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

88 THE PREMENSTRUAL SYNDROMES
in ovariectomized animals, 79–82 whereas higher doses
and longer treatment regimens enhance HPA axis reactivity
to stressors. 83–85 The regulatory effects of changes
in reproductive steroids or menstrual cycle phase on the
HPA axis in women are less well studied. Although some
studies using psychological stressors identified increased
stimulated cortisol in the luteal phase, 86,87 others using
psychological 88,89 or physiological (e.g. insulin-induced
hypoglycemia, exercise) 90,91 stressors failed to find a
luteal phase increase in HPA axis activity.
Altemus et al 92 recently demonstrated that exercisestimulated
HPA responses were increased in the midluteal
compared with the follicular phase. However, in
contrast to a large animal literature documenting the
ability of estradiol to increase HPA axis secretion, Roca
et al 93 found that progesterone, but not estradiol, significantly
increased exercise-stimulated arginine vasopressin
(AVP), adrenocorticotropic hormone (ACTH),
and cortisol secretion compared with a leuprolide-induced
hypogonadal condition or estradiol replacement. The
mechanism by which progesterone augments stimulated
HPA axis activity is currently unknown but could
include the following: modulation of cortisol feedback
restraint of the axis; 79,94–97 neurosteroid-related downregulation
of GABA receptors; 98 and up-regulation of
AVP (consistent with luteal phase reductions in the
threshold for AVP release). 99 Alternatively, Ochedalski
et al suggest that progesterone enhances oxytocininduced
corticotropin-releasing hormone (CRH). 210
ENDOCRINE STUDIES IN PREMENSTRUAL
SYNDROME
Effects of hormone ‘replacement’ therapies
Despite the lack of evidence of ovarian dysfunction in
women with PMS, the view that an abnormality of
corpus luteum function caused PMS endured, largely
because of the temporal association of PMS symptoms
with the luteal phase of the menstrual cycle. Thus, multiple
trials were conducted involving the administration
of progesterone or progestin in women with PMS. 100
The widespread use of progesterone in women with
PMS was considerably diminished, however, by the
results of several recent studies. First, two large doubleblind,
placebo-controlled trials of natural progesterone
(both suppository and oral forms) definitively demonstrated
the lack of efficacy of progesterone compared
with placebo in PMS. 101,102 Secondly, a study employing
a progesterone receptor antagonist, RU-486, with or
without human chorionic gonadotropin demonstrated
that the normal symptoms of PMS could occur independent
of the luteal phase of the menstrual cycle 103
and, therefore, a luteal phase abnormality as a cause of
PMS was no longer tenable.
The belief that PMS reflected a disturbance in
ovarian function led to several trials of oral contraceptives
(OCs) to suppress or regulate ovarian function in
this condition. Earlier cross-sectional studies suggested
that women using OCs experienced fewer PMS symptoms
than non-users, 104–106 although opposite results
were also reported. 107 Most studies demonstrated that
women on OCs reported fewer physical symptoms
(i.e. breast pain, bloating) but did not report fewer
or less severe mood symptoms than non-users. 108–110
In fact, similar prevalence rates of cyclic mood symptoms,
regardless of OC use, were prospectively documented
by Sveindottir and Backstrom, 111 with 2–6%
of women meeting criteria for severe PMS in both OC
users and non-users. Despite similar prevalence rates
of negative mood symptoms in OC users and nonusers,
some clinic-based studies suggested that a subgroup
of women with PMS reported an improvement
in mood symptoms while on OCs. 112–117 Results of
recent controlled trials of OCs in PMS parallel those
of the cross-sectional studies. 118–120 Significant reductions
in symptom severity on OCs compared with
placebo were observed, however, for some physical and
behavioral symptoms, including loss of libido, 119 breast
pain, and bloating, 118 and increased appetite and food
cravings. 120 Thus, with one recent exception, 121 neither
cross-sectional studies nor controlled trials support a
role for any formulation of OCs (tested to date) in
the treatment of PMS.
The efficacy in PMS of estradiol (without the progestin
contained in OCs) and testosterone have also been
tested. Trials of supraphysiological doses of estradiol
with or without testosterone have documented beneficial
effects compared with placebo in women with
PMS. 122–124 Preliminary reports suggest that lower
(more physiological) doses of testosterone alone may
also be effective in the treatment of PMS. 125–127 Lower
doses of estrogen, however, are not more effective than
placebo 128 and, therefore, it is possible that the therapeutic
benefits of the higher-dose estrogens are secondary
to the suppression of ovulation. 124 Nevertheless,
one cannot infer the efficacy of these compounds to
be secondary to ovarian suppression alone, given the
lack of efficacy of OCs which also inhibit ovulation, and
the reported efficacy of compounds such as danazol 129
when administered after ovulation in at least one study. 130
Basal hormone studies
As noted above, the temporal coincidence of symptoms
and the luteal phase in women with PMS led to the
presumption that reproductive endocrine function was