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

110 THE PREMENSTRUAL SYNDROMES
steroids with a stable endogenous hormonal environment.
For this reason, combined OCPs have been used
to treat premenstrual symptoms. 14 Unfortunately, unless
given continuously, the OCPs introduce a new exogenous
hormone cyclicity that results in a confusing picture
when treatment studies are analyzed.
The major trend in the formulation of OCs over the
last 40 years has been a reduction in the doses of both
the estrogen and the progestin components, and, more
recently, chemical alterations of the progestins to provide
less androgenic compounds. 9 Estradiol (ethinyl estradiol)
doses have decreased from 100 �g to 20–30 �g.
The dose of the progestin component has also decreased.
All but one currently prescribed OC still contains a
progestin derived from 19-nortestosterone. Table 12.1
summarizes the pharmacological profile of progesterone,
19-nortestosterone, and a new progestin drospirenone
derived from spironolactone. 15
The palliative effect of OCPs, particularly for physical
premenstrual symptoms, has been suggested by previous
epidemiological and non-placebo-controlled
research. 14,16–18 There have been three randomized,
placebo-controlled trials investigating OCPs in treating
premenstrual symptoms, one evaluating PMS 19 and
two evaluating PMDD. 20,21
In the first randomized trial, a triphasic formulation
reduced physical symptoms but not mood alterations. 19
The study enrolled 82 women with PMS, and the active
treatment was a triphasic OCP (ethinyl estradiol 35 �g
� norethindrone 0.5 mg days 1–7 and 17–21 and 1.0 mg
days 8–16). 19 Differences between the OCP and placebo
were minimal, although mood worsened in the
Table 12.1 Pharmacological profile of progestins (in animal models) a
a + = distinct effect, (+) = negligible effect at therapeutic doses, – = no effect.
b Metabolized to levonorgestrel-3-oxime and levonorgestrel.
c Not available in the USA.
Adapted from Fuhrmann et al. 15
active-treatment group during the hormone-free, postmenstrual
period.
The other two trials evaluated a new progestin,
drospirenone, which possesses spironolactone-like
antimineralocorticoid and antiandrogenic activity. 15
Previous studies of the diuretic spironolactone in PMS
have demonstrated its efficacy in relieving the physical
symptoms (bloating, breast tenderness) and the psychological
symptoms (mood change, irritability) of this
condition. 22–24 The antiandrogenic activity of drospirenone
may improve premenstrual irritability and
acne, 25 which may be due to elevated plasma testosterone
in women with PMS. 26,27
Freeman et al compared placebo to an OCP with
drospirenone 3 mg and ethinyl estradiol 30 �g in a
21/7 platform to 82 women who met PMDD criteria. 20
The active treatment was associated with significantly
greater improvement in appetite, acne, and food cravings,
but there were no differences between groups in
mood symptoms. The lack of between-group differences
in mood symptoms may have been due to the
modest sample size in the setting of a considerable
placebo response rate (43%).
The more positive findings in the Freeman 20 compared
with the Graham 19 study may be due to the use of
a progestin that has antimineralocorticoid and antiandrogenic
properties not observed in the progestins derived
from 19-nortestosterone, such as norethindrone. 15
Recently, a controlled study conducted by Yonkers
et al 21 showed that the drospirenone-containing OCP
formulation administered for 24 of 28 days in a cycle
ameliorated symptoms associated with PMDD compared
Pharmacological activity
Progestins a Progestogenic Antiandrogenic Antimineralocorticoid Androgenic
Progesterone + (+) + –
Drospirenone + + + –
Norgestimateb + – – (+)
Levonorgestrel + – – (+)
Desogestrel + – – (+)
Norethindrone + – – (+)
Cyproterone acetatec + + – –