J Studd, for the Aerodiol Study Group (chelsea and westminister Hosp, London et al
Efficacy and Acceptability of Intranasal 17b-Oestradiol for Menopausal Symptoms: Randomised dose-response study.)
Lancet 353: 1574-1578, 1999
The effectiveness of intranasally administered 17b-estradiol is similar to oral estradiol in reducing menopausal symptoms, and is significantly better than placebo. It is also well tolerated. First pass metabolism is avoided with intranasal administration. Representing a new option for hormone replacement therapy, it provides a reproductible, easily adjustable dosing mechanism.
Editorial comments: Post menopausal estrogen therapy is currently administered mainly by the oral and transdermal routes. The once daily intranasal route of administration is a unique way of administering estrogen that effectively reduces hot flushes more than placebo and similar to oral estradiol. It remains to be determined what the effect of intranasal estradiol is on parameters of bone loss, coronary atherosclerosis, and venous thrombosis. It will be interesting to observe the results of additional studies with this new method of administering estrogen to postmenopausal women.
SR Cummings, S Eckert, et al (Univ of California, San Francisco; Eli Lilly and Co, Indianapolis; Royal Marsden NHS Trust Hosp, Sutton, England; et al )
The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results from the MORE Randomized Trial.
JAMA 281:2189-2197, 1999
Background: Raloxifene hydrochloride, a selective estrogen receptor modulator, has been found to have antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. Whether women taking raloxifene have a lower risk of invasive breast cancer was determined.
Method :This multicenter, randomized, double-blind trial included 7705 postmenopausal women, with a mean age of 66.5. All had osteoporosis to start with.
Findings: Raloxifene reduced the risk of estrogen receptor-positive breast cancer by 90% but not estrogen receptor-negative invasive breast cancer. Raloxifene increased the risk of venous thromboembolic disease but not the risk of endometrial cancer.
Conclusions – In this study, raloxifene treatment reduced the risk of invasive breast cancer by 76% in postmenopausal women with osteoporosis and no previous history of breast cancer. This effect was primarily a result of the markedly decreased risk in estrogen receptor-positive breast cancer.
Editorial comment: Raloxifene was given to postmenopausal women with osteoporosis. Benefits included less breast cancer in the treatment group without the development of endometrial hyperplasia, which does occur with tamoxifen. Osteoporosis also was improved.
Problems include an increased risk of thromboembolism and persistence of hot flashes. Effects on ischaemic heart disease are not clear. Raloxifene did decrease low-density lipoprotein (LDL) but, unlike estrogen, did not increase HDL.
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.
Nina Hannover Bjarnason, Inger Byrjalsen, et al (Ballerup, Denmark)
Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss.
Am J Obstet Gynecol,183:550-60
Objective : The authors purpose was to study combinations of estradiol and gestogene for prevention of bone loss in early postmenopausal women.
Study Design: They randomly assigned 278 healthy, early postmenopausal women to receive either 2mg 17b-estradiol sequentially combined with 25mg gestodene (group 2/25s), 2mg estradiol sequentially combined with 50 mg gestodene (group 1/25s), 1mg estradiol continuously combined with 25mg gestodene (group 1/25c), or placebo.
Conclusion: These results demonstrate that estradiol therapy with 1mg estradiol is fully protective against early postmenopausal bone loss.
Hsu C-S, Shen WW, et al (Taipei Med Univ, Taiwan)
Soy Isoflavone Supplementation in Postmenopausal Women: Effects on Plasma Lipids, Antioxidant Enzyme Activities, and Bone Density
J Reprod Med 46: 221-226, 2001
Conclusion: In this study of postmenopausal women, isoflavone supplementation did not appear to have antioxidant effects. Supplementation with isoflavone alone may not have any hypocholesterolemic effects. Longer term studies are needed to clarify the bone-sparing effects of isoflavone supplementation.
Editor’s Comments: Isoflavones are not as beneficial as estrogen for the relief of vasomotor symptoms.
Yaffe K, Lui L-Y, et al (Univ of California, San Francisco; Univ of Pittsburgh, Pa)
Cognitive Decline in Women in Relation to Non-Protein-Bound Oestradiol Concentrations
Lancet 356: 708-712, 2000
Background: Previous research has found no correlation between total serum estradiol concentrations and cognitive function. However, these measures may not indicate hormone concentrations available to the brain. Whether concentrations of non-protein-bound (free) and loosely bound (bioavailable) sex hormones correlate with cognitive function in older women was determined.
Methods: Four hundred twenty-five women, aged 65 years and older, participated in the study. Free and bioavailable estradiol concentrations, as well as total and free testosterone, were assessed by radioimmunoassay in blood obtained at baseline. Cognitive performance was assessed by means of a modified mini mental status examination (mMMSE) at baseline and 6 years later.
Conclusion: Women with high levels of free and bioavailable estradiol in serum appear to be less likely to have cognitive impairments than women with low concentrations. The current data are consistent with the hypothesis that greater levels of endogenous estrogens prevent cognitive decline.