"Micro" estrogen doses effective for hot flashes

I always say go as low as you can with estrogen dosing, and this is an article proving the wisdom and efficacy of "quarter-dose" estrogen therapy. That is, quarter of the standard dosing. The commentary is by the North American Menopause Society (www.menopause.org), a conventional but solid organization. We always want to be guided by Level 1 evidence -- meaning randomized controlled trials, as this is the way we can make sure we are safe with how we dose hormones. This is an important new study to integrate into your thinking about whether to use estrogen after menopause. Healthy holidays, SG

Microdose of transdermal
17β-estradiol effectively relieves hot flashes

Bachmann GA, Schaefers M, Uddin A, Utian WH. Lowest effective transdermal 17β-estradiol dose for relief of hot
flushes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2007;110:771-779. Level of evidence: I.

A microdose of 17β-estradiol relieves hot flashes
in a significant proportion of postmenopausal
women, found this randomized, double-blind,
placebo-controlled, multicenter trial that
compared a low-dose 2.2 mg 17β-estradiol/0.69
mg levonorgestrel combination transdermal patch
with a microdose 1.0 mg 17β-estradiol
transdermal patch with a placebo patch in healthy
postmenopausal women in 48 centers in the
United States. A total of 425 postmenopausal
women aged 40 years and older (mean age, 52.7
y) were enrolled who had at least 7 moderate or
severe hot flashes per day or at least 50 per week.
The study measured the mean changes from
baseline in frequency and severity of hot flashes
with hormone therapy (HT) compared with
placebo at weeks 4 and 12 of treatment, as well as
the proportion of responders with at least 75% and
90% reduction in frequency of moderate and
severe hot flashes.


Of the total, 145 women received the 17β-
estradiol/levonorgestrel patch, which delivered
0.023 mg/day and 0.0075 mg/day of the drugs,
respectively. There were 147 women who
received the estradiol-only patch, which
delivered 0.014 mg/day of the drug. Placebo
was given to 133 women. The mean weekly
frequency of hot flashes at baseline was similar
for the three groups, as were the mean daily
severity scores.

At week 12, the mean frequency of hot flashes
was significantly reduced in the low-dose group
(–51.80; P < 0.001) and microdose group
(–38.46; P < 0.001) compared with placebo.
Reductions in severity scores for hot flashes
were equally significant in the low-dose and
microdose groups compared with the placebo
group. Reductions in frequency of hot flashes
were larger with the low-dose combination, but
41% of women in the microdose 17β-estradiol
group had a 75% or greater reduction in
frequency of hot flashes from baseline at week
12, and 35% had a 90% reduction in frequency.
In this group, the mean reduction in moderate
and severe hot flashes was 70% after 4 weeks of
treatment and 90% after 8 weeks. The time
frame for the onset of efficacy was similar in the
low-dose 17β-estradiol group. To treat with the
lowest effective dose, the findings support the
notion of starting treatment for hot flashes at the
microdose and then adjusting the dosage upward
if symptom relief is not achieved after 8 weeks.

Comment. In their paper, Bachmann et al report a
significant lowering of hot flashes (at least 7/d or
50/wk) with a microdose of transdermal estradiol
(a patch delivering 0.014 mg/d) with maximum
efficacy at 8 weeks. This is the lowest dose yet
that shows efficacy for hot flashes and suggests
that there is no threshold minimal dose as was
once previously believed. This dose is also known
to protect bone.

The time required to achieve maximum effect is 8
weeks, however, and for some women this may be
unacceptably long. But some patients respond
more quickly so an acceptable reduction may be
seen earlier.

Recent findings about standard-dose HT have
been reassuring, but use of the lowest effective
dose of any medication is an important goal of
clinical practice, presumably because lower doses
are associated with fewer side effects and are
more likely safer.1 Current guidelines around the
world unanimously recommend the use of the
lowest effective dose of HT.

Lower HT doses, when used with adequate doses
of progestogen, have an excellent endometrial
safety profile and in some studies less breast pain.
Surprisingly, in this study breast pain did not
differ between the groups. Microdoses were
associated with less bleeding but the lower dose
was combined with a progestin and only lasted 12
weeks, making comparisons difficult. Some have
suggested that ultralow or microdose estrogen
may not require regular progestogen or that lower
progestogen doses might be safe because little to
no endometrial stimulation is expected at these
doses. The lack of uterine-related consequences of
unopposed ultralow-dose estrogen was
demonstrated in a study of nonhysterectomized
postmenopausal women, aged 60 to 80 years,
receiving unopposed transdermal estradiol (14
μg/d). Compared with placebo, women receiving

estrogen had similar rates of endometrial
hyperplasia, endometrial proliferation, and
vaginal bleeding over the course of 2 years of
treatment.2

The effect of lower estrogen and/or progestogen
doses on breast cancer risk in HT users is
unclear and there is little evidence at this time to
address this important clinical issue. Recent
evidence suggests that ultralow-dose HT has a
neutral effect on mammographic breast density,
which may be a predictor of breast cancer and
make mammographic reading more difficult.3

Overall, low- and ultralow-dose formulations
are increasingly becoming the first choice for
the initial management of menopause-related
symptoms, particularly as women pass from
their most symptomatic phase or, as the authors
point out, wish to restart therapy. Ultralow-dose
regimens may be especially attractive for
relieving menopause-related symptoms as well
as for prevention of bone loss. These factors and
the improved tolerability profile compared with
standard-dose regimens impart a favorable
benefit-risk profile and suggest an important
role for the lowest dose HT regimens in and
postmenopausal management.

Michelle P. Warren, MD
Professor of Medicine and Ob/Gyn
Medical Director, Center for Menopause, Hormone
Disorders, and Women’s Health
Wyeth-Ayerst Professor of Women’s Health
Columbia University
New York, NY
Member, NAMS Professional Education Committee
Member, NAMS Board of Trustees

References:
1. Ettinger B. Personal perspective on low-dosage
estrogen therapy for postmenopausal women. Menopause
1999;6:273-276.
2. Johnson SR, Ettinger B, Macer JL, Ensrud KE, Quan J,
Grady D. Uterine and vaginal effects of unopposed
ultralow-dose transdermal estradiol. Obstet Gynecol
2005;105:779-787.
3. Boyd NF, Rommens JM, Vogt K, et al. Mammo-
graphic breast density as an intermediate phenotype for
breast cancer. Lancet Oncol 2005;6:798-808.