FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000374562> ?p ?o ?g. }

• W2000374562 endingPage "73" @default.
• W2000374562 startingPage "64" @default.
• W2000374562 abstract "The US Food and Drug Administration (FDA) approved marketing of diethylstilbestrol in 1941 and conjugated equine estrogens (CEE) in 1942 for treatment of menopausal symptoms. Estrogen sales doubled and tripled in the mid-1960s to mid-1970s, until 1975, when reports of increased endometrial cancer in estrogen users resulted in a dramatic decline. Estrogen use increased again, with evidence of protective effects of progestins on estrogen-induced endometrial changes, combined with a 1982 report that Premarin (conjugated estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA) retained bone mass and a 1984 National Institutes of Health (NIH) Consensus Conference on Osteoporosis statement that estrogens were the most effective means for preventing bone loss. Despite conflicting reports in 1985 regarding the relation between estrogens and coronary heart disease (CHD), many published observations of reduced CHD risk in estrogen users—reinforced by clinical trial findings in 1995 of favorable lipoprotein changes in women assigned to CEE with or without a progestin—promoted increased use through the 1990s. By 2001, approximately 15 million US women were using estrogen therapy, with or without progestins. The 2002 Women’s Health Initiative (WHI) report of greater harm than benefit of combined CEE plus a progestin resulted in a precipitous decrease in estrogen and progestin use and a serious reevaluation of menopausal hormone therapy, as well as increased interest in alternative approaches to managing menopausal symptoms, including use of “bioidentical” hormones. FDA guidelines regarding treatment indications for vasomotor symptoms, vaginal atrophy, and osteoporosis prevention have resulted in approval of several estrogen (and progestin) formulations, doses, and routes of administration, thereby providing many options for women who seek conventional therapy. The US Food and Drug Administration (FDA) approved marketing of diethylstilbestrol in 1941 and conjugated equine estrogens (CEE) in 1942 for treatment of menopausal symptoms. Estrogen sales doubled and tripled in the mid-1960s to mid-1970s, until 1975, when reports of increased endometrial cancer in estrogen users resulted in a dramatic decline. Estrogen use increased again, with evidence of protective effects of progestins on estrogen-induced endometrial changes, combined with a 1982 report that Premarin (conjugated estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA) retained bone mass and a 1984 National Institutes of Health (NIH) Consensus Conference on Osteoporosis statement that estrogens were the most effective means for preventing bone loss. Despite conflicting reports in 1985 regarding the relation between estrogens and coronary heart disease (CHD), many published observations of reduced CHD risk in estrogen users—reinforced by clinical trial findings in 1995 of favorable lipoprotein changes in women assigned to CEE with or without a progestin—promoted increased use through the 1990s. By 2001, approximately 15 million US women were using estrogen therapy, with or without progestins. The 2002 Women’s Health Initiative (WHI) report of greater harm than benefit of combined CEE plus a progestin resulted in a precipitous decrease in estrogen and progestin use and a serious reevaluation of menopausal hormone therapy, as well as increased interest in alternative approaches to managing menopausal symptoms, including use of “bioidentical” hormones. FDA guidelines regarding treatment indications for vasomotor symptoms, vaginal atrophy, and osteoporosis prevention have resulted in approval of several estrogen (and progestin) formulations, doses, and routes of administration, thereby providing many options for women who seek conventional therapy. A 1992 background paper from the Office of Technology Assessment (OTA) on menopause, hormone therapy (HT), and women’s health, requested by the 102nd US Congress, highlighted the need to conduct randomized clinical trials to assess the short- and long-term health effects of menopausal estrogen and progestin therapy as well as the need for research on alternatives to HT for managing menopausal symptoms.1US Congress, Office of Technology Assessment. The Menopause, Hormone Therapy, and Women’s Health. Washington, DC: US Government Printing Office; May 1992. Publication No. OTA-BP-BA-88.Google Scholar The report recognized the need to understand the natural history of menopause, a universal event in the lives of women, pointing out that in 1991 alone, 1.3 million US women had turned 50 years old, thereby approaching the average age of menopause, and that 35 million US women were already menopausal. (Worth noting is that the first of the baby boomers reached age 45 years in 1990.) The OTA report acknowledged an absence of good data on the prevalence of HT use and noted considerable geographic variation. Recent evidence suggests that approximately 6 million women were using prescription estrogens in 1992. This number climbed steadily to 15 million over the next decade, largely due to the introduction of a combined estrogen and progestin pill that attracted patients who had not previously received HT, yielding an estimated 6 million women using combined oral HT by 2001.2Hersh A.L. Stefanick M.L. Stafford R.S. National use of postmenopausal hormone therapy annual trends and response to recent evidence.JAMA. 2004; 291: 47-53Crossref PubMed Scopus (826) Google Scholar A decade after publication of the OTA report, the Women’s Health Initiative (WHI) trial of combined estrogen and progestin (i.e., the WHI E + P Trial) in 16,608 postmenopausal women with a uterus, aged 50 to 79 years at baseline, was stopped 3 years early, after an average of 5.2 years, because, compared with placebo, the risks (coronary heart disease [CHD], stroke, pulmonary emboli, and breast cancer) had been shown to exceed the benefits (e.g., prevention of hip fracture) in the women assigned to conjugated equine estrogens (CEE) 0.625 mg/day plus daily medroxyprogesterone (MPA) 2.5 mg/day.3Roussow J.E. Anderson G.L. Prentice R.L. et al.Writing Group for the Women’s Health Initiative InvestigatorsRisks and benefits of estrogen plus progestin in healthy postmenopausal women principal results from the Women’s Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Scopus (13746) Google Scholar (CEE and MPA were the most widely prescribed US estrogen and progestin formulations and doses throughout the trial.2Hersh A.L. Stefanick M.L. Stafford R.S. National use of postmenopausal hormone therapy annual trends and response to recent evidence.JAMA. 2004; 291: 47-53Crossref PubMed Scopus (826) Google Scholar) A year and a half later, the WHI trial of CEE only (i.e., the WHI E-Alone Trial), involving 10,739 women, posthysterectomy, aged 50 to 79 years, also was stopped early. The primary reason for the trial’s termination was an increased incidence of stroke in women assigned to CEE compared with placebo, with no evidence of benefit on CHD risk or overall health.4Anderson G.L. Limacher M. Assaf A.R. et al.Women’s Health Initiative Steering CommitteeEffects of conjugated equine estrogen in postmenopausal women with hysterectomy the Women’s Health Initiative randomized controlled trial.JAMA. 2004; 291: 1701-1712Crossref PubMed Scopus (4078) Google Scholar While the WHI hormone trials were under way, the Study of Women’s Health Across the Nation (SWAN), funded by the US National Institute on Aging, the National Institute of Nursing, and the Office of Research on Women’s Health, was collecting information on the natural history of menopause in a multiethnic, community-based cohort consisting of thousands of US women aged 42 to 52 years at the outset of a projected 10-year study period. In 2005, the National Institutes of Health (NIH) convened the State-of-the-Science Conference on Management of Menopause-Related Symptoms to achieve consensus on issues for which the WHI trials, SWAN, and several smaller studies could now provide answers to questions raised in the 1992 OTA report to Congress. This article provides background information regarding estrogens and progestins, including historical context, current US Food and Drug Administration (FDA)–approved formulations, routes of administration and doses, and trends in use, as well as FDA guidance regarding approval for indications of relevance to menopause and a brief description of “natural” or “bioidentical” HT, to help address the following question: What is the evidence for the benefits and harms of commonly used interventions for relief of menopause-related symptoms? Before the 20th century, the medical profession regarded menopause as a physiologic crisis that could result, under certain circumstances, in disease.5Bell S.E. Sociological perspectives on the medicalization of the menopause.Ann N Y Acad Sci. 1990; 592: 173-178Crossref PubMed Scopus (33) Google Scholar It is not clear whether earlier medical concerns focused primarily on the most common menopausal symptoms reported by women today, i.e., vasomotor hot flashes, night sweats, and urogenital symptoms, or on other problems attributed to the “change of life,” for which little evidence was available. As early as 1899 the Merck Manual featured several treatments for the “climacterica,” including a coarse brownish powder available in pills flavored with vanilla or in tablet form, called Ovarin (Ben Labs Ltd., Gujaret, India), which was derived from dried and pulverized cow ovaries and recommended at a dose of 8 to 24 grains 3 times daily.6Seaman B. The Greatest Experiment Ever Performed on Women. Hyperion, New York, NY2003Google Scholar, 7Merck Manual Diagnosis & Therapy. Merck & Co, New York1899Google Scholar Ovarin remained on the market until 1932, about which time oral menopause products, derived from human pregnancy urine, were developed by Adolph Butenandt of Schering AG (Berlin, Germany) and James Bertram Collip of Ayerst (Montreal, Quebec, Canada), to be replaced in the late 1930s by products from the urine of pregnant mares, including the Canadian product Premarin (CEE tablets; Wyeth-Ayerst, Ayerst Organics Ltd., Markham, Ontario, Canada).6Seaman B. The Greatest Experiment Ever Performed on Women. Hyperion, New York, NY2003Google Scholar, 8Seaman B. The history of hormone replacement therapy a timeline.in: Kleinman D.L. Kinchy A.J. Handelson J. Controversies in Science and Technology From Maize to Menopause (Science and Technology in Society). University of Wisconsin Press, Madison, WI2005: 219-235Google Scholar, 9Premarin: discovery of first orally active estrogen; creating a better lifestyle for women. Canada’s Digital Collections [government Web site]. Available at: http://collections.gc.ca/heirloom_series/volume6/290-291.htm. Accessed September 29, 2005.Google Scholar As presented in Table 1, other routes of administration and formulations of sex hormones had already been introduced, including the self-injections of an extract of testicles of dogs and guinea pigs reported in 1889 by the French physiologist Charles Edouard Brown-Sequard,10The Institute of Medicine Committee on Assessing the Need for Clinical Trials of Testosterone Replacement TherapyTestosterone and Aging. The National Academies Press, Washington, DC2004Google Scholar an estrogen patch for menopausal symptoms, introduced by Searle (Chicago, IL) in 1928,11Barrett-Connor E. Cardiovascular endocrinology an epidemiologist looks at hormones and heart disease in women.J Clin Endocrinol Metab. 2003; 88: 4031-4042Crossref PubMed Scopus (70) Google Scholar and ethinyl estradiol, patented by Schering in 1937.8Seaman B. The history of hormone replacement therapy a timeline.in: Kleinman D.L. Kinchy A.J. Handelson J. Controversies in Science and Technology From Maize to Menopause (Science and Technology in Society). University of Wisconsin Press, Madison, WI2005: 219-235Google Scholar, 12Nelson G.L. Pharmaceutical Company Histories, Volume One: Ayerst Laboratories. Woodbine Publishing, Bismarck, ND1983: 141-155Google Scholar The 1938 publication of the formula for diethylstilbestrol (DES) by London biochemist Charles Dodds prompted several pharmaceutical companies to seek FDA approval to market DES for treatment of menopausal symptoms, which was granted in September 1941.6Seaman B. The Greatest Experiment Ever Performed on Women. Hyperion, New York, NY2003Google Scholar In May 1942, the FDA granted permission to Wyeth-Ayerst (Philadelphia, PA) to market Premarin 1.25 mg for treatment of menopausal symptoms and related conditions.13Synthetic generic conjugated estrogens: timeline. US Food and Drug Administration Center for Drug Evaluation and Research [Web site]. Available at: http://www.fda.gov/cder/news/cetimeline.htm. Accessed September 29, 2005.Google Scholar The drug, which was already being prescribed to thousands of Canadian women, was known at the time to contain estrone and equilin and additional estrogens in smaller amounts. The following year, Dr. Robert Greenblatt, an early innovator in hormone delivery systems, and his colleagues published articles on the benefits of testosterone pellets placed under the skin in menopausal women, including the return of “coital pleasure.”8Seaman B. The history of hormone replacement therapy a timeline.in: Kleinman D.L. Kinchy A.J. Handelson J. Controversies in Science and Technology From Maize to Menopause (Science and Technology in Society). University of Wisconsin Press, Madison, WI2005: 219-235Google Scholar, 14Greenblatt R.B. Androgenic therapy in women.J Clin Endocrinol. 1942; 2: 665-666Crossref Scopus (22) Google Scholar, 15Greenblatt R.B. Mortara F. Torpi R. Sexual libido in the female.Am J Obstet Gynecol. 1942; 44: 658-663Scopus (24) Google Scholar By the 1947 publication of the first edition of the Physician’s Desk Reference, 53 formulations, sold by 23 companies, were listed for treating “menopausal disorders.” Several books, written for the general public from the late 1940s and over the course of the ensuing decades, suggested a range of effects of estrogen therapy (ET), thereby promoting its steady increase in use during the 1950s, which doubled and tripled in the mid 1960s to mid 1970s.Table 1Selected historic milestones in menopausal hormone therapyYearDescription1889Brown-Sequard self-administers dog testicular extract to reverse aging1890sOvarin, derived from cow ovaries, used for treating menopause1928Estrogen patch for menopausal symptoms, introduced by SearleSearle, Chicago, IL.1930s (early)Oral products derived from human pregnancy urine used for symptoms1930s (late)Oral products derived from pregnant horse urine used for symptoms1937Ethinyl estradiol patented1938Formula for DES published by Dodds1941FDA approves marketing of DES for treating menopausal symptoms; Albright suggests DES may stimulate bone formation1942FDA approves Premarin†Premarin (conjugated equine estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA). 1.25 mg for treating menopause1943Testosterone pellets implanted under the skin reported to improve coital pleasure1960sOral contraceptives introduced to regulate menses, prevent pregnancy1972FDA: estrogens “probably effective” for select cases of osteoporosis (DESI)1970sCoronary Drug Project randomized trial in men with CHD: CEE (5.0 and 2.5 mg/day) arms stopped due to early excess clotting and cardiovascular disease; risks of blood clot and stroke reported in young women taking (high-dose) oral contraceptives1975Increased endometrial cancer risk reported in estrogen users; FDA orders labeling changes to state high risk1978FDA mandate: by April, all estrogen products should contain warning with messages that estrogen has been proved effective only for hot flashes and vaginal dryness and carries risks of cancer and blood clot1985Conflicting reports published regarding cardiovascular risk in estrogen users: Framingham Heart Study reports increased stroke, blood clot, and coronary risk; Nurses’ Health Study reports reduced CHD risk1986FDA deems estrogens “effective” therapy for osteoporosis1990FDA does not approve estrogen indication for heart disease prevention1994FDA Osteoporosis Guidance: prevention requires 2-yr BMD placebo-controlled, randomized trial regardless of baseline BMD; treatment requires fracture reduction in women with osteoporosis at baseline1995PEPI trial suggests reduced CHD risk for CEE with or without 1 of 3 progestin arms; first combination estrogen + progestin pill (Prempro‡Prempro (CEE = MPA; Wyeth Pharmaceuticals).) is introduced1998HERS trial of women with CHD (with intact uterus) reports no CHD benefit of CEE + MPA over 4.1 yr of follow-up; excess risk in first year2002WHI E + P trial reports risks of CEE + MPA outweigh benefits over 5.2 yr2003FDA “black-box” warning on estrogen products: estrogens and progestins should not be used for prevention of cardiovascular disease; recommends lowest effective dose for shortest duration. FDA assesses but does not approve indication for osteoporosis treatment for combined estrogen + progestin2004WHI E-alone trial reports no overall benefit of CEE only over 6.8 yrBMD = bone mineral density; CEE = conjugated equine estrogens; CHD = coronary heart disease; DES = diethylstilbestrol; DESI = Drug Efficacy Study Implementation; FDA = US Food and Drug Administration; HERS = Heart and Estrogen/progestin Replacement Study; MPA = medroxyprogesterone acetate; PEPI = Postmenopausal Estrogen-Progestin Interventions; WHI = Women’s Health Initiative. Searle, Chicago, IL.† Premarin (conjugated equine estrogen tablets; Wyeth Pharmaceuticals, Philadelphia, PA).‡ Prempro (CEE = MPA; Wyeth Pharmaceuticals). Open table in a new tab BMD = bone mineral density; CEE = conjugated equine estrogens; CHD = coronary heart disease; DES = diethylstilbestrol; DESI = Drug Efficacy Study Implementation; FDA = US Food and Drug Administration; HERS = Heart and Estrogen/progestin Replacement Study; MPA = medroxyprogesterone acetate; PEPI = Postmenopausal Estrogen-Progestin Interventions; WHI = Women’s Health Initiative. Of note, drugs approved before 1962 were required to demonstrate safety but not effectiveness at the time of approval, whereas new drugs were required to demonstrate effectiveness. In 1972, the FDA published a Federal Register notice announcing that a number of estrogen products, including Premarin, had been shown to be effective in the treatment of menopausal symptoms based on an evaluation done under the Drug Efficacy Study Implementation (DESI) program designed to assess the effectiveness of drugs approved for marketing before 1962.13Synthetic generic conjugated estrogens: timeline. US Food and Drug Administration Center for Drug Evaluation and Research [Web site]. Available at: http://www.fda.gov/cder/news/cetimeline.htm. Accessed September 29, 2005.Google Scholar In the same notice, the FDA provided for submission and approval of abbreviated new drug applications (ANDAs) for generic conjugated estrogens. The increase in estrogen use continued despite reports in the 1960s and 1970s of increased thrombosis and severe hypertensive episodes in young women who initiated (high-dose, high-potency) oral contraceptives16Kannel W.B. Oral contraceptive hypertension and thromboembolism.Int J Gynaecol Obstet. 1979; 16: 466-472Google Scholar and of increased thromboembolic events and myocardial infarction in men with known heart disease assigned to Premarin (5 mg and 2.5 mg) as participants in the randomized, placebo-controlled Coronary Drug Project.17The Coronary Drug Project Research GroupThe Coronary Drug Project initial findings leading to modifications of its research protocol.JAMA. 1970; 214: 1303-1313Crossref PubMed Scopus (349) Google Scholar, 18The Coronary Drug Project Research GroupThe Coronary Drug Project findings leading to discontinuation of the 2.5 mg day estrogen group.JAMA. 1973; 226: 652-657Crossref PubMed Scopus (396) Google Scholar On the other hand, reports in 1975 of increased endometrial carcinoma in users of menopausal ET19Smith D.C. Prentice R. Thompson D.J. Herrmann W.L. Association of exogenous estrogen and endometrial carcinoma.N Engl J Med. 1975; 293: 1164-1167Crossref PubMed Scopus (871) Google Scholar, 20Ziel H.K. Finkle W.D. Increased risk of endometrial carcinoma among users of conjugated estrogens.N Engl J Med. 1975; 293: 1167-1170Crossref PubMed Scopus (822) Google Scholar resulted in a precipitous decrease in estrogen use. Following these reports, the FDA ordered labeling changes of estrogen products to state the potentially lethal effect and high risk; according to an FDA mandate, all estrogen products and birth control pills were supposed to contain a comprehensive warning by April 1978, to be dispensed by the pharmacist at the point of sale, to inform users that estrogen had been proved effective only for hot flashes and vaginal dryness but carried risks of cancer and blood clots.6Seaman B. The Greatest Experiment Ever Performed on Women. Hyperion, New York, NY2003Google Scholar, 8Seaman B. The history of hormone replacement therapy a timeline.in: Kleinman D.L. Kinchy A.J. Handelson J. Controversies in Science and Technology From Maize to Menopause (Science and Technology in Society). University of Wisconsin Press, Madison, WI2005: 219-235Google Scholar Subsequent evidence that the addition of a progestin could prevent estrogen-induced endometrial changes halted the pattern of decline, and estrogen use increased steadily from the early 1980s through the 1990s, accompanied by an increase in progestin use by women with a uterus. During this period, when women were being educated about osteoporosis and the fact that heart disease was the leading cause of death in women, the steep increase in menopausal hormone use was likely attributable to the publication of numerous reports suggesting that ET prevents bone loss attributed to menopause and revealing epidemiologic evidence of lower CHD incidence in estrogen users. In 1990, the FDA published a proposal to withdraw from the market generic forms of conjugated estrogen tablets owing to the potential for bioinequivalence and consequent concerns about safety and efficacy. This proposal, which was endorsed by the FDA’s Generic Drugs Advisory Committee in 1991, resulted in FDA withdrawal of approval of all ANDAs.13Synthetic generic conjugated estrogens: timeline. US Food and Drug Administration Center for Drug Evaluation and Research [Web site]. Available at: http://www.fda.gov/cder/news/cetimeline.htm. Accessed September 29, 2005.Google Scholar ANDAs for conjugated estrogen tablets were submitted in 1994, after a 1970 US Pharmacopeia (USP) monograph describing conjugated estrogens as containing sodium estrone sulfate and sodium equilin sulfate was amended in 1992 to include 3 additional estrogens, and in 1995 after Wyeth-Ayerst filed a citizen petition requesting the FDA designate δ-dehydroestrone sulfate (DHES) a concomitant component of conjugated estrogens.8Seaman B. The history of hormone replacement therapy a timeline.in: Kleinman D.L. Kinchy A.J. Handelson J. Controversies in Science and Technology From Maize to Menopause (Science and Technology in Society). University of Wisconsin Press, Madison, WI2005: 219-235Google Scholar, 9Premarin: discovery of first orally active estrogen; creating a better lifestyle for women. Canada’s Digital Collections [government Web site]. Available at: http://collections.gc.ca/heirloom_series/volume6/290-291.htm. Accessed September 29, 2005.Google Scholar In May 1997, the FDA’s Center for Drug Evaluation and Research (CDER) announced that it would not approve synthetic generic forms of Premarin because they had not been shown to have the same active ingredients as the original drug for treating menopausal symptoms and preventing osteoporosis.13Synthetic generic conjugated estrogens: timeline. US Food and Drug Administration Center for Drug Evaluation and Research [Web site]. Available at: http://www.fda.gov/cder/news/cetimeline.htm. Accessed September 29, 2005.Google Scholar A link between low ovarian hormone levels and increased bone loss was reported in 1941 by Albright and colleagues,21Albright F. Smith P.H. Richardson R. Postmenopausal osteoporosis and its clinical features.JAMA. 1941; 117: 2473-2476Crossref Scopus (8) Google Scholar who proposed that DES may be a stimulus for bone formation. Three decades later, the 1972 FDA Federal Register notice on estrogen products, including Premarin, announced that they were “probably effective” for prevention of osteoporosis.13Synthetic generic conjugated estrogens: timeline. US Food and Drug Administration Center for Drug Evaluation and Research [Web site]. Available at: http://www.fda.gov/cder/news/cetimeline.htm. Accessed September 29, 2005.Google Scholar A decade after that, Genant and coworkers22Genant H.K. Cann C.E. Ettinger B. Gordan G.S. Quantitative computed tomography of vertebral spongiosa a sensitive method for detecting early bone loss after oophorectomy.Ann Intern Med. 1982; 97: 699-705Crossref PubMed Scopus (541) Google Scholar reported that in women undergoing surgical menopause, intermediate doses of Premarin maintained bone mass better than low doses of Premarin or placebo, and evidence presented at a 1984 NIH Consensus Development Conference on Osteoporosis resulted in a conclusion that estrogens were the most effective means to prevent bone loss.23NIH Consensus Development Statement on Osteoporosis, April 2–4, 1984. Volume 5, No. 3. Bethesda, MD: US Dept of Health and Human Services, National Institutes of Health, Office of Medical Applications of Research.Google Scholar In 1986, the FDA announced in the Federal Register that short-acting estrogens, including Premarin, were found to be effective for preventing osteoporosis.13Synthetic generic conjugated estrogens: timeline. US Food and Drug Administration Center for Drug Evaluation and Research [Web site]. Available at: http://www.fda.gov/cder/news/cetimeline.htm. Accessed September 29, 2005.Google Scholar The FDA Osteoporosis Guidance was updated in 1994 to distinguish between prevention—based on benefits to bone mineral density (BMD)—and treatment, based on fracture reduction in subjects with osteoporosis at baseline. Although Premarin was already approved for prevention, the 3-year, randomized, placebo-controlled Postmenopausal Estrogen-Progestin Interventions (PEPI) trial confirmed the indication of prevention with a clear demonstration of benefit in both lumbar and hip BMD with CEE alone or combined with any of 3 progestin regimens, including both daily and cyclic MPA and cyclic micronized progesterone, compared with placebo.24The Writing Group for the PEPI TrialEffects of hormone therapy on bone mineral density results from the Post-menopausal Estrogens/Progestins Intervention (PEPI) trial.JAMA. 1996; 276: 1389-1396Crossref PubMed Google Scholar In 1985, the Framingham Heart Study reported a nearly 2-fold increase in risk for cardiovascular disease (CVD) associated with estrogen use over an 8-year period for 1,234 postmenopausal women aged ≥50 years.25Wilson P.W. Garrison R.F. Castelli W.P. Postmenopausal estrogen use, cigarette smoking, and cardiovascular mortality in women over 50 the Framingham study.N Engl J Med. 1985; 313: 1038-1043Crossref PubMed Scopus (495) Google Scholar This observation appeared back-to-back with the first Nurses’ Health Study report of 50% lower risk of CHD in ever- versus never-users of estrogen, for an average 3.5 years of follow-up of 32,317 postmenopausal women aged 30 to 55 years.26Stampfer M.J. Willett W.C. Colditz G.A. Rosner B. Speizer F.E. Hennekens C.H. A prospective study of postmenopausal estrogen therapy and coronary heart disease.N Engl J Med. 1985; 313: 1044-1049Crossref PubMed Scopus (729) Google Scholar The discrepancy between the results of these 2 highly respected prospective cohort studies was attributed to inclusion in the Framingham study of cardiovascular events other than MI and CHD (e.g., angina pectoris, intermittent claudication, transient ischemic attack) and adjustment for high-density lipoprotein (HDL) cholesterol, which was considered possibly inappropriate because, at the time, it was thought to be the most plausible mechanism of action for estrogen. Within the next few years, several other cohort studies corroborated the Nurses’ Health Study finding of reduced CHD risk, including the Lipid Research Clinics Follow-up Study of 2,270 women aged 40 to 69 years who were followed for 8.5 years,27Bush T.L. Barrett-Connor E. Cowan L.D. et al.Cardiovascular mortality and noncontraceptive use of estrogen in women results from the Lipid Research Clinics Program Follow-up Study.Circulation. 1987; 75: 1102-1109Crossref PubMed Scopus (1265) Google Scholar the Leisure World Study of 8,841 women aged 40 through 101 years who were followed for 5.5 years,28Petitti D.B. Perlman J.A. Sidney S. Noncontraceptive estrogen and mortality long-term follow-up of women in the Walnut Creek Study.Obstet Gynecol. 1987; 70: 289-293PubMed Google Scholar and a Kaiser Permanente program cohort of 6,093 women aged 18 to 54 years who were followed for 10 to 13 years.29Henderson B.E. Paganini-Hill A. Ross R.K. Estrogen replacement therapy and protection from acute myocardial infarction.Am J Obstet Gynecol. 1988; 159: 312-317Crossref PubMed Scopus (223) Google Scholar In a 1991 review, Barrett-Connor and Bush30Barrett-Connor E. Bush T.L. Estrogen and coronary heart disease in women.JAMA. 1991; 265: 1861-1867Crossref PubMed Scopus (1205) Google Scholar acknowledged that the weight of the evidence pointed toward a substantial reduction in CHD risk among women using estrogens; however, they also pointed out that overall, women who took es" @default.
• W2000374562 created "2016-06-24" @default.
• W2000374562 creator A5067389037 @default.
• W2000374562 date "2005-12-01" @default.
• W2000374562 modified "2023-10-16" @default.
• W2000374562 title "Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration" @default.
• W2000374562 cites W1586699954 @default.
• W2000374562 cites W1593442063 @default.
• W2000374562 cites W1744026217 @default.
• W2000374562 cites W1977071177 @default.
• W2000374562 cites W1981922048 @default.
• W2000374562 cites W1982268345 @default.
• W2000374562 cites W1983521550 @default.
• W2000374562 cites W2002924549 @default.
• W2000374562 cites W2007841512 @default.
• W2000374562 cites W2018312028 @default.
• W2000374562 cites W2031032707 @default.
• W2000374562 cites W2034381583 @default.
• W2000374562 cites W2037982368 @default.
• W2000374562 cites W2063031738 @default.
• W2000374562 cites W2083659777 @default.
• W2000374562 cites W2106286936 @default.
• W2000374562 cites W2113264115 @default.
• W2000374562 cites W2120955256 @default.
• W2000374562 cites W2131266318 @default.
• W2000374562 cites W2149856308 @default.
• W2000374562 cites W2159876289 @default.
• W2000374562 cites W2161695527 @default.
• W2000374562 cites W2314604683 @default.
• W2000374562 cites W2321712742 @default.
• W2000374562 cites W2341031326 @default.
• W2000374562 cites W2444606553 @default.
• W2000374562 cites W4232354154 @default.
• W2000374562 cites W4240275694 @default.
• W2000374562 cites W4245166850 @default.
• W2000374562 cites W4252406137 @default.
• W2000374562 doi "https://doi.org/10.1016/j.amjmed.2005.09.059" @default.
• W2000374562 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16414329" @default.
• W2000374562 hasPublicationYear "2005" @default.
• W2000374562 type Work @default.
• W2000374562 sameAs 2000374562 @default.
• W2000374562 citedByCount "175" @default.
• W2000374562 countsByYear W20003745622012 @default.
• W2000374562 countsByYear W20003745622013 @default.
• W2000374562 countsByYear W20003745622014 @default.
• W2000374562 countsByYear W20003745622015 @default.
• W2000374562 countsByYear W20003745622016 @default.
• W2000374562 countsByYear W20003745622017 @default.
• W2000374562 countsByYear W20003745622018 @default.
• W2000374562 countsByYear W20003745622019 @default.
• W2000374562 countsByYear W20003745622020 @default.
• W2000374562 countsByYear W20003745622021 @default.
• W2000374562 countsByYear W20003745622022 @default.
• W2000374562 countsByYear W20003745622023 @default.
• W2000374562 crossrefType "journal-article" @default.
• W2000374562 hasAuthorship W2000374562A5067389037 @default.
• W2000374562 hasBestOaLocation W20003745621 @default.
• W2000374562 hasConcept C177713679 @default.
• W2000374562 hasConcept C2780035454 @default.
• W2000374562 hasConcept C3018890749 @default.
• W2000374562 hasConcept C71924100 @default.
• W2000374562 hasConcept C98274493 @default.
• W2000374562 hasConceptScore W2000374562C177713679 @default.
• W2000374562 hasConceptScore W2000374562C2780035454 @default.
• W2000374562 hasConceptScore W2000374562C3018890749 @default.
• W2000374562 hasConceptScore W2000374562C71924100 @default.
• W2000374562 hasConceptScore W2000374562C98274493 @default.
• W2000374562 hasIssue "12" @default.
• W2000374562 hasLocation W20003745621 @default.
• W2000374562 hasLocation W20003745622 @default.
• W2000374562 hasOpenAccess W2000374562 @default.
• W2000374562 hasPrimaryLocation W20003745621 @default.
• W2000374562 hasRelatedWork W2020485319 @default.
• W2000374562 hasRelatedWork W2027240967 @default.
• W2000374562 hasRelatedWork W2097742807 @default.
• W2000374562 hasRelatedWork W2123032775 @default.
• W2000374562 hasRelatedWork W2155391154 @default.
• W2000374562 hasRelatedWork W2418407361 @default.
• W2000374562 hasRelatedWork W2426261983 @default.
• W2000374562 hasRelatedWork W3042701933 @default.
• W2000374562 hasRelatedWork W4252371801 @default.
• W2000374562 hasRelatedWork W4301669357 @default.
• W2000374562 hasVolume "118" @default.
• W2000374562 isParatext "false" @default.
• W2000374562 isRetracted "false" @default.
• W2000374562 magId "2000374562" @default.
• W2000374562 workType "article" @default.