Advertisement

Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor (OTR) in women with symptomatic adenomyosis

Published:September 20, 2012DOI:https://doi.org/10.1016/j.fertnstert.2012.08.038

      Objective

      To evaluate uterine contractility, oxytocin receptor (OTR) expression in myometrial smooth muscle cells (MSMCs) derived from uterine tissues from women with and without adenomyosis correlate OTR expression with uterine contractility and dysmenorrhea severity, and see whether trichostatin A (TSA) and andrographolide inhibit OTR expression.

      Design

      Laboratory study using human tissues.

      Setting

      Academic hospital.

      Patient(s)

      Twenty patients (cases) with histologically confirmed adenomyosis and 10 (controls) with leiomyomas, cervical dysplasia, and cancer but no adenomyosis or endometriosis.

      Intervention(s)

      Dysmenorrhea severity was scored by Visual Analog Scale. Uterine tissue samples were collected during hysterectomy. Myometrial smooth muscle cells derived from tissue samples were cultured and OTR protein levels were measured. The effect of TSA (0.5 or 1 μM) and andrographolide (15 or 30 μM) on OTR expression was evaluated.

      Main Outcome Measure(s)

      Visual Analog Scale scores, and contractile amplitude and frequency. The OTR protein levels in MSMCs were quantified by Western blot analysis.

      Result(s)

      The contractile amplitude and OTR expression levels were significantly higher in cases than in controls. Dysmenorrhea Visual Analog Scale scores correlated positively with contractile amplitude and OTR expression level. Both TSA and andrographolide dose-dependently inhibit OTR expression in MSMC.

      Conclusion(s)

      Oxytocin receptor overexpression in MSMCs may be responsible for increased uterine contractility and adenomyosis-associated dysmenorrhea. Both histone deacetylase inhibitors and andrographolide are therapeutically promising.

      Key Words

      To read this article in full you will need to make a payment

      References

        • Bergeron C.
        • Amant F.
        • Ferenczy A.
        Pathology and physiopathology of adenomyosis.
        Best Pract Res Clin Obstet Gynaecol. 2006; 20: 511-521
        • Farquhar C.
        • Brosens I.
        Medical and surgical management of adenomyosis.
        Best Pract Res Clin Obstet Gynaecol. 2006; 20: 603-616
        • Matalliotakis I.M.
        • Kourtis A.I.
        • Panidis D.K.
        Adenomyosis.
        Obstet Gynecol Clin North Am. 2003; 30 (viii): 63-82
        • Zhang X.
        • Lu B.
        • Huang X.
        • Xu H.
        • Zhou C.
        • Lin J.
        Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine fibroids.
        Fertil Steril. 2009; 92: 1799-1801
        • Zhang X.
        • Lu B.
        • Huang X.
        • Xu H.
        • Zhou C.
        • Lin J.
        Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids.
        Fertil Steril. 2010; 94: 730-737
        • Wang G.
        • Tokushige N.
        • Fraser I.S.
        Nerve fibers and menstrual cycle in peritoneal endometriosis.
        Fertil Steril. 2011; 95: 2772-2774
        • de Ziegler D.
        • Bulletti C.
        • Fanchin R.
        • Epiney M.
        • Brioschi P.A.
        Contractility of thenonpregnant uterus: the follicular phase.
        Ann N Y Acad Sci. 2001; 943: 172-184
        • Ijland M.M.
        • Evers J.L.
        • Dunselman G.A.
        • van Katwijk C.
        • Lo C.R.
        • Hoogland H.J.
        Endometrial wavelike movements during the menstrual cycle.
        Fertil Steril. 1996; 65: 746-749
        • Leyendecker G.
        • Kunz G.
        • Wildt L.
        • Beil D.
        • Deininger H.
        Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility.
        Hum Reprod. 1996; 11: 1542-1551
        • Woodbury R.A.
        • Torpin R.
        • Child G.P.
        • Watson H.
        • Jarboe M.
        Myometrial physiology and its relation to pelvic pain.
        J Am Med Assoc. 1947; 134: 1081-1085
        • Kunz G.
        • Leyendecker G.
        Uterine peristaltic activity during the menstrual cycle: characterization, regulation, function and dysfunction.
        Reprod Biomed Online. 2002; 4: 5-9
        • Kunz G.
        • Noe M.
        • Herbertz M.
        • Leyendecker G.
        Uterine peristalsis during the follicular phase of the menstrual cycle: effects of oestrogen, antioestrogen and oxytocin.
        Hum Reprod Update. 1998; 4: 647-654
        • Vedernikov Y.P.
        • Hartke J.R.
        • de Long M.A.
        • Saade G.R.
        • Garfield R.E.
        Sex hormone effects in non-pregnant rat and human myometrium.
        Eur J Obstet Gynecol Reprod Biol. 2003; 108: 59-66
        • Roth-Brandel U.
        • Bygdeman M.
        • Wiqvist N.
        Effect of intravenous administration of prostaglandin E1, and F2 on the contractility of the non-pregnant human uterus in vivo.
        Acta Obstet Gynecol Scand Suppl. 1970; 5: 19-25
        • Gimpl G.
        • Fahrenholz F.
        The oxytocin receptor system: structure, function, and regulation.
        Physiol Rev. 2001; 81: 629-683
        • Akerlund M.
        • Melin P.
        • Maggi M.
        Potential use of oxytocin and vasopressin V1a antagonists in the treatment of preterm labour and primary dysmenorrhoea.
        Adv Exp Med Biol. 1995; 395: 595-600
        • Abdalla F.M.
        • Marostica E.
        • Picarelli Z.P.
        • Abreu L.C.
        • Avellar M.C.
        • Porto C.S.
        Effect of estrogen on muscarinic acetylcholine receptor expression in rat myometrium.
        Mol Cell Endocrinol. 2004; 213: 139-148
        • Adachi S.
        • Oku M.
        The regulation of oxytocin receptor expression in human myometrial monolayer culture.
        J Smooth Muscle Res. 1995; 31: 175-187
        • Richter O.N.
        • Kubler K.
        • Schmolling J.
        • Kupka M.
        • Reinsberg J.
        • Ulrich U.
        • et al.
        Oxytocin receptor gene expression of estrogen-stimulated human myometrium in extracorporeally perfused non-pregnant uteri.
        Mol Hum Reprod. 2004; 10: 339-346
        • Richter O.N.
        • Tschubel K.
        • Schmolling J.
        • Kupka M.
        • Ulrich U.
        • Wardelmann E.
        Immunohistochemical reactivity of myometrial oxytocin receptor in extracorporeally perfused nonpregnant human uteri.
        Arch Gynecol Obstet. 2003; 269: 16-24
        • Fleming J.G.
        • Spencer T.E.
        • Safe S.H.
        • Bazer F.W.
        Estrogen regulates transcription of the ovine oxytocin receptor gene through GC-rich SP1 promoter elements.
        Endocrinology. 2006; 147: 899-911
        • Terzidou V.
        • Lee Y.
        • Lindstrom T.
        • Johnson M.
        • Thornton S.
        • Bennett P.R.
        Regulation of the human oxytocin receptor by nuclear factor-kappaB and CCAAT/enhancer-binding protein-beta.
        J Clin Endocrinol Metab. 2006; 91: 2317-2326
        • Nie J.
        • Liu X.
        • Guo S.W.
        Immunoreactivity of oxytocin receptor and transient receptor potential vanilloid type 1 and its correlation with dysmenorrhea in adenomyosis.
        Am J Obstet Gynecol. 2010; 202: 346.e1-346.e8
        • Mechsner S.
        • Grum B.
        • Gericke C.
        • Loddenkemper C.
        • Dudenhausen J.W.
        • Ebert A.D.
        Possible roles of oxytocin receptor and vasopressin-1alpha receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri.
        Fertil Steril. 2010; 94: 2541-2546
        • Nie J.
        • Lu Y.
        • Liu X.
        • Guo S.W.
        Immunoreactivity of progesterone receptor isoform B, nuclear factor kappaB, and IkappaBalpha in adenomyosis.
        Fertil Steril. 2009; 92: 886-889
        • Kitawaki J.
        Adenomyosis: the pathophysiology of an oestrogen-dependent disease.
        Best Pract Res Clin Obstet Gynaecol. 2006; 20: 493-502
        • Jichan N.
        • Xishi L.
        • Guo S.W.
        Promoter hypermethylation of progesterone receptor isoform B (PR-B) in adenomyosis and its rectification by a histone deacetylase inhibitor and a demethylation agent.
        Reprod Sci. 2010; 17: 995-1005
        • Liu X.
        • Nie J.
        • Guo S.W.
        Elevated immunoreactivity against Class I histone deacetylases (HDACs) in adenomyosis.
        Gynecol Obstet Invest. 2012; 74: 50-55
        • Liu X.
        • Guo S.W.
        A pilot study on the off-label use of valproic acid to treat adenomyosis.
        Fertil Steril. 2008; 89: 246-250
        • Liu X.
        • Guo S.W.
        Valproic acid alleviates generalized hyperalgesia in mice with induced adenomyosis.
        J Obstet Gynaecol Res. 2011; 37: 696-708
        • Xishi L.
        • Lei Y.
        • Guo S.W.
        Valproic acid as a therapy for adenomyosis: a comparative case series.
        Reprod Sci. 2010; 17: 904-912
        • Mao X.
        • Wang Y.
        • Carter A.V.
        • Zhen X.
        • Guo S.W.
        The retardation of myometrial infiltration, reduction of uterine contractility, and alleviation of generalized hyperalgesia in mice with induced adenomyosis by levo-tetrahydropalmatine (L-THP) and andrographolide.
        Reprod Sci. 2011; 18: 1025-1037
        • Xia Y.F.
        • Ye B.Q.
        • Li Y.D.
        • Wang J.G.
        • He X.J.
        • Lin X.
        • et al.
        Andrographolide attenuates inflammation by inhibition of NF-kappa B activation through covalent modification of reduced cysteine 62 of p50.
        J Immunol. 2004; 173: 4207-4217
        • Ota H.
        • Igarashi S.
        • Sato N.
        • Tanaka H.
        • Tanaka T.
        Involvement of catalase in the endometrium of patients with endometriosis and adenomyosis.
        Fertil Steril. 2002; 78: 804-809
        • Fedele L.
        • Bianchi S.
        • Dorta M.
        • Arcaini L.
        • Zanotti F.
        • Carinelli S.
        Transvaginal ultrasonography in the diagnosis of diffuse adenomyosis.
        Fertil Steril. 1992; 58: 94-97
        • Bazot M.
        • Darai E.
        • Rouger J.
        • Detchev R.
        • Cortez A.
        • Uzan S.
        Limitations of transvaginal sonography for the diagnosis of adenomyosis, with histopathological correlation.
        Ultrasound Obstet Gynecol. 2002; 20: 605-611
        • Meredith S.M.
        • Sanchez-Ramos L.
        • Kaunitz A.M.
        Diagnostic accuracy of transvaginal sonography for the diagnosis of adenomyosis: systematic review and metaanalysis.
        Am J Obstet Gynecol. 2009; 201: 107.e1-107.e6
        • Sakhel K.
        • Abuhamad A.
        Sonography of adenomyosis.
        J Ultrasound Med. 2012; 31: 805-808
        • Akerlund M.
        • Andersson K.E.
        • Ingemarsson I.
        Effects of terbutaline on myometrial activity, uterine blood flow, and lower abdominal pain in women with primary dysmenorrhoea.
        Br J Obstet Gynaecol. 1976; 83: 673-678
        • R Development Core Team
        R: a language and environment for statistical computing.
        R Foundation for Statistical Computing, Vienna, Austria2011
        • Akerlund M.
        Targeting the oxytocin receptor to relax the myometrium.
        Expert Opin Ther Targets. 2006; 10: 423-427
        • Mechsner S.
        • Bartley J.
        • Loddenkemper C.
        • Salomon D.S.
        • Starzinski-Powitz A.
        • Ebert A.D.
        Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts.
        Fertil Steril. 2005; 83: 1220-1231
        • Bulletti C.
        • De Ziegler D.
        • Polli V.
        • Del Ferro E.
        • Palini S.
        • Flamigni C.
        Characteristics of uterine contractility during menses in women with mild to moderate endometriosis.
        Fertil Steril. 2002; 77: 1156-1161
        • Bulletti C.
        • Rossi S.
        • Albonetti A.
        • Polli V.V.
        • De Ziegler D.
        • Massoneau M.
        • et al.
        Uterine contractility in patients with endometriosis.
        J Am Assoc Gynecol Laparosc. 1996; 3: S5
        • Salamanca A.
        • Beltran E.
        Subendometrial contractility in menstrual phase visualized by transvaginal sonography in patients with endometriosis.
        Fertil Steril. 1995; 64: 193-195
        • Kido A.
        • Togashi K.
        • Nishino M.
        • Miyake K.
        • Koyama T.
        • Fujimoto R.
        • et al.
        Cine MR imaging of uterine peristalsis in patients with endometriosis.
        Eur Radiol. 2007; 17: 1813-1819
        • Kitlas A.
        • Oczeretko E.
        • Swiatecka J.
        • Borowska M.
        • Laudanski T.
        Uterine contraction signals—application of the linear synchronization measures.
        Eur J Obstet Gynecol Reprod Biol. 2009; 144: S61-S64
        • Wilson T.
        • Liggins G.C.
        • Whittaker D.J.
        Oxytocin stimulates the release of arachidonic acid and prostaglandin F2 alpha from human decidual cells.
        Prostaglandins. 1988; 35: 771-780
        • Burns P.D.
        • Mendes Jr., J.O.
        • Yemm R.S.
        • Clay C.M.
        • Nelson S.E.
        • Hayes S.H.
        • et al.
        Cellular mechanisms by which oxytocin mediates ovine endometrial prostaglandin F2alpha synthesis: role of G(i) proteins and mitogen-activated protein kinases.
        Biol Reprod. 2001; 65: 1150-1155
        • Sales K.J.
        • Jabbour H.N.
        Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium.
        Reproduction. 2003; 126: 559-567
        • Sales K.J.
        • Grant V.
        • Jabbour H.N.
        Prostaglandin E2 and F2alpha activate the FP receptor and up-regulate cyclooxygenase-2 expression via the cyclic AMP response element.
        Mol Cell Endocrinol. 2008; 285: 51-61
        • Schmid B.
        • Wong S.
        • Mitchell B.F.
        Transcriptional regulation of oxytocin receptor by interleukin-1beta and interleukin-6.
        Endocrinology. 2001; 142: 1380-1385
        • Weston G.C.
        • Haviv I.
        • Rogers P.A.
        Microarray analysis of VEGF-responsive genes in myometrial endothelial cells.
        Mol Hum Reprod. 2002; 8: 855-863
        • Nie J.
        • Lu Y.
        • Liu X.S.
        • Guo S.W.
        Immunoreactivity of progesterone receptor isoform B (PR-B), nuclear factor-κB (NF-κB) and IκBα in adenomyosis.
        Fertil Steril. 2009; 92: 886-889
        • Moynihan A.T.
        • Hehir M.P.
        • Sharkey A.M.
        • Robson S.C.
        • Europe-Finner G.N.
        • Morrison J.J.
        Histone deacetylase inhibitors and a functional potent inhibitory effect on human uterine contractility.
        Am J Obstet Gynecol. 2008; 199: 167.e1-167.e7
        • Lindstrom T.M.
        • Mohan A.R.
        • Johnson M.R.
        • Bennett P.R.
        Histone deacetylase inhibitors exert time-dependent effects on nuclear factor-kappaB but consistently suppress the expression of proinflammatory genes in human myometrial cells.
        Mol Pharmacol. 2008; 74: 109-121
        • Wu Y.
        • Guo S.W.
        Suppression of IL-1beta-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells.
        Eur J Obstet Gynecol Reprod Biol. 2007; 135: 88-93
        • Wu Y.
        • Guo S.W.
        Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780.
        Gynecol Obstet Invest. 2006; 62: 193-205
        • Wu Y.
        • Starzinski-Powitz A.
        • Guo S.W.
        Constitutive and tumor necrosis factor-alpha-stimulated activation of nuclear factor-kappaB in immortalized endometriotic cells and their suppression by trichostatin A.
        Gynecol Obstet Invest. 2010; 70: 23-33
        • Abu-Ghefreh A.A.
        • Canatan H.
        • Ezeamuzie C.I.
        In vitro and in vivo anti-inflammatory effects of andrographolide.
        Int Immunopharmacol. 2009; 9: 313-318
        • Hidalgo M.A.
        • Romero A.
        • Figueroa J.
        • Cortes P.
        • Concha I.I.
        • Hancke J.L.
        • et al.
        Andrographolide interferes with binding of nuclear factor-kappaB to DNA in HL-60-derived neutrophilic cells.
        Br J Pharmacol. 2005; 144: 680-686
        • Varma A.
        • Padh H.
        • Shrivastava N.
        Andrographolide: a new plant-derived antineoplastic entity on horizon.
        Evid Based Complement Alternat Med. 2011; 2011: 815390
        • Wang Y.J.
        • Wang J.T.
        • Fan Q.X.
        • Geng J.G.
        Andrographolide inhibits NF-kappaBeta activation and attenuates neointimal hyperplasia in arterial restenosis.
        Cell Res. 2007; 17: 933-941
        • Ota H.
        • Igarashi S.
        • Sasaki M.
        • Tanaka T.
        Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis.
        Hum Reprod. 2001; 16: 561-566
        • Krikun G.
        • Schatz F.
        • Taylor H.
        • Lockwood C.J.
        Endometriosis and tissue factor.
        Ann N Y Acad Sci. 2008; 1127: 101-105
        • Lin F.L.
        • Wu S.J.
        • Lee S.C.
        • Ng L.T.
        Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent andrographolide.
        Phytother Res. 2009; 23: 958-964
        • Sulaiman M.R.
        • Zakaria Z.A.
        • Abdul Rahman A.
        • Mohamad A.S.
        • Desa M.N.
        • Stanslas J.
        • et al.
        Antinociceptive and antiedematogenic activities of andrographolide isolated from Andrographis paniculata in animal models.
        Biol Res Nurs. 2010; 11: 293-301
        • Burgos R.A.
        • Hancke J.L.
        • Bertoglio J.C.
        • Aguirre V.
        • Arriagada S.
        • Calvo M.
        • et al.
        Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: a prospective randomized placebo-controlled trial.
        Clin Rheumatol. 2009; 28: 931-946
        • Jane M.
        • Minkin C.W.
        What every woman needs to know about menopause.
        Yale University Press, New Haven, CT1997