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

76 THE PREMENSTRUAL SYNDROMES
These endogenous opioid peptides bind to a multiplicity
of opioid receptors, with different opiates possessing
different selectivity for particular receptors. 121
Five opioid receptor types have been proposed, consisting
of the �, �, �, �, and � receptors. 122,123 Morphine
binds preferentially to the �-receptor, enkephalins to
the �-receptor, �-endorphin to the � receptor, and
dynorphin to the � receptor. 124 The distribution of morphine
and enkephalin receptors in the brain has been
investigated with equal numbers in the cerebral cortex
and striatum, twice as many morphine receptors as
enkephalin receptors in the limbic system, hippocampus,
and brainstem, and four times greater morphine receptors
in the thalamus and hypothalamus. 125
Specifically, �-endorphin is a polypeptide containing
31 amino acids with 5–10 times the potency of morphine.
Endorphins regulate gonadotropin secretion and
mediate pain response. Although widely distributed in
the body, endorphins have the highest concentration
within the arcuate nucleus and median eminence of
the hypothalamus and the intermediate lobe of the
pituitary gland. 126,127 The medial basal hypothalamus,
which incorporates the arcuate nucleus, is an area also
highly concentrated in gonodotropin-releasing hormone
(GnRH)- and dopamine-containing cells. 128 High concentrations
of �-endorphin have been found in the
hypophyseal portal blood, suggesting that endogenous
opioids of hypothalamic origin are secreted into the
portal blood and may directly regulate pituitary peptide
hormone secretion. 129 However, most studies support
the notion that endogenous opioids probably decrease
pituitary gonadotropin secretion by exerting effects on
hypothalamic GnRH secretion, where endorphins are
located in close proximity to GnRH-secreting cells,
rather than direct pituitary stimulation. 130–132
The concentration of �-endorphin in the hypophyseal
portal blood varies in relation to the menstrual
cycle. Studies in female monkeys have shown that �endorphin
is present in high concentrations during the
mid-to-late follicular phase and the luteal phase, but
undetectable at the time of menses and after ovariectomy.
133 Chronic administration of estrogen or estrogen
with progesterone in ovariectomized monkeys restored
detectable levels of �-endorphin in the hypophyseal
portal blood. 134 These results suggest that ovarian
steroids effect the release of hypothalamic �-endorphin
into the hypophyseal portal blood, and cyclic changes
in sex steroids during the menstrual cycle may affect
anterior pituitary gonadotropin secretion through a
mechanism involving �-endorphins.
In normal human subjects, opiate administration
results in a significant decrease in luteinizing hormone
(LH) secretion and an increase in prolactin secretion. 135
Naloxone, a competitive opioid antagonist, blocks the
different subtypes of opioid receptors with different
affinities, and has the greatest affinity for the � and �
receptors. Naloxone administered in the late follicular
and mid-luteal phases of the menstrual cycle in women
increases the frequency and amplitude of LH pulses
and circulating LH concentration, which suggests that
endogenous opiates are involved in the regulation of
LH secretion during the high estrogen and estrogen–
progesterone phases of the menstrual cycle. 136,137
However, naloxone has no discernible effect on LH release
during the early follicular phase when ovarian steroid
secretion is minimal, further suggesting that gonadal
steroids modify endogenous opiate activity. 136,138 The
mid-cycle rise of estrogen and progesterone probably
induces central opioid activity. Endogenous opioid
activity is low in oophorectomized women, but estrogen
treatment increases opioid activity and the addition
of a progestin further increases the opioid activity.
For example, in oophorectomized women treated with
chronic conjugated estrogens or conjugated estrogens
with medroxyprogesterone acetate, serum LH increases
during naloxone infusion to levels found in ovulatory
women. 139 In summary, evidence suggests that �endorphin
is an important determinant in modulating
gonadotropin secretion during the menstrual cycle.
Endogenous opioid peptides, affective
symptoms, and PMS
Differences in �-endorphin levels during the menstrual
cycle have been established comparing women with
PMS to controls. The �-endorphin levels are significantly
lower during the luteal phase in women experiencing
PMS. 140,141 Additionally, in control women,
central opioid tone is enhanced during the mid luteal
phase and becomes minimal in the late luteal phase, but
women with PMS have low central opioid activity
during the mid and late luteal phase as indicated by the
loss of naloxone-induced LH release. 142–144 Low opioid
tone has been associated with dysphoria, retarded
motor activity, emotional liability, and lethargy, symptoms
that are similar to those of PMS. 145,146 Therefore,
attenuated central opioid tone may play a role in the
pathophysiology of PMS.
There has also been evidence to suggest that endogenous
opioid peptides may inhibit LH secretion through
influence on the hypothalamic serotonergic system.
Specifically, endogenous opiates seem to induce the
release of serotonin and increase its turnover. 147–151 A
dysfunction in this opioid–serotonin relationship could
also contribute to the development of PMS symptoms,
with decreased central opioid activity leading to lowered
serotonin levels and mood deterioration.