Premenstrual Syndromes : PMS and PMDD - Rutuja :: The site ...

122 THE PREMENSTRUAL SYNDROMES
PERCUTANEOUS ESTRADIOL (PATCHES
AND IMPLANTS)
The only ovulation suppressant treatment of proven
efficacy in placebo-controlled trials which appears suitable
for long-term usage is continuous percutaneous
17�-estradiol combined with cyclical progestogen. Oral
preparations in the standard estradiol doses found in
hormone replacement therapy (HRT) are not sufficient
to suppress ovarian activity. The use of estradiol patches
was first reported in a study in which a 100 mg subcutaneous
implant of estradiol was administered, achieving
serum estradiol levels of around 800 pmol/L; this
proved to be highly effective in every Moos Menstrual
Distress Questionnaire (MDQ) cluster of symptoms
compared with placebo. 6
Estradiol implants are long-lasting and transdermal
estradiol patches were subsequently used so that treatment
could be administered more simply (avoiding a
minor surgical procedure) and be discontinued at short
notice if required. Initially it was found that, 200 �g
estradiol patches suppressed ovulation; they were tested
against placebo in a cross-over trial and found to be
highly effective (Figure 14.1). 7 The study was a randomized,
double-blind, placebo-controlled trial with crossover
at 3 months; 20 patients in the active treatment
group received 200 �g (two � 100 �g) estradiol patches
followed by placebo and 20 patients were treated in
reverse order. Patients completed the MDQ and Premenstrual
Distress Questionnaire (PDQ) daily throughout
the study. After 3 months, both groups showed improvements
in MDQ and PDQ scores. In general, patients
who switched from active treatment to placebo had
deteriorating scores, whereas patients who switched from
placebo to active treatment maintained or improved upon
their initial gains. Significant improvements occurred
1.6
1.2
0.8
0.4
Symptom cluster rating
2
0
0
Placebo - Active
Active - Placebo
Mood swings
1 2 3
Time (months)
after changing to active treatment in 5 of 6 negative
MDQ symptom clusters and in 6 of 10 PDQ symptoms.
However, there was concern that estradiol 200 �g
twice weekly was too high a dose to be used as longterm
therapy. A subsequent observational study 8 showed
that 100 �g estradiol patches twice weekly were as effective
as 200 �g twice weekly in reducing symptom levels
in severe premenstrual syndrome. This dosage was better
tolerated in that there was a lower incidence of nausea
and breast tenderness at initiation of treatment. The
most recent randomized controlled study using 100 �g
estradiol patches showed efficacy over a longer time
period. This was an 8-month placebo-controlled randomized
trial with cross-over at 4 months and a 6-month
extension phase (Figure 14.2). 9 What was particularly
interesting about the findings of this trial was that not
only was there a significant improvement in symptoms
over the initial 8 months but also these improvements
continued through the extension phase of the trial.
Although the authors of this chapter believe that
ovulation suppression by transdermal estrogens can be
a first-line therapy for PMS/PMDD, they are surprised
that the original Lancet paper 7 of a randomized trial
published 18 years ago has not been replicated. Either
the study is considered perfect or there are other possibly
commercial reasons why manufacturers of estradiol
implants and patches have been less enthusiastic about
pursuing a licensed indication for PMS/PMDD than
those producing selective serotonin reuptake inhibitors
(SSRIs).
Practical aspects
Transdermal estradiol patches can be used effectively as
a first-line therapy for PMS/PMDD to treat both psychological
and physical symptoms. Although there have
4 5 6
Figure 14.1 A trial of 200 �g
transdermal estradiol vs
placebo for PMDD – a
6-month randomized
placebo-controlled study
with cross-over at 3 months.
(Adapted from Watson et al, 7
with permission.)