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Biomedical Reviews 4: 71-83 (1995)

The Bulgarian-American Center, Varna, Bulgaria


ISSN1310-392X

OPIOID PEPTIDES IN THE FEMALE REPRODUCTIVE SYSTEM: PHYSIOLOGICAL


IMPLICATIONS

Antonis Makrigiannakis1, Andrew N. Margioris2, Christos Stournams3, andAchitte Gravanis1


Departments oj 'Pharmacology, 2Clinical Chemistry and ^Biochemistry, Medical School, University of Crete,
Heraklion, Greece
SUMMARY

INTRODUCTION

All endogenous opioid peptides derive from three precursor molecules i. e proopiomelanocortin, proenkephalin and
prodynorphin. The endogenous opioid peptides exert their biological effects through opioid receptors. Each endogenous
opioid peptides exhibits higher binding affinity towards a specific type of opioid receptors. Current evidence suggests that
endogenous opioid peptides play important regulatory roles
in reproduction. Endogenous opioid peptides are present
through the hypothalamic-pituitary-gonadal axis. The hypothalamic opioidergic mechanism represents one of the important central control systems of gonadotropin-releasing hormone and gonadotropin release. Opioids mediate the sex steroid effect exerted on gonadotropin-releasing hormone and
luteinizing hormone secretion and play a crucial role in the
integration of several neuroendocrine mechanisms. There is
also evidence that suprahypothalamic mechanism enhances
endogenous opioid inhibition of gonadotropin-releasing hormone. The genes of the endogenous opioid peptides are also
expressed in peripheral reproductive tissues such as the endometrium and placenta. At least part of the endogenous opioid
peptides effects may be paracrine or autocrine in nature. The
possible roles ofopioids in various physiological processes
of the female reproductive system are also reviewed.

Opiate effects on human reproductive function were


recognized long before the isolation of endogenous peptides
with opioid activity (1). Since this discovery, research has expanded greatly and a vast body of literature now documents
the physiology and pathology of endogenous opioid modulation of hormonal and other aspects of reproduction. Endogenous opioid peptides (EOF) are present throughout the hypothalamic-pituitary-gonadal axis as well as in the endometrium
and placenta. Current evidence suggests that EOF play important regulatory roles in reproduction. At least part of EOF
effects may be local, paracrine or autocrine in nature. It is
thus possible that local opioids may be part of microregulatory
loops within each reproductive organ. This review will concentrate on the human data but will refer to animal studies if
important differences occur or if human data are unavailable.
OPIOID PEPTIDES AND PRECURSORS
Met-enkephalin and leu-enkephalin were the original
opioids isolated from porcine brain (1). They share the opioidactive N-terminal sequence Tyr-Gly-Gly-Phe and differ only
in their C-active residue methionine and leucine, respectively.
All opioid peptides share the sequence of either met- or leu-

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enkephalin at their N-terminal, but possess C-terminal extensions of variable length, which may confer greater potency
(2), increased stability against degradation (3) and different
receptor specificity. Analysis of DNA sequence in recent years
has allowed the prediction of the amino-acid sequence of three
precursor molecules (4).
Proopiomelanocortin (POMC) is a glycoprotein of 31 kD and
is the precursor for adrenocorticotropic hormone (ACTH), amelanocyte-stimulating hormone (oc-MSH), p-lipotropin and
also p-endorphin but does not appear to be further processed to
met-enkephalin. The precursor product relationship was first
established by radiolabeling studies on AtT-20 cells which derive from an ACTH-producing tumor or mouse pituitary. The
final posttranslational products of POMC precursor molecule
differ between tissues expressing POMC gene. Thus, in anterior pituitary, the tissue with the highest concentration of
POMC mRNA and POMC derived peptides, ACTH is the most
predominant posttranslational product of POMC and plays an essential role in the hypothalamic-pituitary-adrenal axis.
Proenkephalin is the major biological source of met-enkephalin and its extended forms (met-enkephalin-Arg-Phe, met-enkephalin-Arg-Gly-Leu and peptide E) and one source of leuenkephalin. Proenkephalin-derived peptides, in contrast to
POMC, are all opioids in nature. Each molecule of pro-enkephalin contains seven opioid peptides with the met- or leuenkephalin active core.
Prodynorphin (proenkephalin B) contains 3 copies of leu-enTable 1. Precursor molecules of opioid peptides

Makrigiannakis, Margioris,Stournaras, and Gravanis

kephalin and its extended forms dynorphin, rimorphin


(dynorphin B), leumorphin and a-neo-endorphin. Dynorphin
A, a seventeen amino-acid peptide, was the first posttranslational product of prodynorphin to be isolated (2,5). Dynorphin
A and its two smaller fragments have the highest potency of
all known endogenous opioid peptides in the guinea pig ileum
bioassay, a characteristic attributed to their high-affinity for
the K-opioid receptor. In fact it appears that they are the only
endogenous K-receptor agonists known (6).
The three opioid precursors are of similar molecular size and
also contain a number of sequence homologies, suggesting that
all may have originally derived from an ancestor opioid gene
(Table 1).
OPIOID RECEPTORS
The EOF exert their biological effects through opioid
receptors. Each EOF exhibits higher binding affinity towards
a specific type of opioid receptor. A variety of types of opioid
receptors have been described. Behavioral studies in dogs suggested that opioids could be divided into (J,-, K- or o- agonists
(7). Studies with opioid peptides using bioactivity in peripheral tissue preparations (8), or binding studies of radioactively
labelled ligands in brain tissue (9) confirmed the existence of
(a,, 8, K and possibly e- receptors (Table 2).
The ^-receptor, so named because of its activation by morphine, mediates analgesia, bradycardia and hypothermia. The
K-receptor activated by ketocyclazosine, appears to be responsible for sedation and depression of flexor reflexes, but has no
involvement in skin twitch reflex or pulse rate. A third class
of receptors was named o for its activation by SKF 10.047 (Nallylnormetazosine). For an effect to be considered consequent
to opioid receptor activation, the effect must be reversed by

Table 2. Opioid receptors

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Opioid peptides in female reproductive system

the classical opioid antagonist naloxone or its more potent


analogue, naltrexone. The [i- and K-receptor-mediated events
are readily reversible by naltrexone (7), while physiological
events effected by o-receptors do not (10). An additional class
of opioid receptor identified (11) is activated by the enkephalins and is named 8.
Other receptors considered to be opioid on the basis of their
sensitivity to naloxone have been identified in binding studies, but a clear functional significance associated with them is
lacking. Among these receptors are jj.1-receptors mediating
analgesia and |i2-receptors mediating respiratory depression
(12). These assumptions are based upon the observation that
naloxone antagonizes analgesia but not the respiratory depression induced by morphine. Unfortunately, there is to date no
antagonist that can reverse the respiratory depression without
affecting the analgesia.
Subtypes of K-receptors have also been proposed (13). There
may be as many as four subtypes of the K-receptor based upon
evidence from radioligand binding studies (14). Opioid receptors termed e were originally identified as those mediating
inhibition of electrically evoked twitch in rat vas deferens (15).
These receptors were believed to be selectively activated by Pendorphin. Finally, ?i receptors first described in binding studies in rat brain (16) were defined as having high-affinity for
naloxone, but low affinity for another opioid antagonist,
diprenorphine. A functional role for this class of opioid receptors has not yet been proposed.
LOCALIZATION OF OPIOID PEPTIDES AMD
RECEPTORS

Opioids are localized throughout the central nervous


system in specific neuron tracts, and separated on the basis of
their known precursors (17). All opioids are concentrated in
the hypothalamus, pituitary, periaqueductal grey matter and
spinal cord. Hypothalamic (3-endorphinergic neurons originate
largely in the arcuate nucleus from where they project to the
median eminence as well as other parts of the brain. Enkephalinergic neurons exist in several hypothalamic nuclei while prodynorphin derived peptides are mostly concentrated in the supraoptic and paraventricular nuclei, although some are also
present in the arcuate nucleus and posterior hypothalamus (18).
|i- and K- receptors are present in hypothalamus in roughly
equal numbers but 8-receptors account for less than 10% of
opioid binding (9).
The pituitary contains large amounts of P-endorphin in the
anterior pituitary corticotroph cells and prodynorphin-derived
opioids in the posterior pituitary vasopressin neurons (18).
Met-enkephalin is present in both anterior pituitary somatotrophs (19) and posterior pituitary oxytocin neurons (20).

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73

Outside the central nervous system opioids are concentrated


in the adrenal medulla and other parts of the sympathetic nervous system, and in neurons in the gut. Smaller quantities are
also described in the testis and pancreas (21). P-endorphin
and met-enkephalin both circulate in human plasma (22).
The EOF genes are expressed in most tissues involved in mammalian reproduction. POMC gene is expressed in the hypothalamus (23), gonads (24), endometrium (25) and placenta
(26). In all these tissues P-endorphin appears to represent the
main posttranslational product of POMC. POMC mRNA and
P-endorphin are present in the granulosa, luteal and intestinal
cells of female gonads, in the endometrial cells of uterus, and
in the placental syncytiotrophoblast. The proenkephalin gene
is expressed in hypothalamus and gonads, and the prodynorphin gene in hypothalamus, anterior pituitary gonadotroph
cells, male and female gonads, placenta, and endometrium.
OPIOID PEPTIDES AND CENTRAL REGULATION
OF THE FEMALE REPRODUCTIVE SYSTEM

Prolactin

Administration of morphine (27), the enkephalin analogue


DAMME (FK 33-824) (28), and P-endorphin (29) all cause
prompt release of prolactin in man. In the rat, P-endorphin is
a more potent secretagogue than met-enkephalin (30), or
dynorphin (31), and intraventricular administration of antisera for p-endorphin lowers both basal and stress-induced prolactin secretion (32), suggesting that p-endorphin is indeed
the opioid involved. This is compatible with the naloxone sensitivity of opioid stimulation in man (28) which suggests involvement of |0,- or e- selective opioids. The opioid effect is
blocked by the administration of dopamine agonists and potentiated by dopamine antagonists (33), suggesting that opioids act by inhibition of dopamine release, the major prolactin
inhibitory factor from the median eminence. This concept is
supported by direct experimental evidence in the rat, where
opioids decrease hypothalamic dopamine turnover (34) and
release (35). Most studies have failed to find any direct effect
of opioid peptides on prolactin secretion by isolated pituitary
cells in vitro. In the rat, naloxone lowers basal, stress-induced
and suckling-induced prolactin secretion, suggesting an important physiological role for opioids on prolactin secretion
(36). In contrast, most studies have failed to demonstrate an
effect of naloxone, even at high dosage, on basal or stressinduced release of prolactin in normal subjects (37), nor an
elevated prolactin level in the puerperium (37), or in patients
with prolactinomas (38). A minority of studies has however
reported an inhibition of basal or stress-related prolactin release (39). High doses of nalo-xone may abolish the exerciseinduced release of prolactin in highly trained male athletes
(40). Naloxone infusion (1.6 mg per h) may stimulate pulsa-

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74

tile prolactin release in women during the late follicular and


mid-luteal phases of the menstrual cycle (41) and in women
under oral contraception (42), but not in early follicular or
late luteal phase, or in hypogonadal women. This pulsatile
release of prolactin is synchronous with that of LH, suggesting that a common mechanism, presumably involving luteinizing hormone-releasing hormone (LHRH), mediates the release of both LH and prolactin under these circumstances. Indeed, LHRH may stimulate prolactin release, at least in postmenopausal women (43), and in vitro evidence suggests that
this might involve paracrine gonadotroph-lactotroph interactions (44). In spite of the existence of stimulatory and possibly
inhibitory opioidergic mechanisms for control of prolactin secretion, no clear physiological or pathological role has
emerged.
Gonadotropins

The predominant opioid modulation of gonadotropin secretion is inhibitory. Chronic opiate addiction has been long recognized to cause amenorrhoea and infertility in the female
(45). Morphine and other opiates decrease serum LH (27).
Inhibition of follicle-stimulating hormone (FSH) is less consistently noted, perhaps due to its longer half life in the circulation. Naloxone acutely increases serum LH and possibly FSH
in both sexes, suggesting tonic inhibitory opioid control of
gonadotropin secretion (46). Studies on LH pulsativity indicate an increase in both frequency and amplitude of LH pulses
with naloxone in both sexes (46). In females, this effect is
most marked in the late follicular and particularly mid-luteal
phase of the menstrual cycle, and opioids may thus mediate
the slowing of LH pulsativity seen at this time. In normally
menstruating women, the opioid activity of LH secretion shows
a fluctuation dependent on the menstrual cycle phase. In the
early follicular phase, the opioid activity is low, increasing
proportionately with the ovulatory peak of LH, then remaining high during luteal phase (47). The high progesterone levels during luteal phase of menstrual cycle are suggested to
increase the tone on LH pulsativity (48). Low doses of naloxone
are required to modulate LH release, suggesting primary involvement of \i- or e- receptors (48). However, in the immature rat, hypothalamic injections of antisera to both (3-endorphin and dynorphin raise LH (49), supposing that more than
one opioidergic pathway might be involved. Opioid effects
occur at hypothalamic level and involve modulation of LHRH
release. Thus opioids have no effect on the LH response to the
LHRH test (50). LHRH antagonists block naloxone stimulation in the rat (51), naloxone stimulates the LHRH release
from human hypothalamus in vitro (52), and morphine decreases hypothalamic LHRH content (53).
In man, as in the rat, opioidergic regulation mechanisms appear to be closely connected to the feedback of gonadal ste-

Biomed Rev 4,1995

roids and LHRH secretion. In postmenopausal women, the endogenous opioid tone is impaired, as reflected by the lack of
naloxone effect on plasma LH levels (54). This neuroendocrine response is absent in women with physiological and surgical menopause (54). Estrogen/progestin therapy affects the
normal opioidergic tone and restores a concomitant LH release after naloxone injection (54). This observation in women
has been supported by studies in animals. In fact, naloxone
abolishes the inhibitory effect of sex steroids on LH secretion
in rats (55). This effect disappears after gonadectomy, and
naloxone is no longer able to stimulate LH secretion in male
and female rats. These data suppose that opiodergic regulation of LH secretion is abolished by the removal of sex steroids (56). On the other hand, women under hormonal con- traception are also characterized by the absence of the LH response to naloxone (57). Gonadal steroid feedback on LHRH
may thus be mediated via opioid pathways; however, evidence
as to whether opioids can inhibit LH secretion in postmenopausal woman is contradictory. It is therefore possible that the
presence of gonadal steroids might be necessary for the activation of a separate opioid pathway which inhibits LH release.
Changes in hypothalamic opioid activity have been implicated
in a number of pathological conditions under which gonadotropin secretion is reduced. Patients with oligomenorrhoea or
amenorrhoea secondary to hyperprolactinemia have normal
mean gonadotropin levels but only infrequent LH pulses of
large amplitude (58). Infusion of naloxone in such patients
promptly restores normal LH pulsativity (59) without alterating
the serum prolactin. This suggests that prolactin inhibits LHRH
secretion via opioidergic mechanisms. Similar LH responses
to naloxone have been reported in patients with so-called hypothalamic amenorrhoea and in the amenorrhoeic athletes (60).
The correlation is further confirmed by data showing that induction of ovulation in amenorrhoeic patients restores a normal response of LH to naloxone (61). Disturbances of menstrual
cycle are also correlated with changes in endogenous opioid
activity. The treatment with naltrexone is effective in some
patients with hypothalamic amenorrhoea in restoring the ovulatory menstrual cycle (62). Weight loss-related amenor-rhoea
is also associated with disturbances in LH pulsativity, irreversible by naloxone administration (63). In contrast to the rat, the
majority of patients with anorexia nervosa show no gonadotropin response to naloxone (63), and those patients who do respond may have another preexisting cause for amenorrhoea
(64). Similarly, patients with Kallman's syndrome and idiopathic hypopituitarism show no response to naloxone (65). In
polycystic ovary syndrome, the absence of response of LH to
naloxone has been reported. In these women the hyperandrogenic state leads to an amenorrhoeic state which, in some patients, is opioid-dependent (66). In comparison, menstruating
hyperandrogenic patients have a normal response to naloxone
during luteal phase of menstrual cycle, even in the presence of

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Opioid peptides in female reproductive system

oligomenorrhoea (67). Finally, it has been suggested that opioids might play a role in the premenstrual syndrome (68).

of the primary defect of hypothalamic GnRH production (63).

Central opioid-sex steroid interactions

Oxytocin

In the rat, opioids appear to inhibit oxytocin release in vivo in


response to suckling and other stimuli (69), and naloxone potentiates oxytocin secretion from electrically stimulated rat neurohypophysis in vitro (70). Met-enkephalin is colocalized with
oxytocin in the magnocellular neurons projecting to the posterior pituitary (20) and may thus be coreleased into plasma.
Opioid inhibition of oxytocin release may therefore represent
an ultra-short loop feedback at pituitary level (70). Studies in
the rat have suggested that central inhibitory opioid control of
oxytocin secretion may regulate "spacing" of successive births
during parturition and mediate the interruption of parturition
by environmental stressors (71).

Opioids and sexual maturation

Low plasma sex hormone levels are typical in normal prepubertal children in both sexes. A lack of LH release to naloxone
administration before sexual maturation has been observed
(72). With the advanced stages of pubertal development, the
LH response to naloxone appears in conjuction with the starting of plasma LH pulsativity. The initial increase of LH after
naloxone administration is observed in children at the Tanner
pubertal stage of 4-5 (73). These observations in humans were
confirmed by several studies in rats. The hypothalamus is ready
to produce GnRH before the onset of puberty but pulses of
GnRH may be observed in association with the maturation of
the opioid system. A segmentation of POMC mRNA in the
arcuate nucleus is shown at the onset of puberty in rats (74).
In immature rats, both antagonists and agonists of opioid receptors do not change plasma LH or GnRH-stimulated gonadotropin release from anterior pituitary. Moreover, an agerelated reduction of LH-sensitivity to opioids and lack of decrease of LH secretion after opiate peptide administration has
been described in prepubertal rats. Based on these data some
authors propose to identify the EOF as "gonadostats" (75).

Opioids and hypogonadic states

A failure of naloxone administration in increasing plasma LH


levels has been observed in various primary as well as secondary hypogonadal states. Klinefelter's and Turner's syndromes
are examples of primary hypogonadism (76). In patients with
these syndromes, the naloxone administration is ineffective in
stimulating LH release, even after prolonged sex steroid therapy
(76). Children with idiopathic precocious puberty do not show
any change of plasma LH levels following treatment with
naloxone or naltrexone. Moreover, a failure of the opioidergic
tone is confirmed in patients with Kallman' s syndrome, in view

Biomed Rev 4,1995

A close relationship between the central endogenous opioid


system and sex steroids is confirmed by several studies conducted both in vivo and in vitro. Using autoradiography and
immunocytochemistry, it has been found that arcuate nucleus
of the hypothalamus contains estradiol-concentrating neurons
as well as p-endorphin-like immunoreactivity. A subpopulation of the arcuate nucleus P-endorphin neurons is receptive
to the estradiol (77). Centrally microinfused P-endorphin modifies mammalian "sexual behaviour" and abolishes the estrogen-dependent lordosis in castrated and estrogen primed rats
(78). It has also been reported that estrogen reduces hypothalamic POMC mRNA (79). A small population of hypothalamic P-endorphin producing neurons contains progesterone.
This finding may indicate that the stimulatory effect of progesterone on GnRH and LH secretion is mediated at least in part
by the endogenous opioid system. The reduction of opioid binding sites in mediobasal hypothalamus and preoptic area is
linked to progesterone-induced LH surge (80). An increase of
hypothalamic P-endorphin content has also been observed following a chronic treatment with various progestins in
ovariectomized rats (81).
Taken together these studies indicate that the endogenous
opioid system is involved at least in part in the central control
of GnRH and gonadotropin release. Opioids mediate the sex
steroid effect exerted on GnRH and LH secretion and play a
crucial role in several neuroendocrine mechanisms involved
in reproduction.
OPIOID PEPTIDES AND PERIPHERAL
REGULATION OF THE FEMALE REPRODUCTIVE
SYSTEM

Ovaries

Immunoreactive P-endorphin is present in the ovaries of many


species including rodent (82) and human (83). Most of this
material has the molecular weight of authentic p-endorphin
while a significant percentage exhibits higher molecular weight
(84). It has been reported that the proenkephalin mRNA is
present in rat ovaries and that its concentration changes markedly during the estrus cycle (85). Immunoreactive dynorphin
and prodynorphin mRNA are also detectable in rat ovaries
(86). Immunocytochemical and in situ hybridization data show
that the granulosa and luteal cells appear to be the predominant source of ovarian POMC-derived opioids. The evaluation of p-endorphin in follicular fluid shows a preovulatory
increase of p-endorphin levels, despite constant ACTH and
p-lipotropin concentrations throughout the different phases
of menstrual cycle (87). This pattern appears again in supero-

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76

vulated follicles, supposing the existence of a relationship between follicle maturation and POMC expression. Ovarian Pendorphin (88) and POMC mRNA rise sharply on the evening
of proestrus, suggesting that its synthesis is regulated by gonadotropins and gonadal steroids (89) (Table 3).

prostaglandins, regulate locally the follicle rupture through a


coordinate action on both plasmin production and muscularis
mucosae contraction (91). Follicular P-endorphin could therefore interfere with this mechanism in view of the possible presence of opiate receptors in ovarian cells (92).

The physiological significance of opioids in growing follicle


and in corpus luteum is still unknown (82). Recent data indicate that the immature follicle contains lower P-endorphin
amounts than the preovulatory, fully mature follicle exposed
to gonadotropin stimulation. This confirms that P-endorphin
is the end product of POMC in ovulatory dominant follicle.
The increase of follicular p-endorphin in preovulatory follicle
could be related to the isolated (3-endorphin peak described in
peripheral circulation around the ovulatory period (90). The
absence of a concomitant (3-lipotropin rise has been interpreted as a phenomenon independent of the anterior pituitary
secretion (90). The finding that plasma P-endorphin peak occurs only in the ovulatory cycles (87) led to the hypothesis
that "ovarian endorphin" could contribute to peripheral P-endorphin levels in certain circumstances, such as the ovulation.

In conclusion, all these data demonstrate that the POMC processing in the follicle changes as a function of ovarian endocrine activity. Moreover, the reduced P-endorphin levels in
the luteinized unruptured follicles support the hypothesis that
these peptides could be involved in mechanisms leading to
follicle collapse (83).

A pattern opposite to that described for p-endorphin exists as


far as ACTH and its products are concerned. This indicates
that not only the synthesis of POMC mRNA (82) but also the
posttranslational processing of POMC are a function of the
ovarian cycle. In this respect, the changes of y-endorphin in
follicular fluid are worth mentioning. Since y-endorphin levels are higher in immature follicles than in superovulated ones
and luteinized unruptured follicles, it could be hypothesized
that maturational processes of granulosa cells inhibit the conversion of P-endorphin into Y-endorphin. The peptide pattern
in luteinized unruptured follicles is superimposable to that of
superovulated follicles with the only exception of P-endorphin
levels which remain lower. Since the increased concentration
of P-endorphin is a typical sign of follicle maturation, it is
possible to speculate that this opioid is involved in the ovulation process. Different substances, including progesterone and
Table 3. Expression of endogenous opioids in female reproductive organs

A bbreviations: POMC - proopiomelanocortin, PD YN prodynorphin, PENK - proenkephalin.

Biomed Rev 4,1995

Uterus

All three opioid peptide precursors are synthesized in mammalian uterus. Current experimental evidence suggests that
the POMC gene is expressed in human endometrium and the
size of its transcript is similar to that present in pituitary (25).
The prodynorphin gene is also expressed in human endometrial cells, giving a transcript similar in size to that present in
rat anterior pituitary (93). In the rat uterus, the prodynorphin
gene is also expressed, but the size of its transcript (2.2 Kb) is
200 bases smaller to that reported in rat hypothalamus (86).
The proenkephalin mRNA has also been detected in the
macaque uterus with higher levels observed during the proliferative phase of the menstrual cycle (94), suggesting a regulatory role of estrogens. On the other hand, in the rodent uterus,
progesterone has been shown to increase both met-enkephalin
secretion and proenkephalin A mRNA levels, while the higher
levels of proenkephalin expression occur during metestrus and
diestrus of normally cycling rats (95). These data propose
highly divergent regulator}' mechanisms for proenkephalin expression between primate and rodent uteri. It appears also that
progesterone stimulates endometrial P-endorphin since the
latter is only detectable in the proliferative human endometrium
(96) and increases the secretion of P-endorphin in the uterus
of ovariectomized gilts (97). In Ishikawa human endometrial
cells, which has been shown to be a good in vitro model for
the study of the effects of steroid hormones on human epithelial endometrium, the apparent molecular weight of the secreted P-endorphin is that of authentic p-endorphin (25), while
the bulk of secreted dynorphin had an apparent molecular
weight of 8 kD (93). Estrogen and glucocorticoids decrease |3endorphin secretion from Ishikawa cells (25), while both
progesterone and dihydrotestosterone do not significantly af- j
feet it (25). The antiprogestin-antiglucocorticoid RU-486 acts '
as an agonist, diminishing P-endorphin secretion possibly via
glucocorticoid receptors (25). On the other hand, the secretion of endometrial dynorphins is not affected by any of these
steroids, while LHRH induces a significant increase of
dynorphin secretion without affecting that of P-endorphin (93). ;
These data suggest that the regulation of endometrial opioids \

Opioid peptides in female reproductive system

is type-specific. Thus it is possible that each type of endometrial opioid participates in different local homeostatic loops
and exerts dinstict paracrine effects.
The role that the endometrial opioids plays within the uterine
cavity is still largely unknown. In general, it is postulated that
opioids of peripheral tissue have local, paracrine or autocrine
effects. Endometrial p-endorphin may also act locally, since it
has been shown that K-opioid receptors are present in human
endometrial cells (98) and p-endorphin increases the concentration of estrogen receptors in uterine epithelial cells, thus affecting the sensitivity of endometrium to estrogens (99). In addition, endometrial opioids may exert a number of other functions, such as relaxation of smooth muscle (100). Smooth
muscle bundles contained in the supportive ligaments as well
as in the circular muscle system of the uterus undergo contractions during the preovulatory peak of estrogens. This coordination of muscular contractions plays an important role in
properly orienting the ovary with the infundibulum of the fallopian tube at the time of ovulation, and any pathological condition interfering with this coordination may be a cause of
dysmenorrhea. The preovulatory peak of estrogens by decreasing endometrial p-endorphin release could potentially facilitate the uterine contractions necessary for efficient movement
of the ovum into the tube or the transport of the sperm through
the uterine cavity.
Numerous findings propose an immunological role of opioid
peptides (101). Recent data show that the corticotropin-releasing hormone (CRH) gene is expressed in normal and tumoral
epithelial cells of human endometrium (26). The coexpression
in endometrial epithelial cells of both CRH and POMC suggests that endometrial CRH may have an autocrine or paracrine
effect on endometrial POMC-derived peptide secretion, as in
placenta and testes (26). The involvement of CRH in the inflammatory process has been recently established. CRH has
been detected in inflammatory sites, whereas immunoneutralization of CRH attenuates the inflammatory response (102). It
is possible that endometrial CRH participates in the regulation of immunological events taking place within the uterine
cavity, specifically in egg nidation and implantation. It is
known that (/) the human blastocyst secretes prostaglandin E,
(PGE,) (103), 00 PGE, promotes the attachment and implantation of the blastocyst (103), (/"//) PGE, is a major inducer of
CRH expression in the placenta (104), and (iv) POMC-derived P-endorphin possesses immunosupressive properties
(101). From these data the following scenario during egg implantation could take place: the blastocyst secretes PGE, at
the site of nidation, which among other things, stimulates the
production of CRH from the endometrium; subsequently, CRH
participates in local events culminating in the attachment of
the egg; at the same time, endometrial CRH may also suppress inflammatory response by augmenting the production of

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77

local, endometrial P-endorphin, which will produce a confined immunosupression at the site of nidation, inhibiting the
rejection of the semixenograft. Thus, another potential site of
action of endometrial P-endorphin could be its participation,
along with glucocorticoids, interleukins (26) and CRH, in endometrial immunological events associated with egg implantation. Here, it is worth mentioning that oc-MSH exerts
an antiinflammatory effect (105) and GnRH and LH negatively influence B lymphopoiesis (106).

Placenta

The human placenta is rich in a variety of opioids including


P-endorphin (102), met- and leu-enkephalin and dynorphin
(103) (see Table 3). Synthesis of P-endorphin, p-lipotropin
and ACTH, as well as a number of higher molecular weight
precursors has been demonstrated by pulse-chase experiments
in cultured placental trophoblasts (104). The posttranslational
processing of placental POMC is similar to that in hypothalamus and gonadal tissues since most of the POMC-derived peptides present have the physicochemical characteristics of aMSH and P-endorphin (103). However, as with other reproductive tissues, placental POMC mRNA is by about 300 nucleotides shorter than its pituitary counterpart (107). Prodynorphin-derived opioids have been also detected in human placenta (103). Immunohistochemically, placental POMC-derived
peptides are localized in the villous syncytiotrophoblast, where
most of placental pituitarylike hormones are synthesized (108).
It has been found that POMC-derived peptides are being secreted from perfused human placental slices in vitro and from
placental trophoblasts in culture (104), and the secretion rate
of P-endorphin is higher than that of ACTH (26).
A number of substances affect the secretion of placental POMCderived peptides. CRH-binding sites are present in human placenta (109) and CRH stimulates the secretion of all placental
POMC-derived peptides (26). Glucocorticoids suppress de novo
synthesis of POMC in anterior pituitary corticotrophs (110),
but they appear not to affect the secretion of POMC-derived
peptides from perfused placental slices in vitro. The oxytocin
gene is expressed in reproductive tract tissues and an oxytocin-like substance has been identified in human placenta. The
secretion of all placental POMC-derived peptides is stimulated by oxytocin in a dose-depended manner (26). Prostaglandins increase plasma and amniotic fluid levels of p-endorphin in pregnant women undergoing prostaglandin-induced
therapeutic abortion at the second trimester of pregnancy (111).
In addition, prostaglandins stimulate the secretion of placental POMC-derived peptides (104). Their effect on placental
POMC may be mediated by CRH since the addition of a CRH
antagonist causes a partial block of the stimulatory effect of
prostaglandins on placental POMC (104). K-opioid binding
sites, for which prodynorphin-derived opioids are the main

Makrigiannakis, Margioris,Stournaras, and Gravanis

78

endogenous agonist, are also present (112), suggesting that


placental dynorphins may have a local effect.
The physiological significance of placental POMC-derived peptides remains unknown. They could act either locally or systematically. There are local effects of placental ACTH which
involve stimulation of the release of intrauterine prostaglandins and of the secretion of progesterone and estrogens by
placenta in vitro (113). (3-endorphin has preferential affinity
proposed as the prototype ligand for the e-opioid receptors
identified in the rat vas deferens (114). It appears that opioids
stimulate the secretion of hCG from first trimester human trophoblasts in vitro and reduce placental acetylcholine release
into the fetal vessels (115). In addition, an inhibitory action of
opioid peptides on placental GnRH release, similar to that
found in hypothalamic GnRH neurons, has also been observed
(115). Recent evidence suggests that placental steroid hormones and endogenous opioid peptides may also modulate the
release of GnRH (115). Collectively, these findings suggest
that the locally produced steroids and opioid peptides participate in the overall regulation of hCG secretion by the
syncytiotrophoblast. The presence of receptors for estrogen,
progesterone and opioid peptides in human placenta (116) supports this hypothesis.
As for the distal effects of placental POMC-derived peptides,
it has been suggested that a significant percentage of maternal
plasma ACTH and [3-endorphin originate in placenta. Thus,
placental ACTH may participate in the regulation of the maternal hypothalamus-pituitary-adrenal axis, while placental Pendorphin may play a role in the inhibition of oxytocin,
vassopressin and gonadotropin secretion, the promotion of
prolactin release, and in the modulation of pain threshold during pregnancy and parturition (117).

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Received 10 July 1995


Accepted 25 August 1995

Address for correspondance:


Dr Antonis Makrigiannakis or Dr Achille Gravanis
Department of Pharmacology
Medical School
University of Crete
GR-71110 Heraklion
Greece

Tel: 30(81)542100
Fax: 30(81)542112
E-mail: gravanis@iesl.forth.gr

Biomed Rev 4,1995

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