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

Mean total ESA-max
20
18
16
14
12
10
8
6
4
2
0
Run-in
Double-blind Double-blind
Phase 1
Phase 2
Study phase
Randomization group Active first
Placebo first
been no clinical studies on the use of estradiol gel in
PMDD, it is clear that adequate estradiol levels can be
achieved and thus a beneficial clinical response would
be expected if patients prefer to use this rather than
patches. Treatment with estradiol should be continued
for a minimum of 1 year, as efficacy may improve even
after the initial 6–8 months. As this is not a cure for
PMS/PMDD, patients should be warned that symptoms
can return when treatment is discontinued.
Mild adverse effects occur in 15–20% of users. These
include nausea, breast tenderness, fluid retention,
increased appetite, and patch site skin reactions. Skin
reactions are less common with the newer matrix patch
systems and with estradiol gel. Patients should be counseled
that any adverse effects usually wear off after the
first 6 weeks of use.
Concerns regarding breast and endometrial cancer
risks (as found in menopausal patients) are unfounded in
this age group. The area under the curve (AUC) for
estradiol levels is unchanged (compared with that in
spontaneous cycles), as it is the distribution which is
altered. Note that 100 �g patches produce mid-follicular
estradiol levels (250–350 pmol/L) that are entirely
normal in premenopausal women. Clinical observation
shows no evidence of an increased risk of endometrial
or breast carcinoma in premenopausal women using
percutaneous patches and either cyclical progestogen
or a levonorgestrel-releasing intrauterine system (LNG
IUS). However, hard randomized placebo-controlled
trial data in large populations looking at these major
outcome measures over a long period of time are lacking.
There is no evidence that the risk of venous thromboembolism
is increased by this treatment and recent data in
menopausal women support this finding. 10
MANAGEMENT BY OVARIAN CYCLE SUPPRESSION 123
Follow-up
Contraception
The observation that estradiol 100 �g, producing physiological
levels of serum estradiol, was equally as effective
as estradiol 200 �g in treating PMS, strongly
suggested that the principal mechanism of action was
ovarian suppression. Data have shown that luteal phase
progesterone levels were suppressed to anovulatory
levels by this treatment. However, there are insufficient
data in large enough numbers over a long enough
period of time to recommend estradiol patches as a reliable
ovulation suppression method. Thus, additional
contraception should be used with estradiol therapy,
except when LNG IUS is being used for progestogenic
opposition.
Progestogen intolerance
Figure 14.2 ESA-max
(exponentially smoothed
average maximum scores)
scores for depression of
women randomized to receive
E 2 100 �g patches or
placebo – (an 8-month study
with cross-over at 4 months
and a 6-month extension) –
new data from the authors’
unit. Mean values with
95% CI.
One of the limitations of continuous estrogen therapy
for PMS/PMDD is that the endometrium requires
protection from possible hyperplasia and carcinoma by
the administration of progestogen or progesterone.
Unfortunately, this progestogenic opposition can lead
to a resurgence of PMDD-like symptoms (not usually
as severe as the original symptoms being treated). A
previous study showed that PMDD could be recreated
in postmenopausal women administered cyclical
norethisterone. 11
Attempts to avoid this (see Chapter 18) include
reduction of the duration or dosage of progestogen, but
this must be counterbalanced by the small increased
risk of hyperplasia with progestogen restriction. Sturdee
and colleagues showed that 12 days of progestogen
avoids hyperplasia altogether, but a shorter duration