Hormone Replacement Therapy
Use of Hormone Replacement Therapy by Postmenopausal Women in the United States.
NL Keating et al (Harvard Med School, Boston; Univ of Massachusetts, Amherst).
Ann Intern Med 130: 545-553, 1999.
Sociodemogrpahic factors, such as place of residence and educational level, may be more strongly associated with HRT use than clinical factors, such as risk of cardiovascular disease. Future research should focus on understanding such sociodemographic variations, identifying which groups are most likely to benefit from HRT, and targeting therapy to them.
Editorial comments: The results of this 1995 nationwide survey indicate that about one third of US women aged 50 to 74 years use some form of HRT. Compared with earlier surveys the overall incidence of HRT use in the United States appears to be increasing. It is of interest to note that 45% of the women in this age group who were surveyed had undergone hysterectomy. Nearly 60% of the women who had a hysterectomy were using HRT, compared with only 20% of the women with intact uteri. Concerns about uterine bleeding and progestin side effects appear to reduce HRT use among women with intact uteri.
Hormone Replacement Therapy and Risk of Hip Fracture: Population Based Case – Control Study.
Michaelson K, for the Swedish Hip Fracture Study Group (Univ Hosp, Uppsala, Sweden; Dartmouth Med School, Hanover, NH; Karolinksa Inst, Stockholm; et al). BMJ 316: 1858-1863, 1998.
Optimal fracture protection requires recent HRT use, although treatment can start several years after menopause. The protective effect increases with the duration of use. An estrogen-sparing effect is achieved when the regimen contains progestins.
Editorial comments: There is much useful clinical information in this large population based, case control epidemiology study. The data indicate that long-term use of postmenopausal HRT is necessary to optimally reduce the risk of hip fractures. Since hip fractures usually occur after age 70, women need to take estrogen at least to this age and older as protection against hip fracture disappears 5 years after stopping HRT. The data also demonstrated greater protection against hip fracture when a progestin was added to the estrogen.
Low Dose Estrogen and Calcium Have an Additive Effect on Bone Resorption in Older Women.
KM Prestwood, DL Thompson, AM Kenny, et al (Univ of Conn, Farmington; Univ of Heidelberg, Germany). J Clin Endocrinol Metab 84: 179-183, 1999.
For bone resorption, there is an additive effect of low dose estrogen and calcium. However, there was no effect in older women for bone formation. In older women, the combination of low dose estrogen plus calcium is likely to be more effective than either treatment alone.
Editorial comments: The results of this short-term study in which markers of bone metabolism were measured in older women suggest that the addition of calcium supplementation and vitamin D to estrogen replacement prevents bone resorption to a greater extent than the use of estrogen alone. Clinicians should encourage postmenopausal women to ingest between 1200 and 1500mg of calcium daily and 400 to 800 international units of vitamin D in addition to taking estrogen replacement for maximal prevention of bone loss.
SM Gapstur, M Morrow, TA Sellers (Northwestern Univ, Chicago; Mayo Clinic/Found, Rochester, Minn)
Hormone Replacement Therapy and Risk of Breast Cancer with a Favorable Histology: Results of the lowa Women’s Health Study.
JAMA 281: 2091-2097, 1999.
Editorial comment about this article – Numerous epidemiologic studies have investigated the relationship between postmenopausal estrogen use and risk of breast cancer. The results of these observational studies differ; some report a small increased risk and others show no relation. The major finding of this large cohort study is that use of estrogen for either 5 or fewer years or more than 5 years was not associated with a significantly increased risk of all types of breast cancer. Hormone replacement did not increase the risk of the most common types of breast cancer, invasive ductal or lobular carcinomas, only the uncommon histologic types associated with a favourable prognosis. Thus the results of this study should be reassuring to women who are concerned about using hormone replacement because of a possible increased risk of development of breast cancer.
K Nanda, et al (Duke Univ, Durham, NC)
Hormone-Replacement Therapy and the Risk of Colorectal Cancer: A Meta-analysis.
Obstet Gynecol 93: 880-888, 1999
Conclusion – Among recent postmenopausal HRT users, the risk of colon cancer may be decreased. In HRT users, the risk of fatal colon cancer may also be lower, although data are limited.
This meta-analysis of studies performed to determine the relation of use of HRT to colon cancer found that use of HRT was associated with a significant reduction in risk of developing colon cancer. A similar reduction was noticed in the large Nurses’ Health Study. The risk of developing rectal cancer with HRT was reduced in the Nurses’ Health Study, but not in this meta-analysis. In both the Nurses’ Health Study and the meta-analysis, the protective effect of HRT was limited to current or recent use. Postmenopausal women who are deciding whether or not to use HRT should be informed about these data.
Hormone Replacement Therapy and the Risk of Epithelial Ovarian Carcinoma: A Meta-analysis.
PP Garg, et al (Johns Hopkins Univ, Baltimore, Md; Univ of California, San Francisco) Obstet Gynecol 92:474-479, 1998.
A search through Medline of studies published in a 30 year period was conducted to examine the association of HRT and ovarian cancer.
Conclusion – An increased risk of developing epithelial carcinoma of the ovary may be associated with prolonged use of hormone therapy by postmenopausal women, particularly longer than 10 years. However, there is still not enough epidemiologic evidence to infer causality.
This meta-analysis of published observational studies shows a small increased risk of developing epithelial ovarian carcinoma associated with postmenopausal HRT. However, as the authors conclude, there is not enough epidemiologic evidence to infer that a causal relation exists between HRT and invasive ovarian carcinoma. Certain criteria described by Bradford Hill need to be present to conclude that causality exists between an intervention and an event in observational studies such as those analyzed in this study. One of these criteria is strength of association, which was very weak in this analysis with an odd ratio of 1.15. The increased risk of 1.27 with more than 10 years of hormone use was of borderline statistical significance as the confidence intervals reached 1. Another criterion is consistency in the studies As Table 1 shows the findings of the various studies are inconsistent. Some report no risk, and others report a slightly increased risk of ovarian cancer with use of hormone replacement therapy. Therefore, these do not appear to have sufficient strength to affect the decision of a woman regarding the use of hormone replacement therapy.
Putting the Risk of Breast Cancer in Perspective.
K-A Pillips, et al (Princess Margaret Hosp, Toronto; Ontario Cancer Genetics Networks, Canada; Cancer Care Ontario, Toronto)
N Engl J Med 340: 141-144, 1999.
Background – Women tend to overestimate their risk of breast cancer. This occurs in part because the “1 in 9” statistic often quoted in the media is based on the cumulative lifetime risk for a women aged 85 years or older, yet breast cancer is uncommon at younger ages.
Method :The 1995 Ontario Cancer Registry was examined to determine, based on a cohort of 1000 women, the number who died of breast cancer, lung cancer, or cardiovascular causes (including cerebrovascular events).
Findings: The greatest proportion of deaths caused by breast cancer occurs in middle-aged women, in whom 20% of all deaths are caused by breast cancer. However, at other ages, the proportion of deaths resulting from cardiovascular disease is greater than that caused by breast cancer, particularly for women aged 60 years or older. The proportion of deaths resulting from lung cancer is similar to that caused by breast cancer, with breast cancer deaths peaking in middle age and lung cancer deaths peaking between 50 and 69 years of age.
Conclusion drawn from this study as well as other studies have shown that more women primarily fear cancer (61%) rather than cardiovascular disease (9%), when actually cardiovascular disease is the greatest killer. Better education about the risk of breast cancer is needed, so that patients will not forego important therapies (such as estrogen replacement therapy) for the fear of developing breast cancer.
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.
Peyman Hadji, Olaf Hars et al (Department of Gynaecology & Obstetrics, Marburg, Hamburg, Heildelberg, Germany)
Assessment by quatitative ultrasonometry of the effects of hormone replacement therapy on bone mass.
Am J Obstet Gynecol, March 2000, 182: 529-34
Objective: This study was undetaken to evaluate the impact of hormone replacement therapy on results of quantitative ultrasonometry of the heel.
Study Design: A total of 2006 healthy perimenopausal women (mean age, 52.2) were recruited in 5 German centers: 611 women (30%) had received hormone replacement therapy and 1395 (70%) had not.
Results: Women who were using hormone replacement therapy had significantly higher values (p<.001) than did nonusers for all ultransonographic variables, even after controlling age and body mass index. Women who had used hormone replacement therapy for >3 years had significantly higher values (P<.001) than did matched control subjects for all variables. Differences increased with the duration of hormone replacement therapy use.
Conclusion: Quantitative ultrasonometric measurement at the heel differentiates hormone replacement therapy users from nonusers, reflects duration of hormone replacement therapy use, and could be useful in both clinical trials and patient management.
Lars Ake Mattsson, MD, a Claus Christiansen, PhD, b Jean-Claude Colaue, MD, c Santiago, Palacios, MD, f Peter Kenemans, Bergeron, PhD, d Olivier Chevallier, MD, e Thomas Von Holst, MD, h and Kevin Gangar, MDI [ Goiteborg, Sweden, Ballerup, Denmark, Suresnes, Cergy Pontoise, and Paris, France, Madrid, Spain, Amsterdam, The Netherlands, Heidelberg, Germany, and Ashford, United Kingdom]
Multinational, Double-blind, parallel-group study on Clinical Equivalence of Intranasal and Oral 17b-estradiol for Postmenopausal Symptoms
American Jr. Obstetrics & Gynecology, March 2000, Volume 182, Number-3,
Study Design – In which, 659 postmenopausal women with moderate to severe postmenopausal symptoms intranasal were randomly assigned to receive either 300 mg/d in tranasal 17b-estradiol [S211400] or 2 mg/dl oral micronized estradiol, plus the appropriate placebo, for 24 weeks. All patients also received 10 mg/d dydrogesterone for 14 days per 28-day cycle.
Conclusion – Intranasal administration of 300 mg/d estradiol was at least as effective as oral administration of 2 mg/d estradiol in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the first-pass effect.
Pierre Fugere, MD, a Wim H, Scheele, MD, b Aarti Shah, PhD, b Thomas R. Strack, MD, b Michael D, Glant , MD c, and Elaine Jolly, MDd [ Montreal, Quebec, and Ottawa, Ontario, Canada, and Indianapolis, Indiana]
Uterine Effects of Raloxifene in Comparison with Continuous-Combined Hormone Replacement Therapy in Postmenopausal Women
American Jr. Obstetrics & Gynecology, March 2000, Volume 182, Number-3, Pg. 568-574
Study Design- This randomized, double-blind 24-month study involved 136 postmenopausal women who received raloxifene 150 mg/d or conjugated equine estrogens 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d. After baseline evaluations, endometrial biopsy specimens wee obtained, and endometrial thickness was measured annually by means of transvaginal ultrasonography. Statistical analyses were performed with an intention-to-treat approach.
Results – It was found that in the raloxifene group 94.4% of biopsy specimens showed normal benign postmenopausal endometrium and the continuous-combined hormone replacement therapy only 78.7% of biopsy specimens showed normal benign postmenopausal endometrium. The Mean endometrial thickness was unchanged from baseline with raloxifene and was increased significantly by 0.5 mm at 12 months with continuous-combined hormone replacement therapy.
Conclusion – Raloxifene 150 mg/day did not increase endometrial thickness or cause endometrial proliferation in healthy postmenopausal women.
Samaras K, Hayward CS, Sullivan D, et al ( St Vincent’s Hosp, Darlinghurst, New South Wales, Australia; Royal Prince Alfred Hosp, Camperdown, New South Wales, Australia )
Effects of Postmenopausal Hormone Replacement Therapy on Central Abdominal Fat, Glycemic Control, Lipid Metabolism, and Vascular Factors in Type 2 Diabetes: A Prospective Study.
Diabetes Care 22: 1401-1407, 1999
Methods- Fourteen women participated in the 12-month prospective study. The mean age was 57.5 years, and the mean body mass index was 29.5 kg/m2. The women were assigned randomly to 6 months of observation or HRT before crossover. HRT included 2 mnths of conjugated equine estrogen (CEE), 0.625 mg daily, followed by 4 months of CEE and medroxyprogesterone, 5 mg daily.
Conclusions- for this group of postmenopausal overweight women with type 2 diabetes, HRT was associated with a decrease in central adiposity and an improvement in lipid metabolism and glycemic control. Weight status and cardiovascular parameters remained stable. Further research is needed to determine whether HRT-induced improvements in these cardiovascular risk factors reduce long-term cardiovascular morbidity and mortality.
Editorial comments: Of interest is the higher resting metabolic rate noted among women who were administered HRT.
I Bjorn, M Bixo, K S Nojd et al (Umed, Sweden)
Negative mood changes during hormone replacement therapy:
A comparison between two progestogens
Am J Obstet Gynecol, Dec.2000; 183: 1419-26
Objective: The aim of this study was to compare side effects of medroxyprogesterone acetate and norethindrone acetate during postmenopausal hormone replacement therapy in women with and without a history of premenstrual syndrome.
Study Design: Fifty-one postmenopausal women were randomly selected in a double-blind crossover study. The women received 2mg of estradiol continuously during five 28-days cycles and 10mg of medroxyprogesterone or 1mg of norethindrone sequentially for 12 days of each cycle. Daily symptom rating scales were kept.
Results : The women showed cyclic changes, with negative mood and physical symptoms culminating during the late progestogen phase and positive mood during the estrogen-only phase. Symptoms declined with time but remained after 5 months. Women with a history of premenstrual syndrome responded strongly to both progestogens. Medroxyprogesterone acetate induced less negative and more positive mood symptoms than norethindrone in women with no history of premenstrual syndrome. In both groups medroxyprogestoner caused more physical symptoms than norethindrone.
Conclusion: The addition of medroxyprogesterone to estrogen is preferable to norethindrone with respect to mood symptoms in women without a history of premenstrual syndrome.
G Khastgir and J Studd (London, United Kingdom)
Patients outlook, experience, and satisfaction with hysterectomy, bilateral oophorectomy, and subsequent continuation of hormone replacement therapy.
Am J Obstet Gynecol, Dec.2000; 183: 1427-33
Objective: To investigate patients opinions of hysterectomy, bilateral oophorectomy, and hormone replacement therapy and to evaluate whether their outlook and experience influenced the overall satisfaction and continuation of hormone replacement therapy.
Study Design: A questionnaire survey of 200 patients before and 2 years after hysterectomy with or without bilateral oophorectomy. Postoperatively all patients received long-term estradiol and testosterone replacement. The inquiries of patients views included (1) preoperative awareness of indication and outlook, (2) postoperative recovery, symptom relief, and experiences with hormone replacement therapy, (3) perceived benefits and problems, (4) changes in physical well-being, psychologic state, and sexual activity, (5) continuation of hormone replacement therapy, and (6) overall satisfaction.
Results: The outlook toward hysterectomy, bilateral oophorectomy, and hormone replacement therapy was positive in 77.4%, 87.1% and 76.3%, respectively. The experience was positive in the majority, with a satisfactory postoperative recovery (70.6%), complete symptom relief (77.9%), and minimal side effects with hormone replacement therapy (5.2%). The benefits included improved physical well-being (79.9%), lower depressive symptoms (32.0%), and better sexuality (31.4%). The continuation rate of hormone replacement therapy was 97.4%, and overall satisfaction were outlook toward hysterectomy and incomplete symptom relief.
Conclusion: The outcome of hysterectomy, bilateral oophorectomy, and hormone replacement therapy was satisfactory to most patients.
P.D. Delmas, B Pornel , et al (Lyon, France, Brussels, Belgium, Berlin, Germany, Haugesund, Norway and Warsaw, Poland)
Three-year follow-up of the use of transdermal 17b-estradiol (Menorest) participated in open-label extensions for a third year
Am J Obstet Gynecol, Jan.2001; 184: 32- 40
Study Design: Those patients originally randomly assigned to receive 17b-estradiol continued active treatment with dosage of 25, 50, 75, or 100 mg/d, whereas those originally randomly assigned to receive a placebo patch were switched to an active patch of identical size that delivered 17 b-estradiol at 25, 50, 75, or 100 mg/d. Follow up was conducted, and bone density and other parameters were compared.
Conclusion: The Menorest formulation of transdermal 17b-estradiol maintained bone mineral density gains in postmenopausal women and was well tolerated through a 3-year treatment period. It was also effective in reversing the initial bone loss associated with late commencement of therapy.
M B Sorensen, T Fritz-Hansen, et al (Copenhagen, Denmark)
Temporal changes in cardiac function and cerebral blood flow during sequential postmenopausal hormone replacement.
Am J Obstet Gynecol, Jan.2001; 184: 41-47
Objective: The purpose was to assess the temporal changes in cardiac function and cerebral blood flow during postmenopausal administration of estrogen with and without progestogen.
Study design: Sixteen postmenopausal volunteers were assessed during estradiol plus sequential norethindrone acetate and placebo in two 12 week periods. Temporal changes were measured by magnetic resonance flow mapping 8 times.
Results: Systemic vascular resistance was reduced during estradiol (-6.9%); P<.05), declined further during the addition of norethindrone acetate, and was accompanied by an increase in stroke volume (maximum increase, 5.2%; P<.05) without fluid retention. Both systolic (-5mm Hg; P=.03) and diastolic (-3mm Hg; P= .03) blood pressure were reduced during estradiol. Cerebral blood flow was reduced after 9 weeks of hormone replacement therapy (-37mL/min; P= .01) but increased to baseline after the addition of norethindrone acetate.
Comments: The addition of norethindrone acetate did not reduce the improved cardiac function induced by E2, which supports the use of this progestogen in women with heart disease.
Progestogen withdrawal is known to cause vasoconstriction in hormone-sensitive tissue such as the endometrium during the menstrual phase.
An overall neutral effect of combined HRT on the cerebrovascular circulation is supported by observational data.
Conclusions: Sequential hormone replacement therapy is associated with changes in cardiac function, which are of therapeutic potential in cardiovascular disorders. Sequential hormone replacement therapy exhibits an overall neutral effect on cerebral blood flow.
W. Zoma, R. S. Baker, U. Lang and K. E. Clark (Cincinnati, Ohio, and Giessen, Germany)
Hemodynamic Response to Tibolone in Reproductive and Nonreproductive Tissues in the Sheep
Am J Obstet Gynecol March. 2001; 184: 544-51
Objective : The authors sought to determine the hemodynamic effects of tibolone in reproductive and nonreproductive tissues in the nonpregnant ovariectomized sheep.
Study Design : Six ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, and coronary and uterine blood flow. A dose response curve was generated for intravenous tibolone (1.25, 2.5 and 5 mg) and compared with intravenous 17b-estradiol (1 mg/kg body weight).
To determine whether tibolone-related cardiovascular responses were estrogen receptor mediated and produced by nitric oxide, animals were treated on separate days with either estrogen receptor antagonist ICI 182, 780 or the nitric oxide synthase inhibitor, L-nitroarginine methyl ester.
Conclusion : Tibolone significantly increases coronary and uterine blood flow in ovariectomized ewes. The coronary and uterine vascular responses are mediated via an estrogen receptordependent mechanism and are produced mainly by nitric oxide.
Comments : The tibolone-related increase in cardiac output observed in the study is in agreement with the increase in cardiac output reported by Prelevic et al in postmenopausal women with type 2 diabetes mellitus treated with tibolone. The ability of tibolone to decrease triglycerides, prevent atherosclerotic lesion formation in cholesterol-fed ovariectomized rabbits, and increase coronary blood flow as observed in the present study suggests possible cardioprotective properties.
The increase in uterine blood flow by estrogen and tibolone, which is likely associated with an increase in vaginal blood flow, may explain the improvement in vaginal lubrication, reduction in dyspareunia, and increase in sexual satisfaction reported by postmenopausal women receiving either estrogen replacement therapy or tibolone.
C. Cure-Cure , and P. Cure-Ramirez (Barranquilla, Colombia)
Hormone Replacement Therapy for Bone Protection in Multiparous Women: When To Initiate It
Am J Obstet Gynecol March. 2001; 184: 580-3
Objective : Hormone replacement therapy is used in postmenopausal women to improve symptoms of menopause and to protect bone and the cardiovascular system. The authors evaluated the effects of parity in terms of number of deliveries on bone density and fracture risk at different ages.
Study Design : The authors evaluated 1875 Hispanic women ³50 years old (61.3 ± 8.3 years), 425 with a history of nonselective fractures and 1450 without previous fractures. Body mass index was 27.3 ± 4.3 kg/m2. Bone mineral densities were determined for the total body in 1468 cases, the femur in 221 cases, and the lumbar spine in 189 cases. Women were classified according to lifetime number of deliveries (from 0 to ³5), and bone mineral densities and odds ratios for fracture risk were calculated relative to the number of deliveries.
Results : Bone mineral densities in total body, pelvis, and legs and total calcium and total mineral contents increased (P < .001) with ³2 deliveries among women 50 to 59 years old but not among those ³70 years old. The prevalence of fractures was higher in nulliparous than in multiparous women at all ages. Fracture risk was lower in multiparous women at all age groups, including those ³70 years old (odds ratio, 0.47; 95% confidence interval, 0.26-0.84; P< .006).
Conclusion : Bone mineral density increases with the number of deliveries until the age of 69 years. Fracture prevalence and fracture risk are lower among multiparous women even at older ages. These findings suggest that hormone replacement therapy can be delayed until 65 years of age for multiparous women but should be initiated at the beginning of menopause for nulliparous women.
Comments : Schneider et al have suggested that long-term estrogen-therapy initiated after the age of 60 years seems to offer bone-conserving benefit almost equal to that gained by starting estrogen therapy at menopause.
Jean Marc Ayoubi, Renato Fanchin, et al
Uterorelaxing effects of vaginal progesterone: comparison of two methodologies for assessing uterine contraction frequency on ultrasound scans.
Fert & Ster. Vol.76(4), Oct.2001, pg.736
Objective: To assess the changes in uterine contractility induced by increasing doses of P administered to estrogenized women and to compare two methodologies for assessing uterine contraction frequency from ultrasound scans.
Interventions: P support set to duplicate the luteal phase was provided every 2 days by application of 1.125g of Crinone 4% and 8% or 2.25g of Crinone 8%, containing 45, 90 and 180mg of P per application, respectively.
Main outcome Measures : Changes in uterine contraction frequency following exposure to three doses of vaginal P on ultrasound scans analyzed by visualizing accelerated image sequences and using a previously described three-dimensional (3D)- derived approach.
Results: A decrease in uterine contraction frequency reached statistical significance on the third day of exposure to P without differences between the three dose groups. The two methods for measuring uterine contraction frequency on ultrasound scans were equivalent.
Conclusion : At all three doses studied, the vaginal P gel Crinone administered to estrogenized women induced a profound decrease in uterine contraction frequency that duplicated the changes in contractility described in the luteal phase of the menstrual cycle. Analyzing uterine contraction frequency on accelerated image sequences is as effective as our more complex approach based on identifying contractions on time mode graphs electronically reconstructed using 3D-software.
Using mock E2 and P cycles designed for recipients of donor egg IVF, authors observed and quantified the prompt and profound uteroquiescent effects exerted by P during the early luteal phase. On average, UC frequency decreased by 35% from day 15 to 20, with maximal effects already achieved on the fourth day of exposure to P. Hence, results confirm prior publications reporting of diminished UCs during the luteal phase and outlay the precise time course of this phenomenon.
From our data, authors see that a maximal decrease in UC frequency is achieved at the normal time of embryo implantation. However, study was limited by the lack of a control group. It is highly unlikely, however, that the significant decrease observed parallel with P exposure in all three dose groups could be due to another factor.
Despite original enthusiasm, one must humbly recognize the shortcomings of ultrasound-based analyses of uterine contractility. Ultrasounds provide reliable data on UC frequency. Unfortunately, this approach has so far failed to offer meaningful information on UC amplitude and direction of displacement despite numerous publications, extrapolating of conclusions from visual impressions.
Considering the stimulating effects of E2 on UC frequency, the markedly high levels of E2 seen in IVF-ET cycles are the likely culprits that hamper the relaxing effects of P in IVF-ET.
Further studies are needed to clarify the role of uterine contractility in sperm transport and uterine receptivity, notably in women with endometriosis.
Martina Doren, Alexander Rubig, et al
Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy.
Fert & Ster.vol.75(3), March 2001, pg.554-9
Objective: To determine serum parameters reflective of androgen status in postmenopausal women using two types of hormone replacement therapy (HRT).
Design: Randomized, double-blind, prospective 1-year trial of two oral HRT regimens.
Patients: 100 postmenopausal women ³ 45 years.
Interventions: Daily use of the progestogen tibolone (2.5mg; n=50) or continuous combined 17-b-estradiol (2mg) and norethindrone acetate (E+NA, 1mg; n=50)
Conclusions: Both regimens modify plasma androgens, DHEAS, and SHBG differently. Tibolone decreased the levels of SHBG and substantially increased free T and to a lesser extend increased DHEAS; this may reflect a modification of adrenal androgen production. Continuous combined estradiol and norethindrone acetate HRT suppressed the peripheral plasma androgens mediated by increased levels of SHBG.
Schmidt PJ, Nieman L, et al (NIH, Bethesda, Md)
Estrogen Replacement in Perimenopause-Related Depression: A Preliminary Report
Am J Obstet Gynecol 183: 414-420, 2000
Introduction: The potential role of estrogen in the treatment of depression was suggested more than 100 years ago. Yet, trials examining the use of synthetic forms of estrogen in the treatment of depression have had conflicting results. The effects of the short-term administration of estradiol replacement in 34 perimenopausal women meeting criteria for major or minor depression, especially in the absence of hot flushes, were examined.
Methods: The age of participants was 44 to 55 years. Women with perimenopausal-related depression were randomly assigned in double-blind parallel fashion to receive either 17b-estradiol or placebo for 3 weeks. Women receiving estradiol during the first 3 weeks continued to receive it for an additional 3 weeks. Those who received placebo crossed over to estradiol for 3 weeks. The outcome was evaluated by standardized mood rating scales and a visual analogue scale self-report instrument.
Results: A full or partial therapeutic response was observed in 80% of women receiving 17 b-estradiol and 22% of those receiving placebo.
Conclusion: Estradiol replacement effectively treated perimenopausal depression independent of its salutary effects on vasomotor symptoms. This response to estradiol occurred after 3 weeks of treatment; no further improvement was observed in mood after 6 weeks of estradiol replacement.
Natale V, Albertazzi P, et al (Univ of Bologna, Italy; Maternity Hosp, Bologna, Italy; Hull Royal Infirmary, England)
Exploration of Cyclical Changes in Memory and Mood in Postmenopausal Women Taking Sequential Combined Oestrogen and Progestogen Preparations
Br J Obstet Gynaecol 108: 286-290, 2001
Objective: Although estrogen has beneficial effects on mood and cognition, it must be used in conjunction with progesterone in postmenopausal women who have not had hysterectomies. Little is known about the effect of progesterone on cognition. The effects of progestrogens added to estrogens in sequential combined hormone replacement therapy on memory, mood, sleep, and libido were evaluated.
Methods: Between June and November 1999, 23 postmenopausal women aged 46 to 70 years, taking sequential combined hormone replacement therapy for an average of 15 months, were each interviewed 3 times during the estrogen-progesterone part of the cycle and 3 times during the estrogen-only part of the cycle. Memory, mood (as evaluated by the Sexuality Evaluation Schedule Assessment Monitoring) were assessed in both parts of the cycle.
Editor’s Comments: Other studies have shown that progestins have a negative effect on mood and sense of well-being. For this reason, lower dose of progestins given continously is now being used with greater frequency than the intermittent cyclic use of high doses of progestin. The fact that progestins may enhance memory is of interest and needs to be confirmed in other studies.
Bjorn I, Bixo M, et al (Univ Hosp of Umea, Sweden)
Negative Mood Changes During Hormone Replacement Therapy: A Comparison Between Two Progestogens
Am J Obstet Gynecol 183: 1419-1426, 2000
Conclusion: The addition of medroxyprogesterone to estrogen is preferable to that of norethindrone in terms of mood swings in women without a history of PMS.
Editor’s Comments: Women without a uterus should not be given progestin in addition to estrogen as there is no risk of adenocarcinoma of the endometrium.
For women with a uterus who do not tolerate any progestin, estrogen without a progestin can be administered for 5 days of each 7 days per week. The endometrial effect should then be monitored periodically by pelvic sonography or endometrial biopsy to determine whether endometrial hyperplasia has developed.
Shifren JL, Braunstein GD, et al (Massachusetts Gen Hosp, Boston; Cedars-Sinai Med Ctr, Los Angeles; et al)
Transdermal Testosterone Treatment in Women With Impaired Sexual Function After Oophorectomy
N Engl J Med 343: 682-688, 2000
Methods: During 3 consecutive 12-week treatments subjects were randomly assigned to receive either 2 placebo patches, 1 placebo patch and 1 transdermal testosterone patch (150 mg/day), or 2 testosterone patches (300 mg/day).
At baseline and and at the end of each treatment period, subjects completed the Brief Index of Sexual Functioning for Women (BISFW).
The mean composite PGWBI scores increased by 1 point with placebo, 2 points with lower-dose tetosterone, and 5 points with higher-dose testosterone (P = .04, higher dose vs placebo).
Conclusion: Transdermally delivered testosterone at 300 mg/day, in combination with oral conjugated equine estrogens, increased testosterone levels and improved sexual functioning and well-being after surgically induced menopause in these women.
Editor’s Comments: Bilateral oophorectomy in both premenopausal and postmenopausal women results in significantly decreased circulating testosterone levels. Decreased libido is a frequent symptom following bilateral oophorectomy. Parenteral administration of testosterone has been shown to increase libido, although there is no evidence that orally administered testosterone has a similar effect.
The administration of testosterone by the transdermal patches used in this study increased total, free and bioavailable testosterone levels and improved libido and sense of well-being without adversely affecting lipoprotein levels. When these patches become commercially available, they can be used to improve libido and sense of well being in women who have had bilateral oophorectomy and have problems with decreased libido and sexual enjoyment.
Torgerson DJ, Bell-Syer SEM (Univ of York, Heslington, England)
Hormone Replacement Therapy and Prevention of Nonvertebral Fractures: A Meta-Analysis of Randomized Trials
JAMA 285: 2891-2897, 2001
Methods and Findings: Among those aged 60 years or older, this effect was diminished.
Editor’s Comments: Finally, despite the different types and different doses of estrogen used in the trials reviewed, the majority of the studies- 15 of the 22 trials-reported a reduction in risk of nonvertebral fractures with estrogen use.
Mosekilde L, Beck-Nielsen H, et al (Aarhus Univ, Denmark; Odense Univ, Denmark; et al)
Hormonal Replacement Therapy Reduces Forearm Fracture Incidence in Recent Postmenopausal Women-Results of the Danish Osteoporosis Prevention Study
Maturitas 36: 181-193, 2000
Conclusion: The use of HRT in women in whom menopause had recently occurred may be an effective preventive measure to reduce the number of forearm fractures and possibly the total number of fractures in this population.
Editor’s Comments: This large, well-done prospective semirandomized clinical trial provides importat information about the effects of estrogen on bone when estrogen is given soon after menopause to a group of healthy women.
When estrogen therapy with a progestin (HRT) or unopposed therapy estrogen replacement therapy is given soon after menopause and is continued for 5 years, there is a significant reduction in forearm fractures and in all fractures compared with women who did not take estrogen. It was interesting that the risk of spinal fractures was increased among all participants who took estrogen compared with those who did not (relative risk [RR], 1.80; 95% CI, 0.81-3.96) but was decreased among the 395 women who continued with their hormones for 5 years compared with the 977 who never took hormones (RR, 0.74; 95% CI, 0.20-2.70). This finding indicates that women who stopped taking hormones before 5 years had an increased risk of spinal fractures.
It is also reassuring that in this semirandomized study the risk of having breast cancer was insignificantly reduced among women taking hormones (RR, 0.68; 95% CI, 0.24-1.90) compared with those who did not. Studies of the effect of other agents, such as raloxifene, alendronate, and risedronate, on bone loss have been restricted to women who already have osteoporosis; the studies did not include healthy women, as was done in this study.
These results support the findings observed in several other observational studies, that is, estrogen use in postmenopausal women with osteoporosis prevents bone loss and fractures.
Godsland IF (Imperial College, London)
Effects of Postmenopausal Hormone Replacement Therapy on Lipid, Lipoprotein, and Apolipoprotein (a) Concentrations: Analysis of Studies Published From 1974-2000
Fertil Steril 75: 898-915, 2001
Methods and Findings: Oral estrogen regimens increased triglyceride concentrations, and transdermal estradiol 17-b decreased triglyceride concentrations. Tibolone reduced HDL cholesterol and triglyceride concentrations. Raloxifene decreased LDL cholesterol concentrations.
Conclusion: Route of estrogen administration and type of progesterone determine the differential effects of HRT on lipid and lipoprotein concentrations in postmenopausal women. Further research is needed to interpret the clinical significance of these changes.
Editor’s Comments: This is an excellent summary of the published data regarding the effect of different types of estrogen, with and without different types of progestin, upon the lipid profile in healthy women. Pharmacologic agents, such as statins, which lower LDL cholesterol are associated with a decrease in myocardial infarction and major coronary artery events.
One would expect that the beneficial changes caused by postmenopausal estrogen use upon the lipid factors is a major reason why estrogen replacement therapy given to healthy women has been associated with a reduced incidence of coronary heart disease. Clinicians should consider the extent of the attenuation of the beneficial effect of estrogen upon the lipid factors caused by different types, doses, and regimens of progestins when deciding which type and dose of progestin should be added to the estrogen component in postmenopausal women with a uterus.
Grodstein F, Manson JE, et al (Harvard Med School, Boston)
A Prospective Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease
Ann Intern Med 133: 933-941, 2000
Conclusion: There was a modest increase in risk of stroke among women taking 0.625 mg or more of conjugated estrogen daily and those taking estrogen plus progestin.
Editor’s Comments: The Nurses Health Study is a large prospective observational cohort study involving more than 70,000 postmenopausal women who have been followed up since 1976. The results of this and many other observational studies of healthy women indicate that the use of estrogen, with or without a progestin, decreases the risk of coronary artery disease.
To support the causal relationship of estrogen and reduction in cardiovascular disease, data show that oral estrogen has a beneficial effect on serum lipids as well as on coronary artery blood flow. Nevertheless, there is controversy about the beneficial effect of estrogen on coronary artery disease because a randomized controlled trial of women with existing cardiac disease did not show that estrogen reduced subsequent cardiac events compared with placebo.
The results of this large observational study should enable clinicians to inform healthy postmenopausal women that both estrogen and estrogen plus progestin appear to reduce their likelihood of experiencing coronary artery disease but do not affect the possibility that they will have cerebrovascular disease.
HÆibraaten E, Qvigstad E, et al (Ulleval Univ, Oslo Norway; Parexel Medstat, LillestrÆm, Norway; et al)
Increased Risk of Recurrent Venous Thromboembolism During Hormone Replacement Therapy: Results of the Randomized, Double-Blind, Placebo-Controlled Estrogen in Venous Thromboembolism Trial (EVTET)
Thromb Haemost 84: 961-967, 2000
Introduction: Recent trials indicate a 2- to 4- fold increased risk for current users.
Methods: All participants were postmenopausal women younger than 70 years of age who had previous confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). Women were randomly assigned to treatment with either 2 mg estradiol plus 1 mg norethisterone acetate, 1 tablet daily, or placebo. The main outcome measure was recurrent DVT or PE.
Conclusion: Postmenopausal women younger than 70 years with prior VTE who were receiving continuous HRT had an estimated 2- to 4- fold relative increased risk of VTE. It is recommended that this treatment be avoided in this patient group.
Editor’s Comments: Several recent observational studies have found that women taking postmenopausal HRT have a 2- to 4- fold greater risk of developing VTE. Women with a prior history of VTE are at increased risk of developing recurrent VTE. The results of this randomized trial show that the risk of a subsequent VTE is increased about 5- fold if women with a prior episode of VTE are given a high (2 mg) oral dose of estradiol daily as compared with a placebo control group.
Thus, a prior history of VTE is at least a relative contradiction for oral HRT if the woman is not receiving anticoagulant therapy. It remains to be determined whether transdermal estrogen, which does not increase hepatic globulin production of factors that enhance thrombosis as much as oral estrogen, is also associated with an increased risk of VTE in women with a prior history of this problem.
The effect of lower doses of oral estrogen on the risk of VTE in women with a history of VTE also remains to be determined. Clinicians need to counsel women with a history of VTE about the increased risks of a subsequent event if they take oral HRT.
Ness RB, and the SHARE Study Group (Univ of Pittsburgh, Pa; et al)
Risk of Ovarian Cancer in Relation to Estrogen and Progestin Dose and Use Characteristics of Oral Contraceptives
Am J Epidemiol 152: 233-241, 2000
Introduction: Oral Contraceptives (OCs) are considered to be the most powerful known chemopreventive agents for ovarian cancer. Earlier trials have demonstrated that an OC with 50 mg or more of estrogen diminishes the risk of ovarian cancer. It is not known whether the newer, lower-dose formulations have this same protective effect. Reported are findings of population-based, case-control trial designed to address the impact of dose of OC on its association with ovarian cancer.
Results: Compared with never-users, the adjusted risk of ovarian cancer was decreased by 40% for OC users overall. Longer duration of use provided greater protection, independent of age at initiation.
Conclusion: The protection provided by OC against ovarian cancer seems to be independent of the dose of estrogen or progestin. The diminished risk of ovarian cancer from OC use continues for 30 or more years after discontinuation of the OC and is protective after relatively short durations of exposure (1 to 4 years).
Editor’s Comments: Many case-control and cohort studies have consistently shown that use of OCs reduces the risk of epithelial ovarian cancer. The protective effect persists for decades after the use of OCs has ceased. In this large population-based case-control study, a significant protection against development of ovarian cancer persisted for as long as 30 years after discontinuation of OC use and protection occurred with as little as 1 to 4 years’ total duration of OC use.
With 10 or more years of OC use, there was a 70% reduction in development of ovarian cancer. Most of the earlier studies reported that reduction in ovarian cancer risk occurred with higher OC dose formulations than those currently used.
In this study, a similar amount of protection occurred with the lower-dose OC formulations currently being used. In this study, as well as others, there is no information about the relation of formulations containing only 20 mg of ethinyl estradiol and the subsequent risk of developing ovarian cancer.
DiSaia PJ, Brewster WR, et al (Univ of California, Irvine; Chao Family Comprehensive Cancer Center, Orange, Calif)
Breast Cancer Survival and Hormone Replacement Therapy: A Cohort Analysis
Am J Clin Oncol 23: 541-545, 2000
Introduction: The use of hormone replacement therapy (HRT) after a diagnosis of breast cancer is 1 of the most emotionally charged issues in the field of oncology. Breast cancer survivors are the largest group of former cancer patients in the United States, so there is ample reason to examine this controversy. A matched cohort analysis was performed to examine the impact of HRT on mortality rate in breast cancer survivors.
Results: There was a survival advantage for breast cancer survivors who received HRT versus controls at 15 years after the diagnosis of breast cancer.
Conclusion: This analysis does not indicate that HRT use is associated with compromised survival. In fact, a survival advantage was observed for breast cancer survivors who elected HRT.
Editor’s Comments: About 175,000 women are initially diagnosed with breast cancer each year in the United States. About 70% of these women are still alive 5 years after their diagnosis.
A great deal of controversy and uncertainty exist as to whether to treat these women with estrogen replacement when they become postmenopausal, especially when vasomotor symptoms, atrophic vaginitis, or both develop.
There have been no prospective randomized controlled trials to determine the effect of giving estrogen to postmenopausal breast cancer survivors compared with withholding therapy. This matched-cohort analysis gives clinicians and women and some reassurance that administration of estrogen to women with a history of breast cancer does not increase their overall mortality rate. In fact, in this analysis, the women who took estrogen had a higher rate of survival. This information should be presented to women with a history of breast cancer to aid in their decision-making process regarding the use of exogenous estrogen.