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• W2019909182 abstract "Although fibroids are common benign tumors, their impact on women's quality of life can be considerable. The most frequent symptoms are uterine bleeding, resulting in anemia, and pelvic pain. Fibroids can be of genetic or hormonal origin or arise from intrauterine events. Current options for medical treatment include control of estradiol and progesterone production or action and are discussed in this review. Although curative treatment of fibroids relies on surgical strategies, the current trend is for uterine-sparing treatment to preserve fertility and avoid unnecessary surgery. Currently approved medical treatments include intrauterine progestin delivery to reduce uterine bleeding, GnRH analogues, and, more recently, selective progesterone receptor modulators to control uterine bleeding and reduce fibroid volume. Although fibroids are common benign tumors, their impact on women's quality of life can be considerable. The most frequent symptoms are uterine bleeding, resulting in anemia, and pelvic pain. Fibroids can be of genetic or hormonal origin or arise from intrauterine events. Current options for medical treatment include control of estradiol and progesterone production or action and are discussed in this review. Although curative treatment of fibroids relies on surgical strategies, the current trend is for uterine-sparing treatment to preserve fertility and avoid unnecessary surgery. Currently approved medical treatments include intrauterine progestin delivery to reduce uterine bleeding, GnRH analogues, and, more recently, selective progesterone receptor modulators to control uterine bleeding and reduce fibroid volume. Discuss: You can discuss this article with its authors and other ASRM members at http://fertstertforum.com/chabbertbuffetn-fibroids-growth-medical-treatment/Fibroids are the most common gynecologic tumors, occurring in ∼70% of women over 30 years of age (1Bulun S.E. Uterine fibroids.N Engl J Med. 2013; 369: 1344-1355Crossref PubMed Scopus (3) Google Scholar). They are benign tumors developing in the myometrium. Despite the high incidence of the disease and its impact on women's quality of life, there has been relatively little research on fibroids until recently (2Walker C.L. Stewart E.A. Uterine fibroids: the elephant in the room.Science. 2005; 308: 1589-1592Crossref PubMed Scopus (218) Google Scholar).Fibroids develop from a single myometrial smooth muscle cell and are therefore classified as a clonal disease (3Holdsworth-Carson S.J. Zaitseva M. Vollenhoven B.J. Rogers P.A. Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues.Mol Hum Reprod. 2014; 20: 250-259Crossref PubMed Scopus (2) Google Scholar, 4Linder D. Gartler S.M. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas.Science. 1965; 150: 67-69Crossref PubMed Google Scholar). Risk factors for developing fibroids, apart from ethnic origin and heredity, include situations causing prolonged high exposure to estrogens and/or progesterone, such as early age of menarche (5Segars J.H. Parrott E.C. Nagel J.D. Guo X.C. Gao X. Birnbaum L.S. et al.Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations.Hum Reprod Update. 2014; 20: 309-333Crossref PubMed Scopus (1) Google Scholar, 6Velez Edwards D.R. Baird D.D. Hartmann K.E. Association of age at menarche with increasing number of fibroids in a cohort of women who underwent standardized ultrasound assessment.Am J Epidemiol. 2013; 178: 426-433Crossref PubMed Google Scholar), polycystic ovary syndrome (7Wise L.A. Palmer J.R. Stewart E.A. Rosenberg L. Polycystic ovary syndrome and risk of uterine leiomyomata.Fertil Steril. 2007; 87: 1108-1115Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar), obesity (8Okolo S. Incidence, aetiology and epidemiology of uterine fibroids.Best Pract Res Clin Obstet Gynaecol. 2008; 22: 571-588Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar), and late pregnancy (9Islam M.S. Protic O. Giannubilo S.R. Toti P. Tranquilli A.L. Petraglia F. et al.Uterine leiomyoma: available medical treatments and new possible therapeutic options.J Clin Endocrinol Metab. 2013; 98: 921-934Crossref PubMed Scopus (19) Google Scholar). Consistent with these epidemiologic data, the best known stimulator of tumor growth is the combined action of estrogens and progesterone. Growth factors, cytokines, and chemokines (1Bulun S.E. Uterine fibroids.N Engl J Med. 2013; 369: 1344-1355Crossref PubMed Scopus (3) Google Scholar) have also been described as playing a role. Several animal and in vitro models (5Segars J.H. Parrott E.C. Nagel J.D. Guo X.C. Gao X. Birnbaum L.S. et al.Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations.Hum Reprod Update. 2014; 20: 309-333Crossref PubMed Scopus (1) Google Scholar) developed over the past decade have contributed to a better understanding of the disease.Fibroids are mostly asymptomatic (80%) but can induce symptoms with a high impact on women's health (10Downes E. Sikirica V. Gilabert-Estelles J. Bolge S.C. Dodd S.L. Maroulis C. et al.The burden of uterine fibroids in five European countries.Eur J Obstet Gynecol Reprod Biol. 2010; 152: 96-102Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar) depending on their size and location. Until recently, they were largely classified as being either subserosal or interstitial. However, the International Federation of Gynecology and Obstetrics now recognizse eight subtypes: types 0–2, submucosal; 3–5, interstitial; 5–7, subserosal; and 8, extrauterine (e.g., parametrium; Fig. 1) (11Munro M.G. Critchley H.O. Fraser I.S. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years.Fertil Steril. 2011; 95 (8.e1–3): 2204-2208Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Heavy menstrual bleeding is the most frequent fibroid-related symptom, resulting in reduced quality of life and anemia (5Segars J.H. Parrott E.C. Nagel J.D. Guo X.C. Gao X. Birnbaum L.S. et al.Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations.Hum Reprod Update. 2014; 20: 309-333Crossref PubMed Scopus (1) Google Scholar), and it can be related either to the location of the fibroid (submucosal) or to fibroid-related endometrial dysfunction (11Munro M.G. Critchley H.O. Fraser I.S. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years.Fertil Steril. 2011; 95 (8.e1–3): 2204-2208Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). In addition, associated endometrial lesions may be present in up to 20% women with abnormal uterine bleeding, particularly adenomyosis (12Brucker S.Y. Huebner M. Wallwiener M. Stewart E.A. Ebersoll S. Schoenfisch B. et al.Clinical characteristics indicating adenomyosis coexisting with leiomyomas: a retrospective, questionnaire-based study.Fertil Steril. 2013; 101: 237-241.e1Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 13Hanafi M. Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation.J Hum Reprod Sci. 2013; 6: 189-193Crossref PubMed Google Scholar, 14Naftalin J. Hoo W. Pateman K. Mavrelos D. Foo X. Jurkovic D. Is adenomyosis associated with menorrhagia?.Hum Reprod. 2014; 29: 473-479Crossref PubMed Scopus (1) Google Scholar, 15Nomelini R.S. Ferreira F.A. Borges R.C. Adad S.J. Murta E.F. Frequency of endometriosis and adenomyosis in patients with leiomyomas, gynecologic premalignant, and malignant neoplasias.Clin Exp Obstet Gynecol. 2013; 40: 40-44PubMed Google Scholar). Pretherapeutic workup should, of course, aim to identify these associated conditions, because they may require specific care.Symptoms related to tumor volume are less frequent and include pelvic pain, dyspareunia, and urinary symptoms, such as pollakiuria and dysuria. Fibroid volume can also occasionally result in urinary tract compression and ureteral dilation, which can lead to renal dysfunction. The role of fibroids in infertility is limited and mostly related to submucosal lesions resulting in implantation defects (16Pritts E.A. Parker W.H. Olive D.L. Fibroids and infertility: an updated systematic review of the evidence.Fertil Steril. 2009; 91: 1215-1223Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). Whether large interstitial fibroids can cause infertility through deformation of the uterine cavity is still under discussion (16Pritts E.A. Parker W.H. Olive D.L. Fibroids and infertility: an updated systematic review of the evidence.Fertil Steril. 2009; 91: 1215-1223Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). However, although African women have a high incidence of fibroids and more severe lesions, their rate of fertility remains high even though pregnancy usually occurs at an age where the rate of fibroids is already high: 25–35 years (17National Institute of Demography of Burkina Faso. Evolution of fertility rates by age category (Table 3). In: Population, 2014.Google Scholar).Although bleeding may have a marked impact on their quality of life, women often delay seeking medical advice. This may be because they underestimate the importance of the bleeding (18Reid P.C. Coker A. Coltart R. Assessment of menstrual blood loss using a pictorial chart: a validation study.BJOG. 2000; 107: 320-322Crossref PubMed Google Scholar) or because of a fear of surgical treatment. It is therefore important that women are better informed about medical treatment options.The only curative treatment to date is surgical removal either by myomectomy or hysterectomy. Although alternative surgical strategies have resulted in a reduction of the number of hysterectomies (19Reid P.C. Mukri F. Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics, 1989 to 2002–3.BMJ. 2005; 330: 938-939Crossref PubMed Scopus (49) Google Scholar), 55,000 hysterectomies a year are still performed for fibroids in the United Kingdom and 600,000 in the United States (20Khan A.T. Shehmar M. Gupta J.K. Uterine fibroids: current perspectives.Int J Womens Health. 2014; 6: 95-114PubMed Google Scholar), resulting in a heavy economic burden (21Cardozo E.R. Clark A.D. Banks N.K. Henne M.B. Stegmann B.J. Segars J.H. The estimated annual cost of uterine leiomyomata in the United States.Am J Obstet Gynecol. 2012; 206: 211.e1-211.e9Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). Destruction techniques, by ultrasound or radiofrequency (22Trumm C.G. Stahl R. Clevert D.A. Herzog P. Mindjuk I. Kornprobst S. et al.Magnetic resonance imaging-guided focused ultrasound treatment of symptomatic uterine fibroids: impact of technology advancement on ablation volumes in 115 patients.Invest Radiol. 2013; 48: 359-365Crossref PubMed Scopus (6) Google Scholar), are under evaluation as complementary or associated techniques. Endometrial ablation, either by surgical or physical means, such as thermablation (23Hachmann-Nielsen E. Rudnicki M. Clinical outcome after hydrothermal ablation treatment of menorrhagia in patients with and without submucous myomas.J Minim Invasive Gynecol. 2012; 19: 212-216Abstract Full Text Full Text PDF PubMed Google Scholar), is an alternative option for women close to menopause who would like to avoid surgery (20Khan A.T. Shehmar M. Gupta J.K. Uterine fibroids: current perspectives.Int J Womens Health. 2014; 6: 95-114PubMed Google Scholar). However, the current trend is for uterine-sparing therapeutic strategies, mainly because the age of a first pregnancy is on the increase. Because myomectomy can be detrimental on pregnancy outcome (24Kim M.S. Uhm Y.K. Kim J.Y. Jee B.C. Kim Y.B. Obstetric outcomes after uterine myomectomy: laparoscopic versus laparotomic approach.Obstet Gynecol Sci. 2014; 56: 375-381Crossref Google Scholar), medical options are frequently offered as a first-line option. Medical therapy is also required before surgery in women with fibroid-related anemia to reduce postoperative morbidity (25Musallam K.M. Jamali F.R. Rosendaal F.R. Richards T. Spahn D.R. Khavandi K. et al.Preoperative hematocrit concentration and the risk of stroke in patients undergoing isolated coronary-artery bypass grafting.Anemia. 2013; 2013: 206829Crossref PubMed Scopus (2) Google Scholar) or to facilitate endometrial ablation techniques (26Tan Y.H. Lethaby A. Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding.Cochrane Database Syst Rev. 2013; : CD010241PubMed Google Scholar).Most medical treatments reduce bleeding. Modulators of estrogen signaling, such as aromatase inhibitors, and selective estrogen receptor modulators (SERMs) have been evaluated. Progestins are also used for this purpose but have limited efficacy and can induce tumor growth as discussed below. Finally GnRH analogues and selective progesterone receptor modulators (SPRMs) can be used to reduce both tumor volume and bleeding (Table 1).Table 1Fibroid treatment: hormone production and signalling modulators.Therapeutic classMoleculesTherapeutic effects in women with fibroidsMain adverse eventsStatusReference(s)ProgestinsDanazolBleeding controlFibroid growth87Ke L.Q. Yang K. Li J. Li C.M. Danazol for uterine fibroids.Cochrane Database Syst Rev. 2009; : CD007692PubMed Google ScholarDMPAWeight gain26Tan Y.H. Lethaby A. Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding.Cochrane Database Syst Rev. 2013; : CD010241PubMed Google Scholar, 149Kongnyuy E.J. Wiysonge C.S. Interventions to reduce haemorrhage during myomectomy for fibroids.Cochrane Database Syst Rev. 2009; : CD005355PubMed Google ScholarLNG-IUSExpulsionFDA approval88Sangkomkamhang U.S. Lumbiganon P. Laopaiboon M. Mol B.W. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids.Cochrane Database Syst Rev. 2013; : CD008994PubMed Google ScholarGnRH analoguesLeuprorelin acetateBleeding control, tumor volume reductionHot flushes, bone demineralizationFDA approval90Lethaby A. Vollenhoven B. Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids.Cochrane Database Syst Rev. 2001; : CD000547PubMed Google ScholarSPRMsMifepristoneRapid bleeding controlPAECsFDA approval150Eisinger S.H. Meldrum S. Fiscella K. le Roux H.D. Guzick D.S. Low-dose mifepristone for uterine leiomyomata.Obstet Gynecol. 2003; 101: 243-250Crossref PubMed Scopus (118) Google ScholarUlipristal acetateTumor volume control10Downes E. Sikirica V. Gilabert-Estelles J. Bolge S.C. Dodd S.L. Maroulis C. et al.The burden of uterine fibroids in five European countries.Eur J Obstet Gynecol Reprod Biol. 2010; 152: 96-102Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 75Donnez J. Tomaszewski J. Vazquez F. Bouchard P. Lemieszczuk B. Baro F. et al.Ulipristal acetate versus leuprolide acetate for uterine fibroids.N Engl J Med. 2012; 366: 421-432Crossref PubMed Scopus (80) Google Scholar, 121Donnez J. Vazquez F. Tomaszewski J. Nouri K. Bouchard P. Fauser B.C. et al.Long-term treatment of uterine fibroids with ulipristal acetate.Fertil Steril. 2014; 101: 1565-1573.e1–18Abstract Full Text Full Text PDF PubMed Scopus (2) Google ScholarAsoprisnilBleeding controlPhase IITelapristone acetateTumor volume controlAromatase inhibitorsTumor volume control; limited dataHot flushes, joint painPhase II102Song H. Lu D. Navaratnam K. Shi G. Aromatase inhibitors for uterine fibroids.Cochrane Database Syst Rev. 2013; : CD009505PubMed Google ScholarSERMsRaloxifeneQuestionable efficacyHot flushes, DVTPhase II100Deng L. Wu T. Chen X.Y. Xie L. Yang J. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas.Cochrane Database Syst Rev. 2012; : CD005287PubMed Google ScholarNote: DMPA = depot medroxyprogesterone acetate; DVT = deep vein thrombosis; LNG-IUS = levonorgestrel-delivering intrauterine system; PAECs = progesterone receptor modulator–associated endometrial changes; SERMs = selective estrogen receptor modulators; SPRMs = selective progesterone receptor modulators. Open table in a new tab Fibroid growthAlthough quite a lot is known about the factors contributing to fibroid growth, the pathophysiology of this disease remains largely unelucidated (1Bulun S.E. Uterine fibroids.N Engl J Med. 2013; 369: 1344-1355Crossref PubMed Scopus (3) Google Scholar, 5Segars J.H. Parrott E.C. Nagel J.D. Guo X.C. Gao X. Birnbaum L.S. et al.Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations.Hum Reprod Update. 2014; 20: 309-333Crossref PubMed Scopus (1) Google Scholar).HistologyFibroids are benign tumors developing in the myometrium (Fig. 2) and appear as a disordered organization of the myometrial cells forming spheres and nesting in abundant extracellular matrix (ECM) (9Islam M.S. Protic O. Giannubilo S.R. Toti P. Tranquilli A.L. Petraglia F. et al.Uterine leiomyoma: available medical treatments and new possible therapeutic options.J Clin Endocrinol Metab. 2013; 98: 921-934Crossref PubMed Scopus (19) Google Scholar, 27Malik M. Norian J. McCarthy-Keith D. Britten J. Catherino W.H. Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women.Semin Reprod Med. 2010; 28: 169-179Crossref PubMed Scopus (29) Google Scholar). This results in the classic surgical description of fibroids as firm tumors with a clear dissection plane and easy to enucleate.Figure 2Fibroid growth. CCR = complex chromosomal rearrangement; ECM = extracellular matrix; ER = estrogen receptor; PR = progesterone receptor.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Other histologic presentations have been described, such as cellular fibroids with scarce ECM component or bizarre fibroids with unusual, but nonsuspect, tissue organization. Numerous other forms have also been described (9Islam M.S. Protic O. Giannubilo S.R. Toti P. Tranquilli A.L. Petraglia F. et al.Uterine leiomyoma: available medical treatments and new possible therapeutic options.J Clin Endocrinol Metab. 2013; 98: 921-934Crossref PubMed Scopus (19) Google Scholar), including vascular fibroids, intravascular fibroids, and benign disseminating fibroids (leiomyomatosis) (28Awonuga A.O. Shavell V.I. Imudia A.N. Rotas M. Diamond M.P. Puscheck E.E. Pathogenesis of benign metastasizing leiomyoma: a review.Obstet Gynecol Surv. 2010; 65: 189-195Crossref PubMed Scopus (29) Google Scholar). These latter forms, though benign, can be life-threatening. Preoperative differential diagnosis with sarcoma is mostly based on the analysis of the tumor vascularization on Doppler-coupled ultrasound scan and magnetic resonance imaging (29Yoshida Y. Kiyono Y. Tsujikawa T. Kurokawa T. Okazawa H. Kotsuji F. Additional value of 16alpha-[18F]fluoro-17beta-oestradiol PET for differential diagnosis between uterine sarcoma and leiomyoma in patients with positive or equivocal findings on [18F]fluorodeoxyglucose PET.Eur J Nucl Med Mol Imaging. 2011; 38: 1824-1831Crossref PubMed Scopus (12) Google Scholar). This differential diagnosis is important, especially in the case of a nonsurgical therapeutic option, even though sarcomas are extremely rare, occurring in ∼10 out of 1 million women every year (30Cancer Research UK. Soft tissue sarcoma incidence statistics. In, 2013.Google Scholar).Stem cells may be involved in fibroid growth. Specific myometrial cellular subpopulations exhibiting myometrial stem cell characteristics have been identified (31Ono M. Maruyama T. Masuda H. Kajitani T. Nagashima T. Arase T. et al.Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells.Proc Natl Acad Sci U S A. 2007; 104: 18700-18705Crossref PubMed Scopus (70) Google Scholar) and found to be necessary for fibroid growth in an animal model (32Ono M. Qiang W. Serna V.A. Yin P. Coon J.S. Navarro A. et al.Role of stem cells in human uterine leiomyoma growth.PLoS One. 2012; 7: e36935Crossref PubMed Scopus (16) Google Scholar). These cells appear to be pluripotent and may be tumor initiating (33Mas A. Cervello I. Gil-Sanchis C. Faus A. Ferro J. Pellicer A. et al.Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells.Fertil Steril. 2012; 98: 741-751.e6Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). One single stem cell is thought to give birth to a specific fibroid (which is why it is called a clonal disease) (3Holdsworth-Carson S.J. Zaitseva M. Vollenhoven B.J. Rogers P.A. Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues.Mol Hum Reprod. 2014; 20: 250-259Crossref PubMed Scopus (2) Google Scholar, 4Linder D. Gartler S.M. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas.Science. 1965; 150: 67-69Crossref PubMed Google Scholar). Stem cells present in fibroids, compared with stem cells in normal myometrium, carry mutations of the MED12 (mediator complex subunit 12) gene located on the X chromosome (32Ono M. Qiang W. Serna V.A. Yin P. Coon J.S. Navarro A. et al.Role of stem cells in human uterine leiomyoma growth.PLoS One. 2012; 7: e36935Crossref PubMed Scopus (16) Google Scholar). This suggests a primary role of genetic events in the stem cells to allow tumor growth. MED12 is one of the components involved in the control of transcription initiation in association with the preinitiation complex (34Makinen N. Heinonen H.R. Sjoberg J. Taipale J. Vahteristo P. Aaltonen L.A. Mutation analysis of components of the mediator kinase module in MED12 mutation–negative uterine leiomyomas.Br J Cancer. 2014; 110: 2246-2249Crossref PubMed Google Scholar).Finally, the role of the ECM in fibroid growth, as part of the tumor microenvironment, is also thought to be very important. As previously described, an increase in tumor volume can be related to cell proliferation (cellular fibroids, bizarre fibroids) or ECM accumulation (usual fibroids). ECM in fibroids is abnormal in structure and physical properties (35Rogers R. Norian J. Malik M. Christman G. Abu-Asab M. Chen F. et al.Mechanical homeostasis is altered in uterine leiomyoma.Am J Obstet Gynecol. 2008; 198: 474.e1-474.e11Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar) compared with the normal myometrial ECM. Previous nonhuman animal models have shown discrepancies between human and nonhuman pathophysiology, because tumors in other animals do not include excess ECM (5Segars J.H. Parrott E.C. Nagel J.D. Guo X.C. Gao X. Birnbaum L.S. et al.Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations.Hum Reprod Update. 2014; 20: 309-333Crossref PubMed Scopus (1) Google Scholar). Important discrepancies have also been observed between cellular models of fibroids, without ECM, and in vivo experiments. The role of ECM has been confirmed in a recently developed model of human fibroid xenograft in immunodeficient mice (36Ishikawa H. Ishi K. Serna V.A. Kakazu R. Bulun S.E. Kurita T. Progesterone is essential for maintenance and growth of uterine leiomyoma.Endocrinology. 2010; 151: 2433-2442Crossref PubMed Scopus (46) Google Scholar). Tumor growth control by sex steroids in a paracrine system of regulation has also been described (37Kim J.J. Kurita T. Bulun S.E. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer.Endocr Rev. 2013; 34: 130-162Crossref PubMed Scopus (22) Google Scholar). Estradiol appears to be necessary to allow the progesterone stimulatory action on fibroid growth as discussed below. In addition, E2 and P action seems to be necessary for the production of ECM components, such as collagen types I and II. In fact collagen fibers are overexpressed in the follicular phase of the cycle (38Stewart E.A. Friedman A.J. Peck K. Nowak R.A. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle.J Clin Endocrinol Metab. 1994; 79: 900-906Crossref PubMed Scopus (78) Google Scholar) and the P receptor antagonist asoprisnil down-regulates collagen fiber synthesis in an in vitro model (39Morikawa A. Ohara N. Xu Q. Nakabayashi K. DeManno D.A. Chwalisz K. et al.Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.Hum Reprod. 2008; 23: 944-951Crossref PubMed Scopus (27) Google Scholar).GeneticsApart from the very rare syndromic fibroids associated with aggressive renal cancer in individuals with fumarate hydratase (FH) gene mutations on chromosome 1 (40Alam N.A. Olpin S. Leigh I.M. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer.Br J Dermatol. 2005; 153: 11-17Crossref PubMed Scopus (61) Google Scholar), the genetic component of fibroids remains speculative. Studies into somatic genetic alterations revealed that 50% of fibroids have chromosomal abnormalities. Genetic alterations have been described in 12 out of 26 chromosomes, and nine main candidate genes have been identified: MED12, HMGA2, HMGA1, FH, BHD, TSC2, PCOLCE, ORC5L, and LHFPL3 (1Bulun S.E. Uterine fibroids.N Engl J Med. 2013; 369: 1344-1355Crossref PubMed Scopus (3) Google Scholar, 9Islam M.S. Protic O. Giannubilo S.R. Toti P. Tranquilli A.L. Petraglia F. et al.Uterine leiomyoma: available medical treatments and new possible therapeutic options.J Clin Endocrinol Metab. 2013; 98: 921-934Crossref PubMed Scopus (19) Google Scholar).In addition to somatic gene alterations, epigenetic mechanisms also may be involved independently from specific modifications of the DNA sequence. Differences in DNA methylation, involved in gene transcription repression, have been described in fibroids compared with the normal surrounding myometrium (41Navarro A. Yin P. Monsivais D. Lin S.M. Du P. Wei J.J. et al.Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma.PLoS One. 2012; 7: e33284Crossref PubMed Scopus (15) Google Scholar). Most of these DNA methylation modifications occur in the promoter region of the involved genes, including a number of tumor repressors, such as KLF11, a P receptor target gene. These modifications result in silencing the corresponding genes in fibroids, therefore promoting tumor growth.Other epigenetic modifications may include histone modifications, which modulate gene transcription, and micro-RNAs which modulate protein production downstream of gene transcription. Data on histone modifications are extremely limited to date (42Greathouse K.L. Bredfeldt T. Everitt J.I. Lin K. Berry T. Kannan K. et al.Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis.Mol Cancer Res. 2012; 10: 546-557Crossref PubMed Scopus (11) Google Scholar). Data regarding microRNA (43Marsh E.E. Lin Z. Yin P. Milad M. Chakravarti D. Bulun S.E. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium.Fertil Steril. 2008; 89: 1771-1776Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 44Georgieva B. Milev I. Minkov I. Dimitrova I. Bradford A.P. Baev V. Characterization of the uterine leiomyoma microRNAome by deep sequencing.Genomics. 2012; 99: 275-281Crossref PubMed Scopus (10) Google Scholar) show that several microRNAs are deregulated in fibroids, as well as their target genes.More recently, a whole-genome sequencing study of fibroids from 30 patients (45Mehine M. Kaasinen E. Makinen N. Katainen R. Kampjarvi K. Pitkanen E. et al.Characterization of uterine leiomyomas by whole-genome sequencing.N Engl J Med. 2013; 369: 43-53Crossref PubMed Scopus (17) Google Scholar) has provided complementary information. It was shown that identical variants may be identified in different nodules—up to five different nodules from the same patient—suggesting a common cellular origin. Single mutations have been observed mostly in MED12 and FH genes. Modifications at chromosome 7q locus were frequent, particularly the COL4A5–COL4A6 locus, as well as modifications of the HMGA2 locus on chromosome 12 and RAD51B on chromosome 14. Complex chromosomal rearrangements (CCRs) in fibroids were also observed, sharing common features with chromothripsis, a single-genomic event that results in focal losses and rearrangements in multiple genomic regions. This leads to cell death and apoptosis, but is also involved in carcinogenesis. In fibroids, chromothripsis-like events appear to lead to benign tumor development. None of the samples studied carried TP53 mutations, confirming benignity. CCRs are most probably due to multiple chromosomal breaks and random reassembly, and they promote tumor growth.Risk Factors for FibroidsThe epidemiology of fibroids suggests two distinct patterns depending on ethnic background (46Sweet S. Legro R.S. Coney P. A comparison o" @default.
• W2019909182 created "2016-06-24" @default.
• W2019909182 creator A5009040983 @default.
• W2019909182 creator A5050225719 @default.
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• W2019909182 date "2014-09-01" @default.
• W2019909182 modified "2023-10-14" @default.
• W2019909182 title "Fibroid growth and medical options for treatment" @default.
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