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INTRODUCTION The association of a pharmacologic substance with a negative aftereffect does not always show direct cause and effect. In many instances, several health modifiers are involved; ­ these include heredity, lifestyle, age of use, pregnancy status, and social, cultural, and financial ­ factors. As well, ­ there is often a time lag between linking the drug prescribed to its adverse sequelae. In ­ women’s health, possibly the best-­ known case of iatrogenic prescribing in recent history was for thalidomide. First marketed in Germany in the late 1950s, thalidomide was sold as a safe sedative with many benefits, including as a sleep aid. Soon ­ after, especially in Eu­ rope, Australia, and Japan, the drug was also recommended to pregnant ­ women to manage nausea associated with pregnancy. By 1961, the link between use of thalidomide in pregnancy and birth defects was confirmed by the German pediatrician Widukind Lenz (1). The types of birth defects in male and female fetuses ­ were linked to the time during gestation when exposure occurred. In addition to thalidomide causing phocomelia (limb shortening, absence, or malformation ) in the offspring of ­ these ­ mothers, many ­ children ­ were born with congenital heart disease and ear and ocular abnormalities, and many did not survive. ­ Today, despite the horrific teratogenic effects that thalidomide ­ causes in early pregnancy, the drug continues to be used in nonpregnant individuals for indications that include erythema nodosum leprosum and certain types of cancer. In ­ women’s health care, hormone therapy may be the most publicized physician intervention resulting in iatrogenic consequences, including significant cardiovascular adverse sequelae. Since 1929, when German scientist Adolf Butenandt succeeded in isolating estrone from the urine of pregnant ­ women, estrogen and estrogen-­ related hormones have been at the center of controversy. Even the discovery of estrone was mired in dispute, as American scientist Edward Doisy isolated the identical compound at almost the same time. Doisy received ­ little recognition while Butenandt was awarded the 1939 Noble Prize in chemistry (2).­ Today, the iatrogenic consequences of menopausal hormonal therapy (MHT) are still debated. When MHT is prescribed as estrogen alone, adverse consequences for CHAPTER 13­ Women and Iatrogenic Cardiovascular Disease Menopausal Estrogen as the Prime Suspect Gloria Bachmann, Nancy Phillips, and Margaret Rees Introduction / 157 can be seen as an iatrogenic consequence, but as the iatrogenic potential was unknown at the time of prescribing, ­ were physicians at fault? To currently prescribe DES for the above indications is clearly contraindicated. During the time DES was used, other estrogens , especially conjugated equine estrogens, gained traction with physicians and patients to prevent distressing menopausal symptoms. From the early 1940s through the 1960s, estrogen therapy’s primary aim for the menopausal patient was to treat symptoms that accompany this time of estrogen withdrawal. Estrogen was typically prescribed during the most symptomatic phase of the menopause transition and was discontinued within a year or two. In the 1960s, however, as the lit­ er­ a­ ture proposed the use of estrogen therapy as a preventive medi­ cation, the short-­ term prescribing pattern began to change. A New ­ England Journal of Medicine article published in the mid 1960s advocated estrogen therapy as an intervention not only to treat symptoms but also to prevent adverse metabolic changes (6). Another article, published in the Journal of the American Geriatric Society in the early 1960s, described menopausal ­ women not on estrogen as “castrates” (7). The authors described numerous benefits of estrogen use, including use for “negative nitrogen balance, hypercholesteremia, hypertension, osteoporosis , menopausal arthritic conditions, impairment of carbohydrate metabolism, psychic manifestation , menopausal negativism, effects on skin and mucous membranes, other endocrine disorders , imbalance of the ner­ vous systems and mammary and genital changes.” In 1966, the lead author, Robert A. Wilson, wrote a best-­ selling book, Feminine Forever, that spoke directly to menopausal ­ women about how using estrogen for the rest of their lives would maintain their youthful vigor. In that era, most ­ women ­ were routinely prescribed estrogen starting at menopause , regardless of ­ whether or not they ­ were symptomatic. However, it should be noted that at this time estrogen was prescribed without a progestin and days off estrogen ­ were meant to withdraw the endometrial lining. the patient mostly fall into the category of cardiovascular disease (CVD). When MHT is prescribed as estrogen + progestin, ­ either together continuously or progestin prescribed ­ either cyclically or on specific days of the 28-­ day cycle, the combination has been associated not only with an increased risk of coronary heart disease (CHD), stroke, venous thromboembolism (VTE), and pulmonary embolism (PE), but also with an increased...


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