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

90 THE PREMENSTRUAL SYNDROMES
normal hypothalamic–pituitary–thyroid axis function. 162
Luteal phase decreases in both plasma �-endorphin 163,164
and platelet serotonin uptake 165,166 have been reported
in PMS; neither the diagnostic group-related decreases
nor their confinement to the luteal phase are consistently
observed. 138,167–170 Finally, in a study of CSF,
Eriksson et al 171 observed no differences in CSF monoamine
metabolites in PMS patients compared with controls,
nor were there menstrual cycle-related differences
in either group. Similarly, Parry et al 172 found no cyclerelated
differences (midcycle vs premenstrual) in CSF
ACTH, �-endorphin, GABA, 5-hydroxyindoleacetic acid
(5-HIAA), homovanillic acid (HVA), or norepinephrine;
a slight but significant premenstrual increase in CSF
3-methoxy-4-hydroxyphenyl glycol (MHPG) was noted.
Even if these differences are confirmed, their persistence
across the menstrual cycle would appear to argue
against their direct role in the expression of a disorder
confined to the luteal phase. Presently, then, there is no
clearly demonstrated luteal phase-specific physiological
abnormality in PMS.
Dynamic studies of hormone secretion
Several strategies have been employed to assess hypothalamic
and pituitary function in women with PMS.
First, basal plasma levels of gonadotropins have been
measured across the menstrual cycle in women with
and without PMS. Efforts to distinguish hypothalamic
function from that of the pituitary led to studies of LH
pulsatility (i.e. the frequency of LH pulses rather than
mean LH levels). Additionally, evidence that endogenous
opiate peptides modulated GnRH/LH secretion
during the early- and mid-luteal phase of the menstrual
cycle, when PMS symptoms appear, prompted the use
of pharmacological challenges with opiate antagonists
to indirectly evaluate the level of central opiate tone.
(Alterations in the amount of disinhibition of LH secretion
after the administration of an opiate antagonist
could suggest differences in the secretion of endogenous
opiates that may be relevant to the development of
PMS symptoms.) Finally, acute GnRH challenge studies
have been employed to evaluate stimulated gonadotropin
secretion and, possibly, identify differences in hypothalamic
or pituitary feedback mechanisms and pituitary
gonadotropin reserve. 173
The pattern of pulsatile secretion of LH has been characterized
in women with and without PMS, employing
serial blood sampling (e.g. every 10 minutes) during the
luteal phase of the menstrual cycle. Facchinetti and
coworkers 135,174 observed diagnostic differences in the
pattern of pulsatile secretion of LH during the luteal
phase: women with PMS had an increased frequency
and a decreased amplitude and duration of both LH and
progesterone secretion compared with controls, suggesting
a reduced level of opioid inhibition of LH (frequency)
in PMS during the luteal phase as well as the
possibility of decreased pituitary responsiveness (LH
amplitude) compared with women without PMS.
However, two subsequent studies could not confirm
this finding. 175,176 Similarly, two studies 177,178 using
single-dose administration of naloxone failed to identify
differences between the pattern of secretion of LH
after naloxone during the mid-luteal phase in women
with PMS compared with controls, suggesting the absence
of differences in the central opioid tone in these two
groups of women. However, Rapkin et al 179 employed
a continuous infusion of naloxone in the mid-luteal
phase and observed a significantly blunted LH response
to naloxone. These authors suggested that prolonged
opiate antagonism was necessary to reveal the abnormal
central opioid tone during the mid-luteal phase in
women with PMS. If these findings are confirmed, it is,
nonetheless, premature to suggest that the differences
in naloxone-induced LH secretion reflect a deficiency
of central opiate functions in PMS. Indeed, as suggested
by Rapkin, 179 the regulatory effects of endogenous
opiates, progesterone, and progesterone’s neurosteroid
metabolites on GnRH secretion are part of a complex
physiological system 180,181 and not easily translated, at
this point, into a pathophysiology of PMS.
Four studies have performed GnRH stimulation with
100 or 10 �g doses of GnRH in women with PMS and
controls. 177,178,182,183 No differences have been reported
in the pattern of gonadotropin secretion in single tests
during either the luteal 178 or the follicular phase. 177 In
one study in which GnRH stimulation tests were
performed in both follicular and luteal phases, blunted
progesterone and allopregnanolone secretion after 100 �g
of GnRH were observed in women with PMS compared
with a group of asymptomatic controls, 182 but
gonadotropin levels were not reported, and hence the
source of the blunted progesterone cannot be identified.
The above-noted study by Facchinetti et al 178 observed
lower GnRH-stimulated LH secretion in five women
with PMS than in four controls. Although the observed
LH AUC was not significantly different across diagnostic
groups, the calculated effect size (1.05) between groups
was moderate and suggested that their findings could
reflect a type II error. We used a supraphysiological
dose of GnRH in a larger sample size and, similar to
Facchinetti’s results, women with PMS were not distinguished
from controls by an abnormal LH or FSH
response to GnRH stimulation. Our data and those of
others, then, document no abnormalities of gonadotropin
secretion in response to acute GnRH stimulation in
women with PMS. These data also provide indirect evidence
of normal HPO feedback during the follicular and