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A pilot study on the off-label use of valproic acid to treat adenomyosis

2007; Elsevier BV; Volume: 89; Issue: 1 Linguagem: Inglês

10.1016/j.fertnstert.2006.11.009

1556-5653

Xishi Liu, Sun‐Wei Guo,

Histone Deacetylase Inhibitors Research

Following on the heels of the discovery that endometriosis is an epigenetic disease, we conducted a pilot study on the off-label use of valproic acid to treat adenomyosis. We found that by the end of the 3-month treatment, all three recruited patients reported complete disappearance of dysmenorrhea, with an average of one-third reduction in uterus size. Following on the heels of the discovery that endometriosis is an epigenetic disease, we conducted a pilot study on the off-label use of valproic acid to treat adenomyosis. We found that by the end of the 3-month treatment, all three recruited patients reported complete disappearance of dysmenorrhea, with an average of one-third reduction in uterus size. Adenomyosis, defined as the presence of heterotopic endometrial glands and stroma in the myometrium with adjacent smooth muscle hyperplasia, is a common gynecologic disease with a poorly understood pathogenesis and is responsible for menorrhagia, dysmenorrhea, and subfertility (1Farquhar C. Brosens I. Medical and surgical management of adenomyosis.Best Pract Res Clin Obstet Gynaecol. 2006; 20: 603-616Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Until recently, the diagnosis of adenomyosis was made only after hysterectomy (2Lone F.W. Balogun M. Khan K.S. Adenomyosis: not such an elusive diagnosis any longer.J Obstet Gynaecol. 2006; 26: 225-228Crossref PubMed Scopus (19) Google Scholar), but now moderate to severe adenomyosis can be diagnosed with a fair degree of reliability by ultrasound or magnetic resonance imaging (3Peric H. Fraser I.S. The symptomatology of adenomyosis.Best Pract Res Clin Obstet Gynaecol. 2006; 20: 547-555Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Although the disease is hormone sensitive, progestogenic agents are ineffective. GnRH agonists induce suppression of adenomyosis, yet their use is restricted by short duration (4Bergeron C. Amant F. Ferenczy A. Pathology and physiopathology of adenomyosis.Best Pract Res Clin Obstet Gynaecol. 2006; 20: 511-521Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). In addition, the symptoms reappear after discontinuation of GnRH-agonist therapy (5Grow D.R. Filer R.B. Treatment of adenomyosis with long-term GnRH analogues: a case report.Obstet Gynecol. 1991; 78: 538-539PubMed Google Scholar). Adenomyosis and endometriosis share a great deal of similarities, in terms of definition, estrogen dependency, and symptomatology, and adenomyosis previously was considered a variant of endometriosis (6Ferenczy A. Pathophysiology of adenomyosis.Hum Reprod Update. 1998; 4: 312-322Crossref PubMed Scopus (373) Google Scholar). Persistent dysmenorrhea and nonmenstrual pain after optimal surgical removal of endometriotic lesions may indicate adenomyosis (7Parker J.D. Leondires M. Sinaii N. Premkumar A. Nieman L.K. Stratton P. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis.Fertil Steril. 2006; 86: 711-715Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Evidence is converging that endometriosis, defined as the presence of heterotopic endometrial glands and stroma outside of the uterus, is an epigenetic disease (8Wu Y. Strawn E. Basir Z. Halverson G. Guo S.W. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A and DNMT3B in women with endometriosis.Fertil Steril. 2007; 87: 24-32Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) with aberrant methylation (9Wu Y. Halverson G. Basir Z. Strawn Y. Yan P. Guo S.W. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis.Am J Obstet Gynecol. 2005; 193: 371-380Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 10Wu Y. Strawn E. Basir Z. Halverson G. Guo S.W. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis.Epigenetics. 2006; 1: 106-111Crossref PubMed Scopus (236) Google Scholar) and may thus be ameliorated by demethylation agents and histone deacetylase inhibitors (HDACIs) (11Szyf M. Therapeutic implications of DNA methylation.Future Oncol. 2005; 1: 125-135Crossref PubMed Scopus (26) Google Scholar). Indeed, it recently has been reported that trichostatin A, a potent HDACI, suppresses proliferation of endometrial stromal cells (12Wu 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: 193-205Crossref PubMed Scopus (53) Google Scholar). Further research indicates that endometriotic cells are in fact more than 100-fold more sensitive than endometrial cells to trichostatin A treatment (Wu and Guo, unpublished observation). In addition, trichostatin A suppresses IL-1β–induced COX-2 expression (13Wu Y, Guo SW. Suppression of IL-1β-induced COX-2 expression by trischotatin A (TSA) in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. In press.Google Scholar), and both trichostatin A and valproic acid (VPA) induce cell-cycle arrest in endometrial cells (Wu Y, Guo S-W, unpublished observations). Some circumstantial evidence suggests that adenomyosis may also be an epigenetic disease, just like endometriosis. For example, a recent study finds that retinoblastoma (pRb) is undetected in adenomyosis (14Goumenou A.G. Matalliotakis I.M. Tzardi M. Fragouli I.G. Mahutte N.G. Arici A. p16, retinoblastoma (pRb), and cyclin D1 protein expression in human endometriotic and adenomyotic lesions.Fertil Steril. 2006; 85: 1204-1207Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar), which may result from pRb promoter hypermethylation (15Simpson D.J. Hibberts N.A. McNicol A.M. Clayton R.N. Farrell W.E. Loss of pRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island.Cancer Res. 2000; 60: 1211-1216PubMed Google Scholar). There is compelling reason to believe that HDACIs may be a promising class of compounds for treating endometriosis and perhaps adenomyosis as well. In this article, we report on the off-label use of VPA to treat three cases of adenomyosis, with the aim of determining the feasibility of administering oral VPA in patients with adenomyosis. Valproic acid is a specific and potent HDACI (16Gottlicher M. Minucci S. Zhu P. Kramer O.H. Schimpf A. Giavara S. et al.Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.EMBO J. 2001; 20: 6969-6978Crossref PubMed Scopus (1527) Google Scholar, 17Phiel C.J. Zhang F. Huang E.Y. Guenther M.G. Lazar M.A. Klein P.S. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.J Biol Chem. 2001; 276: 36734-36741Crossref PubMed Scopus (1449) Google Scholar), with known and favorable pharmacokinetic properties. It has been used safely for >2 decades to treat epilepsy and, more recently, bipolar disorders (18Tunnicliff G. Actions of sodium valproate on the central nervous system.J Physiol Pharmacol. 1999; 50: 347-365PubMed Google Scholar, 19Johannessen C.U. Mechanisms of action of valproate: a commentatory.Neurochem Int. 2000; 37: 103-110Crossref PubMed Scopus (322) Google Scholar). After informed consent, we recruited three patients who had been diagnosed with adenomyosis (Table 1). All three patients had moderate to severe dysmenorrhea. They were all married and parous and had normal menstrual cycles (28–30 d). They all had normal hepatic and renal function, as defined by serum transaminases of <1.5× the upper limit of normal, bilirubin of <1.5× the upper limit of normal, and creatinine of 0.05). The purported placebo effect also had to be somewhat long lasting: after 3 months off of the drug, two of three patients still remained pain free. Further, given the proven ability of trichostatin A and VPA in suppressing proliferation of endometrial and endometriotic cells in vitro (11Szyf M. Therapeutic implications of DNA methylation.Future Oncol. 2005; 1: 125-135Crossref PubMed Scopus (26) Google Scholar), the consistent and considerable reduction (∼33%) in uterus size across all three patients suggests that the relief of dysmenorrhea in the two patients is unlikely to be entirely a result of placebo effect. Although the exact mechanisms by which VPA alleviates pain are far from clear, it is possible that VPA treatment may alleviate pelvic pain by inhibiting proliferation; inducing apoptosis and cell-cycle arrest; suppressing COX-2 expression; and inhibiting angiogenesis, adhesion, invasion, and the production of proinflammatory cytokines and chemokines. The suppression of production of proinflammatory cytokines and chemokines alone as a result of VPA treatment may help alleviate pain, because the crosstalk between chemokines and neuronal receptors that regulate pain (20Zhang N. Oppenheim J.J. Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems.J Leukoc Biol. 2005; 78: 1210-1214Crossref PubMed Scopus (55) Google Scholar) may contribute, at least in part, to the adenomyosis-associated pain. It has been reported that RANTES (CCL5) and MIP-1α (CCL3) desensitize μ-opioid receptors (21Zhang N. Rogers T.J. Caterina M. Oppenheim J.J. Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons.J Immunol. 2004; 173: 594-599PubMed Google Scholar) but sensitize the heat- and capsaicin-gated ion-channel transient receptor potential vanilloid 1 (TRPV1) (22Zhang N. Inan S. Cowan A. Sun R. Wang J.M. Rogers T.J. et al.A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.Proc Natl Acad Sci USA. 2005; 102: 4536-4541Crossref PubMed Scopus (205) Google Scholar), which are likely to contribute to pain in adenomyosis and endometriosis. The increased production of proinflammatory chemokines activates their corresponding receptors, which in turn down-regulates the analgesic functions of opioid receptors and up-regulates TRPV1, resulting in enhanced perception of pain at inflammatory sites (23Szabo I. Wetzel M. McCarthy L. Steele A. Henderson E.E. Howard M.Z. et al.Interactions of opioid receptors, chemokines, and chemokine receptors.Adv Exp Med Biol. 2001; 493: 69-74Crossref PubMed Google Scholar, 24Szabo I. Chen X.H. Xin L. Adler M.W. Howard O.M. Oppenheim J.J. et al.Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain.Proc Natl Acad Sci USA. 2002; 99: 10276-10281Crossref PubMed Scopus (204) Google Scholar). It is also interesting to note that cytokine TNFα plays a critical role in the development and maintenance of neuropathic pain (25Woolf C.J. Allchorne A. Safieh-Garabedian B. Poole S. Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha.Br J Pharmacol. 1997; 121: 417-424Crossref PubMed Scopus (563) Google Scholar, 26Junger H. Sorkin L.S. Nociceptive and inflammatory effects of subcutaneous TNFalpha.Pain. 2000; 85: 145-151Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 27Joseph E.K. Levine J.D. Caspase signalling in neuropathic and inflammatory pain in the rat.Eur J Neurosci. 2004; 20: 2896-2902Crossref PubMed Scopus (176) Google Scholar, 28Sommer C. Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia.Neurosci Lett. 2004; 361: 184-187Crossref PubMed Scopus (645) Google Scholar). By suppressing the production of proinflammatory cytokines and chemokines, VPA may alleviate pelvic pain. Although pelvic examination suggests no change in uterus size, a more objective evaluation by ultrasound nonetheless indicates reduction by as much as 60.8% 3 months after taking VPA. A more dramatic reduction in uterus size could be achieved through longer use of VPA because GnRH agonists are typically given for 6 months to relieve dysmenorrhea and menorrhagia (6Ferenczy A. Pathophysiology of adenomyosis.Hum Reprod Update. 1998; 4: 312-322Crossref PubMed Scopus (373) Google Scholar). In addition, the combination of VPA with retinoic acid may also induce further reduction in uterus size because retinoic acid appears to synergize with VPA in suppression of proliferation of endometrial cells (Wu Y, Guo S-W, unpublished observations). We note that the subjective feeling of pelvic pain or lack of it actually is quite important to the well-being of the patient. It was the accelerated return of pelvic pain reported by the patients, rather than the increase in lesion size or number of lesions, that prompted the termination of a recent phase II trial on the use of raloxifene to treat endometriosis (29Stratton P. Sinaii N. Segars J. Koziol D. Wesley R. Zimmer C. et al.Raloxifene accelerates the return of chronic pelvic pain from endometriosis after surgical treatment.Eur J Obstet Gynecol Reprod Biol. 2005; 123 ([abstract]): S22PubMed Google Scholar), despite all encouraging results from animal studies (30Swisher D.K. Tague R.M. Seyler D.E. Effects of the selective estrogen receptor modulator raloxifene on explanted uterine growth in rats.Drug Dev Res. 1995; 36: 43-45Crossref Scopus (23) Google Scholar, 31Fanning P. Keuehl T. Lee R. Pearson S.L. Wincek T. Pliego J. et al.Video mapping to assess efficacy of an antiestrogen (raloxifene) on spontaneous endometriosis in the rhesus monkey, Macaca mulatta.in: Kuehl T.J. Bunkley Day proceedings. Texas A&M University Health Science Center, Temple, TX1996: 51-61Google Scholar, 32Yao Z. Shen X. Capodanno I. Donnelly M. Fenyk-Melody J. Hausamann J. et al.Validation of rat endometriosis model by using raloxifene as a positive control for the evaluation of novel SERM compounds.J Invest Surg. 2005; 18: 177-183Crossref PubMed Scopus (44) Google Scholar). In view of the accumulating evidence that endometriosis is an epigenetic disease and of the indication that it may be rectified by HDACIs, our encouraging pilot results on the off-label use of VPA for treatment of adenomyosis should be greeted with guarded enthusiasm. Obviously, whether VPA or other HDACIs may be truly efficacious in treating adenomyosis and/or endometriosis should await future controlled randomized clinical trials that have optimal treatment duration, sufficient sample sizes, and more objective quantification. If proven efficacious, VPA may be a much cheaper alternative to GnRH agonist therapy, and possibly more efficacious and potent as a result of its potential to rectify epigenetic aberrations, yet with fewer and milder side effects. The authors thank Dr. Gloria Halverson for her constructive comments.