The Emerging Roles of Adiponectin in Female Reproductive System-Associated Disorders and Pregnancy

Abstract

Adiponectin, the most abundant adipose-released cytokine, has an important role in metabolism, primarily through reducing insulin resistance. Reproductive functions are known to be influenced by energy balance and adiponectin may be involved in the underlying mechanisms connecting reproduction and metabolism. Interestingly, adiponectin has been shown to exert actions in the female reproductive system, including the hypothalamic–pituitary–ovarian axis and the endometrium. The peripheral effects of this adipocytokine are mediated mainly via 2 receptors, AdipoR1 and AdipoR2. The expression of these receptors has been reported in the brain, ovaries, endometrium, and the placenta. Thus, adiponectin may influence fertility and pregnancy. Furthermore, adiponectin concentrations and effects have been assessed in some pregnancy-associated disorders and gynecological conditions. The findings may lead to the use of adiponectin or its receptors as therapeutic targets in novel treatment strategies of these disorders.

Keywords

adiponectin gonadotropins pregnancy fertility

Introduction

Adipocytes are not only storage depots for triglycerides but also highly active cells. Adipose tissue plays an important role in modulating various physiological functions through releasing factors with autocrine, paracrine, or endocrine effects.¹ One group of adipose-derived molecules are called adipocytokines. Adiponectin is considered a member of this family and was described for the first time in 1995 after independent research of different laboratories.¹

Adiponectin is a 244-amino acid protein encoded by APM1 gene at chromosome 3q27, and the only source of this substance in the body is considered to be the adipocytes in white adipose tissue.^1,2 The gene product is modified post-translationally by hydroxylation and glycosylation. Full-length form of adiponectin consists of an NH₂-terminal sequence, a compliment C1q-like domain, and a COOH-terminal globular domain.³ More complex structures are formed by multimerization of full-length molecule. Adiponectin is secreted in the form of a trimer (low molecular weight [LMW]), a combination of 2 trimers (middle molecular weight [MMW]), or a structure of 6 trimers (high molecular weight [HMW]).⁴ In addition, another form of adiponectin (globular adiponectin), containing only the COOH-terminal portion, is produced through proteolytic cleavage.³

Adiponectin levels have been reported to be higher in females.¹ Circulating levels of adiponectin are approximately 2 to 3 times lower in males.⁵ Xu et al showed that testosterone selectively decreases circulating HMW adiponectin concentrations by inhibiting its release from adipocytes.⁶ Besides sexual differences, prolonged fasting and severe weight reduction lead to elevated adiponectin levels.¹ Cellular expression of adiponectin messenger RNA (mRNA) and serum concentrations of this adipocytokine are negatively associated with adiposity.^7
–9 Qi et al reported that adiponectin reduces body weight by stimulating energy expenditure after intracerebroventricular administration in mice.¹⁰

Adiponectin is believed to exert notable actions regarding reproduction. Acting through the brain, adiponectin may serve as a link between adipose tissue and the reproductive system. In addition, this adipocytokine may be involved in the pathogenesis of a number of gynecological conditions (eg, endometriosis, leiomyomas, and endometrial cancer). The aim of this study is to summarize the multiple effects of adiponectin on the female reproductive system by focusing on its role in modulation of the reproductive endocrine axis.

Adiponectin Receptors

The actions of adiponectin are mediated mainly through 2 transmembrane receptors, AdipoR1 and AdipoR2.¹¹ These receptors have been localized to tissues throughout the body, including the central nervous system.¹² The AdipoR1 and AdipoR2 are members of the family of progestin adipoQ receptors.¹ Although AdipoR1 and AdipoR2 have 7 transmembrane domains like G-coupled receptors, they differ from this receptor category in topology (cytoplasmic N terminus and extracellular C terminus).¹³ Hug et al described additional receptors for adiponectin, such as t-cadherin.¹⁴ t-Cadherin is a glycolipid-anchored extracellular protein identified as a receptor for hexameric and HMW forms of this adipocytokine.¹³

The AdipoR1 and AdipoR2 show distinct expression patterns and bind full-length or globular adiponectin with different affinity. The AdipoR1 is expressed principally in skeletal muscle and binds primarily globular adiponectin.¹² On the other hand, AdipoR2 is widely distributed in the liver and binds full-length adiponectin with higher affinity than globular adiponectin.¹⁵ Cellular effects of adiponectin are mediated through adenosine monophosphate-activated protein kinase (AMPK) pathway, peroxisome proliferator-activated receptor α (PPARα) pathway, or by activating p38 mitogen-activated protein kinase.¹⁶ A significant interaction between the 2 receptors signaling is observed in skeletal muscle; both receptors activate AMPK and PPARα in order to increase the glucose uptake and fatty acid oxidation.¹⁶ In contrast, distinct signaling pathways have been reported after activation of AdipoR1 and AdipoR2 in the liver. The AdipoR1 activates AMPK to reduce gluconeogenesis, whereas AdipoR2 signaling is believed to involve PPARα-mediated increase of fatty acid oxidation.¹⁶

Hypothalamic–Pituitary–Ovarian Axis

Wide expression of adiponectin receptors has been demonstrated in the brain, including regions of the mouse hypothalamus, brainstem, cortical neurons, and endothelial cells as well as in whole brain and pituitary extracts.¹⁷ Wen et al reported AdipoR1 and AdipoR2 expression in GT1-7 hypothalamic gonadotropin-releasing hormone (GnRH) neuron cells.¹⁸ Both receptors are also expressed in mouse LβT2 immortalized gonadotrope cells.¹⁹ In humans, adiponectin receptors are present in the pituitary gland and brain.²⁰ However, permeability studies indicate that adiponectin does not passively cross the blood–brain barrier.^21,22 This may be explained due to its large multimeric circulating size.²³ In contrast, globular adiponectin administered intravenously has been shown to increase the cerebral spinal fluid levels.¹⁰ Thus, circulating adiponectin may gain access to the central nervous system through the ventricular space, as supported by another study that demonstrated the detection of adiponectin complexes in human cerebrospinal fluid.²⁴ Another possibility is the local adiponectin synthesis in the central nervous system. Interestingly, the production of adiponectin in the chicken diencephalon supports this hypothesis.²⁵

Adiponectin inhibits GnRH secretion from GT1-7 hypothalamic cells through the activation of AMPK pathway.¹⁸ Recently, KiSS-1 gene transcription in GT1-7 cells was reported to be reduced by adiponectin through the stimulation of the same pathway.²⁶ Notably, hypothalamic KiSS-1 gene transcription is the upstream signal of GnRH. Cheng et al showed that AMPK stimulated by adiponectin reduces extracellular signal-regulated kinase phosphorylation, which may impair GnRH release in GT1-7 cells.²⁷ Furthermore, adiponectin was found to cause hyperpolarization of plasma membrane potentials and decreased calcium influx in these cells.¹⁸ Lu et al reported that adiponectin acutely decreases basal and GnRH-stimulated luteinizing hormone (LH) secretion from LβT2 gonadotrope cells, without altering follicle stimulating hormone (FSH) levels.¹⁹ This action was exerted through the increased AMPK phosphorylation. The authors concluded that pituitary AMPK may serve as an energy sensor of the nutritional status and accordingly regulate gonadotropin secretion in order to control reproduction.

Adiponectin may also have specific role in modulating oxytocin-secreting neuron excitability. Paraventricular nucleus (PVN) is a bilateral hypothalamic nucleus that functions as an autonomic control center.²⁸ Vasopressin and oxytocin secretion through axonal projections to the posterior pituitary is modulated by a subgroup of neuroendocrine cells (magnocellular neurons) within the PVN.²⁸ The expression of both adiponectin receptors was demonstrated in PVN using reverse transcriptase-polymerase chain reaction techniques.²⁸ Previously, intracerebroventricular administration of adiponectin was shown to increase c-fos positive neurons in PVN, suggesting potent activating effects of this adipocytokine in the subgroups of PVN neurons.¹⁰ Hoyda et al investigated adiponectin actions in the regulation of excitability of magnocellular neurons.²⁸ According to the findings, adiponectin exerted different effects on distinct subpopulations of magnocellular neurons, selective hyperpolarization of oxytocin neurons, hyperpolarization or depolarization of vasopressin neurons, and no effect on neurons expressing oxytocin and vasopressin. Notably, these findings may explain increased oxytocin release in the obese population.²⁸

At the level of the ovaries, the main adiponectin mediators (AMPK and PPARs) are believed to be involved in ovarian cell proliferation, steroidogenesis, and oocyte maturation.²⁹ The AdipoR1 and AdipoR2 ovarian expression has been reported in rodents, chickens, and cows.³⁰ In the chicken ovary, AdipoR1 is twice as abundant in granulosa cells as in theca cells, whereas AdipoR2 is equally expressed in the 2 cellular subgroups.³¹ Chabrolle et al showed that adiponectin is mainly expressed in theca cells of the chicken ovary.³¹ Adiponectin receptors were also detected in the rat ovary, more precisely in theca-interstitial cells, the corpus luteum, and oocytes, but less abundantly in granulosa cells.³² Following human chorionic gonadotropin (hCG)/pregnant mare serum gonadotropin (PMSG) therapy, increased AdipoR1 mRNA and protein were observed in immature rat ovary.³² On the other hand, mRNA and protein levels of AdipoR2 were found to be unchanged.³² Regarding the cellular localization of adiponectin in rats, stronger expression was detected in theca-interstitial cells compared to granulosa cells.³² Ovarian adiponectin concentrations were elevated after hCG/PMSG therapy, whereas plasma levels were decreased.³² Recombinant human adiponectin also promoted the synthesis of progesterone and estradiol from primary rat granulosa cells in response to insulin-like growth factor I (IGF-1).³² Furthermore, the presence of AdipoR1 and AdipoR2 has been demonstrated in porcine theca and granulosa cells.¹³ Both receptors were reported to be expressed in porcine oocytes and cumulus cells of small and large follicles.³³ Follicular fluid adiponectin levels were found similar to those detected in the serum.²⁹ Ledoux et al showed that recombinant adiponectin treatment, alone or in combination with insulin and gonadotropins, induces gene expression resulting in prostaglandin and vascular endothelial growth factor production in ovarian granulosa cells.¹³ In addition, Chappaz et al found that adiponectin promoted meiotic maturation and in vitro embryo development of porcine oocytes.³³ Finally, adiponectin and its receptors have been detected in bovine granulosa, theca, and cumulus cells as well as in corpus luteum and in oocytes.³⁰ The LH- and insulin-induced release of progesterone and androstenedione from bovine theca cells was found to be decreased by adiponectin.³⁴ Moreover, Maillard et al demonstrated that insulin-induced secretion of progesterone and estradiol was reduced by recombinant human adiponectin in bovine granulosa cells.³⁰

Adiponectin receptors are also present in human ovarian cells.¹ Gutman et al reported the in vivo induction of adiponectin by gonadotropins in the human ovary.³⁵ Treatment with recombinant LH during the late follicular phase may enhance follicular insulin sensitivity, causing decreased androgen levels via elevated adiponectin synthesis.³⁵ Lagaly et al reported that the inhibitory actions of adiponectin on stereoidogenesis are mainly localized to theca cells.³⁴ The authors concluded that LH and IGF-I may be involved in the regulation of the response of theca cells to adiponectin. Interestingly, insulin-induced proliferation of theca cells from large follicles and granulosa cell function were unaffected by adiponectin.³⁴ Moreover, it was found that AdipoR2 mRNA was increased by LH in theca cells, but not in granulosa cells.³⁴

Dafopoulos et al found that serum adiponectin concentrations do not change during the normal menstrual cycle, suggesting that adiponectin release may not be influenced by ovarian steroid dynamics throughout the cycle.³⁶ In addition, it has been reported that the regulation of adiponectin release in women is not affected by ovarian hormones, since exogenous administration of estrogen in pre- and postmenopausal women did not affect the adiponectin levels in blood.³⁷ In the same study, it was also shown that the depletion of endogenous estrogen, via ovariectomy in premenopausal women, had no effect on serum adiponectin levels.³⁷ However, after treatment with GnRH agonist for 2 months, ovarian suppression in young-eugonadal women was associated with an increase in circulating adiponectin levels.³⁸ On the other hand, Liu et al studied whether adiponectin levels are influenced by ovarian hyperstimulation in women undergoing in vitro fertilization (IVF).³⁹ During an IVF cycle, a decrease in serum adiponectin levels was observed from the baseline to the day of hCG injection, partly explained as a result of the negative impact of high estradiol concentrations on adiponectin synthesis. However, estradiol levels on the day of hCG injection were not associated with adiponectin concentrations. In contrast, the serum adiponectin levels increased after hCG treatment, which was associated with elevated progesterone concentrations after transfer. Bersinger et al examined the potential of adiponectin to serve as a marker of success in intracytoplasmic sperm injection/embryo transfer cycles.⁴⁰ Serum adiponectin concentrations were compared before and after ovarian hyperstimulation between women who became pregnant and those with implantation failure. According to their findings, circulating adiponectin levels were higher in the first group on the day of oocyte retrieval as well as the preceding 3 days. This statistically significant difference was not observed at the beginning of the stimulation phase. However, adiponectin levels in the follicular fluid were not correlated with the fertilization rates. In another study, Liu et al concluded that adiponectin may serve as a better marker of adequate follicular development during IVF compared to body weight or body mass index (BMI).⁴¹ Adiponectin levels on the day prior to gonadotropin administration were found to correlate positively with the number of oocytes retrieved. Moreover, basal adiponectin concentrations were significantly higher in participants who conceived.

Embryo Implantation and Placental Function

The establishment of pregnancy depends on 2 critical events, embryo implantation and placentation. Lord et al reported high expression of AdipoR1 and AdipoR2 in the porcine endometrium.⁴² Both receptors were also demonstrated to be present in the endometrial and glandular human epithelium and in stromal fibroblasts.⁴³ Interestingly, transcript levels were higher during the mid-luteal phase of the cycle, which corresponds to the implantation period. These findings suggest that adiponectin may have a role in the implantation process. Dos Santos et al compared the expression of adiponectin and its receptors in the endometrium during the window of implantation between women with recurrent implantation failure and fertile controls.⁴⁴ Endometrial adiponectin expression was similar in both the groups, whereas the expression of AdipoR1 and AdipoR2 was decreased in the first group. Since adiponectin receptors may be involved in the development of uterine receptivity, AdipoR1 and AdipoR2 expression profile could serve as a novel factor for prediction of implantation failure. Moreover, Benaitreau et al suggested that adiponectin should be considered as regulator of early placental development exerting antiproliferative effects in trophoblastic cells in humans.⁴⁵ During placentation, trophoblast cells differentiate into 2 cell types with distinct properties. Syncytiotrophoblasts exert endocrine effects, whereas cytotrophoblasts show invasive and proliferative properties in order to ensure successful implantation.⁴⁵

Adiponectin was suggested to be released by human and rodent placentas.^46,47 However, placental adiponectin mRNA expression was not confirmed in other studies.^48,49 Both adiponectin receptors were found to be expressed in freshly isolated cytotrophoblast cells from human placenta and in human primary trophoblast cells in culture.⁵⁰ Tie et al demonstrated the expression of AdipoR2, but not AdipoR1, in placental cytotrophoblasts and syncytiotrophoblasts.⁵¹ Thus, the placenta may be target of maternal adiponectin in the complex regulation of placental environment. Notably, Jones et al demonstrated that full-length adiponectin inhibits insulin signaling in primary human trophoblast cells in contrast to the insulin-sensitizing actions of this adipocytokine in liver and muscle.¹⁶

Fetal Physiology and Development

According to Mazaki-Tovi et al, maternal adiponectin levels are significantly lower than cord blood adiponectin concentrations, suggesting a fetal source of the hormone.⁵² Pinar et al demonstrated that both HMW and LMW adiponectin are present in fetal plasma.⁴⁸ Using immunodetection techniques, the authors reported that adiponectin was detected in vascular endothelial cells of fetal organs, including skeletal muscle, kidney, and brain. Umbilical cord serum adiponectin was positively correlated with fetal birth weight and fetoplacental weight ratio.^53
–55 Another study has shown that adiponectin levels in umbilical cord blood was significantly lower in large-for-gestation neonates, therefore suggesting that a negative feedback mechanism between adipose tissue and adiponectin level may be functional in their fetus.⁵⁶ Moreover, lower cord blood adiponectin concentrations have been associated with a more intense weight gain during the first 6 months of life as well as an elevated BMI and central adiposity at age 3.⁵⁷

Fetal development is influenced by adverse events during gestation, which may program the fetus to develop, later in life, insulin resistance and related metabolic diseases. In animal models, ethanol exposure during pregnancy causes intrauterine growth restriction and is associated with glucose intolerance and insulin resistance in the adult offspring. It has been suggested that these later events of ethanol action are not mediated by changes in adiponectin levels.^58,59 Furthermore, fetal growth is highly dependent on the placental amino acid transport. Nutrient transporters are stimulated by insulin and IGF-II.¹⁶ Jones et al demonstrated that insulin-stimulated trophoblast system A amino acid transport is attenuated by full-length adiponectin.¹⁶ Thus, inhibited amino acid transport may have important consequences for fetal growth in pregnancies characterized by altered maternal adiponectin concentrations.¹⁶ Whether there is a correlation between umbilical cord and amniotic fluid levels of adiponectin has not been investigated so far. Kalampokas et al investigated the association of amniotic fluid adiponectin levels with second trimester fetal growth in small-for-gestational age (SGA), large-for-gestational age, and appropriate-for-gestational age fetuses.⁶⁰ No statistically significant differences were observed except from the higher levels of adiponectin in very severely SGA fetuses. In addition, according to Hersoug and Linneberg, certain immunological changes might be transmitted to the fetus by epigenetic inheritance, causing impaired tolerance to antigens and skewing of the immune system toward a Th2 cytokine profile.⁶¹ Based on their hypothesis, adiponectin may be involved in the underlying mechanisms responsible for the immunological changes transmitted to the fetus. Finally, many metabolic, immune, and hormonal pathways are being developed during the perinatal period. Research on the regulation of adiponectin in this period may offer valuable evidence. Mantzoros et al reported that adiponectin is negatively correlated with IGF-II in newborns, whereas a marginally significant positive association was demonstrated between adiponectin and birth length.⁶²

Adiponectin in Pregnancy-Associated Disorders and Other Gynecological Conditions

Preeclampsia

Mazaki-Tovi et al reported no significant alterations in adiponectin concentrations during the 3 trimesters of pregnancy.⁶³ In contrast, Catalano et al demonstrated lower adiponectin levels in the third trimester than in the pregravid condition.⁶⁴Maternal adiponectin is independently associated with blood pressure in women with uncomplicated pregnancies.⁶⁵ Preeclampsia is a serious cardiovascular complication of pregnancy. The pathogenesis of preeclampsia includes 2 stages; the abnormal placental implantation (first stage) leads to endothelial dysfunction (second stage) through oxidative stress and disrupting angiogenesis.⁶⁶ Reduced adiponectin expression was reported in placental tissues from patients with severe preeclampsia.⁶⁶ Adiponectin and its receptor AdipoR1 may have a role in placental angiogenesis in these patients and adiponectin-induced placental apoptosis could be mediated via AdipoR1.⁶⁷ However, Nanda et al reported elevated serum adiponectin levels at 11 to 13 weeks in women that develop early-onset preeclampsia though a mechanism unrelated to impaired placentation.⁶⁸

Differential patterns of maternal adiponectin levels have been reported in preeclampsia compared to normal pregnancies.⁶⁹ Given the insulin-sensitizing properties of this adipokine, the differences could be explained based on the hypothesis that adiponectin may be part of a response mechanism to restore insulin sensitivity in preeclampsia. D’Anna et al investigated the adiponectin levels in 36 women with preeclampsia and 36 uncomplicated pregnant women who delivered at term.⁷⁰ Plasma adiponectin concentrations in participants of the first group were lower in the first trimester and higher at delivery versus those in the control group. Moreover, first-trimester mean plasma adiponectin levels in the late-onset subgroup of preeclamptic patients were lower compared to the concentrations in the early-onset subgroup. Interestingly, adiponectin levels were found to be lower in overweight patients with preeclempsia compared to those of normal weight.⁷¹ In another study, HMW adiponectin and total adiponectin serum levels were significantly higher in patients with preeclampsia and were positively correlated with the markers of insulin sensitivity.⁶⁹ Abd-Alaleem et al divided 60 pregnant women with mild preeclampsia, severe preeclampsia, or normal pregnancy into 3 equal groups.⁷² Significantly, higher adiponectin concentrations were measured in preeclamptic patients and the elevation was marked in the more severe cases of the disorder. Furthermore, adiponectin levels were negatively correlated with arterial blood pressure in all groups. Liu et al reported higher adiponectin levels in preeclamptic patients not only in serum but also in breast milk.⁷³ In contrast, lower levels were observed in umbilical cord blood when compared to cases of normal pregnancy. The authors concluded that hyperadiponectinemia in preeclampsia may be associated with reduced degradation/elimination rather than increased production of this adipocytokine.⁷³ Interestingly, higher cord blood adiponectin concentrations were demonstrated in preeclamptic patients with preterm pregnancies or pregnancies with spontaneous contractions, possibly reflecting the need of energy optimization in preeclampsia.⁷⁴ However, the use of the first-trimester serum adiponectin levels as a prognostic factor of preeclampsia remains contradictory, since maternal concentrations may not be useful in predicting subsequent development of the disorder.⁷⁵ According to Dalamaga et al, maternal serum adiponectin concentrations were not associated with preeclampsia at the time of diagnosis.⁷⁶

Gestational Diabetes

Normal pregnancy depends on a highly regulated balance in glucose delivery between maternal tissues and the fetoplacental unit. Metabolic effects of adiponectin may influence pregnancy. A moderate increase in circulating adiponectin levels has been associated with the inhibition of both the expression of hepatic gluconeogenic enzymes and the rate of endogenous glucose production.⁷⁷ Hara et al reported that whole-body insulin sensitivity is linked with adiponectin levels.⁷⁸ Adiponectin promotes insulin effect in the liver.^77,79 Furthermore, insulin release is enhanced by adiponectin through the stimulation of insulin granules exocytosis and the upregulation of insulin gene expression.⁸⁰ In early pregnancy, insulin release is elevated. However, insulin sensitivity remains stable or may be decreased or even increased.^81,82 On the other hand, insulin resistance is observed in late pregnancy.⁸²

Gestational diabetes is a pregnancy disorder associated with placental dysfunction coursing with metabolic alterations at the fetoplacental microvascular and macrovascular endothelium.⁸³ Gestational diabetes is developed in 5% to 10% of all pregnant women.⁸⁴ Fetal overgrowth, traumatic birth injuries, and increased risk of metabolic syndrome later in life are potent complications of these pregnancies.¹⁶ Adiponectin levels have been assessed in women with gestational diabetes. Class A2 and B gestational diabetes were associated with decreased adiponectin concentrations, similar to those observed in other insulin-resistant disorders.⁸⁵ Vitoratos et al reported suppressed serum adiponectin levels in gestational diabetes both during pregnancy and after delivery.⁸⁶ Lower adiponectin levels were demonstrated in the third trimester, independent of patients’ BMI.⁸⁷ Ballesteros et al showed that cord blood adiponectin concentrations are independently associated with maternal levels of adipocytokine, but they are not related to the diagnosis of gestational diabetes mellitus.⁸⁸

Serum adiponectin concentrations during pregnancy were negatively associated with homeostasis model assessment of insulin resistance.⁸⁶ However, the observed reduction in adiponectin levels might not only reflect the maternal insulin resistance during pregnancy. Hypoadiponectinemia may contribute to the impaired glucose metabolism in these patients.⁸⁹ Gestational diabetes mellitus is linked to persistent metabolic dysfunction at 3 years postpartum, regardless of other clinical risk factors.⁹⁰ Approximately, 30% of the women with previous gestational diabetes have metabolic syndrome and are in greater danger of developing type 2 diabetes mellitus within 5 years of diagnosis.⁹¹ Vrachnis et al concluded that adiponectin may be involved in insulin sensitivity dysregulation of these women.⁹¹

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) affects 5% to 10% of women of reproductive age.⁹² The principle features of this syndrome include biochemical or clinical hyperandrogenism, chronic anovulation, and sonographic findings of polycystic ovaries.⁹³ Patients with PCOS are characterized by impaired fertility rates mainly linked to metabolic disorders, including insulin resistance and hyperinsulinemia.⁹⁴ van Houten et al developed a mouse model of the syndrome which showed the metabolic and reproductive features associated with PCOS in humans.⁹⁵ Hypoadiponectinemia and decreased portion of HMW adiponectin have been demonstrated in PCOS.^96,97 Toulis et al concluded that reduced adiponectin concentrations are probably correlated with insulin resistance.⁹⁸ Interestingly, Mazloomi et al showed that low vitamin D levels may be linked to PCOS-associated hypoadiponectinemia through BMI-independent mechanisms.⁹⁹ Bik et al demonstrated a negative correlation between adiponectin in PCOS and testosterone, cholesterol, triglycerides, glucose, and diastolic blood pressure.¹⁰⁰ Moreover, the adipose tissue in PCOS is characterized by hypertrophic adipocytes and impairments in lipolysis and insulin action.¹⁰¹ Adiponectin content in subcutaneous adipocytes was found to be suppressed.⁹⁶ Glucose-intolerant patients also had lower intracellular HMW adiponectin.⁹⁶ A close association of intraabdominal fat mass, reduced adiponectin levels, and insulin resistance was reported in nonobese patients.¹⁰² In another study, epicardial adipose tissue thickness was increased in patients with PCOS.¹⁰³ However, it was not correlated with the plasma adiponectin levels. Finally, the mechanism of action of metformin, an insulin-sensitizing drug used for the treatment of PCOS, involves AMPK signaling pathway through which adiponectin actions are partly exerted.⁹⁴ The treatment of PCOS include insulin-sensitizing agents, such as metformin and thiazolidinediones, and adiponectin plasma concentrations seem to be related to the administration of these agents.²⁹

Endometriosis

Adiponectin may be involved in the pathogenesis of endometriosis which is a leading cause of infertility. Takemura et al found that serum adiponectin concentrations are inversely correlated with both endometriosis scores and adhesion scores of the revised American Society for Reproductive Medicine classification of endometriosis.¹⁰⁴ However, adiponectin concentrations in the peritoneal fluid were found not to be associated with endometriosis.¹⁰⁵ In infertile women, Pandey et al also showed that peritoneal fluid adiponectin levels did not differ in patients with pelvic endometriosis and controls.¹⁰⁶ On the other hand, Takemura et al previously demonstrated that adiponectin levels in the peritoneal fluid were lower in patients with stage III/IV endometriosis than those with stage I/II and without endometriosis.¹⁰⁷ More data are needed to elucidate whether adiponectin may have a role in the pathogenesis of endometriosis.

Leiomyomas and Endometrial Cancer

Reduced plasma adiponectin concentrations may have an important role in the development of metabolic syndrome which is associated with uterine leiomyomas.¹⁰⁸ Chen et al evaluated the adiponectin levels in women with uterine leiomyomas and showed that serum adiponectin is significantly lower in patients with myomatous uterus compared to normal participants.¹⁰⁹ In addition, Wakabayashi et al reported that adiponectin repressed proliferation in rat uterine leiomyoma ELT-3 cells, which express AdipoR1 and AdipoR2, without inducing apoptosis.¹⁰⁸

Adipocytokines have been linked to the pathogenesis of endometrial cancer. Partly, the association between obesity, as a risk factor, and endometrial cancer may be based on the actions of adipocytokines, including leptin and adiponectin.¹¹⁰ Low adiponectin concentrations were reported to mediate the effect of obesity on this type of cancer in the previous studies.¹¹¹ Adiponectin may influence the risk of cancer through its well-established correlations to insulin resistance and, possibly, via direct actions on cancer cells.¹¹² Epidemiological and research studies support the hypothesis that insulin resistance is associated with endometrial malignancies, and metformin was shown to have therapeutic potential for endometrial cancer.¹¹³ Interestingly, polymorphisms in the gene that encodes adiponectin may have a role in endometrial cancer risk.¹¹⁴ However, in a recent study, prediagnostic adiponectin concentrations were not predictive of this risk.¹¹⁵ In addition, serum leptin/adiponectin ratio was demonstrated to be independently associated with endometrial cancer development.¹¹⁶ Moon et al reported no statistical difference in the expression of adiponectin receptors between endometrial malignancies and nonneoplastic tissues in humans, but the authors reported higher relative expression level of AdipoR1 in neoplastic tissues.¹¹¹ Interestingly, adiponectin was found to inhibit leptin-stimulated proliferation of HEC-1A and RL95-2 endometrial cancer cell lines.¹¹⁰ Adiponectin also suppressed the proliferation of KLE and RL95-2 cell lines acting through adiponectin receptors.¹¹¹ Finally, Wu et al reported that adiponectin inhibits leptin-induced metastasis phenotype of aggressive SPEC-2 endometrial cancer cell line by downregulating JAK/STAT3 signaling pathway via AMPK activation.¹¹⁰

Conclusions

Adiponectin, the most abundant cytokine released by adipose tissue, has been reported to modulate various physiological processes. The pleiotropic role of this adipocytokine in the body is also supported by the wide distribution of adiponectin receptors in different tissues. The female reproductive system is influenced by adiponectin, which may also be involved in the pathogenesis of some pregnancy-associated disorders and gynecological conditions. Thus, in the future, adiponectin or its receptors may be used as targets for the development of novel therapeutic strategies in this field.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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