Notelovitz Morris, Cassel Diane, Hille Darcy, et al, Gainesville, Florida, Collegeville, Pennyslvania, and Antony, France.
Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause.
Am J of Obstet & Gynec., Jan 2000p.7-12
The physiologic state of menopause is characterized by a progressive loss of ovarian function, with a resulting decrease in circulating estrogen concentration. The classic symptoms of estrogen deficiency after natural or surgical menopause are periods of episodic flushing and sweating. These symptoms, which are reported to develop in approximately 70% to 80% of postmenopausal women, appear to be directly correlated with the degree of estrogen deficiency. Hormone replacement therapy with oral or transdermal estrogen has been shown to be effective in alleviating the vasomotor symptoms of menopause and also in reducing associated risks of cardiovascular mortality and bone fractures. If given unopposed, however, the doses of estrogen required to provide symptom relief and protective benefits can increase the risk of endometrial hyperplasia and carcinoma. The addition of progestins to hormone replacement therapy regimens has been shown to successfully prevent such adverse endometrial effects without compromising the benefits of estrogen therapy.
Transdermal estrogen delivery systems for postmenopausal estrogen deficiency may have advantages with respect to oral therapy, such as improved convenience, controlled sustained release of estrogen, predictable absorption, lack of gastrointestinal side effects, circumvention of first-pass circulation through the liver, lower biliary cholesterol saturation index, slower metabolism to less-active estrogens, and potentially better compliance than with oral regimens. Moreover, a more physiologically appropriate estrogen/estradiol ratio is obtained and maintained than is achieved with oral hormonal replacement therapy regimens. It has been anticipated that transdermal delivery of progestins could confer similar advantages.
Preliminary experience with a combination estrogen plus progestin transdermal system suggested that administration in a sequentially worn regimen of a combination patch with an estrogen-only patch can successfully relieve menopausal symptoms and provide good cycle control. Norethindrone acetate, a progestin commonly used in hormone replacement therapy regimens, displays skin flux characteristics favorable for transdermal delivery. This study was designed to evaluate the efficacy of 3 dosage levels of transdermal norethindrone acetate (140,250, and 400 mg/d) when administered sequentially with continuous transdermal estradiol (50 mg/d) in reducing moderate to severe vasomotor symptoms associated with menopause.
Study design: This was a 12-week double-blind trial of 220 healthy postmenopausal women with ³8 moderate to severe hot flushes and sweating episodes per day.
Women were randomly assigned to wear transdermal placebo patches or a transdermal patch releasing 50 mg/day 17b-estradiol alone (Vivelle) for days 1 to 14 of each cycle and a combination patch releasing 50 mg/day 17b-estradiol plus 1 of 3 dosage levels (140, 240 or 400 mg/day) of norethindorne acetate (combipatch) for days 15 through 28.
Result : There was a significant reduction by the second week in the mean number of daily hot flushes from baseline to end point with all 3 doses of estradiol plus norethindrone acetate compared with placebo. Significant reductions in the mean intensity of hot flushes and sweating were also noted with estradiol plus norethindrone acetate compared with placebo. The incidences of adverse events with all 3 doses of estradiol plus norethindrone acetate and with placebo were comparable.
Conclusion: An estradiol plus norethindrone acetate transdermal delivery system administered in a continuous sequential regimen with transdermal estradiol was well tolerated and effective for the treatment of moderate to severe vasomotor symptoms in postmenopausal women
Kamali Parvis, Muller Tanja, Lang Uwe and III Clapp James F. Giessen, Germany and Cleveland, Ohio
Cardiovascular responses of perimenopausal women to hormonal replacement therapy.
Am J Obstet & Gynecol Jan 2000;182:17-22
Cardiovascular disease, in particular, coronary heart disease, remains the leading cause of death in most developed countries. The sociodemographic factors responsible for this appear to be dietary habit, increased incidences of both obesity and sedentary lifestyles, and increased longevity. For women there is strong evidence that postmenopausal estrogen deficiency increases age specific cardiovascular risk. Epidemiologic data show that coronary heart disease represents the leading cause of death among postmenopausal women and also among young women with estrogen deficiency after either surgically induced or premature menopause. Women in these groups who are treated with hormone replacement therapy have lower rates of coronary heart disease and also a 20% to 40% reduction in cardiovascular mortality rate. The mechanisms underling this beneficial effect are not completely understood, but estrogen replacement therapy does alter most women’s lipid profiles. Without estrogen replacement, low-density lipoprotein cholesterol levels rise dramatically and often exceed the levels observed in men. This increase is caused by a decrease in the number of low-density lipoprotein cholesterol receptors and is reversed by estrogen replacement therapy, which increases the number of low density lipoprotein cholesterol receptors, reduces circulating low-density lipoprotein cholesterol and lipoprotein concentrations, and raises high-density lipoprotein cholesterol levels.
Hormone replacement therapy also directly affects cardiovascular function. Estrogen is known to increase blood flow in reproductive tissues, skin, and myocardium and to relax coronary artery smooth muscle. Estrogen’s effects on cardiac structure and function in human beings, however, are controversial. Several uncontrolled studies have reported either an increase in ventricular wall thickness or an improvement in systolic and diastolic function; in contrast, the only randomized, double-blind, placebo-controlled, crossover trial to date reported that short-term estrogen replacement did not alter multiple parameters of cardiac structure and function.
The purpose of this study was to attempt to resolve this issue by serial evaluation of cardiovascular function in perimenopausal women before and during the first 21 weeks of combined hormone replacement therapy. The hypothesis was that combined hormone replacement therapy alters both central and peripheral cardiovascular parameters during the first several months of therapy.
Study Design: Serial estimates of blood pressure, heart rate, stroke volume, and venous capacitance were obtained before and at 1,5,9, and 21 weeks after the beginning of hormone replacement therapy with daily estradiol and intermittent norethindrone. Measurements were performed by means of electrocardiography, automated blood pressure measurement, echocardiography, and plethysmography.
Results: Hormone replacement therapy did not alter heart rate, blood pressure, or venous capacitance. End-diastolic volume and stroke volume was unchanged after 1 week of hormone replacement therapy, but rose thereafter. After 5 weeks of hormone replacement end-diastolic volume and stoke volume were increased by 13 ±5 cc and 9 ±2cc, respectively, and after 9 weeks the increase totaled 23±5ml and 17 ± 3ml, respectively. As a result cardiac output rose progressively to a level 1.1 ± 0.3 L/min (18%) greater than pretreatment values and systemic vascular resistance fell 15%. These changes were associated with a 3-fold increase in serum estradiol levels.
Conclusion : The studied regimen of hormone replacement therapy produces progressive cardiac remodeling and peripheral vasodilatation during the first 2 months of therapy.
Margolis Harold S, Handsfield H Hunter, Jacobs R Jake et al for the Hepatitis B-WARE Study Group.
Evaluation of office-based intervention to improve prevention counseling for patients at risk for sexually acquired hepatitis B virus infection.
Am J Obst. Gynec. 182, Jan 2000, 1-6
Hepatitis B virus infection remains a major public health problem in the United States, with an estimated 250,000 new infections annually during the past decade. Most infections occur among young adults, and most of these result from exposures during high-risk activities.
Sexual transmission accounts for >50% of hepatitis B virus infections, and although the proportion of infections attributable to men who have sex with men has declined the proportion of infections among persons with multiple heterosexual partners has increased.
Although hepatitis B vaccine has been available for almost 2 decades, vaccination of adults at high risk has been problematic. Until routine infant and adolescent vaccination has produced cohorts of adults protected against hepatitis B virus infection, however, large number of adults will continue to face the health and economic consequence of hepatitis B virus-related liver disease.
Except for those at occupational risk of hepatitis B virus infection, adults at risk have not been vaccinated for a number of reasons. These include lack of awareness by health care professionals and the public of risk factors for infection; lack of counseling concerning the disease, its consequences, and means of prevention; and lack of programs to vaccinate adults at risk for infection. Surveillance data indicate that between 30% and 40% of patients with acute hepatitis B had a previously diagnosed sexually transmitted disease as quoted in Unpublished observation by S Goldstein, et al for the Centers for Disease Control and Prevention.
These healthcare encounters for treatment of sexually transmitted diseases should be considered missed opportunities for hepatitis B vaccination. However, there have been few attempts to evaluate the feasibility of identifying persons at risk for sexually transmitted hepatitis B virus infection and providing counseling and vaccination.
The aim of this study was to determine the effectiveness of tools to identify and counsel patients at risk for sexually transmitted hepatitis B virus infection. Physicians were randomly assigned to either an intervention group or a control group. The intervention group was provided with materials intended to encourage patients to return for counseling and to guide counseling concerning prevention of hepatitis B virus infection. Baseline data on 457 patients at risk for hepatitis B virus infection showed that 7% had received prevention counseling and 2% had begun hepatitis B vaccination. Counseling was least likely to occur in obstetric-gynecologic practices, among uninsured patients, and among patients whose only risk factor was a diagnosis of a sexually transmitted disease. After a 6-month intervention period 25% of the intervention group patients and 7% of the control group patients had been counseled (P <. 01). Vaccination was more likely among intervention group patients (8% vs <1%; P<.001). The use of tools to identify and counsel patients at risk for sexually transmitted hepatitis B virus infection resulted in increased office-based prevention activities.