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Maturitas 59 (2008) 2–6
Ultra low-dose hormone replacement therapy and
bone protection in postmenopausal women
Marco Gambacciani ∗ , Barbara Cappagli, Massimo Ciaponi, Antonia Pepe,
Francesca Vacca, Andrea Riccardo Genazzani
Department of Obstetrics and Gynecology, Pisa University Hospital, Pisa, Italy
Received 28 January 2007; received in revised form 31 August 2007; accepted 22 October 2007
Abstract
Objectives: The aim of the present study was to evaluate the effects of low doses of hormone replacement therapy (HRT) in
normal young postmenopausal women.
Methods: In an open trial healthy, non-obese postmenopausal women received for 2 years a low-dose continuous combined HRT
(LD-HRT) containing 1 mg estradiol + 0.5 mg norethisterone acetate each pill for 28 days, or 0.5 mg of 17␤-estradiol and 0.25 mg
of norethisterone acetate (Ultra low dose, Ultra-LD-HRT) along with 1000 mg of calcium per day. Control group consisted of
women receiving only 1000 mg of calcium per day, for 2 years. Menopausal symptoms were evaluated by the Green climacteric
scale for the first 12 weeks of the study while bleeding profiles, bone mineral density (BMD) and bone turnover were assessed
for 24 months.
Results: LD-HRT and Ultra-LD-HRT were effective in reducing menopausal clinical symptoms. In the control group, BMD
significantly (P < 0.05) decreased at the spine (−2.8 ± 0.2%), and femoral neck (−2.8 ± 0.7%). In LD-HRT treated group BMD
showed a significant (P < 0.05) increase at the spine (5.2 ± 0.7%), and femoral neck (2.8 ± 0.4%) after 24 months. In the UltraLD-HRT treated women spine and femoral neck BMD showed a significant (P < 0.05) increase (2.0 ± 0.3 and 1.8 ± 0.3%,
respectively) after 24 months. In these women treated with LD-HRT and Ultra-LD-HRT the BMD values were significantly
(P < 0.05) different from those measured in calcium-treated women.
Conclusions: LD-HRT and Ultra-LD-HRT can alleviate subjective symptoms providing an effective protection against the
postmenopausal decrease of BMD.
© 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Menopause; Low-dose hormone replacement therapy; Bone mineral density; Osteoporosis
1. Introduction
∗ Corresponding author at: Department of Obstetrics and Gynecology “Piero Fioretti”, University of Pisa, Via Roma 67, 56100 Pisa,
Italy. Tel.: +39 050 592385; fax: +39 050 993058.
E-mail address: margamba@tin.it (M. Gambacciani).
Osteoporosis is a risk factor for fractures at all skeletal sites [1–2]. Estrogen deficiency is a key factor in
the pathogenesis of postmenopausal osteoporosis. The
0378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2007.10.007
M. Gambacciani et al. / Maturitas 59 (2008) 2–6
perimenopausal period is associated with a significant
bone loss [3,4]. In addition, an accelerated loss accompanies the cessation of ovarian hormone production [5].
Postmenopausal administration of hormones has been
used both to prevent and to treat osteoporosis [6,7]. Several studies have demonstrated that doses of 0.625 mg
of conjugated estrogens and 2 mg of 17␤-estradiol prevent early postmenopausal bone loss. [8–12]. Based
on various epidemiological and observational studies,
HRT users have a decreased risk of fracture [13–17],
and this reduction is confirmed by a clinical randomized trial, the Women’s Health Initiative (WHI)
trial [18,19]. The minimum effective dose of HRT
has been questioned. The usually prescribed dosage
of postmenopausal estrogen therapy has declined progressively and in the past 10 years, use of lower dose
HRT has grown in popularity. At present, the regimens containing 0.30 mg of conjugated estrogens, or
1 mg micronized oral 17␤-estradiol are considered lowdose HRT (LD-HRT). Various studies have assessed
the efficacy LD-HRT in the prevention of osteoporosis
in postmenopausal women [20–30], while providing
symptomatic relief from subjective symptoms associated with menopause and improving quality of life
(QoL) [31]. The aim of the present study was to further evaluate the effects of low doses of HRT in normal
postmenopausal women.
2. Materials and methods
This study was approved by Ethical Committee
of our Department and an informed consent was
obtained from each subject. Postmenopausal women
(PMW) included in the study were recruited from
the Climacteric Clinic of our Department. Women
had amenorrhea for at least 12 months before treatment, and plasma gonadotropin and estradiol levels
in the postmenopausal range for our laboratory
[follicle-stimulating hormone (FSH) > 40 U/L; estradiol (E2) < 25 pg/ml] [32]. All patients were without
diseases known to influence calcium metabolism and
none had history of glucocorticoid treatment. None
had been treated with hormones in the 12 months
before the study. In an open trial healthy, non-obese
postmenopausal women received for 2 years a lowdose continuous combined HRT (LD-HRT) containing
1 mg estradiol + 0.5 mg norethisterone acetate each pill
3
for 28 days, or 0.5 mg of 17␤-estradiol and 0.25 mg
of norethisterone acetate (Ultra-low-dose, Ultra-LDHRT) along with 1000 mg of calcium per day. Control
group consisted of women receiving only 1000 mg of
calcium per day, for 2 years.
The subjective symptoms were evaluated by the
visuoanalogic scale, and bleeding pattern was recorded
in diaries given to the patient to record the days and
characteristics of bleeding episodes during the observation period. The BMD (mg/cm2 ) of lumbar vertebrae
(L2-L4) was measured in supine position with the
legs elevated to minimize lordosis, by dual energy Xray absorptiometry using a Lunar DPX (Lunar Corp.,
Madison, WI, U.S.A.) [5]. The measurements were
performed at baseline and at the end of the 24-month
follow up. The long-term stability of the instrument was
assessed by measuring a spine phantom every other day
for a 2-year period, resulting in a coefficient of variation
of 0.5%.
Results are reported as the mean ± S.E. Statistical analysis used the factorial analysis of variance to
compare baseline values, and the two-way analysis of
variance for repeated measures to analyze the longitudinal data, as appropriate. The post hoc comparison
was made by Scheffe’s F-test. The results are reported
as the mean ± S.E. Statistical analysis used the factorial
analysis of variance to compare baseline values, and the
two-way analysis of variance for repeated measures to
analyze the longitudinal data, as appropriate, using Stat
View (SAS Institute Inc. 1998, Version 5.0.1).
3. Results
The groups were well matched and no significant
differences in age, menopausal state, or BMI were
present (Table 1). The vasomotor symptoms and the
sleep disturbances were evaluated by a visuoanalogic
scale (VSA) before and after 12 weeks of treatment
(Fig. 1). In women treated with LD-HRT and Ultra-LDHRT there were significant improvement, presented in
VAS score versus corresponding control group values.
In the control group, spine and femoral
neck BMD significantly (P < 0.05) decreased
from the baseline values of 1.076 ± 0.029 to
1.046 ± 0.023 g/cm2 (−2.8 ± 0.2%), and from
0.896 ± 0.024 to 0.871 ± 0.027 g/cm2 (−2.8 ± 0.7%),
respectively. In LD-HRT treated group spine and
4
M. Gambacciani et al. / Maturitas 59 (2008) 2–6
Table 1
Baseline characteristics of participants who completed the study
Age (year)
YSM
BMI (kg/m2 )
Control
LD-HRT
Utra-LD-HRT
56.6 ± 0.5
6.4 ± 0.4
25.5 ± 0.8
56.7 ± 0.3
6 ± 0.6
25.5 ± 0.5
56.6 ± 0.5
6.5 ± 0.5
25.7 ± 0.6
The results are reported as the mean (±S.E.). Control group:
postmenopausal women receiving 1000 mg of calcium per day;
LD-HRT: postmenopausal women receiving oral pill containing
1 mg estradiol + 0.5 mg noretisterone acetate per day; Ultra-LDHRT: postmenopausal women receiving oral pill containing 0.5 mg
of 17␤-estradiol and 0.25 mg of norethisterone acetate (Ultra low
dose,); YSM: years since menopause; BMI: body mass index.
femoral neck BMD showed a significant (P < 0.05)
increase from the baseline values of 1.039 ± 0.09
to 1.093 ± 0.01 g/cm2 (5.2 ± 0.7%), and from
0.854 ± 0.024 to 0.878 ± 0.023 g/cm2 (2.8 ± 0.4%)
after 24 months (Fig. 2). In the Ultra-LD-HRT treated
women spine and femoral neck BMD showed a
significant (P < 0.05) increase from the baseline values
of 1.053 ± 0.09 to 1.074 ± 0.01 g/cm2 (2.0 ± 0.3%),
Fig. 2. Patterns of BMD (g/cm2 ) of spine and femoral neck, in
women treated with only 1000 mg of calcium per day (control group),
LD-HRT (1 mg estradiol + 0.5 mg norethisterone acetate) or UltraLD-HRT (0.5 mg of 17␤-estradiol and 0.25 mg of norethisterone
acetate) along with 1000 mg of calcium per day. The results are
expressed as percent of variation vs. basal values. Measured at the
end of the 2-year follow up study. *P < .05 vs. corresponding control
group values.
and from 0.874 ± 0.014 to 0.890 ± 0.014 g/cm2
(1.8 ± 0.3%) after 24 months, respectively (Fig. 2). In
these women treated with LD-HRT and Ultra-LD-HRT
the BMD values were significantly (P < 0.05) different
from those measured in calcium-treated women.
4. Discussion
Fig. 1. Percent variation over the basal values of the visuoanalogic
scale scores referred for hot flushes and sleep disturbances in postmenopausal women treated with only 1000 mg of calcium per day
(control group), LD-HRT (1 mg estradiol + 0.5 mg norethisterone
acetate) or Ultra-LD-HRT (0.5 mg of 17␤-estradiol and 0.25 mg of
norethisterone acetate) along with 1000 mg of calcium per day. The
results are expressed as percent of variation vs. basal values. Measured at the end of the 12th week of treatment (VAS, a visuoanalogic
scale). *P < .05 vs. corresponding control group values.
Present data demonstrate that in relatively young
postmenopausal women treated with either LD-HRT
and Ultra-LD-HRT, significant improvement in vasomotor symptoms was evident. The central HRT
indication is the relief of postmenopausal symptoms,
with major improvement in QoL [31]. Present study
shows that also Ultra-LD-HRT is effective in improving
menopausal symptoms and can prevent the bone loss
related to the estrogen deprivation. Our data are in line
with a 2-year multicenter, double-blind, randomized,
placebo-controlled study, which showed that a dose of
17␤-estradiol as low as 0.5 mg is effective in prevention of bone mineral density loss in postmenopausal
M. Gambacciani et al. / Maturitas 59 (2008) 2–6
women [33]. However, the addition of NETA seems
to enhance the response in BMD observed with lower
estradiol doses of [33]. Our data further support the
contention that osteoporosis prevention can be considered the main added benefit of very low dose estradiol
prescribed in conjunction with low dose norethisterone
acetate for subjective symptoms while adjusting the
hormone dose to individual patient’s needs, preferences
and requirements. Recently, it has been reported that
even limited HRT use in menopausal women may produce substantial fracture reduction later in life [34].
This is an important information regarding HRT that
should not be considered any longer just a tool to reduce
subjective symptoms. For the prevention of osteoporosis in postmenopausal women, the benefit-risk balance
of lower doses of HRT has not been studied in any
large randomised clinical trial. However, lower estrogen doses produce fewer side effects and are expected
to generate less risks [35], maintaining a comparable efficacy on symptoms and similar bone sparing
effects. Thus, the use of LD-HRT and Ultra-LD-HRT
for osteoporosis prevention should be encouraged. In
conclusion, LD-HRT and Ultra-LD-HRT can prevent
postmenopausal bone loss and appears to be useful
alternative to higher dosages in the prevention and
treatment of climacteric symptoms. Attention of clinical researchers should focus on the effects of lower
dosage estrogen on osteoporotic fractures and other
health outcomes.
Conﬂict of interest
Authors do not have any financial, personal, political
or academic conflict of interest capable of influencing
their judgments.
Acknowledgements
The Authors would like to thank Ms. Enrica Palmeri
and Ms. Gabriella Campani for assistance in the completion of the study.
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