Recent clinical trials show that low-dose estrogen reduces the number of moderate to severe vasomotor episodes by 65%. This reduction is about midway between the 35% to 40% reduction observed with placebo and the 75% to 80% reduction observed with standard dosage. Compared with standard dosages whose effects are substantial by 4 weeks, relief with lower dosages is not maximal until 8 to 12 weeks. Women using lower dosages of estrogen experience 50% lower rates of irregular bleeding or breast tenderness compared with individuals taking standard dosages. Despite several lower dosage hormone therapy (HT) formulations being approved by the US Food and Drug Administration (FDA) and brought to market, their uptake by healthcare providers has been slow. Most women who have continued HT after reports of the Women’s Health Initiative (WHI) were published take estrogen at the standard dosage; only a minority of these individuals report receiving guidance about switching to a lower dosage. The purpose of this review is to summarize the clinical trial data showing, on one hand, effects of various dosages of estrogen on vasomotor symptoms and, on the other hand, the effects of these same doses on troublesome adverse events, particularly vaginal bleeding or breast tenderness. It is time to reconsider the current estrogen dosage recommendation on the basis of symptom benefit versus symptom nuisance. Furthermore, healthcare providers need to learn how and when to prescribe lower dosages of HT to optimize patient acceptance and continuation.
The purpose of this review is to summarize the clinical trial data showing, on one hand, effects of various dosages of estrogen on vasomotor symptoms and, on the other hand, the effects of these same dosages on troublesome adverse events, particularly vaginal bleeding or breast tenderness. It is time to reconsider the current estrogen dosage recommendation on the basis of symptom benefit versus symptom nuisance. Furthermore, healthcare providers need to learn how and when to prescribe lower dosages of hormone therapy (HT) to optimize patient acceptance and continuation.
Many expert groups, including the US Food and Drug Administration (FDA)
1US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Labeling Guidance for Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Prescribing Information for Health Care Providers and Patient Labeling [revision 1]. Rockville, MD: Division of Drug Information, Center for Drug Evaluation and Research; February 2004. Available at: http://www.fda.gov/cder/guidance/5670dft.doc. Accessed February 15, 2005.
and the American College of Obstetrics and Gynecology (ACOG),
2American College of Obstetricians and Gynecologists Women’s Health Care Physicians
Executive summary hormone therapy.
have suggested HT should be prescribed at the lowest possible dose for the shortest possible time. For the purpose of this review, 0.3 mg conjugated estrogens daily or its equivalent (e.g., 0.5 mg oral micronized estradiol, 25 μg transdermal estradiol, or 2.5 μg ethinyl estradiol) is considered low dosage.
Despite admonitions to use estrogen at lower dosages, recent nationwide surveys show that the vast majority of postmenopausal women continue to take the standard dosage.
3- Hersh A.L.
- Stefanik M.L.
- Stafford R.S.
National use of postmenopausal hormone therapy.
, 4- Buist D.S.M.
- Newton K.M.
- Miglioretti D.L.
- et al.
Hormone therapy prescribing patterns in the United States.
In the wake of publications from the Women’s Health Initiative (WHI), use of a lower dosage increased only about 6% in the ensuing 6 to 12 months.
3- Hersh A.L.
- Stefanik M.L.
- Stafford R.S.
National use of postmenopausal hormone therapy.
, 4- Buist D.S.M.
- Newton K.M.
- Miglioretti D.L.
- et al.
Hormone therapy prescribing patterns in the United States.
In part, this could be due to the lack of knowledge about the effectiveness, tolerability, and potential benefits of lower estrogen dosages.
In January 2003, the FDA published draft guidance for clinical evaluation of vasomotor symptoms.
5US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Recommendations for Clinical Evaluation[draft guidance]. Rockville, MD: Division of Drug Information, Center for Drug Evaluation and Research; January 2003. Available at: http://www.fda.gov/cder/guidance/5412dft.doc. Accessed February 15, 2005.
Included in this guideline are definitions of vasomotor symptoms and severity. Severity is defined as mild (sensation of heat without sweating), moderate (sensation of heat with sweating), or severe (sensation of heat with sweating, causing cessation of activity). To be included in studies, postmenopausal women must have a minimum of 7 to 8 moderate to severe vasomotor episodes per day or 50 to 60 per week. The FDA further defines the following 4 primary study end points with regard to moderate to severe vasomotor episodes: changes in frequency measured from baseline to 4 weeks; changes in frequency from baseline to 12 weeks; changes in severity from baseline to 4 weeks; and changes in severity from baseline to 12 weeks. Statistically significant differences from findings in control subjects must be shown at 4 weeks and sustained through 12 weeks.
The typical evolution of vasomotor symptoms during 12-week trials is schematized in
Figure 1.
6- Speroff L.
- Whitcomb R.W.
- Kempert N.J.
- Boyd R.A.
- Paulissen J.B.
- Rowan J.P.
Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.
, 7- Utian W.H.
- Burry K.A.
- Archer D.F.
- et al.
Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim®) compared with placebo on vasomotor symptoms in highly symptomatic patients.
, 8- Parsey K.
- Ellman H.
- Rajman M.
Transdermal Estradiol Investigators
Randomized, controlled comparison of transdermal estradiol with oral conjugated estrogens for the relief of hot flushes.
, 9- Speroff L.
- Symons J.
- Kempfert N.
- Rowan J.
The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (femHRT®) on the frequency and intensity of vasomotor symptoms.
, 10- Notelovitz M.
- Lenihan Jr, J.P.
- McDermott M.
- Kerber I.J.
- Nanavati N.
- Arce J.-C.
Initial 17β-estradiol dose for treating vasomotor symptoms.
, 11- Notelovitz M.
- Mattox J.H.
Suppression of vasomotor and vulvovaginal symptoms with continuous oral 17β-estradiol.
, 12- Utian W.H.
- Shoupe D.
- Bachman G.
- Pinkerton J.V.
- Pickar J.H.
Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogen and medroxyprogesterone acetate.
, 13- Utian W.H.
- Lederman S.A.
- Willimas B.M.
- Vega R.Y.
- Koltun W.D.
- Leonard T.W.
Relief of hot flushes with new plant-derived 10-component synthetic conjugated estrogens.
Dose-related effects are seen throughout, but differences among doses are greatest at 4 weeks and tend to be less after 8 to 12 weeks. In this typical scenario, given a mean frequency of 80 moderate to severe vasomotor episodes per week at baseline, the mean reductions observed after 12 weeks would be about 30 per week (38%) for placebo, 50 per week (63%) for low-dose estrogen, and 70 per week (83%) for standard-dosage estrogen. Based on the known variance in vasomotor episodes, a study will have 90% power to show differences of about 20 episodes per week if there are 50 evaluable subjects per group. Thus, most studies indicate statistically significant reductions from baseline to 12 weeks in all treatment groups (including placebo), but those with smaller numbers of subjects or those with fewer moderate to severe vasomotor episodes per subject are not expected to show statistically significant reductions with placebo or a lower estrogen dosage, especially at 4 weeks.
Table 1 shows 4- and 12-week reductions reported for low-dosage estrogens; these cluster around 50% at 4 weeks and 75% at 12 weeks.
6- Speroff L.
- Whitcomb R.W.
- Kempert N.J.
- Boyd R.A.
- Paulissen J.B.
- Rowan J.P.
Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.
, 7- Utian W.H.
- Burry K.A.
- Archer D.F.
- et al.
Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim®) compared with placebo on vasomotor symptoms in highly symptomatic patients.
, 8- Parsey K.
- Ellman H.
- Rajman M.
Transdermal Estradiol Investigators
Randomized, controlled comparison of transdermal estradiol with oral conjugated estrogens for the relief of hot flushes.
, 9- Speroff L.
- Symons J.
- Kempfert N.
- Rowan J.
The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (femHRT®) on the frequency and intensity of vasomotor symptoms.
, 10- Notelovitz M.
- Lenihan Jr, J.P.
- McDermott M.
- Kerber I.J.
- Nanavati N.
- Arce J.-C.
Initial 17β-estradiol dose for treating vasomotor symptoms.
, 11- Notelovitz M.
- Mattox J.H.
Suppression of vasomotor and vulvovaginal symptoms with continuous oral 17β-estradiol.
, 12- Utian W.H.
- Shoupe D.
- Bachman G.
- Pinkerton J.V.
- Pickar J.H.
Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogen and medroxyprogesterone acetate.
, 13- Utian W.H.
- Lederman S.A.
- Willimas B.M.
- Vega R.Y.
- Koltun W.D.
- Leonard T.W.
Relief of hot flushes with new plant-derived 10-component synthetic conjugated estrogens.
These 12-week reductions are about twice those observed with placebo, but less than the 80% to 85% reductions typically observed with the standard estrogen dosage. In the United States, several half-strength estrogens are approved for reduction of vasomotor symptoms, and the FDA guidance for labeling estrogen products states, “patients should be started at the lowest dose”
1US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Labeling Guidance for Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Prescribing Information for Health Care Providers and Patient Labeling [revision 1]. Rockville, MD: Division of Drug Information, Center for Drug Evaluation and Research; February 2004. Available at: http://www.fda.gov/cder/guidance/5670dft.doc. Accessed February 15, 2005.
; only if there is lack of adequate response should the dosage be increased.
Table 1Percentage reductions in frequency of moderate to severe vasomotor episodes observed with various low-dosage estrogen formulations
CEE = conjugated equine estrogens.
Compared with women using standard dosages, those using low dosages of estrogens are less likely to have unacceptable side effects, such as irregular or heavy bleeding (
Table 2)
7- Utian W.H.
- Burry K.A.
- Archer D.F.
- et al.
Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim®) compared with placebo on vasomotor symptoms in highly symptomatic patients.
, 10- Notelovitz M.
- Lenihan Jr, J.P.
- McDermott M.
- Kerber I.J.
- Nanavati N.
- Arce J.-C.
Initial 17β-estradiol dose for treating vasomotor symptoms.
, 14- Trabal J.F.
- Lenihan J.P.
- Melchione T.E.
- et al.
Low-dose unopposed estrogens preliminary findings on the frequency and duration of vaginal bleeding in postmenopausal women receiving esterified estrogens over a two-year period.
, 15- Archer D.F.
- Dorin M.
- Lewis V.
- Schneider D.L.
- Pickar J.H.
Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding.
or breast tenderness (
Table 3).
6- Speroff L.
- Whitcomb R.W.
- Kempert N.J.
- Boyd R.A.
- Paulissen J.B.
- Rowan J.P.
Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.
, 7- Utian W.H.
- Burry K.A.
- Archer D.F.
- et al.
Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim®) compared with placebo on vasomotor symptoms in highly symptomatic patients.
, 12- Utian W.H.
- Shoupe D.
- Bachman G.
- Pinkerton J.V.
- Pickar J.H.
Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogen and medroxyprogesterone acetate.
, 13- Utian W.H.
- Lederman S.A.
- Willimas B.M.
- Vega R.Y.
- Koltun W.D.
- Leonard T.W.
Relief of hot flushes with new plant-derived 10-component synthetic conjugated estrogens.
, 16- Notelovitz M.
- John V.A.
- Good W.R.
Effectiveness of Alora® estradiol matrix delivery system in improving lumbar bone mineral density in healthy, postmenopausal women.
Compared with the standard dosage, the lower dosage typically produces half the incidence of these 2 side effects. Women less troubled by local breast symptoms are likely to perceive the lower dosage as being safer, and this perception is quite important in their commitment to long-term use. Because discontinuation of HT is largely due to unacceptable side effects (e.g., bleeding and breast tenderness),
17- Ettinger B.
- Pressman A.R.
Effect of age on reasons for initiation and discontinuation of hormone replacement therapy.
long-term continuance may be improved if lower dosages are given.
Table 2Incidence of vaginal bleeding in clinical trials (by dosage of estrogen)
CEE = conjugated equine estrogens.
Table 3Incidence of breast tenderness in clinical trials (by dosage of estrogen)
When prescribing low-dosage estrogen, one can safely use less progestin (either a lower daily dose or less frequent cycles). Although currently there is no consensus regarding the best dose and schedule for progestin cotherapy for either standard-dosage or low-dosage estrogens, adverse health outcomes in the WHI have prompted many to seek ways to reduce progestin exposure. Tolerability and endometrial safety of continuous combined low-dose HT has now been extensively studied.
18- Pickar J.H.
- Yeh I.-T.
- Wheeler J.E.
- Cunnane M.F.
- Speroff L.
Endometrial effects of lower doses of conjugated estrogens and medroxyprogesterone acetate.
, 19Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.
When using low-dosage estrogen, low-dose coprescribed progestin (e.g., 1.5 mg medroxyprogesterone acetate) is adequate to protect the endometrium from hyperplasia.
18- Pickar J.H.
- Yeh I.-T.
- Wheeler J.E.
- Cunnane M.F.
- Speroff L.
Endometrial effects of lower doses of conjugated estrogens and medroxyprogesterone acetate.
, 19Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.
Low-dose continuous combined regimens produce a much lower incidence of breakthrough bleeding compared with standard doses.
15- Archer D.F.
- Dorin M.
- Lewis V.
- Schneider D.L.
- Pickar J.H.
Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding.
, 19Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.
Among various cyclic HT regimens currently in use, monthly addition of 5 mg medroxyprogesterone for 12 days is most common. However, longer intervals between progestin additions are possible, particularly when using lower estrogen doses. A 3 monthly addition of 10 mg medroxyprogesterone for 14 days was demonstrated to be safe (about 1% per year endometrial hyperplasia rate) when added to standard-dosage estrogen
20- Ettinger B.
- Selby J.
- Citron J.T.
- et al.
Cyclic hormone replacement therapy using quarterly progestin.
and would be ample to protect the endometrium in women taking low-dosage therapy. When using low-dosage estrogen, 6 monthly progestin cycles also appear safe and tolerable
21- Ettinger B.
- Pressman A.
- VanGessel A.
Low-dosage esterified estrogen opposed by progestin at 6-month intervals.
; <50% of women using this regimen have any cyclic bleeding and only 9% have breakthrough bleeding between 6-month cycles. In unusual circumstances, unopposed low-dose estrogen with appropriate endometrial monitoring may be the best clinical choice despite the presence of the uterus. The annual rate of endometrial hyperplasia is about 15% in women exposed to standard doses of unopposed estrogen. Those receiving half-strength estrogen might be expected to show a 50% lower rate of hyperplasia (e.g., 7% to 8%), yet they appear to have little or no greater risk of hyperplasia than women receiving placebo.
14- Trabal J.F.
- Lenihan J.P.
- Melchione T.E.
- et al.
Low-dose unopposed estrogens preliminary findings on the frequency and duration of vaginal bleeding in postmenopausal women receiving esterified estrogens over a two-year period.
, 19Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.
Proliferation produced by estrogen is dose-related and low-dosage therapy produces approximately 50% as much endometrial growth as the standard dosage,
22- Ettinger B.
- Bainton L.
- Upmalis D.H.
- Citron J.T.
- VanGessel A.
Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women.
but there may be an estrogen threshold below which hyperplasia rarely develops.
Low-dose estrogen is likely to become the preferred HT option because of its superior tolerability and greater potential for patient acceptance. Healthcare providers should now make every attempt to reduce dosages to the lowest level acceptable (i.e., controls menopausal symptoms). Apparently, however, dose reduction is not being widely practiced.
23The 2004 Gallup Study of Women’s Experiences with Hormone Replacement Therapy. Princeton, NJ: Multi-sponsor Surveys, Inc. Catalog No. 257. Available at: http://www.multi-sponsorsurveys.com. Accessed February 17, 2005.
In 2004, a survey of women aged ≥45 years who were current users of HT and who had consulted their physicians in the prior 2 years showed that only 28% reported that their provider had recommended a lower dosage.
23The 2004 Gallup Study of Women’s Experiences with Hormone Replacement Therapy. Princeton, NJ: Multi-sponsor Surveys, Inc. Catalog No. 257. Available at: http://www.multi-sponsorsurveys.com. Accessed February 17, 2005.
Women being started on low-dosage estrogen should be counseled that relief of vasomotor symptoms will take some time (not becoming maximal until 8 to 12 weeks) and that some vasomotor episodes are likely to persist (at about one third the previous rate). For women continuing standard HT, providers should attempt dosage reduction. In a study measuring symptoms in women switching from standard to half-strength estrogen dosage, only 6.5% returned to the standard dosage because of unacceptable vasomotor symptoms.
21- Ettinger B.
- Pressman A.
- VanGessel A.
Low-dosage esterified estrogen opposed by progestin at 6-month intervals.
Gradual tapering of the dosage can be accomplished by alternate day oral therapy or by reduction in transdermal patch strength.
Summary
Low-dosage estrogen relieves vasomotor symptoms and has a low rate of unacceptable side effects, such as troublesome bleeding or breast tenderness. Now that several lower dosage formulations are FDA approved and being actively marketed, healthcare providers and their patients should consider these new options that are currently used infrequently. Furthermore, it is now appropriate to plan studies of low-dose estrogen to document adequately its risks and benefits.
References
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Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.
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Suppression of vasomotor and vulvovaginal symptoms with continuous oral 17β-estradiol.
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Effect of age on reasons for initiation and discontinuation of hormone replacement therapy.
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Article info
Footnotes
The opinions offered at the National Institutes of Health (NIH) State-of-the-Science Conference on Management of Menopause-Related Symptoms and published herein are not necessarily those of the National Institute on Aging (NIA) and the Office of Medical Applications of Research (OMAR) or any of the cosponsoring institutes, offices, or centers of the NIH. Although the NIA and OMAR organized this meeting, this article is not intended as a statement of Federal guidelines or policy.
Publication of the online supplement was made possible by funding from the NIA and the National Center for Complementary and Alternative Medicine of the NIH, US Department of Health & Human Services.
Copyright
© 2005 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
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