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

disturbed in these patients. Comparisons of basal plasma
hormone levels in women with PMS and controls,
however, have revealed no consistent diagnosis-related
differences. Specifically, we observed no diagnosis-related
differences in the plasma levels, areas under the curve
(AUCs), or patterns of hormone secretion for estradiol,
progesterone, follicle-stimulating hormone (FSH), or
luteinizing hormone (LH), 131 findings consistent with
those of Backstrom et al 132 comparing patients with high
and low degrees of cyclical mood change. In subsequent
additions to the conflicting literature, Wang et al 133
observed increased estradiol and decreased progesterone
levels in women with PMS, Redei and Freeman 134
reported non-significant increases in both estradiol and
progesterone, and Facchinetti et al 135 found no differences
from controls in integrated progesterone levels.
Results for studies of androgen levels have been similarly
inconsistent, demonstrating both normal and
decreased testosterone levels 136–138 and elevated and
decreased free testosterone levels. 137,138 Abnormalities
of gonadotropin secretion have been observed (albeit
inconsistently) in several studies, with reports of both
higher 139 and lower 140 mid-luteal plasma FSH levels,
delayed follicular development and prolonged follicular
phase after corpus lute-ectomy 140 suggestive of
decreased FSH or increased inhibin secretion, and no
diagnosis-related differences in plasma LH 133,139–141
but a correlation in women with PMS between higher
LH levels and more severe symptoms. In summation,
then, there is no consistent or convincing evidence that
PMS is characterized by abnormal circulating plasma
levels of gonadal steroids or gonadotropins or by
hypothalamic–pituitary–ovarian (HPO) axis dysfunction.
Several studies do, however, suggest that levels of
estrogen, progesterone, or neurosteroids (e.g. pregnenolone
sulfate) may be correlated with symptom
severity in women with PMS (see below). 133,142,143
Recent speculations about the etiology of PMS have
focused on putative abnormal neurosteroid levels.
Observations central to these speculations include the
following:
1. The GABA receptor (the presumed mediator of
anxiolysis) is positively modulated by the 5a- and
5b-reduced metabolites of progesterone (allopregnanolone
and pregnanolone, respectively).10
2. Withdrawal of progesterone in rats produces anxiety
and insensitivity to benzodiazepines due to withdrawal
of allopregnanolone, with consequent
induction of GABA A � 4 subunit levels and inhibition
of GABA currents. 98,144
3. Allopregnanolone displays anxiolytic effects in several
animal anxiety models 145–147 and may be involved
in the stress response. 148
PATHOPHYSIOLOGY I: ROLE OF OVARIAN STEROIDS 89
4. Decreased plasma allopregnanolone levels are seen
in major depressive disorder and in depression
associated with alcohol withdrawal, with an increase
in levels seen in plasma and cerebrospinal fluid (CSF)
following successful antidepressant treatment. 149–152
5. Antidepressants may promote the reductive activity
of one of the neurosteroid synthetic enzymes
(3�-HSOR), thus favoring the formation of allopregnanolone.
153
6. PMS patients show differences in pregnanolonemodulated
saccadic eye velocity (SEV) and sedation
in the luteal phase compared with controls 154
(although the reported differences seem attributable
to an SEV response to vehicle in those with
PMS and a blunted sedation response in the follicular
phase in controls).
7. High-severity PMS patients show blunted SEV and
sedation responses to GABA A receptor agonists –
pregnanolone 154 or midazolam 155 – compared with
low-severity PMS patients.
Whereas one investigator observed decreased serum
allopregnanolone levels in women with PMS compared
with controls on menstrual cycle day 26, 156 other studies
showed no diagnosis-related differences in allopregnanolone
or pregnanolone, 133,157 nor any difference
in allopregnanolone levels in women with PMS before
and after successful treatment with citalopram. 158 Wang
et al 133 did find that if two cycles differed in the AUC
of a hormone by more than 10%, the cycle with the
lower levels of allopregnanolone and higher levels of E 2 ,
pregnanolone, and pregnenolone sulfate was accompanied
by higher levels of symptom severity. Additionally,
in a study in which progesterone was administered
to women with leuprolide-suppressed ovarian function,
women with PMS, but not comparison women,
showed a significant relationship between symptom
development and declining allopregnanolone levels
during progesterone administration.
Studies of a variety of other endocrine factors in
patients with PMS have been similarly unrevealing. In
general, no differences have been observed in basal
plasma cortisol levels, urinary free cortisol, the circadian
pattern of plasma cortisol secretion, or basal
plasma ACTH levels. 159 (Both decreased ACTH levels
in PMS patients across the menstrual cycle and no differences
from controls have been reported. 138,160,161 )
Similarly, studies of other hormones have done little to
elucidate the cause of PMS. Despite the appearance of
abnormal baseline thyroid function in 10% of our
subjects and abnormal (both blunted and exaggerated)
thyroid-stimulating hormone (TSH) response to
thyrotropin-releasing hormone (TRH) in 30% of our
subjects, the vast majority of patients with PMS have