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Effects of Low-Dose Hormone Therapy on Menopausal Symptoms, Bone Mineral Density, Endometrium, and the Cardiovascular System: a Review of Randomized Clinical Trials

Posted on: Wednesday, 8 June 2005, 03:00 CDT

ABSTRACT

Objectives First, to determine the extent of the effects of low- dose hormone therapy (HT) on menopausal symptoms, bone mineral density, endometrium, and the cardiovascular system, and, second, to determine the adverse effects of low-dose HT.

Methods A literature review of electronic databases was conducted to identify all prospective, randomized trials comparing the effects of low-dose HT with placebo or standard-dose therapy, using key words such as: hormone replacement therapy (HRT), low-dose HRT/ conjugated equine estrogens (CEE)/estradiol, lower-dose HRT/CEE/ estradiol, ultra-low-dose HRT/CEE/estradiol, menopause, cardiovascular risk, bone metabolism.

Results Low-dose HT has been shown to improve menopausal and vulvovaginal atrophic symptoms, compared to placebo, and is less likely to give rise to unacceptable side-effects, including irregular bleeding and/or breast tenderness. When compared to standard-dose HT, the low-dose HT has comparable effects on a range of menopausal symptoms and on bone density and has similar beneficial effects on surrogate end-points of coronary heart disease.

Conclusions A change to low-dose HT has been advocated following adverse findings in recent trials of standard-dose HT. Although a literature review has shown low-dose HT to alleviate menopausal symptoms and maintain or improve bone density with fewer side- effects than standard-dose therapy, further research is required to determine what effect the lower-dose therapy will have on fracture, cardiovascular and breast disease.

Key words: LOW-DOSE HORMONE THERAPY, MENOPAUSAL SYMPTOMS, BONE MINERAL DENSITY, ENDOMETRIUM, CARDIOVASCULAR SYSTEM

INTRODUCTION

Following the release of data from both arms of The Women's Health Initiative randomized trial1,2 and The Million Women Study3, regulatory authorities and professional bodies4-9 have recommended that postmenopausal hormone therapy should be prescribed in the lowest effective dose.

Ideally, the dose regimen chosen should provide adequate alleviation of symptoms together with protection of the skeleton and endometrium whilst, at the same time, minimizing unwanted side- effects, including adverse cardiovascular outcomes and breast cancer.

To evaluate the efficacy of existing low-dose hormone therapy regimens, we carried out a literature review of low-dose HT. Different opinions exist on estrogen dosages that qualify as 'low dose'. In the USA, standard therapy for women has been regarded as 0.625 mg conjugated equine estrogens (CEE) or its equivalent. Some American commentators regard 1 mg of micronized estradiol amongst those equivalents. In Europe and the UK, the standard dose used was CEE 0.625 mg, micronized estradiol 2 mg or a transdcrmal patch containing 50 g of estradiol9-13. Dosages equivalent or below standard doses are generally considered low-dose HT, as in Table 1.

The objectives of the study were, first, to determine the effects of low-dose HT on menopausal symptoms, bone, endometrium, and the cardiovascular system, and, second, to determine the adverse effects of low-dose HT.

METHODS

We conducted topic-specific searches using electronic databases, including the MEDLINE database for the period January 1966 through December 2003 (limited to English-language articles). We used the medical subject headings: hormone replacement therapy (HRT), low- dose HRT/CEE/ estradiol, lower-dose HRT/CEE/estradiol, ultra-low- dose HRT/CEE/estradiol, menopause, cardiovascular risk, bone metabolism. The Cochrane Library was also searched. Additional studies were obtained by reviewing reference lists of pertinent studies, reviews and editorials. To be included in this review, the study must have been a prospective, randomized, clinical trial containing at least one low-dose HT group and clinical outcomes of interest.

Table 1 The classification of oral and transdermal doses of different estrogen preparations

We used vasomotor symptoms, quality of life and urogenital problems as the end-points of menopausal symptoms. Of the endometrial studies, we included only those which provided endpoint endometrial biopsy specimen assessments. Of the cardiovascular system studies, as there were no data on end-point cardiovascular disease, we assessed surrogate markers of cardiovascular health, including lipid profiles, inflammatory markers, lipoproteins, prothrombotic factors, coronary atherosclerosis, and cardiovascular function. Bone markers and bone mineral density were used to evaluate the effects of HT on bone health because no fracture data were available.

RESULTS

Effects of low-dose HT on menopausal symptoms

The results of this review (Table 2) showed that there was a significant reduction in vasomotor symptoms in low-dose HT groups, including oral or transdermal routes, unopposed or combined HT, and estradiol or CEE compared to placebo14-22. Symptoms decreased significantly by the third week after initiation of treatment14- 17,19-21 and reached a nadir during week 420, and were then maintained for the duration of treatment14-22.

No studies compared the efficacy of low-dose estradiol and conjugated estrogens or oral and transdermal delivery systems. We noted a trend suggesting that low-dose CEE combined with medroxyprogesterone acetate (MPA) may be better than equivalent low doses of unopposed CEE for vasomotor symptom relief17. This finding may be due to enhancement of symptom relief by MPA with doses of CEE lower than 0.625 mg.

Table 2 Studies of the effects of low-dose hormone therapy on menopausal symptoms

Table 2 Studies of the effects of low-dose hormone therapy on menopausal symptoms

Studies comparing low-dose (estrogen + progestin) and standard- dose HT (estrogen + progestin) showed no statistically significant difference between the two in the relief of vasomotor symptoms17,19,20,23-26, although a dose-related trend was seen in one study of unopposed transdermal estradiol replacement20.

Other menopausal symptoms, including somatic symptoms, psychological symptoms such as anxiety and depression, and sexual problems, were also decreased significantly after 3 weeks of treatment compared with placebo15,16. In one study14 of a validated quality-of-life system, the Women's Health Questionnaire, low-dose HT was shown to improve overall scoring on menopausal quality of life, including vasomotor symptoms. Another study27 showed no significant difference between low-dose HT and placebo on menopausal scores by the Kupperman Index, psychological well-being and quality of life. These findings may be affected by the population studied, which had low menopausal symptoms, anxiety and depression levels, and also had high quality-of-life scores.

Both oral and transdermal low-dose HT increased superficial cell counts in the vaginal maturation index and also improved urogenital symptoms17,28.

Effects of low-dose HT on the cardiovascular system

Conjugated equine estrogen 0.3 mg significantly increased levels of high density lipoprotein (HDL) cholesterol29-31 and reduced levels of low density lipoprotein (LDL) cholesterol29-33 and total cholesterol29,30,32,33 by the same order of magnitude as standard- dose HT. There were widely different effects on triglyceride levels. In some studies29,33, triglyceride levels significantly increased with the higher doses of 0.625 and 1.25 mg but decreased with the low-dose CEE 0.3 mg; one study32 showed no difference between CEE 0.3 mg and CEE 0.625 mg doses whilst others30,31 showed that low- dose CEE 0.3 mg increased triglyceride levels as much as standard- dose CEE 0.625 mg. There was no dose-related effect on LDL cholesterol or total cholesterol30.

Significantly increased levels of HDL cholesterol25,34,35 and reduced LDL cholesterol23,25,34-40 and total cholesterol23,25,37-40 were seen with orally administered estradiol 1 mg and transdermal estradiol 0.025 mg20. The effects of estradiol 1 mg on triglycerides were variable and, as with CEE, some studies showed no change23,34,36-39, whilst others reported a significant increase25,35,40. Relatively limited information on esterified estrogen at the low dose of 0.3 mg/day suggested lesser effect on HDL cholesterol, LDL cholesterol, and total cholesterol than at standard and high doses41. There was no dose dependency on the effects of total cholesterol, LDL cholesterol and HDL cholesterol23,25.

LDL particle size was decreased in the CEE 0.625 mg group but not changed in the low-dose CEE 0.3 mg group32. MDA-modified LDL was decreased in both the CEE 0.3 and 0.625 mg groups29. There was decreased susceptibility of LDL to oxidation in low-dose CEE 0.3 mg but no change in CEE 0.625 mg32. There were varying effects of HT on apolipoprotein A-1 (Apo A-1). One study31 showed that Apo A-1 was increased by both CEE 0.3 and 0.625 mg, but another33 showed a decrease in the CEE 0.3 mg group in contrast to the CEE 0.625 and 1.25 mg groups. One study31 showed that Apo B was decreased in both standard-dose and low-dose HT. The others33,40 showed no change with low-dose HT but a significant decrease with standard-dose and high- dose HT. Lipoprotein(a) was significantly decreased by both standard- dose and low-dose HT30,31,33,38

Low-dose HT decreased cell adhesion molecules, B\SR37, PAI-1, protein S, and antithrombin III activity31,40 and led to a decrease31,33,36,37,43 or no change40 in fibrinogen and factor VII activity. Low-dose HT did not increase C-reactive protein levels compared to placebo37. Minimal changes were observed in carbohydrate metabolism in the low-dose HT group31,40,42.

Some studies showed significantly increased blood flow at the forearm and brachial arteries in both low-dose and standard-dose groups29,30 and significantly decreased progression of atherosclerosis in low-dose compared with placebo35 groups. This latter finding was not consistent, however, and other studies showed low-dose HT did not inhibit progression of coronary, carotid, and femoral artery atherosclerosis34'36'43 and did not affect systolic cardiac function44.

Effects of low-dose HT on bone

Our review showed that low-dose HT (including oral or transdermal delivery, CEE, estradiol, or esterified estrogen) with adequate intake of calcium and vitamin D increased bone mineral density (BMD) at the spine16,41,45-56, femoral neck, and hip46-51,54,55 and decreased markers of bone turnover15,23,46,48,49,52,53,57,58 in both early and late postmenopausal women. Some studies15,41,45,52,53 showed that femoral neck BMD did not increase significantly in low- dose HT. This may be because, in most of these studies, younger women less than 60 years were recruited (mean age range, 51-58 years). These studies did show that low-dose HT maintained BMD compared to a significant decrease in the control group.

There was a trend towards a significant dose-response effect for spine41,45,49-51,54-56, but not for hip BMD47,49-51 which, at the spine, increased 2-6.2% in 1-4 years after low-dose HT treatment16,41,45-56. This was slightly less than for standard-dose HT which showed a 2.5-8.5% increase in BMD at the spine41,45,49- 51,54-56. Two studies56,58 showed that the combination of low-dose HT plus calcium is likely to be more effective than either treatment alone. They suggested that, in postmenopausal women, there appeared to be a synergism between low-dose HT and calcium.

Effects of low-dose HT on endometrium

In unopposed standard-dose estrogen therapy, the incidences of endometrial hyperplasia and cancer were 8-45.4%20,41,59-62 and 0.4%62, respectively after treatment for up to 3 years; these rates were significantly higher than for unopposed low-dose estrogen therapy, which showed endometrial hyperplasia of 0.37-7% and cancer of 0%20,41,59,60.

In sequential and continuous low-dose HT, the incidences of endometrial hyperplasia were 0%63 and 0-0.8%26,51,59,60,63-65, respectively, the same as in the untreated population59,60. This was also significantly less than standard-dose HT, for which the rates of endometrial hyperplasia were 0.5-5% and 0.4-0.8% in sequential and continuous standard-dose HT, respectively61,62,64.

In one study63, a well-differentiated endometrioid adenocarcinoma (FIGO stage 1A or 1B) was encountered in three of 442 (0.68%) women in the end-of-treatment biopsy: one in the sequential estradiol 1 mg/ dydrogesterone 5 mg group and two in the sequential estradiol 2 mg/ dydrogesterone 20 mg group. One malignancy occurring in a 58-year- old woman in the 1/5 mg group was diagnosed after 3.5 months in the study because of an irregular bleeding pattern. Her baseline biopsy had revealed cyclic-type proliferative endometrium. The other two malignancies were detected in the biopsies taken at cycle 13 in 49- year-old and 50-year-old women, both of which were in the 2/20 mg group. The baseline biopsies were scored as atrophic/inactive and insufficient, respectively. The incidence of endometrial carcinoma in this study was 0.68%, as compared to the Postmenopausal Estrogen/ Progestin Interventions (PEPI)61 trials in which the incidence was 0.8% in asymptomatic postmenopausal women not receiving HRT. Woodruff and Pickar62 found an incidence of endometrial cancer of 0.4%.

Safety and side-effect concerns with low-dose HT

The estrogen and progestin arms of The Women's Health Initiative (WHI) trial and the Million Study1,3 showed that current use of HT is associated with an increase of breast cancer risk. Although the recently published estrogen-only arm of WHI showed no increase in breast cancer risk for users of standard-dose (0.625 mg) unopposed CEE after more than 7 years2, the risk reported for users of comhined therapy using this dose of estrogen has led major professional societies and specialist Colleges to re-evaluate their recommendations for the use of HT, including advice to use the lowest effective dose of HT for the shortest time required for symptom relief4-9. However, at the moment, there are no studies that have examined the effect of low-dose HT on breast cancer risk or on mammography. Such studies should be initiated as a matter of urgency.

Since women commonly identify irregular or withdrawal bleeding and breast tenderness as obstacles to the use of HT66,67, in this review we used breast tenderness and endometrial bleeding to assess side-effects of low-dose HT. Many studies19,20,25,45,63,68-70 showed a dose-related effect on per vaginal bleeding with estrogens. During the first 3 months of continuous combined treatment19,48,52, 63-80% of low-dose HT users reported no bleeding, increasing to 82-97% after 12 months19,48,52,68, a higher rate of amenorrhea than that seen with standard-dose HT, which showed a 0-50% rate of amenorrhea in the first 3 months19, increasing to 60-75.5% after 12 months19,68. One study16 showed no difference in bleeding between low-dose HT and no treatment after 2 years.

The incidence of breast tenderness was higher in hormone treatment groups compared to placebo49,50,53,55,57,58 and also followed a dose relationship49,50,55,57, with a lower incidence observed with the low dose. One study46 showed no significant difference in breast tenderness between the estradiol 0.25 mg group and the placebo group.

DISCUSSION

The decline in estrogen that results from a reduction of the number of oocytes and cessation of ovarian sex hormone production leads to vasomotor and urogenital symptoms in many peri- and postmenopausal women. Conventional HT has been shown to significantly alleviate these symptoms71,72; however, recent studies have also highlighted an increased risk of breast cancer with HT use1,3, leading many women to prematurely discontinue their treatment, often with a consequent return of symptoms. Professional bodies and regulatory authorities have recommended that HT be used for the shortest period possible in the lowest effective dose4-9. Significant relief from hot flushes with low-dose HT has been found in this review and low-dose HT is also effective in treating urogenital symptoms that result from estrogen loss.

As there were no data on end-point cardiovascular disease, we assessed surrogate markers of cardiovascular health, including lipid profiles, inflammatory markers, lipoproteins, prothrombotic factors, coronary atherosclerosis, and cardiovascular function. Postmenopausal low-dose estrogens raised HDL cholesterol levels and lowered total and LDL cholesterol levels. Their effects on serum triglycerides were widely different.

Oral standard-dose estrogens induced increases in plasma triglyceride associated with reduced LDL particle size32,73,74. Some evidence suggests that this change in particle size may be associated with an increased risk of oxidative change and plaque instability in human coronary atherosclerotic lesions74. In this review, we found low-dose HT either decreased or did not change plasma triglyceride levels. Thus, low-dose HT may not reduce LDL particle size in the same way as the standard-dose HT. One study32 supports this hypothesis, showing that oral CEE 0.3 mg does not decrease LDL particle diameter or decrease oxidative susceptibility of LDL.

With regard to lipoprotein(a) level, it tended to be decreased with low-dose HT. However, there were varying effects on apolipoprotein and the reasons for the difference are still unclear.

Other changes seen in potentially protective surrogate markers of heart disease included either a decrease or no change in inflammatory markers, a decrease in endothelial markers37, a modest change in carbohydrate metabolism31,40,42, vasodilatation29,30, and a decrease in fibrinogen and factor VII activity31,33,36,37,43. Antithrombin III and protein S activity were decreased in several studies31,40 but plasminogen activity was increased and PAI-1 decreased31, perhaps leading to a neutral thrombotic effect.

We found that low-dose HT could not inhibit progression of atherosclerosis34,36,43, even though one study showed that the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed micronized 17β-estradiol 1 mg35. This may be an effect that is dependent on endothelial age and disease, as has been suggested by others76- 78.

In summary, this review shows that low-dose HT induces favorable changes in lipid profiles, lipoproteins, antioxidant effect, inflammatory markers and endothelial function and modest changes in carbohydrate metabolism and hemostatic factors. However, this review should be interpreted with caution, since the studies reviewed differed widely in design, quality, and a given formulation of HT. Whether favorable changes in surrogate markers of cardiovascular health induced by HT result in better cardiovascular outcomes remains unclear and further studies of hard end-points are required.

Low-dose HT combined with adequate additional intake of calcium and vitamin D produced a significant bone-sparing effect in both early postmenopausal and elderly women. The increase in lumbar spine BMD of 2-6.2%16,41,45-56 and femoral neck BMD of 0.5-2.9%46- 48,50,51,55 in 1-4 years after treatment with low-dose HT is slightly smaller than standard-dose HT and alendronate, but of a similar order to that seen with raloxifene, whichhas been shown to reduce vertebral fractures in postmenopausal women. In a 3-year study of raloxifene79 on vertebral fracture risk, the increase in lumbar spine BMD was 2.6% compared with placebo, and this was associated with 39% reduction in new vertebral fractures. The incidence of non-vertebral fractures did not decrease in this trial. Alendronate treatment resulted80 in 8.3% and 3.8% increases of BMD for lumbar spine and femoral neck, respectively after treatment for 4 years. These changes were associated with a 44% decrease in vertebral fractures and a 36% decrease in non-vertebral fractures. The difference in BMD changes between low-dose HT and standard-dose HT may be due to the lower doses used. Unlike trials of bisphosphonates, most studies of low-dose HT recruited women with more normal BMD or osteopenia, with only a small sample of women with osteoporosis.

It is thus not possible to say whether the improvements seen in bone density with low-dose HT will result in a decrease in fracture rates. Further prospective randomized trials on appropriate populations of postmenopausal women are required to answer this important question.

Since endometrial cancer has a relatively low incidence rate, the surrogate endpoint in clinical trials has mostly been the incidence of endometrial hyperplasia. Our review shows a lower level of endometrial hyperplasia for users of low-dose HT, whether it be unopposed estrogen, sequential or continuous combined estrogen and progestin therapy, when compared to higher doses. We were unable to draw any conclusions on endometrial cancer rates.

In summary, low-dose HT is an effective treatment of vasomotor symptoms and urogenital atrophy. Combination estrogen + progestin therapy provides adequate endometrial protection with higher early rates of amenorrhea and fewer side-effects than those seen with higher-dose regimens. Although there are no data for low-dose HT on clinical end-points in bone fracture and cardiovascular disease, our review found low-dose HT has favorable effects on surrogate markers of both these conditions.

Conflict of interest Nil.

Source of funding Nil.

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K. Peeyananjarassri and R. Baber*

Department of Obstetrics and Gynecology, Faculty of Medicine, Songklanagarind Hospital, Hat-Yai, Songkhla, Thailand; * Department of Obstetrics and Gynecology, Faculty of Medicine, Royal North Shore Hospital, University of Sydney, New South Wales, Australia

Correspondence: Dr K. Peeyananjarassri, Department of Obstetrics and Gynecology, Faculty of Medicine, Songklanagarind Hospital, Hat- Yai, Songkhla, Thailand, 90110

ORIGINAL ARTICLE

2005 International Menopause Society

DOI: 10.1080/13697130400012288

Received 05-05-04

Revised 11-07-04

Accepted 21-07-04

Copyright CRC Press Mar 2005

Source: Climacteric

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