Uterine fibroids – what’s new?

Uterine fibroids – what’s new? | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/6-2109" }, "headline": "Uterine fibroids – what’s new?", "datePublished": "2017-12-07T16:34:56", "dateModified": "2017-12-07T16:34:56", "author": [ { "@type": "Person", "name": "Alistair R.W. Williams" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "Uterine fibroids are the commonest benign tumours of women and affect all races with a cumulative lifetime risk of around 70%. Despite their high prevalence and the heavy economic burden of treatment, fibroids have received remarkably little attention compared to common female malignant tumours. This article reviews recent progress in understanding the biological nature of fibroids, their life cycle and their molecular genetic origins. Recent progress in surgical and interventional management is briefly reviewed, and medical management options, including treatment with selective progesterone receptor modulators, are also discussed." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/6-2109", "name": "Uterine fibroids – what’s new?" } } ] } Home Browse Uterine fibroids – what’s new? ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Williams ARW. Uterine fibroids – what’s new? [version 1; peer review: 3 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):2109 ( https://doi.org/10.12688/f1000research.12172.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Uterine fibroids – what’s new? [version 1; peer review: 3 approved] Alistair R.W. Williams https://orcid.org/0000-0002-7085-4525 Alistair R.W. Williams https://orcid.org/0000-0002-7085-4525 PUBLISHED 07 Dec 2017 Author details Author details Department of Pathology, Royal Infirmary of Edinburgh, University of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK Alistair R.W. Williams Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Uterine fibroids are the commonest benign tumours of women and affect all races with a cumulative lifetime risk of around 70%. Despite their high prevalence and the heavy economic burden of treatment, fibroids have received remarkably little attention compared to common female malignant tumours. This article reviews recent progress in understanding the biological nature of fibroids, their life cycle and their molecular genetic origins. Recent progress in surgical and interventional management is briefly reviewed, and medical management options, including treatment with selective progesterone receptor modulators, are also discussed. READ ALL READ LESS Keywords uterine fibroids, leiomyomas, molecular, life cycle, management Corresponding Author(s) Alistair R.W. Williams ( [email protected] ) Close Corresponding author: Alistair R.W. Williams Competing interests: The author has current consultancies with Bayer, PregLem, Gedeon Richter and HRA Pharma. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2017 Williams ARW. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Williams ARW. Uterine fibroids – what’s new? [version 1; peer review: 3 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):2109 ( https://doi.org/10.12688/f1000research.12172.1 ) First published: 07 Dec 2017, 6 (F1000 Faculty Rev):2109 ( https://doi.org/10.12688/f1000research.12172.1 ) Latest published: 07 Dec 2017, 6 (F1000 Faculty Rev):2109 ( https://doi.org/10.12688/f1000research.12172.1 ) Introduction Uterine fibroids (leiomyomas) are benign monoclonal tumours of smooth muscle, taking origin in the myometrium. They are the commonest benign tumours of the uterus, and are typically round well-circumscribed masses. They are usually multiple, and can range in size from a few millimetres to massive growths of 20cm diameter and more. The aetiology is largely unknown, but they are oestrogen- and progesterone-dependent tumours, very rare before menarche, common in reproductive life, and frequently regress in size after menopause 1 . By age 50, it is estimated that 70% of women will have one or more uterine fibroids, with around 30% of patients symptomatic and requesting treatment. Women of all races are affected, but fibroids are commoner, and develop at an earlier age, in women of African origin 2 . By age 35 years, 60% of African-American women will have fibroids, compared to 40% in Caucasian women of the same age. Other risk factors include age (increasing incidence with age up to the menopause, then usually decreasing in size), nulliparity, genetic factors, early menarche, caffeine, alcohol, obesity and hypertension 3 . Symptoms of fibroids are abnormal uterine bleeding, pelvic pain, dyspareunia, obstructive effects on bladder or rectum, and infertility. Fibroid size does not necessarily determine the severity of clinical symptoms. In a large online survey conducted in eight countries with at least 2,500 participants in each country (4000 in USA), 59.8% of women with a diagnosis of uterine fibroids self-reported heavy and prolonged vaginal bleeding compared to 37.4% in those without fibroids 4 . Pelvic pain at various times in the menstrual cycle and during sexual intercourse were also significantly increased in fibroid patients. Excessive vaginal blood loss can lead to severe anaemia which can even be life-threatening, yet some patients do not recognise the severity of the problem, may consider their blood loss to be normal, and do not seek help 5 . Uterine fibroids place a large economic burden both on the women who suffer from them, and on the health systems and societies in which they live. Symptoms may lead to significant loss of working time, and in a large survey 24% of women perceived symptoms as a contributing factor in failure to achieve career aspirations 6 . Direct surgical costs alone are high – in the USA, 200,000 hysterectomies are performed annually for fibroids 7 , and when medications, inpatient and outpatient hospital attendances are added, the annual costs are estimated at between 4–9 billion US dollars 8 . These costs do not include lost work time, and other consequences such as spontaneous abortions, pre-term delivery and Caesarean sections. Imaging techniques are the mainstay of diagnosis, with transabdominal or transvaginal ultrasound the most commonly used modality, as it is widely available, inexpensive and usually definitive in diagnosis. MRI may be used to delineate the number, size and location of fibroids in certain cases, and hysteroscopy may be useful to distinguish between subendometrial fibroids and large endometrial polyps. Neither imaging nor hysteroscopic methods are currently reliable in distinguishing benign fibroids from sarcomatous uterine tumours. Surgical treatment takes the form of hysterectomy or myomectomy, the choice depending on the size, number and extent of fibroids, and on the patient’s wishes with regard to fertility. Hysteroscopic or laparoscopic myomectomy are considered safe and effective options, but laparoscopic hysterectomy is usually still the standard surgical option in women who do not wish to retain fertility 3 . It should be noted, however, that hysterectomy is not free from short term and long term sequelae – 1 in 30 women suffers a major adverse event, and mortality may be between 0.4-1.1 per 1000 operations 9 . Non-surgical interventional treatments also include uterine artery embolization (UAE), and high-frequency MR-guided focussed ultrasound surgery. Until recently, medical management of fibroids was largely confined to symptomatic treatment of pain and bleeding, and the use of gonadotropin-releasing hormone (GnRH) analogues. The latter lead to a hypo-oestrogenic state, fibroids undergo shrinkage, and blood loss and anaemia can be corrected, but duration of treatment is limited by side effects of menopausal symptoms and loss of bone mineral density. More recently, a newer group of agents, the selective progesterone receptor modulators (SPRMs), have shown considerable effectiveness in the medical management of fibroid patients 10 . As well as their effects on fibroid shrinkage, in most patients SPRM treatment leads to rapid control of heavy menstrual bleeding, and correction of anaemia. Oestrogen levels remain at around mid-follicular levels, and, as a consequence, menopausal symptoms and bone loss are not encountered regularly. Histopathology Fibroids are correctly known as leiomyomas, being benign tumours of smooth muscle, taking origin in the myometrium. As the fibroid grows, the cells differentiate into four different cell types that can be reliably characterised: smooth muscle cells, vascular smooth muscle cells and two different subpopulations of fibroblasts. It has been shown that all four cell types derive from a single clonal origin 11 . Macroscopically, the lesions are usually multiple, pale, firm and rubbery, with a whorled cut surface, well demarcated from adjacent myometrium. There may be areas of mucoid change, haemorrhage, or necrosis and calcification visible on gross inspection. Microscopically, they are composed of spindle cells arranged in fascicles that interweave to form a circumscribed lesion. Mitotic activity may be observed, but there are usually less than 5 mitoses per 10 high power fields (HPF), and no atypical forms. Mitotic activity is significantly higher in the secretory phase of the cycle 12 , an observation that suggests importance of progesterone and its receptor PR in fibroid growth. There is a great degree of variability in the amount of extracellular matrix and collagen in fibroids, leading to considerable heterogeneity in histological patterns. Degenerative changes may be superimposed, including hyaline and myxoid change, hydropic degeneration, necrosis and calcification. Notwithstanding this variability in the usual type of leiomyoma, there are several distinct histological variants that may cause some diagnostic difficulty to the histopathologist. Cellular leiomyoma is significantly more cellular than the usual type, but shows no nuclear atypia, a low mitotic index (4 or less mitoses per 10 HPF), and no necrosis. Leiomyoma with bizarre nuclei (previously termed atypical or symplastic leiomyoma) characteristically shows highly pleomorphic extremely bizarre nuclei, often in a background of more typical leiomyoma cells. Mitotic activity is usually low, but karyorrhexis may mimic atypical mitoses, and the histopathologist must be cautious not to diagnose sarcoma, as these are benign lesions. Mitotically active leiomyoma shows a high mitotic index (>10 mitoses per 10 HPF), but no other concerning features, with an absence of nuclear atypia and necrosis. These are likely endocrine related, as they are seen in the reproductive age group, and have been reportedly associated with hormone therapy. Dissecting (‘cotyledenoid’) leiomyoma is a rare variant which shows locally invasive growth sometimes extending outwith the uterus, often with a prominent degree of hydropic change. Diffuse leiomyomatosis is a rare condition in which multitudes of benign-appearing leiomyomatous nodules blend with uterine smooth muscle, and may extend beyond the uterus into the peritoneal cavity forming tumour-like nodules, grossly resembling disseminated gynaecological cancers. The process is benign, and surgical removal is curative. An uncommon but troublesome group of tumours show histological appearances that may arouse concern about possible leiomyosarcoma, but which fall short of definitively malignant lesions. Described as atypical smooth muscle neoplasms , or smooth muscle tumours of uncertain malignant potential (STUMP), such lesions show an intermediate level of mitotic activity (5 – 10 mitoses per 10 HPF), variable necrosis or myxoid change, and a degree of nuclear atypia, sometimes with epithelioid cell morphology. The prognosis of such tumours is unpredictable, but recurrence occurs in approximately 10 – 15% of cases. A promising approach to prediction of outcome in such lesions has recently been described 13 in which comparative genomic hybridisation was used to clearly stratify a series of uterine STUMP into two separate prognostic groups: one with prognosis similar to leiomyoma, the other with outcome similar to low grade leiomyosarcoma. Leiomyosarcoma is a frankly malignant neoplasm of smooth muscle origin. Whilst most appear to occur de novo from myometrium, there is evidence that up to 20 – 30% may arise from pre-existing benign smooth muscle tumours (see below). This must be a rare event, considering how common benign fibroids are and the rarity of leiomyosarcoma. Life Cycle of Fibroids A careful morphological review 14 led to the hypothesis that fibroid formation may represent an abnormal response to injury. This proposes that normal myometrium may be subject to repeated injury through vasoconstriction and hypoxia during menstruation, and that development of fibroids may represent a reaction to that injury. There are intriguing parallels with processes of wound healing, keloid formation and even the reaction to injury occurring in blood vessels in the formation of atherosclerosis. Additional evidence from Ciarmela’s group 15 suggests the action of an inflammatory trigger to excessive production of extracellular matrix by activated myofibroblastic cells in fibroids. Uterine fibroids have a self-limited life cycle of proliferative growth, synthesis of collagen, increasing deposition of extracellular matrix, decreasing vascularity, and ultimately senescence and involution through ischaemic degeneration and inanition 14 . Four phases in the life cycle of fibroids have been described, defined somewhat arbitrarily and representing a continuous process, progressing through phenotypic transformation of the proliferating contractile myocyte and evolutionary selection of a single clone. There is increasing deposition of collagen, and as the process of fibroid growth and development evolves, the phenotype of the clonally proliferating myocytes changes from contractile to collagen synthesising, with significant elaboration of extracellular ground substance. Myocytes become separated from vessels by increased amounts of extracellular matrix, and angiogenesis does not keep up with the increasing size of the fibroid. Ischaemia eventually occurs, and there is cessation of myocyte proliferation and cellular atrophy. In the end stage, there is abundant hyaline matrix enclosing islands of atrophic myocytes, and there may be necrosis and calcification. Processes of cell death, resorption and reclamation now occur, termed ‘inanosis’ by the authors. These differ from necrosis and apoptosis in their morphology, in their long, protracted durations, and in the absence of any inflammatory or phagocytic response to cell death. Genetic and Molecular Aspects of Aetiology Several lines of evidence point to a significant genetic predisposition to development of uterine fibroids. Women with first degree relatives having fibroids have an increased incidence 16 , and monozygotic twins have higher concordance for fibroids than dizygotic 17 . Up to around 50% of uterine leiomyomas show cytogenetic alterations, including trisomy of chromosome 12, deletions in the long arm of chromosome 7, rearrangements of 12q15 and mutations in MED12 and HMGA2 genes. There is evidence for the existence of a population of cells with stem or progenitor cell characteristics, which can be isolated from normal myometrium and from leiomyoma tissues 18 . It is hypothesised that activating mutations occurring in this cell type give rise to the clonal population of myocytes making up the leiomyoma. Intriguingly, a recent study using whole genome sequencing of uterine leiomyomas showed that multiple fibroid nodules within the uterus can be clonally related, indicating a single cell origin of multiple leiomyomas 19 . This study also reported the occurrence in fibroids of complex chromosomal rearrangements resembling chromothripsis, apparently occurring as a single chromosomal shattering event with up to 20 or more double-stranded breaks, followed by random reassembly. The authors suggest that tumour formation occurs when reassembly leads to the juxtaposition and activation of tumour-promoting genes. Epigenetic mechanisms are also likely to have a key role in fibroid formation. Several tumour suppressor genes have been shown to be abnormally hypermethylated in fibroids compared to adjacent myometrium 20 , as are collagen-related genes and a subset of ER response genes 21 . MED12 Exome sequencing a small series of leiomyoma tissues identified a high frequency of somatic mutations in MED12 (also known as mediator complex subunit 12) gene 22 , and a subsequent larger survey of 225 fibroids from 80 patients identified MED12 mutations in 70% 23 , making MED12 the most frequently altered gene in leiomyomas. MED12 is an X-linked gene that encodes a subunit of the mediator complex that is central to regulation of transcription, and is a crucial element in canonical WNT signalling, known to interact with β-catenin. Most mutations occur in a highly conserved area of exon 2 of the gene, with around 50% occurring as mis-sense mutations of codon 44, and it has been suggested that these may represent ‘gain of function’ alleles 24 . Less frequently, mutations occur at the intron 1/exon 2 boundary, and even more rarely in exon 1, respectively. There is an inverse correlation between presence of MED12 mutation and leiomyoma size, suggesting that lesions of differing sizes may have different aetiological pathways. MED12 mutations seem relatively specific for leiomyoma, and also occur in around 10 – 20% of leiomyosarcomas 25 , 26 . However, the same type of mutation has also been found in chronic lymphocytic leukaemia 27 , and malignant phyllodes tumour of the breast 28 . HMGA2 Cytogenetically visible alterations in 12q14-15 and 6p21 have been observed in leiomyomas, and rearrangements at these loci map to genes encoding high mobility group proteins HMGA2 and HMGA1, respectively, leading to their overexpression. Overexpression of HMGA2 was found to be the second most frequent genetic alteration in leiomyomas, being present in 7.5–10% 26 . Overexpression was exclusively found in leiomyomas that did not have mutation of MED12 , indicating the likelihood of two separate and mutually exclusive pathways of fibroid development 29 . Each group has differing global gene expression profiles, and further evidence indicates that leiomyomas with alterations of MED12 and HMGA2 show different behaviours. In a study of 289 fibroids from 120 patients, it was found that over 85% of MED12 mutated lesions occurred as multiple uterine nodules, whereas 70% of HMGA2 mutated lesions were single nodules 30 . Rarely, uterine leiomyomas may be part of the hereditary leiomyomatosis and renal cell cancer syndrome caused by heterozygous germline mutations in the fumarate hydratase ( FH ) gene. The disorder has an autosomal dominant pattern of inheritance, and is clinically characterised by the occurrence of multiple (10 to over 100) cutaneous leiomyomas, often painful, occurring in a segmental pattern on trunk and extremities. Leiomyomas in this syndrome present a unique global gene expression profile, without overlap with those associated with MED12 or HMGA2 mutations 23 . Advances in surgical and interventional management of fibroids For many years, hysterectomy has been the treatment of choice for uterine fibroids, and is still the most commonly used treatment. Laparoscopic hysterectomy rates may exceed 90% in some departments, but other surgical and interventional treatments are increasingly available 3 . The treatment selected often depends on the patient’s age, her willingness to undergo what is perceived to be a major surgical procedure, and her desires for future fertility or complete amenorrhoea. Guidelines exist in the literature, but there are few clinical trials comparing different treatments. Hysteroscopic myomectomy is suitable for fibroids of certain sizes and locations, being most suited to smaller pedunculated submucous lesions which can be removed by transection of the base with a resectoscopic loop. Some smaller intramural fibroids may be removed hysteroscopically in one- or two-step procedures that involve slicing the lesion into chips, or use of an intrauterine morcellator. Laparoscopic myomectomy is technically more challenging than open laparotomy, but reproductive outcomes are similar, post-operative morbidity is much less and recovery times much shorter. Fibroids are usually removed with the aid of a power morcellator. Morcellation has the drawback of potential peritoneal dissemination of unrecognised uterine sarcoma, and although the risk may have been overemphasised, it remains a theoretical concern. While recognising the difficulty of histopathological diagnosis in specimens obtained after power morcellation, a large series of 10,731 laparoscopic hysterectomies 31 found the incidence of malignancy in morcellated surgical specimens to be 0.06% (six cases). Non-surgical interventional treatments include UAE, an effective and safe alternative to hysterectomy in women in whom retention of fertility is not a priority, although there is little evidence of any poorer fertility outcome with UAE compared to myomectomy 32 . Although this treatment has similar outcomes to surgery in terms of patient satisfaction, risk of major complications and fertility outcome, there is a higher rate of minor complications and subsequent surgical intervention within two to five years, with between 15 and 32% of women requiring further surgery 33 . High frequency magnetic resonance guided focussed ultrasound is a technique whereby ultrasonic energy is directed with MR guidance to within the fibroid, where thermal ablation by coagulative tissue necrosis occurs. The method is not yet widely used, as it is currently expensive, is suitable for only a minority of fibroid patients, and has unknown implications for future fertility 34 . Medical management of fibroids First line management of uterine fibroids usually involves symptomatic treatment of heavy menstrual bleeding, with use of inexpensive non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytic agents including tranexamic acid, or contraceptive steroids including the levonorgestrel intrauterine system (Mirena), the latter only suitable for patients in whom the uterine cavity is not distorted by fibroids 35 . Although bleeding symptoms may be alleviated, there is no evidence of fibroid shrinkage, indeed there is reason to believe that progestogen therapy may induce proliferation of leiomyoma cells. Shrinkage of fibroids can, however, be achieved by treatment with GnRH agonists, or with SPRMs. Continuous administration of a GnRH agonist leads to downregulation of pituitary GnRH receptors, with consequent decreased production of FSH and LH, and subsequently of ovarian steroids. Treatment for three to six months has been shown to result in decreased uterine and fibroid size, and duration of hospital stay after surgery 36 . However, the hypo-oestrogenic state induced by GnRH agonist treatment results in menopausal side effects, including loss of bone mineral density, that limit treatment duration usually to six months or less. While there is some evidence that add-back therapy can offer some advantages in these situations 37 , unwanted side effects of therapy with GnRH analogues remain a problem. It has also been observed that rapid regrowth of fibroids occurs after cessation of GnRH treatment. Selective progesterone receptor modulators in management The advent of SPRMs has opened a new and promising avenue of treatment for many patients. The effectiveness of these agents is based on the premise that fibroids show progesterone dependence, and blockade or modulation of progesterone activity at PR results in cessation of proliferation and induction of apoptosis in the fibroid, with consequent shrinkage. SPRMs also rapidly induce amenorrhoea in most patients, providing additional welcome symptomatic relief of bleeding. The mechanism whereby amenorrhoea is induced remains unknown, but it is believed to be a direct effect on the endometrium. Clinical trials of SPRMs in treatment of fibroids have been carried out using a variety of agents, including mifepristone 38 , telapristone acetate 39 , asoprisnil 40 , ulipristal acetate 41 , and vilaprisan 42 . SPRMs induce characteristic morphological changes in endometrium that have not been observed with other pharmaceutical agents, and have been designated PAEC (progesterone receptor modulator-associated endometrial changes 43 ). Uninterrupted treatment with SPRMs for six months or more induces endometrial thickening, and to avoid associated complications, successful clinical trials have utilised an interrupted regime of three months on treatment followed by one month off, with menstrual shedding of the endometrium. In 2012, following large Phase III clinical trials, ulipristal acetate was the first SPRM to be granted a licence from the European Medicines Agency for use in the pre-surgical treatment of fibroids, and it is now being used in many countries worldwide. Early Phase III trials showed that one course of 5 mg ulipristal acetate orally for 12 weeks led to a mean 20–35% reduction in fibroid volume, and that the reduction in volume was maintained for up to 6 months following end of treatment 10 , 41 . Treatment was also associated with rapid control of uterine bleeding in over 80% of patients. Subsequent trials showed that further fibroid shrinkage occurred with repeated courses, with median reduction in fibroid volume of 71.8% after 4 courses 44 . Histopathological assessment of fibroids resected after ulipristal acetate treatment has shown induction of apoptosis and remodelling of extracellular matrix in the lesions 45 . Subsequent studies established endometrial safety of up to eight courses, using a repeated interrupted regime of three months treatment followed by one month off treatment with menstrual shedding 46 . As oestrogen levels are not suppressed on treatment, menopausal symptoms and bone mineral loss are not significant clinical issues. Ulipristal acetate is now licensed for repeated 12 week courses, but must be prescribed with a one month break between courses, to avoid adverse endometrial effects. A retrospective analysis of 21 patients who enrolled in two of the clinical trials of ulipristal acetate, who had myomectomies and wished pregnancy after treatment, reported successful pregnancies in 15 patients (71%), with birth of 13 healthy babies and 6 early miscarriages 47 . What Does the Future Hold? After many years of relative neglect, the pathogenesis of uterine fibroids is now receiving more attention, and we are beginning to gain a foothold in understanding the molecular genesis of these very common and troublesome tumours. These are the first necessary steps in the journey towards effective non-surgical treatment and perhaps even prevention. Excellent progress has been made in the laparoscopic surgical treatment of fibroids and this will continue, perhaps with robotic and other developments. However, the long-term goal must be to develop effective medical treatments, and the advent of SPRMs opens up the prospect of safe therapy without the troublesome side effects of previous medical treatments, with the potential to greatly improve the quality of life of huge numbers of women around the world. Competing interests The author has current consultancies with Bayer, PregLem, Gedeon Richter and HRA Pharma. Grant information The author(s) declared that no grants were involved in supporting this work. F1000 recommended References 1. Cramer SF, Patel A: The frequency of uterine leiomyomas. Am J Clin Pathol. 1990; 94 (4): 435–8. PubMed Abstract | Publisher Full Text 2. Baird DD, Dunson DB, Hill MC, et al. : High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003; 188 (1): 100–7. PubMed Abstract | Publisher Full Text | F1000 Recommendation 3. Donnez J, Dolmans M: Uterine fibroid management: from the present to the future. Hum Reprod Update. 2016; 22 (6): 665–86. PubMed Abstract | Publisher Full Text 4. Zimmermann A, Bernuit D, Gerlinger C, et al. : Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health. 2012; 12 : 6. PubMed Abstract | Publisher Full Text | Free Full Text 5. Nelson AL, Ritchie JJ: Severe anemia from heavy menstrual bleeding requires heightened attention. Am J Obstet Gynecol. 2015; 213 (1): 97.e1–6. PubMed Abstract | Publisher Full Text | F1000 Recommendation 6. Borah BJ, Nicholson WK, Bradley L, et al. : The impact of uterine leiomyomas: a national survey of affected women. Am J Obstet Gynecol. 2013; 209 (4): 319.e1–319.e20. PubMed Abstract | Publisher Full Text | Free Full Text 7. Farquhar CM, Steiner CA: Hysterectomy rates in the United States 1990–1997. Obstet Gynecol. 2002; 99 (2): 229–34. PubMed Abstract | Publisher Full Text 8. Cardozo ER, Clark AD, Banks NK, et al. : The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012; 206 (3): 211.e1–9. PubMed Abstract | Publisher Full Text | Free Full Text 9. Lethaby A, Shepperd S, Cooke I, et al. : Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000; (2): CD000329. PubMed Abstract | Publisher Full Text 10. Donnez J, Tomaszewski J, Vázquez F, et al. : Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012; 366 (5): 421–32. PubMed Abstract | Publisher Full Text | F1000 Recommendation 11. Holdsworth-Carson SJ, Zaitseva M, Vollenhoven BJ, et al. : Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues. Mol Hum Reprod. 2014; 20 (3): 250–9. PubMed Abstract | Publisher Full Text | F1000 Recommendation 12. Kawaguchi K, Fujii S, Konishi I, et al. : Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol. 1989; 160 (3): 637–41. PubMed Abstract | Publisher Full Text 13. Croce S, Ribeiro A, Brulard C, et al. : Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions. Mod Pathol. 2015; 28 (7): 1001–10. PubMed Abstract | Publisher Full Text | F1000 Recommendation 14. Flake GP, Moore AB, Sutton D, et al. : The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation. Obstet Gynecol Int. 2013; 2013 : 528376. PubMed Abstract | Publisher Full Text | Free Full Text 15. Protic O, Toti P, Islam MS, et al. : Possible involvement of inflammatory/reparative processes in the development of uterine fibroids. Cell Tissue Res. 2016; 364 (2): 415–27. PubMed Abstract | Publisher Full Text | F1000 Recommendation 16. Vikhlyaeva EM, Khodzhaeva ZS, Fantschenko ND: Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet. 1995; 51 (2): 127–31. PubMed Abstract | Publisher Full Text 17. Treloar SA, Martin NG, Dennerstein L, et al. : Pathways to hysterectomy: insights from longitudinal twin research. Am J Obstet Gynecol. 1992; 167 (1): 82–8. PubMed Abstract | Publisher Full Text 18. Ono M, Maruyama T, Masuda H, 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 (47): 18700–5. PubMed Abstract | Publisher Full Text | Free Full Text 19. Mehine M, Kaasinen E, Mäkinen N, et al. : Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med. 2013; 369 (1): 43–53. PubMed Abstract | Publisher Full Text | F1000 Recommendation 20. Navarro A, Yin P, Monsivais D, et al. : Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One. 2012; 7 (3): e33284. PubMed Abstract | Publisher Full Text | Free Full Text 21. Maekawa R, Sato S, Yamagata Y, et al. : Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. PLoS One. 2013; 8 (6): e66632. PubMed Abstract | Publisher Full Text | Free Full Text 22. Mäkinen N, Mehine M, Tolvanen J, et al. : MED12 , the mediator complex subunit 12 gene , is mutated at high frequency in uterine leiomyomas. Science. 2011; 334 (6053): 252–5. PubMed Abstract | Publisher Full Text | F1000 Recommendation 23. Mäkinen N, Kämpjärvi K, Frizzell N, et al. : Characterization of MED12 , HMGA2 , and FH alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer. 2017; 16 (1): 101. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 24. Commandeur AE, Styer AK, Teixeira JM: Epidemiological and genetic clues for molecular mechanisms involved in uterine leiomyoma development and growth. Hum Reprod Update. 2015; 21 (5): 593–615. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 25. Ravegnini G, Mariño-Enriquez A, Slater J, et al. : MED12 mutations in leiomyosarcoma and extrauterine leiomyoma. Mod Pathol. 2013; 26 (5): 743–9. PubMed Abstract | Publisher Full Text 26. Bertsch E, Qiang W, Zhang Q, et al. : MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol. 2014; 27 (8): 1144–53. PubMed Abstract | Publisher Full Text | Free Full Text 27. Kämpjärvi K, Järvinen TM, Heikkinen T, et al. : Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia. Oncotarget. 2015; 6 (3): 1884–8. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 28. Cani AK, Hovelson DH, McDaniel AS, et al. : Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors. Mol Cancer Res. 2015; 13 (4): 613–9. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 29. Markowski DN, Bartnitzke S, Löning T, et al. : MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups. Int J Cancer. 2012; 131 (7): 1528–36. PubMed Abstract | Publisher Full Text 30. Markowski DN, Helmke BM, Bartnitzke S, et al. : Uterine fibroids: do we deal with more than one disease? Int J Gynecol Pathol. 2014; 33 (6): 568–72. PubMed Abstract | Publisher Full Text | F1000 Recommendation 31. Bojahr B, De Wilde RL, Tchartchian G: Malignancy rate of 10,731 uteri morcellated during laparoscopic supracervical hysterectomy (LASH). Arch Gynecol Obstet. 2015; 292 (3): 665–72. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 32. Dariushnia SR, Nikolic B, Stokes LS, et al. : Quality improvement guidelines for uterine artery embolization for symptomatic leiomyomata. J Vasc Interv Radiol. 2014; 25 (11): 1737–47. PubMed Abstract | Publisher Full Text 33. Gupta JK, Sinha A, Lumsden MA, et al. : Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014; (12): CD005073. PubMed Abstract | Publisher Full Text | F1000 Recommendation 34. Zupi E, Centini G, Sabbioni L, et al. : Nonsurgical Alternatives for Uterine Fibroids. Best Pract Res Clin Obstet Gynaecol. 2016; 34 : 122–31. PubMed Abstract | Publisher Full Text 35. Sangkomkamhang US, Lumbiganon P, Laopaiboon M, et al. : Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev. 2013; (2): CD008994. PubMed Abstract | Publisher Full Text 36. Lethaby A, Vollenhoven B, Sowter M: Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001; (2): CD000547. PubMed Abstract | Publisher Full Text 37. Moroni RM, Martins WP, Ferriani RA, et al. : Add-back therapy with GnRH analogues for uterine fibroids. Cochrane Database Syst Rev. 2015; (3): CD010854. PubMed Abstract | Publisher Full Text | F1000 Recommendation 38. Engman M, Granberg S, Williams AR, et al. : Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial. Hum Reprod. 2009; 24 (8): 1870–9. PubMed Abstract | Publisher Full Text | F1000 Recommendation 39. Ioffe OB, Zaino RJ, Mutter GL: Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator. Mod Pathol. 2009; 22 (3): 450–9. PubMed Abstract | Publisher Full Text | F1000 Recommendation 40. Chwalisz K, Larsen L, Mattia-Goldberg C, et al. : A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata. Fertil Steril. 2007; 87 (6): 1399–412. PubMed Abstract | Publisher Full Text 41. Donnez J, Tatarchuk TF, Bouchard P, et al. : Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012; 366 (5): 409–20. PubMed Abstract | Publisher Full Text | F1000 Recommendation 42. Schütt B, Kaiser A, Schultze-Mosgau MH, et al. : Pharmacodynamics and safety of the novel selective progesterone receptor modulator vilaprisan: a double-blind, randomized, placebo-controlled phase 1 trial in healthy women. Hum Reprod. 2016; 31 (8): 1703–12. PubMed Abstract | Publisher Full Text | F1000 Recommendation 43. Mutter GL, Bergeron C, Deligdisch L, et al. : The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol. 2008; 21 (5): 591–8. PubMed Abstract | Publisher Full Text 44. Donnez J, Vázquez F, Tomaszewski J, et al. : Long-term treatment of uterine fibroids with ulipristal acetate ☆. Fertil Steril. 2014; 101 (6): 1565–73.e1–18. PubMed Abstract | Publisher Full Text | F1000 Recommendation 45. Courtoy GE, Donnez J, Marbaix E, et al. : In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment. Fertil Steril. 2015; 104 (2): 426–34.e1. PubMed Abstract | Publisher Full Text | F1000 Recommendation 46. Fauser BC, Donnez J, Bouchard P, et al. : Safety after extended repeated use of ulipristal acetate for uterine fibroids. PLoS One. 2017; 12 (3): e0173523. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation 47. Luyckx M, Squifflet JL, Jadoul P, et al. : First series of 18 pregnancies after ulipristal acetate treatment for uterine fibroids. Fertil Steril. 2014; 102 (5): 1404–9. PubMed Abstract | Publisher Full Text | F1000 Recommendation Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 07 Dec 2017 ADD YOUR COMMENT Comment Author details Author details Department of Pathology, Royal Infirmary of Edinburgh, University of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK Alistair R.W. Williams Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests The author has current consultancies with Bayer, PregLem, Gedeon Richter and HRA Pharma. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 07 Dec 2017, 6:2109 https://doi.org/10.12688/f1000research.12172.1 Copyright © 2017 Williams ARW. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Williams ARW. Uterine fibroids – what’s new? [version 1; peer review: 3 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):2109 ( https://doi.org/10.12688/f1000research.12172.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Jörn Bullerdiek , Institute of Medical Genetics, University Rostock Medical Center, Germany Competing interests: Current consultancy with Gedeon Richter. (for version 1) Elizabeth Stewart , Department of Obstetrics and Gynecology, Mayo Clinic, USA Competing interests: No competing interests were declared. (for version 1) Pasquapina Ciarmela , Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Italy Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 07 Dec 2017 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 07 Dec 17 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Jörn Bullerdiek , Institute of Medical Genetics, University Rostock Medical Center, Germany Competing interests: Current consultancy with Gedeon Richter. View more View less Elizabeth Stewart , Department of Obstetrics and Gynecology, Mayo Clinic, USA Competing interests: No competing interests were declared. View more View less Pasquapina Ciarmela , Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Italy Competing interests: No competing interests were declared. View more View less Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Uterine fibroids \– what\’s new?".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/6-2109/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/6-2109/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/6-2109/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Williams ARW'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/6-2109/v1/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/6-2109", templates : { twitter : "Uterine fibroids \– what\’s new?. Williams ARW, published by " + "@F1000Research" + ", https://f1000research.com/articles/6-2109/v1" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/12172/13176") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("faculty-reviews", "article", "13176"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "28193": 0, "26961": 0, "28194": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "aa467f6d-f72e-492f-a878-186e96f68712"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });