Impact of the opioid system on the reproductive axis

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Impact of the opioid system on the reproductive axis € ttcher, M.D., M.A.,a Beata Seeber, M.D., M.S.C.E.,a Gerhard Leyendecker, M.D.,b Bettina Bo and Ludwig Wildt, M.D.a a Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Innsbruck, Austria; and b Kinderwunschzentrum Darmstadt, Darmstadt, Germany

Endogenous opioids, first described more than 40 years ago, have long been recognized for their main role as important neuromodulators within the central nervous system. More recently endogenous opioids and their receptor have been identified in a variety of reproductive and nonreproductive tissues outside the central nervous system. Their role within these tissues and organs, however, is only incompletely understood. In the central nervous system, endogenous opioids inhibit pulsatile GnRH release, in part mediating the stress response within the central nervous–pituitary gonadal axis, resulting in hypothalamic amenorrhea. In the ovary, the presence of endogenous opioids primarily produced by granulosa cells has been demonstrated within the follicular fluid, likely influencing oocyte maturation. In hypothalamic amenorrhea, normal cycles can be restored by the administration of opioid antagonists, such as naltrexone. In polycystic ovarian syndrome, endogenous opioids have found to be elevated and may stimulate insulin secretion from the endocrine pancreas. This effect can be inhibited by opioid antagonists, resulting in a decrease of circulating insulin levels in response to glucose challenge. Endogenous opioids may also play a role in the pathogenesis of ovarian hyperstimulation syndrome. In summary, endogenous opioids exert a wide variety of actions within the reproductive system and are worthy of further scientific study. (Fertil SterilÒ 2017;-:-–-. Ó2017 by American Society for Reproductive Medicine.) Key Words: b-Endorphin, endogenous opioids, hypothalamic amenorrhea, naltrexone, polycystic ovary syndrome, reproductive hormone axis Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/ 16110-fertility-and-sterility/posts/17546-24165

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ndogenous opioid peptides are derived from proopiomelanocortin (POMC), proenkephalin, and prodynorphin and exert their effects via binding to G protein–coupled receptors. As such, ‘‘opioids’’ are to be distinguished from ‘‘opiates,’’ the latter of which are synthetically derived alkaloids. Three main classes of opioid receptors mediate the functions of the opioid peptides: m (OPRM1), k (OPRK1), and d (OPRD1), each of which has specificity for specific ligands. Endogenous opioids play a major role in the central nervous system with regard to stress management, cognition, mood, and pain perception. They are important for the regulation of central

nervous system reproductive physiology, principally through their inhibitory effects on pulsatile GnRH secretion from the hypothalamus (1). In the periphery, the opioid system is known to be involved in regulating carbohydrate metabolism and immune system functions (2). Very recently researchers have reported the expression of opioid receptors in peripheral reproductive tissues, namely in the granulosa cell of the ovarian follicle, the oocyte, and in the human endometrium (3–5). The clinical correlates of these findings include effects on follicular maturation and embryo implantation, topics that are being further studied.

Received April 11, 2017; accepted June 6, 2017. B.B. has nothing to disclose. B.S. has nothing to disclose. G.L. has nothing to disclose. L.W. has nothing to disclose. B.B. and B.S. should be considered similar in author order. Reprint requests: Ludwig Wildt, M.D., Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, Innsbruck A-6020, Austria (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2017 0015-0282/$36.00 Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2017.06.009 VOL. - NO. - / - 2017

In this review we aim to [1] summarize the role of endogenous opioids in female reproductive physiology by presenting evidence for both central as well as peripheral actions, [2] describe the effects of opiate agonists and antagonists on reproductive function, and [3] present the pathophysiology of the opioid system as it relates to particular gynecologic disease processes.

OPIOIDS IN CENTRAL NERVOUS SYSTEM Several specific opioid receptor types exist, all belonging to the family of Gi/Go protein–coupled receptors with a seven-transmembrane domain (6). These opioid subsystems have specific functions with different affinities for different opioid peptides. With regard to the reproductive axis, the m-opioid receptor system plays a particularly important role through the binding of b- endorphin, which is produced from precursor molecules in the pituitary 1

VIEWS AND REVIEWS gland and in the hypothalamus. Upon binding, b-endorphins inhibit pulsatile GnRH secretion from the hypothalamus. In turn the endogenous opioid system is activated through stressful situations, such as strenuous physical exercise, as well as psychological stressors. In this context, multiple studies have applied behavioral tasks and painful stimuli to demonstrate an increase in endogenous opioid activity (7– 9). In women an increase of endogenous opioids has been shown following times of stress, starvation, and anorexia nervosa (10), as reflected by the inhibition of the hypothalamic pulse generator and resulting in a decline of circulating levels of FSH and LH (11). The resultant failure to produce adequate pituitary FSH leads to failure of follicular maturation and results in anovulation. This is known as hypothalamic ovarian insufficiency or hypogonadotropic hypogonadism. Similarly, endogenous opioids may stimulate prolactin levels (12), which in turn secondarily inhibit pulsatile GnRH secretion. In this context, Vuong et al. (8) showed that acute administration of opioids/opiates leads to increased levels of prolactin, whereas opioid antagonists administered acutely and chronically yielded inconsistent results. As demonstrated by Ferin et al. (13), female sex steroids may strongly influence the production of endogenous opioids, as well as cycle-dependent b-endorphin synthesis, opioid receptor expression, and altered binding characteristics (14). It has been shown in female rats that the number of m-opioid receptors depends on the cycle phase and decreases when E2 levels rise (15). In humans, regulation of m-opioid receptors was analyzed using positron emission tomography (PET) during the follicular and again during the luteal phase (16). No differences in binding potential were found between cycle phases, but associations between levels of E2, LH pulse amplitude and frequency, and binding measures in the amygdala were shown in the follicular phase. Interestingly, b-endorphin levels did not correlate with m-opioid binding in the analyzed brain regions. These findings imply that peripheral b-endorphin measurements do not necessarily represent central opioid activity (16). The same group examined the influence of E2 on neurotransmission, which is mediated by m-opioid receptors. Female subjects were examined using PET during the early follicular phase, before and after transdermal exposure to E2. Additionally, pain stimuli were applied with an infusion into the masseter muscle via a computer-controlled system. For improved comparison, a placebo group and male subjects were also analyzed. The endogenous opioid system was activated in situations with high estrogen (E) levels, leading to lower pain ratings. Conversely, pain perception was enhanced in the presence of low estrogen, suggesting a reduction of opioid tone (9). The following pattern of opioid tone and gonadotropin and GnRH secretion dependent on menstrual cycle phase has been suggested by Leyendecker et al. (17). In the early follicular phase pulsatile GnRH secretion is uninhibited by a low opioid tone. When E2 levels rise in the midfollicular phase the opioid tone rises concomitantly, leading to a slowing of GnRH pulses and to an increase in LH pulse amplitude. In 2

the luteal phase, P levels induce a high opioid tone, consequently reducing the frequency of GnRH and LH pulses. With the advent of menstruation, E2 and P levels as well as opioid activity decline, leading again to a resumption of pulsatile GnRH secretion with a high frequency.

CENTRAL EFFECTS OF OPIATE AGONISTS AND ANTAGONISTS The association between the opioid system and ovarian function has been further supported by the fact that exogenous opiates inhibit pulsatile gonadotropin secretion in human as well as in animals. Conversely opiate antagonists, such as naloxone and naltrexone, lead to an increase in LH levels. This effect could only be demonstrated in the luteal phase but not during the follicular phase of the cycle (18, 19). Likewise, no effect on gonadotropin secretion by opioid antagonists was seen in postmenopausal women (20) and in early puberty (21), further underscoring the relationship between the opioid system and circulating sex steroids. Long-term intrathecal administration of opiates has been shown to evoke anovulatory irregular cycles and amenorrhea through hypogonadotropic hypogonadism (22). A suppression of sex steroids has been found after transdermal and oral administration of opiates for nonmalignant pain (23). The opiate-mediated effect on sex steroid levels may also have an inhibitory impact on sexual desire and behavior (22), as demonstrated mainly in men (24). It has been shown by several authors that the administration of the opioid antagonist naltrexone, which can be administered orally, leads to resumption of pulsatile gonadotropin secretion followed by restoration of menstrual cycles and pregnancies in patients with hypothalamic amenorrhea (11, 25, 26). Specifically, in patients with hypothalamic amenorrhea, naltrexone was administered over a period of 28 days, leading to follicular growth, ovulation, and corpus luteum formation with P secretion. After discontinuation of therapy, the patients returned to their previous hypothalamic amenorrheic state (11). The opioid antagonist naltrexone has additional effects on the hypothalamic–pituitary–adrenal axis. After treatment with naltrexone, a significant increase in ACTH and cortisol levels was shown in female smokers, especially in those women who were periovulatory, but not in male smokers (27). Smokers were chosen as the study cohort because naltrexone is one drug being used for smoking cessation (28). Therefore it is particularly interesting that women seem to be more sensitive to opioid antagonists. This is in accordance with the finding that the response of the hypothalamic–pituitary–adrenal axis to stress is sex- and cycle-phase dependent (29). Furthermore, the opioid system exerts an influence on oxytocin secretion, another hormone involved in female reproduction. Oxytocin, a nonapeptide released from the posterior lobe of the pituitary gland, is a major regulator of the onset of labor, uterine contractions, breast feeding, and bonding. It remains to be elucidated whether opiate receptors exist in the pituitary gland (30). Indirect evidence points to the existence of opiate receptors in the posterior lobe of the VOL. - NO. - / - 2017

Fertility and Sterility® pituitary because oxytocin secretion can be inhibited by opioid receptor agonists in animals and humans.

PERIPHERAL ACTION OF THE OPIOID SYSTEM IN REPRODUCTION Although the presence of the opioid system and its role in the central regulation of reproductive hormone production has been established, its role in female peripheral reproductive tissues is just being elucidated. More than 30 years ago, Petraglia et al. (31) showed that b-endorphin and metenkephalin were present in peritoneal fluid as well as ovarian follicular fluid. Interestingly, in healthy menstruating women the concentration of these endogenous opioids was 10 to 40 times that measured in serum, implicating a possible local production. Furthermore, the largest follicles had the highest concentrations of opioids, whereas concentrations in postmenopausal women were undetectable. These early studies provide indirect evidence for a role of opioids in human oocyte maturation. Prompted by reports of opioid receptors in oocytes of several animal models (32), Agirregoitia et al. (4) aimed to confirm the presence of all three receptor types in human oocytes and to compare their expression and distribution at various stages of oocyte maturation. Using Western blot analysis, the researchers identified the presence of proteins corresponding to the d (OPRD1), k (OPRK1), and m (OPRM1) receptors. With immunofluorescence, the OPRD1 pattern remained the same across different stages of oocyte maturity from germinal vesicle to metaphase II stage. Immunostaining patterns changed for the other receptors, OPRK1 and OPRM1, with localization at the periphery in the germinal vesicle stage and more internally or homogenously at metaphase I and metaphase II. These results imply that the endogenous opioids present in the follicular fluid exert a paracrine effect by binding to opiate receptors found on the oocyte, thus playing a role in the maturation of the oocyte. There has been recent interest in studying the follicular micro-environment, especially as it relates to cross-talk between the granulosa and cumulus cells and the maturing oocyte (33). Oocytes are known to secrete critical factors, such as growth differentiation factor 9 and bone morphogenetic protein 15, thereby activating signaling pathways for gene regulation and cellular processes in the neighboring somatic cells. Whether oocytes are also capable of secreting opioids remains to be elucidated. Dell'Aquila et al. (34) demonstrated that mural granulosa cells express the messenger RNA coding for the m-opioid receptor. Recently Lunger et al. (3) demonstrated the presence of OPRM1 opioid receptors in nonluteinized human granulosa cell lines, as well as in luteinized primary human granulosa cells. The authors also confirmed the expression of the opioid precursor POMC in the cytoplasm of granulosa cells using immunocytochemical staining (unpublished data). Upon incubation of primary granulosa cells with the opiate antagonist naloxone, the researchers found a significant decrease in vascular endothelial growth factor (VEGF) secretion compared with controls. Because previous experimental evidence has shown that endogenous opioids stimulate angioVOL. - NO. - / - 2017

genesis in other cells (retinal epithelial cells and dermal microvascular endothelial cells) (35–38), these results likewise suggest that opioids may play a role in regulating the function of granulosa cells via a paracrine or autocrine effect. There is evidence to suggest that the opioid system is present in the uterine cavity and plays a role in endometrial function. Petraglia et al. (39) demonstrated the presence of the endogenous opioid peptides b-endorphin and methionineenkaphalin in the uterine fluid of fertile women. The two peptides were not detectable in the uterine fluid of untreated postmenopausal women but were present in those women after hormone replacement with E and P. Subsequently POMCand prodynorphin-derived opioid peptides were shown to be synthesized by the human endometrium epithelial cell–derived Ishikawa cell line and by primary mammalian endometrial tissues (40, 41). Estradiol and dexamethasone could suppress the secretion of the opioid b-endorphin, but not dynorphin, by the Ishikawa cells. On the other hand, GnRH increased the secretion of only dynorphin, suggesting that each type of opioid peptide is specifically regulated and may play a distinct role in endometrial physiology. There seems to be an interaction between steroid hormones and opioids in the endometrium. Vertes et al. (42) showed that b-endorphin leads to an increase in the concentration of estrogen receptors in uterine epithelial cells, making the endometrium more sensitive to estrogen. Recently the localization of the mopioid receptor in the human endometrium was studied at five different points in the menstrual cycle (5). Totorikaguena et al. found that the expression of OPRM1 messenger RNA and protein changed throughout the cycle, with maximum values achieved at the time of ovulation. The authors concluded from these findings that the m-opiate receptor could have several functions in the complex remodeling process of monthly endometrial cyclicity and potentially in the early events of reproduction. The potential adverse effects of opiates on embryo development and implantation in mice have been demonstrated. These researchers showed that preimplantation embryos express all opioid receptor subtypes and that the administration of morphine can derail the normal preimplantation development of the embryo and cause delay in development to the blastocyst stage. Concurrently, systemic morphine treatment derails normal uterine receptivity in mice by inducing impaired luminal epithelial differentiation, decreasing stromal cell proliferation, and inducing poor angiogenesis. These effects on uterine receptivity were independent of any change in ovarian E or P secretion (43). Not only endometrium but also myometrium may be the target of endogenous opioids. Endometrial opioids may affect the myometrium through their inhibitory–relaxant effect on smooth muscle. As such they might influence the regulation of myometrial contractility that is essential for the transport of sperm across the uterine cavity and into the fallopian tubes (40). Opioids present in the ovary and uterus, like those in most peripheral tissues, exert local (paracrine or autocrine) effects and take part in regulating their microenvironment. Future studies should elucidate the specific roles of opioids in 3

VIEWS AND REVIEWS reproductive events, especially their influences on oocyte maturation and embryo implantation.

PATHOPHYSIOLOGY OF OPIOID SYSTEM IN SPECIAL SITUATIONS OF FEMALE REPRODUCTION The interaction between hypothalamic and pituitary hormones is influenced by the endogenous opioid system as summarized in Figure 1. Therefore, opioids play a critical role in the pathogenesis of different reproductive pathologic conditions, such as hypothalamic amenorrhea and polycystic ovary syndrome.

Hypothalamic Amenorrhea In patients with hypothalamic amenorrhea, originally defined as amenorrhea of suprapituitary origin, the pulsatile secretion of GnRH is reduced or completely absent (44). Clinical symptoms depend on the extent of this reduction and range from corpus luteum insufficiency to anovulatory cycles and in severe cases to primary or secondary amenorrhea. This reflects the pathophysiologic continuum of reduced pulsatile GnRH release (45). It has been shown that treatment with the opioid antagonist naltrexone in the majority of such cases stemming from a functional deficit induces a normalization of the menstrual cycle and even successful pregnancies (11, 46). Women with anatomic deficits, such as those with Kallmann syndrome, do not respond to naltrexone. This effect of naltrexone administration resulted in an increase in the frequency and amplitude of gonadotropin pulses secondary to an increase in hypothalamic pulsatile GnRH secretion. The increase in LH pulse amplitudes persisted over the entire duration of treatment of 6 months (47) or up to 630 days (11). Even in patients suffering from anovulatory cycles, higher ovulation rates resulted after treatment with naltrexone or naltrexone in combination with clomiphene, versus clomiphene alone (48). After a treatment course of 9 months with daily naltrexone doses of 50–150 mg, Wildt et al. reported a per-cycle pregnancy rate of 29% (25). Therefore, naltrexone may be considered as an alternative therapy for hypothalamic ovarian insufficiency, with few side- effects limited to mild nausea, headaches, and sleep disturbances (11). Naltrexone has also been shown to be effective for inducing ovulation and pregnancy in a patient with hyperprolactinemia who was resistant to dopamine agonist treatment (25). Interestingly, naltrexone can also be used as a diagnostic tool to differentiate the cause of amenorrhea: in a subgroup of female patients with congenital adrenal hyperplasia suffering from primary or secondary amenorrhea initially thought to be caused by hyperandrogenemia, naltrexone was shown to induce or restore normal menstrual cycles. This observation suggests that there may be a hypothalamic component to the ovarian insufficiency in these patients and not solely a hyperandrogenemic etiology (49).

Polycystic Ovary Syndrome Polycystic ovary syndrome (PCOS) is a common cause of ovulatory dysfunction in reproductive-age women. In addi4

tion to the generally accepted criteria (50, 51), there is a high prevalence of metabolic disorders, especially insulin resistance in up to 50% of women, glucose intolerance, and signs of the metabolic syndrome. Pilot studies administering 50 mg daily naltrexone to women with PCOS and insulin resistance showed a dramatic decline in insulin levels after 3–7 weeks of treatment (11). Subsequent studies corroborated these findings, with a significant decline in serum androgens independent of any change in body mass index (52). Because treatment durations did not exceed 9 weeks, no significant changes in clinical parameters like hirsutism, acne, or cycle irregularities could be demonstrated. Fruzzetti et al. (53) continued the treatment with naltrexone for 6 months and showed a significant decline in body mass index and cycle irregularities, as well as a decrease in androgen levels in a cohort of obese patients with a body mass index >25 kg/m2. Presumably both weight loss and a change in the opioid response contributed to the improvement in metabolic parameters. These studies confirm that opioids play a central role in the pathogenesis of insulin resistance in PCOS. It was hypothesized that the increase of opioid activity leads to only minimal reduction in pulses of the GnRH pulse generator, nonetheless resulting in elevated LH levels. Consequently, an increase in the LH/FSH ratio results in an increase in androgen levels.

FIGURE 1

Influence of the opioid system at multiple levels of the female reproductive system. At the level of the central nervous system, endogenous opioids (EOPs) inhibit pulsatile secretion of GnRH, decreasing the release of FSH and LH from the pituitary. At the ovarian level, endogenous opioids have been measured in follicular fluid, and m-opioid receptors (MOR) have been identified in granulosa cells and oocytes. Endogenous opioids likely play a role in the maturation of the oocyte and in granulosa cell-oocyte crosstalk. Endogenous opioids have been measured in uterine fluid and m-opioid receptors identified in endometrium. The opioid system likely plays a role in embryo implantation. Endogenous opioids stimulate pancreatic cell insulin secretion, likely via paracrine and autocrine mechanisms. € ttcher. Opioid system and female reproduction. Fertil Steril 2017. Bo

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Fertility and Sterility® b-Endorphin–containing cells have been identified in areas surrounding the pancreatic b-cells, and opioids have been shown to stimulate insulin secretion (52, 54). It is therefore tempting to speculate that locally elevated opioid activity stimulates insulin secretion from the pancreas. Insulin resistance develops as a consequence of the downregulation of hepatic insulin receptors, thereby increasing insulin levels in peripheral blood (52). It should be noted that opioids are generally regarded as inhibitory neurotransmitters, and the stimulatory effect on LH in PCOS patients should be considered as paradox (2). The interaction between opiates and insulin secretion has been validated in a study of patients with PCOS who were treated with pulsatile administration of GnRH in combination with naltrexone. This treatment resulted in an improvement of the LH response and ovulation rates. A decrease in insulin secretion was also shown and, interestingly, mainly observed in hyperinsulinemic patients (55). A similar effect was demonstrated by Lanzone et al. (56): patients with PCOS showed no significant changes of the LH/FSH response using a GnRH test after naltrexone treatment for 4 weeks compared to baseline GnRH test. No differences in LH responses compared with healthy controls were evident after naltrexone treatment. Levels of FSH remained unchanged, suggesting a selective sensitizing effect of opioids on LH (56). In a comparison of three different therapeutic approaches (metformin, naltrexone, or a combination of an oral antiandrogenic contraceptive in combination with prednisolone) in patients with PCOS over 3 months, significant improvements in ovulation rates as well as in hyperandrogenemia were shown in all groups. No concurrent change in metabolic parameters was seen, leading to the conclusion that insulin resistance is only one component influencing hyperandrogenemic anovulation (57). It has been shown that patients with PCOS present with elevated levels of b-endorphins (58) independent from the individual body mass index (59, 60). Most of the pituitary cells with insulin receptors also show immunoreactions for the mopioid receptor agonist b-endorphin (61). A very interesting finding is the relationship between insulin resistance and mopioid neurotransmission in patients with PCOS (62): insulin-resistant patients had a greater limbic availability of m-opioid receptors than controls on PET. Typical brain areas for opioid neurotransmission are the amygdala and nucleus accumbens, which influence the regulation of appetite and mood. A correlation of receptor availability to the grade of insulin resistance was found. After metformin therapy the opioid receptor availability was within normal range. These findings suggest that an improvement of insulin sensitivity can lead to an alteration of dysregulated opioid neurotransmission centrally. The presence of opioid receptors on granulosa cells and the link to granulosa cell VEGF secretion has been discussed above. In subsequent work, Lunger et al. (63) challenged granulosa cells obtained from women with PCOS and from controls in vitro with the opiate antagonist naloxone, insulin, or both and measured VEGF in culture supernatant. They found that baseline VEGF levels were higher in PCOS than in controls, could be increased by insulin, and could be VOL. - NO. - / - 2017

reduced by exposing the cells to naloxone. This study further implicates the regulatory effects of opioids on granulosa cell function but also demonstrates inherent differences in granulosa cell stemming from PCOS and non-PCOS women. Potential future therapeutic options for treating ovarian hyperstimulation syndrome, a common complication of ovarian stimulation in PCOS women mediated by high VEGF levels, by targeting the opiate signaling system deserve further study. As reviewed in this communication, endogenous opioids serve as important neuromodulators as well as signaling peptides within several reproductive organs and tissues. In addition to the central nervous system, these include the endocrine pancreas and the different compartments of the ovary, including the ovarian follicles and the oocyte, as well as the endometrium. We have shown that endogenous opioids may play an important role in hypothalamic amenorrhea and in insulin resistance associated with hyperandrogenemia and PCOS. The availability of specific antagonists, such as naloxone or naltrexone, offers unique therapeutic options to modulate the pathophysiologic conditions. The efficacy of these agents in hypothalamic amenorrhea as well as in insulin resistance has been demonstrated in research studies, which we summarized in this review. Additional potential clinical uses, such as for the prevention or treatment of ovarian hyperstimulation syndrome and other disorders of female reproduction, deserve further study. Future research into the role of endogenous opioids in reproductive disorders may lead to a better understanding of the pathophysiology of female reproduction as well as to novel treatments options.

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