer over 5.6 years (59 vs 93 cases; 34 fewer [95% CI, 9-51]), diabetes over 5.6 years (403 vs 482 cases; 78 fewer [95% CI, 15-133]), and fractures over 5 years (864 vs 1094 cases; 230 fewer [95% CI, 66-372]). Risks, per 10 000 persons, were significantly increased for invasive breast cancer (242 vs 191 cases; 51 more [95% CI, 6-106]), gallbladder disease (723 vs 463 cases; 260 more [95% CI, 169-364]), stroke (187 vs 135 cases; 52 more [95% CI, 12-104]), and venous thromboembolism (246 vs 126 cases; 120 more [95% CI, 68-185]) over 5.6 years; probable dementia (179 vs 91 cases; 88 more [95% CI, 15-212]) over 4.0 years; and urinary incontinence (1707 vs 1145 cases; 562 more [95% CI, 412-726]) over 1 year.

CONCLUSIONS AND RELEVANCE

Use of hormone therapy in postmenopausal persons for the primary prevention of chronic conditions was associated with some benefits but also with an increased risk of harms.

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Huang AJ, Grady D. Menopausal Hormone Therapy for Prevention of Chronic Conditions: When Is Enough, Enough? JAMA 2022;328:1712-1713. [PMID: 36318153 DOI: 10.1001/jama.2022.19098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]

Okumura A, Kondo E, Kubo-Kaneda M, Yoshida K, Ikeda T. Efficacy of minodronic acid for the prevention of osteoporosis in premenopausal women with gynaecologic disease who undergo bilateral oophorectomy: a single-centre, non-randomised controlled, experimental study. J OBSTET GYNAECOL 2022;42:3591-3599. [PMID: 36200398 DOI: 10.1080/01443615.2022.2130202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2022]

Abstract

We evaluated the efficacy of minodronic acid for osteoporosis prevention after bilateral oophorectomy for gynaecologic disease in premenopausal women. Bone mineral density (BMD) and young adult mean (YAM) data from the lumbar vertebrae and femur and bone alkaline phosphatase (BAP)/tartrate-resistant acid phosphatase 5 b (TRACP 5 b) data were obtained for 101 patients. The primary endpoint was the efficacy of minodronic acid for osteoporosis prevention. Fifty-five and 31 patients were assigned to medication and no medication groups, respectively. The decrease in BMD and YAM and the increase in BAP/TRACP-5b were significantly more suppressed in the medication group. There were no significant between-group differences in age at oophorectomy, cancer type, body mass index (BMI), and adjuvant therapy. There were no adverse events due to minodronic acid. Minodronic acid may prevent osteoporosis after oophorectomy in premenopausal women with gynaecologic disease, independent of age at oophorectomy, cancer type, BMI, or adjuvant therapy. Impact statementWhat is already known on this subject? Although the current strategy for osteoporosis prevention after premenopausal bilateral oophorectomy (b-OVX) is hormone therapy (HT), there is no consensus on the treatment duration or adverse events.What do the results of this study add? Therefore, we planned a prospective study to evaluate the efficacy of prophylactic treatment for osteoporosis after b-OVX in premenopausal women with gynaecologic disease using minodronic acid, an oral bisphosphonate, which have a strong evidence of the treatment for osteoporosis. The result showed minodronic acid significantly suppressed the decrease in bone mineral density (BMD) and young adult mean (YAM) and the increase in bone alkaline phosphatase (BAP)/tartrate-resistant acid phosphatase 5b (TRACP 5b). Minodronic acid may prevent osteoporosis after oophorectomy in premenopausal women with gynaecologic disease, independent of age at oophorectomy, cancer type, BMI, or adjuvant therapy.What are the implications of these findings for clinical practice and/or further research? Minodronic acid treatment for osteoporosis prevention after premenopausal b-OVX may be effective as a therapeutic agent after the cessation of HT, or alternative for patients who are contraindicated for HT in breast cancer and thrombosis and should be administered with caution with a history of uterine or ovarian cancer.

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López García-Franco A, Baeyens Fernández JA, Iglesias Piñeiro MJ, Alonso Coello P, Ruiz Cabello C, Pereira Iglesias A, Landa Goñi J. [Preventive activities in women. PAPPS update 2022]. Aten Primaria 2022;54 Suppl 1:102471. [PMID: 36435585 PMCID: PMC9705224 DOI: 10.1016/j.aprim.2022.102471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022] Open

Abstract

In the 2022 PAPPS update we present those specific preventive activities for women's health, except those related to cancer prevention (which are included in another document) and those aspects related to differential gender morbidity, a cross-cutting aspect for all working groups. Contraception is an essential preventive activity, considering basic the right to decide both the number of children and the time to have them. We must inform about the possible contraceptive methods, guaranteeing the monitoring of their safety, efficacy and effectiveness (tables are included on changing from one method to another to preserve contraceptive protection). We must inform about emergency contraception and propose it in the event of unprotected intercourse. All this will be done through opportunistic screening without requiring screening for thrombophilia or dyslipidemia, but for arterial hypertension. Pregnancy is an important life experience and the family doctor should not remain oblivious. We must be competent both in the preconception consultation (recommending the intake of folic acid, avoiding exposure to occupational and environmental risks, screening for certain pathologies and assessing the intake of drugs not indicated during pregnancy) and in the monitoring of pregnancy. Whether or not we monitor the pregnancy, we must not disregard its control, taking advantage of this period to promote healthy lifestyles and participating in the intercurrent processes that may occur. Menopause in general and osteoporosis in particular exemplify the strategy of medicalization of vital processes that has been followed from different instances and organizations. In our update we address the prevention and treatment of symptoms secondary to estrogen deprivation. We also propose the prevention of osteoporosis, including carrying out densitometry based on the risk of fracture in the next 10 years, and therefore densitometric screening is not recommended in women under 60 years of age. In risk assessment we recommend the use of the frax tool or better, the calibration of the risk of hip fracture with prevalence data from our setting. We linked the indication for treatment with the Z-Score (bone mineral density compared with women of the same age), as it is a condition associated with aging.

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Jett S, Schelbaum E, Jang G, Boneu Yepez C, Dyke JP, Pahlajani S, Diaz Brinton R, Mosconi L. Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer's disease. Front Aging Neurosci 2022;14:948219. [PMID: 35928995 PMCID: PMC9344010 DOI: 10.3389/fnagi.2022.948219] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/28/2022] [Indexed: 01/19/2023] Open

Abstract

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women's brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer's disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women's health practices.

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Lu J, Hu D, Ma C, Shuai B. Advances in Our Understanding of the Mechanism of Action of Drugs (including Traditional Chinese Medicines) for the Intervention and Treatment of Osteoporosis. Front Pharmacol 2022;13:938447. [PMID: 35774616 PMCID: PMC9237325 DOI: 10.3389/fphar.2022.938447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022] Open

Rush SK, Ma X, Newton MA, Rose SL. A Revised Markov Model Evaluating Oophorectomy at the Time of Hysterectomy for Benign Indication: Age 65 Years Revisited. Obstet Gynecol 2022;139:735-744. [PMID: 35576331 PMCID: PMC9015029 DOI: 10.1097/aog.0000000000004732] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/22/2021] [Accepted: 01/04/2022] [Indexed: 01/05/2023]

Abstract

OBJECTIVE

To perform an updated Markov modeling to assess the optimal age for bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indication.

METHODS

We performed a literature review that assessed hazard ratios (HRs) for mortality by disease, age, hysterectomy with or without BSO, and estrogen therapy use. Base mortality rates were derived from national vital statistics data. A Markov model from reported HRs predicted the proportion of the population staying alive to age 80 years by 1-year and 5-year age groups at time of surgery, from age 45 to 55 years. Those younger than age 50 years were modeled as either taking postoperative estrogen or not; those 50 and older were modeled as not receiving estrogen. Computations were performed with R 3.5.1, using Bayesian integration for HR uncertainty.

RESULTS

Performing salpingo-oophorectomy before age 50 years for those not taking estrogen yields a lower survival proportion to age 80 years than hysterectomy alone before age 50 years (52.8% [Bayesian CI 40.7-59.7] vs 63.5% [Bayesian CI 62.2-64.9]). At or after age 50 years, there were similar proportions of those living to age 80 years with hysterectomy alone (66.4%, Bayesian CI 65.0-67.6) compared with concurrent salpingo-oophorectomy (66.9%, Bayesian CI 64.4-69.0). Importantly, those taking estrogen when salpingo-oophorectomy was performed before age 50 years had similar proportions of cardiovascular disease, stroke, and people living to age 80 years as those undergoing hysterectomy alone or those undergoing hysterectomy and salpingo-oophorectomy at age 50 years and older.

CONCLUSION

This updated Markov model argues for the consideration of concurrent salpingo-oophorectomy for patients who are undergoing hysterectomy at age 50 and older and suggests that initiating estrogen in those who need salpingo-oophorectomy before age 50 years mitigates increased mortality risk.

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Jett S, Malviya N, Schelbaum E, Jang G, Jahan E, Clancy K, Hristov H, Pahlajani S, Niotis K, Loeb-Zeitlin S, Havryliuk Y, Isaacson R, Brinton RD, Mosconi L. Endogenous and Exogenous Estrogen Exposures: How Women's Reproductive Health Can Drive Brain Aging and Inform Alzheimer's Prevention. Front Aging Neurosci 2022;14:831807. [PMID: 35356299 PMCID: PMC8959926 DOI: 10.3389/fnagi.2022.831807] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/07/2022] [Indexed: 01/14/2023] Open

Abstract

After advanced age, female sex is the major risk factor for late-onset Alzheimer's disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10-20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.

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Yoshida Y, Chen Z, Baudier RL, Krousel-Wood M, Anderson AH, Fonseca VA, Mauvais-Jarvis F. Menopausal hormone therapy and risk of cardiovascular events in women with prediabetes or type 2 diabetes: A pooled analysis of 2917 postmenopausal women. Atherosclerosis 2022;344:13-19. [PMID: 35114556 PMCID: PMC8905583 DOI: 10.1016/j.atherosclerosis.2022.01.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 11/30/2022]

Tan DA, Dayu ARB. Menopausal hormone therapy: why we should no longer be afraid of the breast cancer risk. Climacteric 2022;25:362-368. [PMID: 35147073 DOI: 10.1080/13697137.2022.2035711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]

Pan M, Pan X, Zhou J, Wang J, Qi Q, Wang L. Update on hormone therapy for the management of postmenopausal women. Biosci Trends 2022;16:46-57. [PMID: 35013031 DOI: 10.5582/bst.2021.01418] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]

Abstract

Hormone therapy (HT) has been used in postmenopausal women for decades in clinical practice. With further analysis and newer studies, the benefits and risks of HT have been repeatedly verified and discussed. HT is recommended for the treatment of vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM) and the prevention of osteoporosis. However, the precise association between HT and the risks of cardiovascular diseases, venous thromboembolism, neurodegenerative diseases, breast cancer, and endometrial cancer remains controversial. Therefore, determining how to take advantage of and control the risks of HT by adjusting the initiation time, regimen, and duration is crucial. Recent studies have indicated that HT is not related to the risk of all-cause, cardiovascular, or breast cancer mortality although it might increase the incidence of some chronic diseases. For symptomatic postmenopausal women under the age of 60 without contraindications, early initiation of HT is safe and probably has a mortality benefit over the long term. Initiating HT close to menopause at the lowest effective dose is more likely to have maximal benefits and the lowest risks. Transdermal and vaginal HT may have a lower risk, but recent evidence suggests additional clinical benefits of oral HT formulations in relieving VMS and preventing osteoporosis. The pooled cohort risk equation for atherosclerotic cardiovascular disease (ASCVD) and the free app named Menopro can be used to perform individual risk assessments. In addition, Chinese herbal medicines have benefits in alleviating hot flashes, depression, and menopausal symptoms, although further data are needed to strongly support their efficacy. Acupuncture and electroacupuncture have definite efficacy in the treatment of postmenopausal symptoms with few adverse effects, so they are a reasonable option as an alternative therapy for high-risk women. This review discusses the history of, guidelines on, and strategies for HT in order to make suggestions based on the most up-to-date evidence for the management of postmenopausal women.

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Bojar I, Raczkiewicz D, Gujski M, Humeniuk E, Wdowiak A, Owoc A, Pinkas J. Oestrogen receptor α gene polymorphisms, insomnia, and cognitive functions in perimenopausal and postmenopausal women in non-manual employment. Arch Med Sci 2022;18:1318-1328. [PMID: 36160335 PMCID: PMC9479593 DOI: 10.5114/aoms.2020.94977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/05/2019] [Indexed: 11/17/2022] Open

Singh P, Covassin N, Marlatt K, Gadde KM, Heymsfield SB. Obesity, Body Composition, and Sex Hormones: Implications for Cardiovascular Risk. Compr Physiol 2021;12:2949-2993. [PMID: 34964120 PMCID: PMC10068688 DOI: 10.1002/cphy.c210014] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]

Bakhidze EV, Belyaeva AV, Berlev IV, Anisimov VN, Belyaev AM. Menopausal Hormonal Therapy and Breast Cancer. ADVANCES IN GERONTOLOGY 2021. [DOI: 10.1134/s2079057021040020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]

Flores VA, Pal L, Manson JE. Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment. Endocr Rev 2021;42:720-752. [PMID: 33858012 DOI: 10.1210/endrev/bnab011] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Indexed: 12/22/2022]

Deng Y, Jin H. Effects of menopausal hormone therapy-based on the role of estrogens, progestogens, and their metabolites in proliferation of breast cancer cells. Cancer Biol Med 2021;19:j.issn.2095-3941.2021.0344. [PMID: 34779589 PMCID: PMC9088189 DOI: 10.20892/j.issn.2095-3941.2021.0344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 09/30/2021] [Indexed: 11/11/2022] Open

The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density. Drugs 2021;81:1831-1858. [PMID: 34724173 PMCID: PMC8578161 DOI: 10.1007/s40265-021-01625-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2021] [Indexed: 12/26/2022]

Adekunle AO, Adzika GK, Mprah R, Ndzie Noah ML, Adu-Amankwaah J, Rizvi R, Akhter N, Sun H. Predominance of Heart Failure With Preserved Ejection Fraction in Postmenopausal Women: Intra- and Extra-Cardiomyocyte Maladaptive Alterations Scaffolded by Estrogen Deficiency. Front Cell Dev Biol 2021;9:685996. [PMID: 34660569 PMCID: PMC8511782 DOI: 10.3389/fcell.2021.685996] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open

Natari RB, Hollingworth SA, Clavarino AM, Dingle KD, McGuire TM. Long term impact of the WHI studies on information-seeking and decision-making in menopause symptoms management: a longitudinal analysis of questions to a medicines call centre. BMC WOMENS HEALTH 2021;21:348. [PMID: 34607596 PMCID: PMC8491426 DOI: 10.1186/s12905-021-01478-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/01/2021] [Indexed: 11/10/2022]

Abstract

BACKGROUND

While women are taking a greater role in decisions about menopause symptom management, the legacy of the Women's Health Initiative (WHI) studies persist. Despite hormone therapy (HT) being effective in reducing all-cause mortality, many women seeking relief of menopausal symptoms exaggerate HT harms and overstate the perceived benefits or ignore the risks of alternative therapies. We aimed to explore the longitudinal impact of the widely-publicised WHI 2002 study on women's information-seeking and describe determinants of decision-making about managing menopausal symptoms.

METHODS

In a longitudinal analysis of both quantitative and qualitative data, we explored consumer questions about menopause-related medicines received by two Australian medicines call centres (1996-2010) before, during, and after WHI 2002. We analysed calls by age and gender of caller and patient, their relationship, postcode, enquiry type, and motivation to help-seek. We compared calls regarding HT and herbal medicines (HM) with the rest of calls, and thematically analysed question narratives across the three time-periods.

RESULTS

There were 1,829 menopause-related calls received of over this time-period, with a call surge, primarily from women in their mid-fifties, in the two months after the WHI 2002 publication. Two in three calls were motivated by negative media reports as women sought support for decision-making, primarily reassurance to cease HT. While HT safety concerns persisted for eight years post-publication, the nature of information-seeking changed over time. Callers subsequently sought reassurance to use menopause treatments together with their other medicines; and pursued HT substitutes, including HM, in response to HT product discontinuation.

CONCLUSIONS

Women sought information or reassurance to support a decision, based on dynamic changes in internal (symptom or risk intolerance, attitude towards menopause and treatment preferences) and external factors (perceived source trust and changes in treatment availability). In assessing HT benefit versus risk, women tend to overestimate risk with HT safety concerns persisting over time. Decision-making in managing menopause symptoms is complex and dynamic. Reassurance to reach or justify decisions from a perceived trusted source can support informed decision-making.

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Thamman R. Are we there yet? Menopausal hormone therapy for primary cardiovascular disease prevention. Heart 2021;107:1106-1108. [PMID: 34031159 DOI: 10.1136/heartjnl-2020-318390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open

Jiang X, Bossert A, Parthasarathy KN, Leaman K, Minassian SS, Schnatz PF, Woodland MB. Safety assessment of compounded non-FDA-approved hormonal therapy versus FDA-approved hormonal therapy in treating postmenopausal women. Menopause 2021;28:867-874. [PMID: 33973545 DOI: 10.1097/gme.0000000000001782] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]

Gosset A, Robin G, Letombe B, Pouillès JM, Trémollieres F. [Menopause hormone treatment in practice. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines]. GYNECOLOGIE, OBSTETRIQUE, FERTILITE & SENOLOGIE 2021;49:358-372. [PMID: 33757922 DOI: 10.1016/j.gofs.2021.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]

The Women's Health Initiative Estrogen-alone Trial had differential disease and medical expenditure consequences across age groups. ACTA ACUST UNITED AC 2021;27:632-639. [PMID: 32132440 DOI: 10.1097/gme.0000000000001517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]

Abstract

OBJECTIVES

The Women's Health Initiative (WHI) randomized trial identified age differences in the benefit-risk profile of estrogen-alone (ET) use. The impact of WHI trial on disease-associated medical expenditures attributable to subsequent decreased ET utilization has, however, not been measured. Therefore, the objective of this analysis was to quantify the age-specific disease-associated medical expenditures attributable to reduced ET utilization after the WHI Hormone Therapy (HT) trials.

METHODS

Population-level disease counts and associated expenditures between 2003 and 2015 were compared between an observed ET-user population versus a hypothetical ET-user population assuming absence of the WHI HT trials, constructed by extrapolating ET utilization rates from 1996 to 2002 assuming pre-WHI HT rates would have continued without publication of the WHI HT trial data (2002-2004). Analyses were stratified by age (50-59, 60-69, and 70-79 years). Input data were extracted from Medical Expenditure Panel Survey and the literature. The primary outcomes were: ET utilization, chronic diseases (breast cancer, stroke, coronary heart disease, colorectal cancer, pulmonary embolism, and hip fracture) and disease-associated direct medical expenditures.

RESULTS

Over 13 years, the decline in ET utilization was associated with $4.1 billion expenditure for excess chronic diseases (37,549 excess events) among women in their 50s, compared to savings of $1.5 billion and $4.4 billion for diseases averted by lower ET utilization among women in their 60s (13,495 fewer events) and 70s (40,792 fewer events), respectively.

CONCLUSION

The decline in ET utilization had differential disease and expenditure consequences by age groups in the United States. These results are limited by the lack of inclusion of vasomotor symptom benefit and costs of alternative medications for these symptoms in the analysis.

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Singh V, Reddy R, Sinha A, Marturi V, Panditharadyula SS, Bala A. A Review on Phytopharmaceuticals having Concomitant Experimental Anti-diabetic and Anti-cancer Effects as Potential Sources for Targeted Therapies Against Insulin-mediated Breast Cancer Cell Invasion and Migration. CURRENT CANCER THERAPY REVIEWS 2021. [DOI: 10.2174/1573394716999200831113335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]

Wang Y, Wang W, Feng Y, Tan Z, Yang X, Peng D, Zhao Y, Dong H, Zheng Q, Zeng X, Zou Y, Sun A. What is behind the fear of cancer during menopausal hormone therapy in China? Arch Gynecol Obstet 2021;304:1353-1361. [PMID: 33813609 DOI: 10.1007/s00404-021-06052-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 03/27/2021] [Indexed: 11/27/2022]

San Diego ERN, Ahuja NA, Johnson BM, Leak CL, Relyea G, Lewis JC, French N, Harmon BE. Prevalence of Cardiovascular Disease Risk Factors by Key Demographic Variables Among Mid-South Church Leaders from 2012 to 2017. JOURNAL OF RELIGION AND HEALTH 2021;60:1125-1140. [PMID: 33389434 DOI: 10.1007/s10943-020-01135-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/10/2020] [Indexed: 06/12/2023]

Ndzie Noah ML, Adzika GK, Mprah R, Adekunle AO, Adu-Amankwaah J, Sun H. Sex-Gender Disparities in Cardiovascular Diseases: The Effects of Estrogen on eNOS, Lipid Profile, and NFATs During Catecholamine Stress. Front Cardiovasc Med 2021;8:639946. [PMID: 33644139 PMCID: PMC7907444 DOI: 10.3389/fcvm.2021.639946] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open

Cox A, Capone M, Matzelle D, Vertegel A, Bredikhin M, Varma A, Haque A, Shields DC, Banik NL. Nanoparticle-Based Estrogen Delivery to Spinal Cord Injury Site Reduces Local Parenchymal Destruction and Improves Functional Recovery. J Neurotrauma 2021;38:342-352. [PMID: 32680442 PMCID: PMC11864116 DOI: 10.1089/neu.2020.7047] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open

Hormonersatztherapie und vaskuläres Risiko. GYNAKOLOGISCHE ENDOKRINOLOGIE 2020. [DOI: 10.1007/s10304-020-00308-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]

Muhammad JS, Bajbouj K, Shafarin J, Hamad M. Estrogen-induced epigenetic silencing of FTH1 and TFRC genes reduces liver cancer cell growth and survival. Epigenetics 2020;15:1302-1318. [PMID: 32476555 PMCID: PMC7678938 DOI: 10.1080/15592294.2020.1770917] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/19/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open

Rozenberg S, Al-Daghri N, Aubertin-Leheudre M, Brandi ML, Cano A, Collins P, Cooper C, Genazzani AR, Hillard T, Kanis JA, Kaufman JM, Lambrinoudaki I, Laslop A, McCloskey E, Palacios S, Prieto-Alhambra D, Reginster JY, Rizzoli R, Rosano G, Trémollieres F, Harvey NC. Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis? Osteoporos Int 2020;31:2271-2286. [PMID: 32642851 PMCID: PMC7661391 DOI: 10.1007/s00198-020-05497-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 05/04/2020] [Indexed: 12/21/2022]

Affiliation(s)

S Rozenberg Department of Obstetrics and Gynecology CHU St Pierre, Université Libre de Bruxelles, Vrije Universiteit, Brussels, Belgium
N Al-Daghri Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
M Aubertin-Leheudre Department of Physical Activity Sciences, Faculty of Sciences, Université du Québec à Montréal, CRIUGM, Montreal, Québec, Canada
M-L Brandi Department of Biochemical, Experimental and Clinical Sciences, University of Florence, Florence, Italy Unit of Bone and Mineral Diseases, University Hospital of Florence, Florence, Italy
A Cano Department of Obstetrics and Gynecology, University of Valencia and INCLIVA Health Research Institute, Valencia, Spain
P Collins National Heart and Lung Institute, Imperial College London, London, UK Royal Brompton Hospital, Royal Brompton Campus, Sydney Street, London, UK
C Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, UK NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
A R Genazzani Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
T Hillard Department of Obstetrics & Gynaecology, Poole Hospital NHS Trust, Poole, UK
J A Kanis Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK
J-M Kaufman Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
I Lambrinoudaki Menopause Unit, 2nd Department of Obstetrics and Gynecology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
A Laslop Scientific Office, Federal Office for Safety in Health Care, Vienna, Austria
E McCloskey Centre for Integrated research in Musculoskeletal Ageing, Mellanby Centre for Bone Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
S Palacios Director of Palacios Institute of Women's Health, Madrid, Spain
D Prieto-Alhambra Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
J-Y Reginster WHO Collaborating Center for Public Health Aspects of Musculoskeletal Health and Aging, Division of Public Health, Epidemiology and Health Economics, University of Liège, Liege, Belgium Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
R Rizzoli Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
G Rosano IRCCS San Raffaele, Rome, Italy
F Trémollieres Menopause Center, Hôpital Paule de Viguier, University Hospital of Toulouse and INSERM U1048-I2MC-Equipe 9, Toulouse, France
N C Harvey MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, UK.

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Wang SM, Pfeiffer RM, Gierach GL, Falk RT. Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort. Breast Cancer Res 2020;22:129. [PMID: 33239054 PMCID: PMC7687781 DOI: 10.1186/s13058-020-01365-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/01/2020] [Indexed: 11/10/2022] Open

Abstract

Background

Menopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.

Methods

We investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50–71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women’s Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.

Results

Eight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95–1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04–1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44–1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39–2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99–1.30).

Conclusions

ET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.

Supplementary information

The online version contains supplementary material available at 10.1186/s13058-020-01365-9.

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Machin N, Ragni MV. Hormones and thrombosis: risk across the reproductive years and beyond. Transl Res 2020;225:9-19. [PMID: 32599096 PMCID: PMC11867114 DOI: 10.1016/j.trsl.2020.06.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/18/2020] [Accepted: 06/24/2020] [Indexed: 11/30/2022]

López García-Franco A, Baeyens Fernández JA, Bailón Muñoz E, Iglesias Piñeiro MJ, Ortega Del Moral A, Coello PA, Ruiz Cabello C, Landa Goñi J, Arribas Mir L. [Preventive activities in women's care]. Aten Primaria 2020;52 Suppl 2:125-148. [PMID: 33388112 PMCID: PMC7801221 DOI: 10.1016/j.aprim.2020.09.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022] Open

Jordan VC. Molecular Mechanism for Breast Cancer Incidence in the Women's Health Initiative. Cancer Prev Res (Phila) 2020;13:807-816. [DOI: 10.1158/1940-6207.capr-20-0082] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/13/2020] [Accepted: 07/10/2020] [Indexed: 11/16/2022]

Maximov PY, Abderrahman B, Hawsawi YM, Chen Y, Foulds CE, Jain A, Malovannaya A, Fan P, Curpan RF, Han R, Fanning SW, Broom BM, Quintana Rincon DM, Greenland JA, Greene GL, Jordan VC. The Structure-Function Relationship of Angular Estrogens and Estrogen Receptor Alpha to Initiate Estrogen-Induced Apoptosis in Breast Cancer Cells. Mol Pharmacol 2020;98:24-37. [PMID: 32362585 PMCID: PMC7294906 DOI: 10.1124/mol.120.119776] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/16/2020] [Indexed: 12/17/2022] Open

Abstract

High-dose synthetic estrogen therapy was the standard treatment of advanced breast cancer for three decades until the discovery of tamoxifen. A range of substituted triphenylethylene synthetic estrogens and diethylstilbestrol were used. It is now known that low doses of estrogens can cause apoptosis in long-term estrogen deprived (LTED) breast cancer cells resistant to antiestrogens. This action of estrogen can explain the reduced breast cancer incidence in postmenopausal women over 60 who are taking conjugated equine estrogens and the beneficial effect of low-dose estrogen treatment of patients with acquired aromatase inhibitor resistance in clinical trials. To decipher the molecular mechanism of estrogens at the estrogen receptor (ER) complex by different types of estrogens-planar [17β-estradiol (E2)] and angular triphenylethylene (TPE) derivatives-we have synthesized a small series of compounds with either no substitutions on the TPE phenyl ring containing the antiestrogenic side chain of endoxifen or a free hydroxyl. In the first week of treatment with E2 the LTED cells undergo apoptosis completely. By contrast, the test TPE derivatives act as antiestrogens with a free para-hydroxyl on the phenyl ring that contains an antiestrogenic side chain in endoxifen. This inhibits early E2-induced apoptosis if a free hydroxyl is present. No substitution at the site occupied by the antiestrogenic side chain of endoxifen results in early apoptosis similar to planar E2 The TPE compounds recruit coregulators to the ER differentially and predictably, leading to delayed apoptosis in these cells. SIGNIFICANCE STATEMENT: In this paper we investigate the role of the structure-function relationship of a panel of synthetic triphenylethylene (TPE) derivatives and a novel mechanism of estrogen-induced cell death in breast cancer, which is now clinically relevant. Our study indicates that these TPE derivatives, depending on the positioning of the hydroxyl groups, induce various conformations of the estrogen receptor's ligand-binding domain, which in turn produces differential recruitment of coregulators and subsequently different apoptotic effects on the antiestrogen-resistant breast cancer cells.

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Affiliation(s)

Philipp Y Maximov Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Balkees Abderrahman Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Yousef M Hawsawi Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Yue Chen Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Charles E Foulds Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Antrix Jain Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Anna Malovannaya Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Ping Fan Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Ramona F Curpan Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Ross Han Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Sean W Fanning Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Bradley M Broom Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Daniela M Quintana Rincon Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Jeffery A Greenland Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Geoffrey L Greene Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
V Craig Jordan Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)

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