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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. Margioris

2 , Christos Stournams

3 , andAchitte Gravanis

1

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

Heraklion, Greece

• All endogenous opioid peptides derive from three pre-

cursor molecules i. e proopiomelanocortin, proenkephalin and

prodynorphin. The endogenous opioid peptides exert their bio-

logical effects through opioid receptors. Each endogenous

opioid peptides exhibits higher binding affinity towards a spe-

cific 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 hypo-

thalamic opioidergic mechanism represents one of the impor-

tant central control systems of gonadotropin-releasing hor-mone and gonadotropin release. Opioids mediate the sex ste-

roid 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 hor-

mone. The genes of the endogenous opioid peptides are also

expressed in peripheral reproductive tissues such as the en-

dometrium 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 wererecognized long before the isolation of endogenous peptideswith opioid activity (1). Since this discovery, research has ex-panded greatly and a vast body of literature now documentsthe physiology and pathology of endogenous opioid modula-tion of hormonal and other aspects of reproduction. Endog-enous opioid peptides (EOF) are present throughout the hypo-thalamic-pituitary-gonadal axis as well as in the endometriumand placenta. Current evidence suggests that EOF play im-portant regulatory roles in reproduction. At least part of EOF

effects may be local, paracrine or autocrine in nature. It isthus possible that local opioids may be part of microregulatoryloops within each reproductive organ. This review will con-centrate on the human data but will refer to animal studies ifimportant 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 opioid-active N-terminal sequence Tyr-Gly-Gly-Phe and differ onlyin their C-active residue methionine and leucine, respectively.All opioid peptides share the sequence of either met- or leu-

INTRODUCTION SUMMARY


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Makrigiannakis, Margioris,Stournaras, and Gravanis

enkephalin at their N-terminal, but possess C-terminal exten-sions of variable length, which may confer greater potency

(2), increased stability against degradation (3) and differentreceptor specificity. Analysis of DNA sequence in recent yearshas allowed the prediction of the amino-acid sequence of threeprecursor molecules (4).

Proopiomelanocortin (POMC) is a glycoprotein of 31 kD andis the precursor for adrenocorticotropic hormone (ACTH), a-melanocyte-stimulating hormone (oc-MSH), p-lipotropin andalso p-endorphin but does not appear to be further processed tomet-enkephalin. The precursor product relationship was firstestablished by radiolabeling studies on AtT-20 cells which de-rive from an ACTH-producing tumor or mouse pituitary. Thefinal posttranslational products of POMC precursor molecule

differ between tissues expressing POMC gene. Thus, in ante-rior pituitary, the tissue with the highest concentration ofPOMC mRNA and POMC derived peptides, ACTH is the mostpredominant posttranslational product of POMC and plays an es-sential role in the hypothalamic-pituitary-adrenal axis.

Proenkephalin is the major biological source of met-enkepha-lin and its extended forms (met-enkephalin-Arg-Phe, met-en-kephalin-Arg-Gly-Leu and peptide E) and one source of leu-enkephalin. Proenkephalin-derived peptides, in contrast toPOMC, are all opioids in nature. Each molecule of pro-en-kephalin contains seven opioid peptides with the met- or leu-enkephalin active core.

Prodynorphin (proenkephalin B) contains 3 copies of leu-en-

Table 1. Precursor molecules of opioid peptides

kephalin and its extended forms dynorphin, rimorphin(dynorphin B), leumorphin and a-neo-endorphin. Dynorphin

A, a seventeen amino-acid peptide, was the first posttransla-tional product of prodynorphin to be isolated (2,5). DynorphinA and its two smaller fragments have the highest potency ofall known endogenous opioid peptides in the guinea pig ileumbioassay, a characteristic attributed to their high-affinity forthe K-opioid receptor. In fact it appears that they are the onlyendogenous K-receptor agonists known (6).

The three opioid precursors are of similar molecular size andalso contain a number of sequence homologies, suggesting thatall may have originally derived from an ancestor opioid gene(Table 1).

OPIOID RECEPTORS

• The EOF exert their biological effects through opioidreceptors. Each EOF exhibits higher binding affinity towardsa specific type of opioid receptor. A variety of types of opioidreceptors have been described. Behavioral studies in dogs sug-gested that opioids could be divided into (J,-, K- or o- agonists(7). Studies with opioid peptides using bioactivity in periph-eral tissue preparations (8), or binding studies of radioactivelylabelled ligands in brain tissue (9) confirmed the existence of(a,, 8, Kand possibly e- receptors (Table 2).

The ^-receptor, so named because of its activation by mor-phine, mediates analgesia, bradycardia and hypothermia. TheK-receptor activated by ketocyclazosine, appears to be respon-sible for sedation and depression of flexor reflexes, but has noinvolvement in skin twitch reflex or pulse rate. A third classof receptors was named o for its activation by SKF 10.047 (N-allylnormetazosine). For an effect to be considered consequentto 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 potentanalogue, naltrexone. The [i- and K-receptor-mediated events

are readily reversible by naltrexone (7), while physiologicalevents effected by o-receptors do not (10). An additional classof opioid receptor identified (11) is activated by the enkepha-lins and is named 8.

Other receptors considered to be opioid on the basis of theirsensitivity to naloxone have been identified in binding stud-ies, but a clear functional significance associated with them islacking. Among these receptors are jj.1-receptors mediatinganalgesia and |i2-receptors mediating respiratory depression(12). These assumptions are based upon the observation thatnaloxone antagonizes analgesia but not the respiratory depres-sion induced by morphine. Unfortunately, there is to date noantagonist that can reverse the respiratory depression withoutaffecting the analgesia.

Subtypes of K-receptors have also been proposed (13). Theremay be as many as four subtypes of the K-receptor based uponevidence from radioligand binding studies (14). Opioid re-ceptors termed e were originally identified as those mediatinginhibition of electrically evoked twitch in rat vas deferens (15).These receptors were believed to be selectively activated by P-endorphin. Finally, ?i receptors first described in binding stud-ies in rat brain (16) were defined as having high-affinity fornaloxone, but low affinity for another opioid antagonist,

diprenorphine. A functional role for this class of opioid recep-tors has not yet been proposed.

LOCALIZATION OF OPIOID PEPTIDES AMD

RECEPTORS

• Opioids are localized throughout the central nervoussystem in specific neuron tracts, and separated on the basis oftheir known precursors (17). All opioids are concentrated inthe hypothalamus, pituitary, periaqueductal grey matter andspinal cord. Hypothalamic (3-endorphinergic neurons originatelargely in the arcuate nucleus from where they project to themedian eminence as well as other parts of the brain. Enkepha-

linergic neurons exist in several hypothalamic nuclei while pro-dynorphin derived peptides are mostly concentrated in the su-praoptic and paraventricular nuclei, although some are alsopresent in the arcuate nucleus and posterior hypothalamus (18).|i- and K- receptors are present in hypothalamus in roughlyequal numbers but 8-receptors account for less than 10% ofopioid binding (9).

The pituitary contains large amounts of P-endorphin in theanterior pituitary corticotroph cells and prodynorphin-derivedopioids in the posterior pituitary vasopressin neurons (18).Met-enkephalin is present in both anterior pituitary soma-

totrophs (19) and posterior pituitary oxytocin neurons (20).

Outside the central nervous system opioids are concentratedin the adrenal medulla and other parts of the sympathetic ner-

vous system, and in neurons in the gut. Smaller quantities arealso described in the testis and pancreas (21). P-endorphinand met-enkephalin both circulate in human plasma (22).

The EOF genes are expressed in most tissues involved in mam-malian reproduction. POMC gene is expressed in the hypo-thalamus (23), gonads (24), endometrium (25) and placenta(26). In all these tissues P-endorphin appears to represent themain posttranslational product of POMC. POMC mRNA andP-endorphin are present in the granulosa, luteal and intestinalcells of female gonads, in the endometrial cells of uterus, andin the placental syncytiotrophoblast. The proenkephalin geneis expressed in hypothalamus and gonads, and the prodynor-phin gene in hypothalamus, anterior pituitary gonadotrophcells, male and female gonads, placenta, and endometrium.

OPIOID PEPTIDES AND CENTRAL REGULATION

OF THE FEMALE REPRODUCTIVE SYSTEM

• Prolactin

Administration of morphine (27), the enkephalin analogueDAMME (FK 33-824) (28), and P-endorphin (29) all causeprompt release of prolactin in man. In the rat, P-endorphin isa more potent secretagogue than met-enkephalin (30), or

dynorphin (31), and intraventricular administration of antis-era for p-endorphin lowers both basal and stress-induced pro-lactin secretion (32), suggesting that p-endorphin is indeedthe opioid involved. This is compatible with the naloxone sen-sitivity of opioid stimulation in man (28) which suggests in-volvement of |0,- or e- selective opioids. The opioid effect isblocked by the administration of dopamine agonists and po-tentiated by dopamine antagonists (33), suggesting that opio-ids act by inhibition of dopamine release, the major prolactininhibitory factor from the median eminence. This concept issupported by direct experimental evidence in the rat, whereopioids decrease hypothalamic dopamine turnover (34) andrelease (35). Most studies have failed to find any direct effect

of opioid peptides on prolactin secretion by isolated pituitarycells in vitro. In the rat, naloxone lowers basal, stress-inducedand suckling-induced prolactin secretion, suggesting an im-portant physiological role for opioids on prolactin secretion(36). In contrast, most studies have failed to demonstrate aneffect of naloxone, even at high dosage, on basal or stress-induced release of prolactin in normal subjects (37), nor anelevated prolactin level in the puerperium (37), or in patientswith prolactinomas (38). A minority of studies has howeverreported an inhibition of basal or stress-related prolactin re-lease (39). High doses of nalo-xone may abolish the exercise-induced release of prolactin in highly trained male athletes

(40). Naloxone infusion (1.6 mg per h) may stimulate pulsa-

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tile prolactin release in women during the late follicular andmid-luteal phases of the menstrual cycle (41) and in women

under oral contraception (42), but not in early follicular orlate luteal phase, or in hypogonadal women. This pulsatilerelease of prolactin is synchronous with that of LH, suggest-ing that a common mechanism, presumably involving lutein-izing hormone-releasing hormone (LHRH), mediates the re-lease of both LH and prolactin under these circumstances. In-deed, LHRH may stimulate prolactin release, at least in post-menopausal women (43), and in vitro evidence suggests thatthis might involve paracrine gonadotroph-lactotroph interac-tions (44). In spite of the existence of stimulatory and possiblyinhibitory opioidergic mechanisms for control of prolactin se-cretion, no clear physiological or pathological role hasemerged.

Gonadotropins

The predominant opioid modulation of gonadotropin secre-tion is inhibitory. Chronic opiate addiction has been long rec-ognized 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 con-sistently noted, perhaps due to its longer half life in the circu-lation. Naloxone acutely increases serum LH and possibly FSHin both sexes, suggesting tonic inhibitory opioid control ofgonadotropin secretion (46). Studies on LH pulsativity indi-cate an increase in both frequency and amplitude of LH pulseswith naloxone in both sexes (46). In females, this effect ismost marked in the late follicular and particularly mid-lutealphase of the menstrual cycle, and opioids may thus mediatethe slowing of LH pulsativity seen at this time. In normallymenstruating women, the opioid activity of LH secretion showsa fluctuation dependent on the menstrual cycle phase. In theearly follicular phase, the opioid activity is low, increasingproportionately with the ovulatory peak of LH, then remain-ing high during luteal phase (47). The high progesterone lev-els during luteal phase of menstrual cycle are suggested toincrease the tone on LH pulsativity (48). Low doses of naloxoneare required to modulate LH release, suggesting primary in-

volvement of \i- or e- receptors (48). However, in the imma-ture rat, hypothalamic injections of antisera to both (3-endor-phin and dynorphin raise LH (49), supposing that more thanone opioidergic pathway might be involved. Opioid effectsoccur at hypothalamic level and involve modulation of LHRHrelease. Thus opioids have no effect on the LH response to theLHRH test (50). LHRH antagonists block naloxone stimula-tion in the rat (51), naloxone stimulates the LHRH releasefrom human hypothalamus in vitro (52), and morphine de-creases hypothalamic LHRH content (53).

In man, as in the rat, opioidergic regulation mechanisms ap-

pear to be closely connected to the feedback of gonadal ste-

roids and LHRH secretion. In postmenopausal women, the en-dogenous opioid tone is impaired, as reflected by the lack of

naloxone effect on plasma LH levels (54). This neuroendo-crine response is absent in women with physiological and sur-gical menopause (54). Estrogen/progestin therapy affects thenormal opioidergic tone and restores a concomitant LH re-lease after naloxone injection (54). This observation in womenhas been supported by studies in animals. In fact, naloxoneabolishes the inhibitory effect of sex steroids on LH secretionin rats (55). This effect disappears after gonadectomy, andnaloxone is no longer able to stimulate LH secretion in maleand female rats. These data suppose that opiodergic regula-tion of LH secretion is abolished by the removal of sex ste-roids (56). On the other hand, women under hormonal con- -traception are also characterized by the absence of the LH re-

sponse to naloxone (57). Gonadal steroid feedback on LHRHmay thus be mediated via opioid pathways; however, evidenceas to whether opioids can inhibit LH secretion in postmeno-pausal woman is contradictory. It is therefore possible that thepresence of gonadal steroids might be necessary for the acti-vation of a separate opioid pathway which inhibits LH release.

Changes in hypothalamic opioid activity have been implicatedin a number of pathological conditions under which gonadot-ropin secretion is reduced. Patients with oligomenorrhoea oramenorrhoea secondary to hyperprolactinemia have normalmean gonadotropin levels but only infrequent LH pulses oflarge amplitude (58). Infusion of naloxone in such patientspromptly restores normal LH pulsativity (59) without alteratingthe serum prolactin. This suggests that prolactin inhibits LHRHsecretion via opioidergic mechanisms. Similar LH responsesto naloxone have been reported in patients with so-called hy-pothalamic amenorrhoea and in the amenorrhoeic athletes (60).The correlation is further confirmed by data showing that in-duction of ovulation in amenorrhoeic patients restores a nor-mal response of LH to naloxone (61). Disturbances of menstrualcycle are also correlated with changes in endogenous opioidactivity. The treatment with naltrexone is effective in somepatients with hypothalamic amenorrhoea in restoring the ovu-latory menstrual cycle (62). Weight loss-related amenor-rhoea

is also associated with disturbances in LH pulsativity, irrevers-ible by naloxone administration (63). In contrast to the rat, themajority of patients with anorexia nervosa show no gonadot-ropin response to naloxone (63), and those patients who do re-spond may have another preexisting cause for amenorrhoea(64). Similarly, patients with Kallman's syndrome and idio-pathic hypopituitarism show no response to naloxone (65). Inpolycystic ovary syndrome, the absence of response of LH tonaloxone has been reported. In these women the hyperandro-genic state leads to an amenorrhoeic state which, in some pa-tients, is opioid-dependent (66). In comparison, menstruatinghyperandrogenic patients have a normal response to naloxoneduring luteal phase of menstrual cycle, even in the presence of

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

Oxytocin

In the rat, opioids appear to inhibit oxytocin release in vivo inresponse to suckling and other stimuli (69), and naloxone po-tentiates oxytocin secretion from electrically stimulated rat neu-rohypophysis in vitro (70). Met-enkephalin is colocalized withoxytocin in the magnocellular neurons projecting to the pos-terior pituitary (20) and may thus be coreleased into plasma.Opioid inhibition of oxytocin release may therefore representan ultra-short loop feedback at pituitary level (70). Studies inthe rat have suggested that central inhibitory opioid control ofoxytocin secretion may regulate "spacing" of successive birthsduring parturition and mediate the interruption of parturitionby environmental stressors (71).

• Opioids and sexual maturation

Low plasma sex hormone levels are typical in normal prepuber-tal children in both sexes. A lack of LH release to naloxoneadministration before sexual maturation has been observed(72). With the advanced stages of pubertal development, theLH response to naloxone appears in conjuction with the start-ing of plasma LH pulsativity. The initial increase of LH afternaloxone administration is observed in children at the Tanner

pubertal stage of 4-5 (73). These observations in humans wereconfirmed by several studies in rats. The hypothalamus is readyto produce GnRH before the onset of puberty but pulses ofGnRH may be observed in association with the maturation ofthe opioid system. A segmentation of POMC mRNA in thearcuate nucleus is shown at the onset of puberty in rats (74).In immature rats, both antagonists and agonists of opioid re-ceptors do not change plasma LH or GnRH-stimulated gona-dotropin release from anterior pituitary. Moreover, an age-related reduction of LH-sensitivity to opioids and lack of de-crease of LH secretion after opiate peptide administration hasbeen described in prepubertal rats. Based on these data someauthors propose to identify the EOF as "gonadostats" (75).

• Opioids and hypogonadic states

A failure of naloxone administration in increasing plasma LHlevels has been observed in various primary as well as second-ary hypogonadal states. Klinefelter's and Turner's syndromesare examples of primary hypogonadism (76). In patients withthese syndromes, the naloxone administration is ineffective instimulating LH release, even after prolonged sex steroid therapy(76). Children with idiopathic precocious puberty do not showany change of plasma LH levels following treatment withnaloxone or naltrexone. Moreover, a failure of the opioidergictone is confirmed in patients with Kallman' s syndrome, in view

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

• Central opioid-sex steroid interactions

A close relationship between the central endogenous opioidsystem and sex steroids is confirmed by several studies con-ducted both in vivo and in vitro. Using autoradiography andimmunocytochemistry, it has been found that arcuate nucleusof the hypothalamus contains estradiol-concentrating neuronsas well as p-endorphin-like immunoreactivity. A subpopula-tion of the arcuate nucleus P-endorphin neurons is receptiveto the estradiol (77). Centrally microinfused P-endorphin modi-fies mammalian "sexual behaviour" and abolishes the estro-gen-dependent lordosis in castrated and estrogen primed rats(78). It has also been reported that estrogen reduces hypotha-lamic POMC mRNA (79). A small population of hypotha-lamic P-endorphin producing neurons contains progesterone.This finding may indicate that the stimulatory effect of proges-terone on GnRH and LH secretion is mediated at least in partby the endogenous opioid system. The reduction of opioid bind-ing sites in mediobasal hypothalamus and preoptic area islinked to progesterone-induced LH surge (80). An increase ofhypothalamic P-endorphin content has also been observed fol-lowing a chronic treatment with various progestins inovariectomized rats (81).

Taken together these studies indicate that the endogenous

opioid system is involved at least in part in the central controlof GnRH and gonadotropin release. Opioids mediate the sexsteroid effect exerted on GnRH and LH secretion and play acrucial role in several neuroendocrine mechanisms involvedin 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 thismaterial has the molecular weight of authentic p-endorphinwhile a significant percentage exhibits higher molecular weight(84). It has been reported that the proenkephalin mRNA ispresent in rat ovaries and that its concentration changes mark-edly during the estrus cycle (85). Immunoreactive dynorphinand prodynorphin mRNA are also detectable in rat ovaries(86). Immunocytochemical and in situ hybridization data showthat the granulosa and luteal cells appear to be the predomi-nant source of ovarian POMC-derived opioids. The evalua-tion of p-endorphin in follicular fluid shows a preovulatoryincrease of p-endorphin levels, despite constant ACTH and

p-lipotropin concentrations throughout the different phasesof menstrual cycle (87). This pattern appears again in supero-

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vulated follicles, supposing the existence of a relationship be-tween follicle maturation and POMC expression. Ovarian P-

endorphin (88) and POMC mRNA rise sharply on the eveningof proestrus, suggesting that its synthesis is regulated by go-nadotropins and gonadal steroids (89) (Table 3).

The physiological significance of opioids in growing follicleand in corpus luteum is still unknown (82). Recent data indi-cate that the immature follicle contains lower P-endorphinamounts than the preovulatory, fully mature follicle exposedto gonadotropin stimulation. This confirms that P-endorphinis the end product of POMC in ovulatory dominant follicle.The increase of follicular p-endorphin in preovulatory folliclecould be related to the isolated (3-endorphin peak described inperipheral circulation around the ovulatory period (90). The

absence of a concomitant (3-lipotropin rise has been inter-preted as a phenomenon independent of the anterior pituitarysecretion (90). The finding that plasma P-endorphin peak oc-curs only in the ovulatory cycles (87) led to the hypothesisthat "ovarian endorphin" could contribute to peripheral P-en-dorphin levels in certain circumstances, such as the ovula-tion.

A pattern opposite to that described for p-endorphin exists asfar as ACTH and its products are concerned. This indicatesthat not only the synthesis of POMC mRNA (82) but also theposttranslational processing of POMC are a function of theovarian cycle. In this respect, the changes of y-endorphin infollicular fluid are worth mentioning. Since y-endorphin lev-els are higher in immature follicles than in superovulated onesand luteinized unruptured follicles, it could be hypothesizedthat maturational processes of granulosa cells inhibit the con-version of P-endorphin into Y-endorphin. The peptide patternin luteinized unruptured follicles is superimposable to that ofsuperovulated follicles with the only exception of P-endorphinlevels which remain lower. Since the increased concentrationof P-endorphin is a typical sign of follicle maturation, it ispossible to speculate that this opioid is involved in the ovula-tion process. Different substances, including progesterone and

Table 3. Expression of endogenous opioids in female repro-ductive organs

prostaglandins, regulate locally the follicle rupture through acoordinate action on both plasmin production and muscularis

mucosae contraction (91). Follicular P-endorphin could there-fore interfere with this mechanism in view of the possible pres-ence of opiate receptors in ovarian cells (92).

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

• Uterus

All three opioid peptide precursors are synthesized in mam-malian uterus. Current experimental evidence suggests thatthe POMC gene is expressed in human endometrium and thesize of its transcript is similar to that present in pituitary (25).The prodynorphin gene is also expressed in human endome-trial cells, giving a transcript similar in size to that present inrat anterior pituitary (93). In the rat uterus, the prodynorphingene is also expressed, but the size of its transcript (2.2 Kb) is200 bases smaller to that reported in rat hypothalamus (86).The proenkephalin mRNA has also been detected in themacaque uterus with higher levels observed during the prolif-erative phase of the menstrual cycle (94), suggesting a regula-tory role of estrogens. On the other hand, in the rodent uterus,progesterone has been shown to increase both met-enkephalinsecretion and proenkephalin A mRNA levels, while the higherlevels of proenkephalin expression occur during metestrus anddiestrus of normally cycling rats (95). These data proposehighly divergent regulator}' mechanisms for proenkephalin ex-pression between primate and rodent uteri. It appears also thatprogesterone stimulates endometrial P-endorphin since thelatter is only detectable in the proliferative human endometrium(96) and increases the secretion of P-endorphin in the uterusof ovariectomized gilts (97). In Ishikawa human endometrialcells, which has been shown to be a good in vitro model forthe study of the effects of steroid hormones on human epithe-

lial endometrium, the apparent molecular weight of the se-creted P-endorphin is that of authentic p-endorphin (25), whilethe bulk of secreted dynorphin had an apparent molecularweight of 8 kD (93). Estrogen and glucocorticoids decrease |3-endorphin secretion from Ishikawa cells (25), while bothprogesterone and dihydrotestosterone do not significantly af- jfeet it (25). The antiprogestin-antiglucocorticoid RU-486 acts '•as an agonist, diminishing P-endorphin secretion possibly viaglucocorticoid receptors (25). On the other hand, the secre-tion of endometrial dynorphins is not affected by any of thesesteroids, while LHRH induces a significant increase ofdynorphin secretion without affecting that of P-endorphin (93). ;These data suggest that the regulation of endometrial opioids \

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A bbreviations: POMC - proopiomelanocortin, PD YN -

prodynorphin, PENK - proenkephalin.

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is type-specific. Thus it is possible that each type of endome-trial opioid participates in different local homeostatic loops

and exerts dinstict paracrine effects.

The role that the endometrial opioids plays within the uterinecavity is still largely unknown. In general, it is postulated thatopioids of peripheral tissue have local, paracrine or autocrineeffects. Endometrial p-endorphin may also act locally, since ithas been shown that K-opioid receptors are present in humanendometrial cells (98) and p-endorphin increases the concen-tration of estrogen receptors in uterine epithelial cells, thus af-fecting the sensitivity of endometrium to estrogens (99). In ad-dition, endometrial opioids may exert a number of other func-tions, such as relaxation of smooth muscle (100). Smoothmuscle bundles contained in the supportive ligaments as wellas in the circular muscle system of the uterus undergo contrac-tions during the preovulatory peak of estrogens. This coordi-nation of muscular contractions plays an important role inproperly orienting the ovary with the infundibulum of the fal-lopian tube at the time of ovulation, and any pathological con-dition interfering with this coordination may be a cause ofdysmenorrhea. The preovulatory peak of estrogens by decreas-ing endometrial p-endorphin release could potentially facili-tate the uterine contractions necessary for efficient movementof the ovum into the tube or the transport of the sperm throughthe uterine cavity.

Numerous findings propose an immunological role of opioidpeptides (101). Recent data show that the corticotropin-releas-ing hormone (CRH) gene is expressed in normal and tumoralepithelial cells of human endometrium (26). The coexpressionin endometrial epithelial cells of both CRH and POMC sug-gests that endometrial CRH may have an autocrine or paracrineeffect on endometrial POMC-derived peptide secretion, as inplacenta and testes (26). The involvement of CRH in the in-flammatory process has been recently established. CRH hasbeen detected in inflammatory sites, whereas immunoneutrali-zation of CRH attenuates the inflammatory response (102). Itis possible that endometrial CRH participates in the regula-tion of immunological events taking place within the uterine

cavity, specifically in egg nidation and implantation. It isknown that (/) the human blastocyst secretes prostaglandin E,(PGE,) (103), 00 PGE, promotes the attachment and implan-tation of the blastocyst (103), (/"//) PGE, is a major inducer ofCRH expression in the placenta (104), and (iv) POMC-de-rived P-endorphin possesses immunosupressive properties(101). From these data the following scenario during egg im-plantation could take place: the blastocyst secretes PGE, atthe site of nidation, which among other things, stimulates theproduction of CRH from the endometrium; subsequently, CRHparticipates in local events culminating in the attachment ofthe egg; at the same time, endometrial CRH may also sup-press inflammatory response by augmenting the production of

local, endometrial P-endorphin, which will produce a con-fined immunosupression at the site of nidation, inhibiting the

rejection of the semixenograft. Thus, another potential site ofaction of endometrial P-endorphin could be its participation,along with glucocorticoids, interleukins (26) and CRH, in en-dometrial immunological events associated with egg im-plantation. Here, it is worth mentioning that oc-MSH exertsan antiinflammatory effect (105) and GnRH and LH nega-tively influence B lymphopoiesis (106).

• Placenta

The human placenta is rich in a variety of opioids includingP-endorphin (102), met- and leu-enkephalin and dynorphin(103) (see Table 3). Synthesis of P-endorphin, p-lipotropinand ACTH, as well as a number of higher molecular weightprecursors has been demonstrated by pulse-chase experimentsin cultured placental trophoblasts (104). The posttranslationalprocessing of placental POMC is similar to that in hypothala-mus and gonadal tissues since most of the POMC-derived pep-tides present have the physicochemical characteristics of a-MSH and P-endorphin (103). However, as with other repro-ductive tissues, placental POMC mRNA is by about 300 nucle-otides shorter than its pituitary counterpart (107). Prodynor-phin-derived opioids have been also detected in human pla-centa (103). Immunohistochemically, placental POMC-derivedpeptides 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 se-creted from perfused human placental slices in vitro and fromplacental trophoblasts in culture (104), and the secretion rateof P-endorphin is higher than that of ACTH (26).

A number of substances affect the secretion of placental POMC-derived peptides. CRH-binding sites are present in human pla-centa (109) and CRH stimulates the secretion of all placentalPOMC-derived peptides (26). Glucocorticoids suppress de novosynthesis of POMC in anterior pituitary corticotrophs (110),but they appear not to affect the secretion of POMC-derivedpeptides from perfused placental slices in vitro. The oxytocin

gene is expressed in reproductive tract tissues and an oxyto-cin-like substance has been identified in human placenta. Thesecretion of all placental POMC-derived peptides is stimu-lated by oxytocin in a dose-depended manner (26). Prostag-landins increase plasma and amniotic fluid levels of p-endor-phin in pregnant women undergoing prostaglandin-inducedtherapeutic abortion at the second trimester of pregnancy (111).In addition, prostaglandins stimulate the secretion of placen-tal POMC-derived peptides (104). Their effect on placentalPOMC may be mediated by CRH since the addition of a CRHantagonist causes a partial block of the stimulatory effect ofprostaglandins on placental POMC (104). K-opioid bindingsites, for which prodynorphin-derived opioids are the main

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endogenous agonist, are also present (112), suggesting thatplacental dynorphins may have a local effect.

The physiological significance of placental POMC-derived pep-tides remains unknown. They could act either locally or sys-tematically. There are local effects of placental ACTH whichinvolve stimulation of the release of intrauterine prostaglan-dins and of the secretion of progesterone and estrogens byplacenta in vitro (113). (3-endorphin has preferential affinityproposed as the prototype ligand for the e-opioid receptorsidentified in the rat vas deferens (114). It appears that opioidsstimulate the secretion of hCG from first trimester human tro-phoblasts in vitro and reduce placental acetylcholine releaseinto the fetal vessels (115). In addition, an inhibitory action ofopioid peptides on placental GnRH release, similar to that

found in hypothalamic GnRH neurons, has also been observed(115). Recent evidence suggests that placental steroid hor-mones and endogenous opioid peptides may also modulate therelease of GnRH (115). Collectively, these findings suggestthat the locally produced steroids and opioid peptides partici-pate in the overall regulation of hCG secretion by thesyncytiotrophoblast. The presence of receptors for estrogen,progesterone and opioid peptides in human placenta (116) sup-ports this hypothesis.

As for the distal effects of placental POMC-derived peptides,it has been suggested that a significant percentage of maternalplasma ACTH and [3-endorphin originate in placenta. Thus,placental ACTH may participate in the regulation of the ma-ternal hypothalamus-pituitary-adrenal axis, while placental P-endorphin may play a role in the inhibition of oxytocin,vassopressin and gonadotropin secretion, the promotion ofprolactin release, and in the modulation of pain threshold dur-ing 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: [email protected]

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1995, opioid peptides in the female reproductive system physiological implications

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