Hormonal Therapy

Hormonal Therapy Hormonal Therapy The Estrogen Controversy Reviewed by Dong Duek Kwon, MD, Michael Chancellor, MD University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA [Rev Urol. 2003;5(2):131-132] © 2003 MedReviews, LLC ost people would agree that one of the most important pieces of medical news in 2002 was the announcement that hormone replacement therapies in women cause more harm than good. In the July 17, 2002 issue of the Journal of the American Medical Association (JAMA), two landmark papers reported that the overall health risks associated with the use of combined estrogen plus progestin exceeded the benefits. This startling announcement made the headlines of every newspaper, TV newscast, and news magazine in the nation and across the world. Some of the consequences of these two papers included an immediate 50% reduction in the number of estrogen/progestin prescriptions dispensed and class-action lawsuits against the makers of these drugs. The impact of these two studies hit close to home. We remember a number of conversations within our own families about the pros and cons of hormone replacement therapy (HRT) and how convinced we were of its benefits. Because this development clearly affects every single medical specialty, we will review these two papers in this issue. Moreover, we will speculate on what this means to urologists who have used HRT for voiding dysfunction, incontinence, and urinary tract infection (UTI). M Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321–333. Although the U.S. Food and Drug Administration approved hormone therapy for indications that include relief of menopausal symptoms and prevention of osteoporosis, its long-term use has been in vogue to prevent a range of chronic conditions, especially heart disease. Hormonal therapy has also been widely used by gynecologists and urologists for a variety of lower urinary tract symptoms, including urge and stress incontinence and recurrent UTIs. Estrogen alone was the dominant hormone until the increased risk of endometrial cancer led to the addition of progestins for women with an intact uterus. From the mid-1980s on, combined estrogen/progestin use steadily increased until approximately 38% of postmenopausal women in the United States used HRT. In the year 2000, 46 million prescriptions were written for Premarin (conjugated estrogens), making it the second most frequently prescribed medication in the United States. The Women's Health Initiative (WHI) is the first randomized, primary prevention trial of postmenopausal women using hormones. What made this study headline news is that the Data and Safety Monitoring Board (DSMB) of the National Institutes of Health terminated the The bottom line of the WHI study is that healthy postmenopausal women should not use estrogen/progestin to prevent chronic disease. part of the study that compared estrogen/progestin with placebo early. The DSMB recommended stopping the trial because women receiving the active drug had an increased risk of invasive breast cancer, and an overall measure suggested that the treatment was causing more harm than good. The decision to stop the trial after an average follow-up of 5.2 years (planned duration, 8.5 years) was made when these results met predetermined levels of harm. However, several other outcomes also suggested harm, including increased coronary heart disease, stroke, and pulmonary embolism. The beneficial results included reductions in colorectal cancer and hip fracture. The results of the WHI study are consistent with the growing body of literature on the effects of combination estrogen/progestin. In this study the increased risk of breast cancer associated with the duration of HRT and the reductions in the risk of colon cancer and fractures were in the expected direction and magnitude shown in the literature. The risk for stroke and venous thromboembolism continued throughout the 5 years of therapy, whereas the elevated risk of coronary heart disease was largely limited to the first year of therapy. The purpose of healthy women under-going long-term estrogen/progestin therapy is to preserve health and prevent disease. The results of this landmark study provide strong evidence that the opposite is happening, even if the absolute risk is low. The bottom line of the WHI study is VOL. 5 NO. 2 2003 REVIEWS IN UROLOGY 131 Hormonal Therapy continued that healthy postmenopausal women should not use estrogen/progestin to prevent chronic disease. What does this study mean to urologists? Unfortunately, no urological issues were assessed in the study. We think it is logical to extrapolate from the study results that estrogen/progestin must be considered unproven for the If hormone therapy is used for urological symptoms, the potential for harm may be greater than the unproven, perceived benefit. prevention or therapy of urological conditions such as urge or stress incontinence, overactive bladder, or UTIs unless these claims can be supported by well-designed and executed scientific studies. Moreover, if hormone therapy is used for urological symptoms, the potential for harm may be greater than the unproven, perceived benefit. Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer Lacey JV, Jr, Mink PJ, Lubin JH, et al. JAMA. 2002;288:334–341. In the same issue of JAMA, Lacey and colleagues reported the results of their follow-up study of a 1979-1998 cohort of women who were recruited to participate in the Breast Cancer Detection Demonstration Project, a nationwide breast-cancer screening program conducted at 29 U.S. centers. The objective of this study was to determine whether HRT using estrogen only, estrogen/progestin only, or estrogen only followed by estrogen/progestin increases the risk of ovarian cancer. More than 44,000 postmenopausal women (mean age at start of follow-up, 56.6 years) participated in the study. In 1979, the National Cancer Institute added questions concerning ovarian cancer and its suspected risk factors (including HRT) to the follow-up questionnaires. The analyses of these data by Lacey and colleagues show that women who used estrogen-only HRT had a significantly increased risk of later development of ovarian cancer. Everyone knows that elderly women frequently develop severe osteoporosis, resulting in a life complicated by constant back pain and repeated fractures. By the 1970s, it had become clear that the use of estrogenic substances at or near the time of menopause could prevent or treat osteoporosis, and these drugs became widely prescribed and taken for this purpose. Even before the bone-sparing effects of estrogen were known, these agents had been used extensively for the treatment of menopausal symptoms, primarily vasomotor 132 VOL. 5 NO. 2 2003 REVIEWS IN UROLOGY instability and vaginal atrophy. Estrogens were also thought to prevent coronary artery disease and to delay the onset of Alzheimer’s disease. It is not surprising that the pharmaceutical industry developed numerous estrogenic agents that could be swallowed, placed in the vagina, applied with a patch, or rubbed into the skin, and that these agents have been prescribed for and are now used by millions of women. However, recent secondary prevention studies provide compelling evidence that there is no protection against further cardiovascular events for women with coronary heart disease who take these agents, and there may be real harm. Lacey and colleagues identified 329 women who developed ovarian cancer during the follow-up. When adjusted for age, type of menopause, and use of oral contraceptives, the results showed that the use of estrogen only was significantly associated with ovarian cancer. The study concluded that women who used estrogen-only replacement therapy, particularly for 10 or more years, were at significantly increased risk of ovarian cancer. Women who used short-term estrogen/progestin–only replacement therapy were not at increased risk. Doctors who counsel women about HRT must consider the unique needs of each patient and attempt to weigh the benefits and risks of therapy on an individual basis. Currently, certain benefits such as prevention of osteoporosis and treatment of vasomotor symptoms are acknowledged. Any postmenopausal women who have not had a hysterectomy, however, should not receive estrogen only, as there is an unquestionable increased risk of endometrial, breast, and ovarian cancer. Urinary Tract Infections Management of Urinary Tract Infections in Children: Simplifying the Controversies? Reviewed by J. Curtis Nickel, MD Department of Urology, Queen’s University, Kingston, Ontario, Canada [Rev Urol. 2003;5(2):132-134] T he management of urinary tract infections (UTIs) in children has confused urologists for decades. The controversy regarding whom to investigate, how to