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

124 THE PREMENSTRUAL SYNDROMES
(10 or 7 days) was associated with a 2–4% risk of
hyperplasia. 11 These were data from a study of estrogen
therapy in postmenopausal women and so not directly
relevant. However, a study of PMS/PMDD from the
authors’ unit (unpublished data) 9 of longer-term treatment
with the 100 �g estradiol dosage using a lower
dose of cyclical norethisterone acetate (1 mg) for only
10 days each cycle has shown benefit over placebo for
eight cycles, with continued improvement in a 6-month
extension. Not surprisingly, the incidence of progestogen
intolerance was reduced with this regimen. There
were no reported cases of endometrial thickening (a surrogate
for endometrial hyperplasia assessed by transvaginal
ultrasound) in this study, despite the lower dose
and shorter duration of progestogen. 13
Work is now ongoing in the authors’ unit to show if
use of a natural progesterone or LNG IUS (Mirena) as
progestogenic opposition can maximize efficacy while
minimizing PMDD-like side effects. In the interim, it is
possible to use a LNG IUS, progesterone pessaries, or
progesterone gel 8% in the progestogen-intolerant
woman. 13,14
There is then clearcut evidence that estradiol can be
used to manage PMS/PMDD by suppressing ovulation.
There is also clear evidence that the LNG IUS protects
from endometrial hyperplasia. Only limited evidence
exists as yet to demonstrate efficacy of the combination
(Domoney et al, unpublished data). No studies have
been undertaken to directly compare hormonal therapy
with drugs such as the SSRIs.
DANAZOL
Cycle suppression may also be achieved using danazol,
an androgenic steroid. Mansel and Wisby first assessed
the effect of danazol on PMS symptoms and showed
benefit only for breast tenderness. 15 Other studies have
shown greater benefit. 15,16 A relatively recent randomized,
double-blind, cross-over study compared three
successive cycles of danazol at a dose of 200 mg bd to
three cycles of placebo: 17 28 of 31 women completed at
least one cycle of treatment while recording symptoms.
From this study, the authors demonstrated that danazol
at a dose of 200 mg bd was superior to placebo for the
relief of severe PMS during the premenstrual period for
the main outcome measures. However, this superiority
is muted or even reversed when the entire cycle is considered.
This may be explained by the fact that danazol
therapy does have some nuisance side effects that may
interfere with the usual symptom-free late follicular
phase of women with PMS. One solution suggested for
this problem might be to limit treatment to the luteal
phase only. It is clear that luteal phase only treatment
with 200 mg danazol effectively reduces breast symptoms
with minimal side effects.
Practical aspects
Danazol is an effective treatment for PMS and patients
should be counseled that it is an option. However, the
potential for masculinizing side effects usually acts as a
deterrent in the majority of women. Thus, due to its
masculinizing side effects, especially at higher, cyclesuppressing
doses, danazol is not commonly used for
treatment of premenstrual syndrome. High doses of
danazol reliably suppress ovulation but are more likely
to induce masculinization. Lower doses avoid such side
effects but as ovulation suppression becomes less reliable
the risk of pregnancy with the risk of masculinization
of a female fetus becomes significant. All women
taking danazol, whatever the dose, should use adequate
contraception.
GONADOTROPIN-RELEASING
HORMONE ANALOGUES
Gonadotropin-releasing hormone (GnRH) analogues
have been successfully employed to suppress gonadal
steroid production in conditions such as breast cancer,
fibroids, and endometriosis. A recent meta-analysis of
GnRH analogues has confirmed their efficacy compared
with placebo (Figure 14.3). 18 Seventy-one patients
on active treatment were identified in seven trials. The
overall standardized mean difference (SMD) for all
trials was �1.19 (CI �1.88 to �0.51) (Cohen criteria:
0.3 � small, 0.5 � medium, 1.0 � large effect). The
odds ratio (OR) for benefit was 8.66 (95% CI
2.52–30.26). The SMD was �1.43 and OR � 13.38
(CI 3.9–46) if data were taken only from anovulation
trials. Efficacy of symptom relief was greater for physical
than for behavioral symptoms (physical SMD ��1.16
(CI �1.53 to �0.79); behavioral SMD � �0.68
(CI �1.11 to �0.25)) but difference was not significant
p � 0.484. One trial used low-dose GnRH analogue to
avoid ovulation suppression but did not show clinical
significance over placebo. 19
Thus, GnRH analogue therapy results in profound
cycle suppression and elimination of premenstrual symptoms.
In practice, lack of efficacy suggests that the diagnosis
should be questioned rather than considered a
limitation of therapy. GnRH analogues are usually recommended
as second- or even third-line treatment due
to their hypoestrogenic side effects, but in the opinion
of the authors they are extremely valuable as first-line
therapy in women with the most severe PMDD.