Recent advances in the understanding and management of polycystic ovary syndrome

Recent advances in the understanding and management... | 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/8-565" }, "headline": "Recent advances in the understanding and management of polycystic ovary syndrome", "datePublished": "2019-04-26T16:59:26", "dateModified": "2019-04-26T16:59:26", "author": [ { "@type": "Person", "name": "Ana L. Rocha" }, { "@type": "Person", "name": "Flávia R. Oliveira" }, { "@type": "Person", "name": "Rosana C. Azevedo" }, { "@type": "Person", "name": "Virginia A. Silva" }, { "@type": "Person", "name": "Thais M. Peres" }, { "@type": "Person", "name": "Ana L. Candido" }, { "@type": "Person", "name": "Karina B. Gomes" }, { "@type": "Person", "name": "Fernando M. Reis" } ], "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": "Polycystic ovary syndrome (PCOS) is a multifaceted condition characterized by chronic anovulation and excess ovarian activity, in contrast to other causes of anovulation that involve ovarian dormancy or primary insufficiency. Recent studies indicated that PCOS is associated with low-grade chronic inflammation and that women with PCOS are at increased risk of non-alcoholic fatty liver disease. The inflammatory and metabolic derangements associated with PCOS are explained in part by the coexistence of insulin resistance and obesity but are further fueled by the androgen excess. New insights into the regulation of hormones and cytokines in muscle and fat tissue support the concept that PCOS is a systemic syndrome. The therapeutic plan should be tailored to the patient phenotype, complaints, and reproductive desire. Of note, the aromatase inhibitor letrozole seems to be more effective than the reference drug clomiphene citrate to treat infertility due to PCOS. Integral management by a multidisciplinary team may help the patients to adhere to lifestyle interventions and thereby reduce body adiposity and recover their metabolic and reproductive health." } { "@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/8-565/v1", "name": "Recent advances in the understanding and management of polycystic..." } } ] } Home Browse Recent advances in the understanding and management of polycystic... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Rocha AL, Oliveira FR, Azevedo RC et al. Recent advances in the understanding and management of polycystic ovary syndrome [version 1; peer review: 3 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):565 ( https://doi.org/10.12688/f1000research.15318.1 ) 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 Recent advances in the understanding and management of polycystic ovary syndrome [version 1; peer review: 3 approved] Ana L. Rocha 1 , Flávia R. Oliveira 1 , Rosana C. Azevedo 2 , [...] Virginia A. Silva 1 , Thais M. Peres 1 , Ana L. Candido 2 , Karina B. Gomes https://orcid.org/0000-0002-6870-2063 3 , Fernando M. Reis https://orcid.org/0000-0002-9258-7472 1 Ana L. Rocha 1 , Flávia R. Oliveira 1 , [...] Rosana C. Azevedo 2 , Virginia A. Silva 1 , Thais M. Peres 1 , Ana L. Candido 2 , Karina B. Gomes https://orcid.org/0000-0002-6870-2063 3 , Fernando M. Reis https://orcid.org/0000-0002-9258-7472 1 PUBLISHED 26 Apr 2019 Author details Author details 1 Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 2 Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 3 Department of Clinical and Toxicological Analysis, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Ana L. Rocha Roles: Conceptualization, Data Curation, Writing – Original Draft Preparation Flávia R. Oliveira Roles: Data Curation, Writing – Original Draft Preparation Rosana C. Azevedo Roles: Conceptualization, Data Curation, Writing – Review & Editing Virginia A. Silva Roles: Data Curation, Writing – Original Draft Preparation Thais M. Peres Roles: Data Curation, Writing – Original Draft Preparation Ana L. Candido Roles: Project Administration, Supervision, Writing – Review & Editing Karina B. Gomes Roles: Conceptualization, Supervision, Writing – Review & Editing Fernando M. Reis Roles: Conceptualization, Data Curation, Methodology, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Polycystic ovary syndrome (PCOS) is a multifaceted condition characterized by chronic anovulation and excess ovarian activity, in contrast to other causes of anovulation that involve ovarian dormancy or primary insufficiency. Recent studies indicated that PCOS is associated with low-grade chronic inflammation and that women with PCOS are at increased risk of non-alcoholic fatty liver disease. The inflammatory and metabolic derangements associated with PCOS are explained in part by the coexistence of insulin resistance and obesity but are further fueled by the androgen excess. New insights into the regulation of hormones and cytokines in muscle and fat tissue support the concept that PCOS is a systemic syndrome. The therapeutic plan should be tailored to the patient phenotype, complaints, and reproductive desire. Of note, the aromatase inhibitor letrozole seems to be more effective than the reference drug clomiphene citrate to treat infertility due to PCOS. Integral management by a multidisciplinary team may help the patients to adhere to lifestyle interventions and thereby reduce body adiposity and recover their metabolic and reproductive health. READ ALL READ LESS Keywords polycystic ovary syndrome, PCOS, insulin resistance, infertility, menstrual irregularity Corresponding Author(s) Fernando M. Reis ( [email protected] ) Close Corresponding author: Fernando M. Reis Competing interests: No competing interests were disclosed. Grant information: This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2019 Rocha AL et al . 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: Rocha AL, Oliveira FR, Azevedo RC et al. Recent advances in the understanding and management of polycystic ovary syndrome [version 1; peer review: 3 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):565 ( https://doi.org/10.12688/f1000research.15318.1 ) First published: 26 Apr 2019, 8 (F1000 Faculty Rev):565 ( https://doi.org/10.12688/f1000research.15318.1 ) Latest published: 26 Apr 2019, 8 (F1000 Faculty Rev):565 ( https://doi.org/10.12688/f1000research.15318.1 ) Introduction Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, presenting with several possible combinations of signs and symptoms and a range of phenotypes, which may include reproductive, endocrine, and metabolic alterations. PCOS is characterized by hypothalamic–pituitary–ovary axis dysfunction and anovulation but, unlike other causes of ovulatory failure that feature insufficient ovarian follicle growth or suppressed gonadotropin secretion (or both), PCOS typically includes androgen excess and subtle alterations (not detected by routine tests) in serum levels of gonadotropins and estrogens. PCOS has the potential for serious consequences, including increased risk for the development of endometrial hyperplasia and neoplasia 1 . Furthermore, extra-reproductive manifestations of PCOS include insulin resistance (IR), metabolic syndrome (MS), and low-grade chronic inflammation 2 – 6 . In recent years, many advances have been made in the understanding of pathophysiological mechanisms ( Figure 1 ) and thereby in the diagnosis and management of PCOS. We will discuss a limited number of such advancements according to our view of which ones have been more impactful on the health care of women with this syndrome. Figure 1. Schematic representation of some pathophysiological mechanisms of polycystic ovary syndrome. The main clinical manifestations are shown in rectangular boxes. Androgens are responsible for dermatological symptoms, while sustained estrogen production by the ovaries and subcutaneous fat without progesterone opposition produces menstrual irregularity and increases the risk of endometrial hyperplasia. Adipokines and myokines may also be involved in the metabolic alterations associated with the syndrome. Insulin resistance and the compensatory hyperinsulinemia are central mechanisms that perpetuate anovulation and lead to metabolic complications. AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; IGF-I, insulin-like growth factor I; LH, luteinizing hormone; NAFLD, non-alcoholic fatty liver disease; SHBG, sex hormone–binding globulin. Advances and challenges in PCOS understanding The Rotterdam Consensus, held jointly by the European and the North American associations of reproductive medicine in 2003, defined the diagnostic criteria of PCOS which remain the most used worldwide for both individual diagnosis and research 7 . It defined PCOS as the presence of any two of three features: hyperandrogenism (clinical or biochemical), ovulatory dysfunction (often manifested by menstrual irregularities), and polycystic ovarian morphology (PCOM) by ultrasound. The syndrome is a diagnosis of exclusion that should be established only after evaluation of other causes of anovulation or androgen excess (or both): hypogonadism, hypo- or hyperthyroidism, hyperprolactinemia, 21-hydroxylase deficiency, Cushing’s syndrome, and androgen-producing tumors 7 . Despite some controversy about the appropriateness of the Rotterdam criteria to guide PCOS treatments, their utility to predict reproductive outcomes is well established 8 . A recent guideline from the International PCOS Network recommended use of the Rotterdam criteria in adults and the requirement of both oligo-anovulation and hyperandrogenism for PCOS diagnosis in adolescents 9 . There are several combinations of signs and symptoms that may be accounted for in the diagnosis of PCOS, resulting in different phenotypes for the same syndrome. To better understand the pathogenesis of the syndrome, it is important to compare the genetic profiles of women whose diagnosis was based on the different phenotypes. A recent genome-wide meta-analysis from over 10,000 PCOS cases identified 14 independent loci associated with the risk for PCOS, including three novel loci 10 . This large-scale study found no difference between the various clinical phenotypes for the association with most of the PCOS-susceptibility loci, suggesting that common genetic traits may underlie the different phenotypes. Hyperandrogenism is an important clinical characteristic of the syndrome since it is associated with worse prognosis and higher risk of metabolic and cardiovascular disease 11 . However, recent genetic findings suggest that it may not be the only driver of PCOS manifestations 10 , 12 . As diagnosed by the Rotterdam criteria, hyperandrogenism is present in about 60 to 80% of cases. Biochemical hyperandrogenism remains a diagnostic challenge because the assay methods are poorly standardized, there are no universal cutoffs for diagnosis, and some assays for free testosterone quantification are unreliable 13 , 14 . Thus, until a sensitive, reproducible, and widely validated testosterone assay becomes available and affordable for clinical practice, the assessment of biochemical hyperandrogenism to confirm or discard PCOS should rely on total serum testosterone, sex hormone–binding globulin (SHBG), and free androgen index using local cutoffs 13 , 15 . Anti-Müllerian hormone (AMH) is a glycoprotein secreted by the granulosa cells of pre-antral and small antral follicles. AMH plays an essential role in sexual differentiation and gonadal function, besides central effects on the hypothalamic–pituitary–gonadal axis. A straightforward experimental study demonstrated that AMH receptor is expressed in gonadotropin-releasing hormone (GnRH) neurons and that intracerebroventricular administration of AMH increases GnRH-dependent luteinizing hormone (LH) pulsatile release 16 . There is accumulating evidence that GnRH pulsatility is perturbed in women with PCOS, leading to increased LH pulsatility, which plays an important role in PCOS pathophysiology 17 . Serum AMH levels are typically increased in PCOS 18 and therefore AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility in women with PCOS 16 . Metabolic profile IR is so common in PCOS that it can be considered an integral part of the syndrome. IR and glucose metabolism deregulation are currently supposed to play a pathogenic role in the disease. IR leads to compensatory hyperinsulinemia, which increases ovarian androgen synthesis both by direct ovarian actions and by stimulating LH secretion 3 . IR also induces dyslipidemia, and women with PCOS have an increased risk of type 2 diabetes mellitus and cardiovascular disease 5 . Another potential metabolic complication of PCOS is non-alcoholic fatty liver disease (NAFLD), defined as hepatic steatosis not explained by alcohol or other specific etiologic agents. NAFLD is mechanistically and epidemiologically linked to obesity, IR, and MS 19 . PCOS is associated with increased risk of NAFLD regardless of the presence of obesity, suggesting that the relationship between PCOS and NAFLD is also explained by other features of PCOS, such as IR and androgen excess. In fact, a systematic review and meta-analysis showed a higher prevalence of NAFLD among women with hyperandrogenic PCOS compared with other phenotypes of the syndrome, while serum androgen levels were higher in PCOS women with NAFLD compared with PCOS women without NAFLD 20 . Adipokines and inflammation mediators released by the adipose tissue also contribute to the metabolic alterations found in PCOS 6 . In addition, a number of growth factors, cytokines, and reactive oxygen species produced by the ovaries, liver, and other tissues create a state of chronic inflammation that concurs to maintain the metabolic imbalance of the syndrome 4 , 6 . During the past decade, skeletal muscle has also been identified as a secretory organ that releases cytokines and other peptides, called myokines. Irisin has been identified as an exercise-induced myokine and has been proposed to mediate the beneficial effects of exercise on metabolism 21 . Irisin can induce a change in characteristics of white adipocytes that acquire a “brown” phenotype. This change includes the activation of uncoupling protein 1 (UCP-1), leading to increased respiration and energy expenditure 21 , 22 . Irisin is also produced at lower amounts outside the skeletal muscle 23 . Brain-derived irisin mediates anxiolytic effects of aerobic exercise 24 and protects the brain from synaptic and memory loss in an animal model of Alzheimer’s disease 25 . Furthermore, in vivo irisin infusion improves bone mass and architecture in young male mice 23 . The expression of irisin is positively associated with body mass index (BMI) and muscle mass, and irisin metabolism is abnormal in patients with type 2 diabetes or gestational diabetes 26 . Zhang et al . observed that serum irisin levels were associated with hyperandrogenism but not with oligovulation or PCOM in women with PCOS 27 . A recent meta-analysis showed that, after adjustment for BMI, patients with PCOS seem to have normal irisin levels; however, irisin response to hyperinsulinemia might be impaired in patients with PCOS 28 . It is uncertain whether PCOS is somehow associated with low serum levels of vitamin D. A systematic review found 12 studies with very heterogeneous results and their meta-analysis suggested lower serum 25-(OH)D in PCOS versus controls but no differences in serum 1,25(OH) 2 D between the two groups 29 . More importantly, if a woman with PCOS has vitamin D deficiency, she will be at increased risk of metabolic comorbidities. Vitamin D supplementation may reduce chronic inflammation markers in women with PCOS and vitamin D deficiency 30 , 31 but there is no evidence that such therapy improves the metabolic status of patients 29 . Polycystic ovarian morphology and the diagnosis of PCOS PCOM is one of three criteria for diagnosis of PCOS. PCOM is defined as follicle number per ovary of at least 12 or ovarian volume of at least 10 mL or both 7 . However, the latest generation of ultrasound devices (maximal probe frequencies that exceed 8 MHz) is more sensitive and yields a larger follicle count in the general population; therefore, the current use of the old cutoff can overestimate the prevalence of PCOM 32 . A group of experts recently proposed the use of higher in-house thresholds (that is, 19 to 25 follicles per ovary) to define PCOM with the new ultrasound machines 33 . Serum AMH levels correlate with follicle number in women with PCOS. Some studies found a good concordance between serum AMH levels and ultrasound results for the diagnosis of PCOM. These studies suggest that serum AMH could be a proxy for ovarian follicle count and an alternative marker of PCOM to be used interchangeably with ultrasound depending on serum AMH and ovarian follicle count availability 34 . Recent studies show that high levels of AMH (>35 pmol/L) have a good correlation with the diagnosis of PCOM at ultrasound 34 . However, serum AMH levels should not yet be used as a marker or as a single test for the diagnosis and detection of PCOS 9 , 33 . PCOS at different stages of life The progression of PCOS during different life stages is poorly known because of the paucity of cohort studies with long-term follow-up. A study compared clinical and biochemical parameters of PCOS women and healthy controls who visited a medical center at a mean age of 29 years and returned 6 years later on average. In this longitudinal sample, aging was associated with an increase in the number of regular menstrual cycles, a decrease in serum androgen levels, and a decrease in IR 18 . The reasons for this attenuation of PCOS features over time are not clear. Other studies have focused on PCOS manifestations in specific age groups, as detailed below. PCOS in childhood. The interaction between a genetic predisposition and some prenatal and postnatal environmental factors seems to take part in the pathophysiology of PCOS. Intrauterine growth retardation or small for gestational age (or both) and high levels of androgens during the intrauterine period could lead to an increased production of glucocorticoids which may induce epigenetic modifications and increase the risk of PCOS 35 . PCOS in adolescence. PCOS is often diagnosed in adolescence. Menstrual irregularity, acne, and hirsutism are the major findings in this age group. However, these features of PCOS overlap with those of normal adolescence. Family history of PCOS, overweight or low birth weight, exposure to androgens during gestation, precocious puberty, obesity, and IR are risk factors that are related to the development of the syndrome. The diagnosis of PCOS during adolescence is based on stricter criteria than in adult women. It requires unequivocal hyperandrogenism (for example, moderate to severe hirsutism or persistent elevation of serum testosterone levels or both) and ovulatory dysfunction that persists for more than 2 years after menarche 36 . Recent studies showed that adolescents with PCOS have increased risk of MS and should be advised to adopt a healthy lifestyle at once 37 . When a diagnosis of PCOS has been established, the possibility of IR manifestations and quality of life issues should be considered. Obesity, overweight, and hyperinsulinemia may be present in adolescents. In addition, eating disorders (bulimia, anorexia, and binge eating) and inadequate diets with large amounts of hypercaloric and industrialized foods are common in adolescence. Dietary orientation, stimulation to physical activity, and self-care should be part of the integral care for adolescent girls. PCOS in postmenopausal women. Women with PCOS persist with hyperandrogenism even after menopausal transition and continue to manifest metabolic alterations and MS with increased risk of cardiovascular disease. Therefore, postmenopausal women with a history of PCOS during the reproductive years may still have manifestations of the syndrome 9 , 38 . Advances and challenges in PCOS management Treatment of PCOS should be proposed not only to alleviate symptoms but also to prevent the occurrence of long-term complications. Combined oral contraceptives and antiandrogens are the standard care to reduce androgen levels and treat symptoms while providing endometrial protection 39 . However, the therapeutic plan should be tailored depending on the desire (or not) of the patient to become pregnant, need for aesthetic approach, and the presence of concomitant metabolic alterations. The overall goals of therapy of women with PCOS include the mitigation of hyperandrogenic symptoms, management of metabolic abnormalities and reduction of risk factors for type 2 diabetes and cardiovascular disease, prevention of endometrial hyperplasia, planning and obtaining a safe pregnancy if desired, and improving general well-being and quality of life. These goals are ideally achieved by a multidisciplinary team providing patient-centered care ( Figure 2 ). Figure 2. Patient-centered care by a multidisciplinary team may help reach the main goals of polycystic ovary syndrome management. These goals are symptom relief, safe fertility planning, general well-being, and prevention of long-term complications. Metabolism The first line of treatment in patients with PCOS should be the improvement in lifestyle. In overweight and obese patients, weight loss due to changes in diet and physical activity decreases serum insulin and androgen levels and reduces the risk of developing glucose intolerance and type 2 diabetes 5 . Pharmacological interventions are indicated in the presence of IR/glucose intolerance or dyslipidemia that persist after lifestyle modifications 40 . Metformin is the most commonly used drug for the metabolic control of these patients 41 . The therapeutic effects of metformin as insulin-sensitizing and hypoglycemic agent have been well confirmed in women with PCOS 42 . However, despite what is commonly believed or what observational uncontrolled studies suggest 41 , there is no convincing evidence that metformin reduces BMI in women with PCOS compared with placebo 42 . The addition of metformin may have minimal benefit on the BMI of women who receive antiandrogen and combined oral contraceptive 39 . Metformin does not seem to decrease body adiposity as it has little if any effect on reducing waist circumference and serum triglyceride levels in women with PCOS 42 . Current studies are exploring the hypothesis that genomic variants define the responsiveness to metformin therapy among women with PCOS 43 . Since metformin often has gastrointestinal side effects, new pharmaceutical preparations especially designed for vaginal delivery are under development and so far have been effective in a preclinical model of PCOS 44 . Liraglutide is a glucagon-like peptide receptor 1 agonist approved for treating type 2 diabetes and obesity. In obese women with PCOS, liraglutide was effective to induce significant weight loss and reduce waist circumference 45 . Orlisat is a lipase inhibitor labeled for treatment of obesity. In overweight or obese women with PCOS, orlistat is effective to induce weight loss and improve clinical and biochemical markers of hyperandrogenism and IR 46 . Myo- and D-chiro-inositol are insulin-sensitizing agents that act as second messengers in insulin signaling. These compounds have been evaluated as possible alternatives to metformin in PCOS women with IR. Inositol isoforms mediate insulin activity in many target organs, including the ovary, as detailed in a recent review 47 . In a mouse model of PCOM induced by constant light exposure, the theca/granulosa cell layer thickness ratio and the time to pregnancy were reduced by treatment with myo-inositol and D-chiro-inositol in a 40:1 molar ratio 48 . Earlier clinical studies without a placebo or metformin group showed a decrease in serum testosterone along with an increase in SHBG levels after 6 months of treatment with myo-inositol alone or associated with D-chiro-inositol 49 and no difference between D-chiro-inositol alone or combined with myo-inositol on the number of mature oocytes retrieved for in vitro fertilization (IVF) 50 . A recent meta-analysis concluded that myo-inositol supplementation for IVF did not improve oocyte or embryo quality 51 . Given the current body of evidence, we believe that inositol therapy may become an alternative for metabolic improvement of PCOS women who do not tolerate metformin, but robust data with a face-to-face comparison between inositols and metformin are still missing. Three small, single-center randomized controlled studies published in 2017 addressed this question and found better results with either myo-inositol 52 or metformin 53 or similar benefits with the two drugs 54 . According to the International PCOS Network, inositol (in any form) should be considered an experimental therapy in PCOS 9 . Quality of life PCOS manifests in women at reproductive age when issues such as finding a partner, initiating sex life, and forming a family are often very relevant. Factors that negatively affect physical appearance or femininity or compromise fertility are sources of great anxiety and can lead to imbalances in the psychosexual sphere 55 . The psychological impact of PCOS may even surpass that of chronic diseases such as asthma, diabetes, arthritis, and coronary heart disease 56 . Depression and anxiety are highly prevalent in women with PCOS. Dokras et al . found a fourfold increase in the prevalence of depressive symptoms in patients with the syndrome when compared with controls, even after adjustment for BMI 57 . Daily fatigue and sleep disorders, changes in appetite, and loss of interest in everyday activities were the most common symptoms 58 . Thus, the evaluation of quality of life in women with PCOS is essential for better care and clinical management of these patients ( Figure 3 ). Figure 3. Objectives of assessing the quality of life in women with polycystic ovary syndrome. Infertility In overweight or obese patients with PCOS who wish to conceive, lifestyle modifications aimed at weight loss should be the milestone of preconception counseling. Loss of 5 to 7% of body weight may be effective to promote menstrual cycle regularization and spontaneous ovulation 40 . If the woman is unable to lose weight or does not restore ovulatory cycles, treatment should be individualized while taking into account the duration of infertility, the woman’s age, the risks of pregnancy at this time, and the factors that may be related to her difficulty to lose weight. Preconception care includes folic acid supplementation at a dose of 0.4 mg/day and cessation of smoking and alcohol consumption. The second line of treatment (after lifestyle interventions) is ovulation induction. This step must be preceded by careful evaluation of other causes of infertility, such as male factor or tubal obstruction, which demand IVF and may coexist with PCOS. Clomiphene citrate (CC) is the reference therapy for ovulation induction in anovulatory women with PCOS. In the absence of ovulation for three cycles of CC at the highest dose (150 mg/day), the woman can be considered non-responsive and another drug should be introduced as an adjuvant or substitute for CC. Compared with placebo, metformin reduces serum testosterone levels and increases the frequency of spontaneous ovulation and regular menstrual cycles in patients with PCOS 42 . However, because it achieves lower live birth rates compared with CC, metformin is no longer recommended to induce ovulation 42 , 59 . Furthermore, there is no conclusive evidence about whether the association of metformin with CC differs from CC alone in live birth rates. This makes sense, as the addition of metformin to CC increases the ovulation and clinical pregnancy rates but also the miscarriage rate compared with CC alone 42 , 60 . In women resistant to CC, limited evidence suggests that adding metformin may increase the pregnancy rate 59 . Maintaining metformin during gestation does not seem to prevent adverse outcomes 42 , 59 , 61 , 62 and may indeed increase the risk of future overweight in offspring 63 . The aromatase inhibitor letrozole at a dose of 2.5 mg/day may be used as an alternative to induce ovulation in patients who have failed to respond to CC. Many studies suggest that letrozole can be used as first-line therapy in ovulation induction but this use remains off-label. The dose may be increased by 2.5 mg/day to a maximum of 7.5 mg/day. The major advantage of letrozole over CC is better ovulation-inducing response, especially in obese patients, which translates into higher pregnancy and live birth rates 60 , 64 . Preliminary data also suggest that letrozole is superior to metformin plus CC to induce ovulation as assessed by the clinical pregnancy rate in an open-label randomized clinical trial 65 . In case of failure of oral ovulation inducers to achieve pregnancy, injectable gonadotropins combined with timed intercourse, intrauterine insemination, or IVF may be used. The addition of metformin to gonadotropins has shown some benefit in low-complexity treatments (timed intercourse or intaruterine insemination) but not in IVF 62 , 66 . Preliminary results suggest that liraglutide at low dose can help to improve the outcome of IVF treatment in obese women with PCOS 67 . Women with PCOS should be advised about the most opportune moment for pregnancy, taking into account the obstetric, metabolic, and cardiovascular risks that may be present 68 , 69 . Therefore, safe contraception is part of the integral care 70 as it allows postponing pregnancy while implementing lifestyle interventions to lose fat mass and improve the metabolic homeostasis in order to obtain not just a pregnancy but a successful full-term pregnancy with both mother and baby in good health. Summary and conclusions New insights into the cross-talk between muscle, fat, brain, and ovary tissue support the concept that PCOS is a systemic syndrome. The classic reproductive and dermatological features of PCOS are just the visible part of a more complex mechanism ( Figure 1 ). The inflammatory and metabolic derangements associated with PCOS are explained in part by the coexistence of IR and obesity but are further fueled by the androgen excess. The therapeutic plan should be tailored to the patient phenotype, complaints, and reproductive desire. Medical treatments have not seen any breakthrough in recent years. Of note, the aromatase inhibitor letrozole seems to be more effective than the reference drug CC to treat infertility due to PCOS. Integral management by a multidisciplinary team may help patients to adhere to lifestyle interventions and thereby reduce body adiposity and recover their metabolic and reproductive health. Author contributions ALR performed the bibliographic search and drafted the manuscript. FRO, RCA, VAS, and TMP assisted in the bibliographic search and in the preparation of text and figures. ALC and KBG evaluated the evidence and edited the manuscript for significant content. FMR conceived the review, evaluated the evidence, and corrected the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content. Grant information This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Faculty Opinions recommended References 1. Barry JA, Azizia MM, Hardiman PJ: Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014; 20 (5): 748–58. PubMed Abstract | Publisher Full Text | Free Full Text 2. Çakıroğlu Y, Vural F, Vural B: The inflammatory markers in polycystic ovary syndrome: association with obesity and IVF outcomes. J Endocrinol Invest. 2016; 39 (8): 899–907. PubMed Abstract | Publisher Full Text 3. de Leo V, Musacchio MC, Cappelli V, et al. : Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol. 2016; 14 (1): 38. PubMed Abstract | Publisher Full Text | Free Full Text 4. Durmus U, Duran C, Ecirli S: Visceral adiposity index levels in overweight and/or obese, and non-obese patients with polycystic ovary syndrome and its relationship with metabolic and inflammatory parameters. J Endocrinol Invest. 2017; 40 (5): 487–97. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 5. McCartney CR, Marshall JC: CLINICAL PRACTICE. Polycystic Ovary Syndrome. N Engl J Med. 2016; 375 (1): 54–64. PubMed Abstract | Publisher Full Text | Free Full Text 6. Spritzer PM, Lecke SB, Satler F, et al. : Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction. 2015; 149 (5): R219–R227. PubMed Abstract | Publisher Full Text 7. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004; 81 (1): 19–25. PubMed Abstract | Publisher Full Text 8. Wang R, Mol BW: The Rotterdam criteria for polycystic ovary syndrome: evidence-based criteria? Hum Reprod. 2017; 32 (2): 261–4. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 9. Teede HJ, Misso ML, Costello MF, et al. : Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018; 33 (9): 1602–18. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 10. Day F, Karaderi T, Jones MR, et al. : Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018; 14 (12): e1007813. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 11. Daan NM, Jaspers L, Koster MP, et al. : Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features. Hum Reprod. 2015; 30 (10): 2376–86. PubMed Abstract | Publisher Full Text 12. Dumesic DA, Oberfield SE, Stener-Victorin E, et al. : Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015; 36 (5): 487–525. PubMed Abstract | Publisher Full Text | Free Full Text 13. Legro RS, Arslanian SA, Ehrmann DA, et al. : Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013; 98 (12): 4565–92. PubMed Abstract | Publisher Full Text | Free Full Text 14. Wierman ME, Arlt W, Basson R, et al. : Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99 (10): 3489–510. PubMed Abstract | Publisher Full Text 15. Mario FM, Graff SK, Spritzer PM: Habitual physical activity is associated with improved anthropometric and androgenic profile in PCOS: a cross-sectional study. J Endocrinol Invest. 2017; 40 (4): 377–84. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 16. Cimino I, Casoni F, Liu X, et al. : Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat Commun. 2016; 7 : 10055. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 17. Katulski K, Podfigurna A, Czyzyk A, et al. : Kisspeptin and LH pulsatile temporal coupling in PCOS patients. Endocrine. 2018; 61 (1): 149–57. PubMed Abstract | Publisher Full Text | Free Full Text 18. Brown ZA, Louwers YV, Fong SL, et al. : The phenotype of polycystic ovary syndrome ameliorates with aging. Fertil Steril. 2011; 96 (5): 1259–65. PubMed Abstract | Publisher Full Text 19. Mishra A, Younossi ZM: Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease. J Clin Exp Hepatol. 2012; 2 (2): 135–44. PubMed Abstract | Publisher Full Text | Free Full Text 20. Rocha ALL, Faria LC, Guimarães TCM, et al. : Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Invest. 2017; 40 (12): 1279–88. PubMed Abstract | Publisher Full Text 21. Boström P, Wu J, Jedrychowski MP, et al. : A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012; 481 (7382): 463–8. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 22. Polyzos SA, Anastasilakis AD, Efstathiadou ZA, et al. : Irisin in metabolic diseases. Endocrine. 2018; 59 (2): 260–74. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 23. Colaianni G, Cuscito C, Mongelli T, et al. : The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A. 2015; 112 (39): 12157–62. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 24. Uysal N, Yuksel O, Kizildag S, et al. : Regular aerobic exercise correlates with reduced anxiety and incresed levels of irisin in brain and white adipose tissue. Neurosci Lett. 2018; 676 : 92–7. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 25. Lourenco MV, Frozza RL, de Freitas GB, et al. : Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med. 2019; 25 (1): 165–75. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 26. Moreno-Navarrete JM, Ortega F, Serrano M, et al. : Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab. 2013; 98 (4): E769–78. PubMed Abstract | Publisher Full Text 27. Zhang L, Fang X, Li L, et al. : The association between circulating irisin levels and different phenotypes of polycystic ovary syndrome. J Endocrinol Invest. 2018; 41 (12): 1401–7. PubMed Abstract | Publisher Full Text 28. Cai X, Qiu S, Li L, et al. : Circulating irisin in patients with polycystic ovary syndrome: a meta-analysis. Reprod Biomed Online. 2018; 36 (2): 172–80. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 29. He C, Lin Z, Robb SW, et al. : Serum Vitamin D Levels and Polycystic Ovary syndrome: A Systematic Review and Meta-Analysis. Nutrients. 2015; 7 (6): 4555–77. PubMed Abstract | Publisher Full Text | Free Full Text 30. Foroozanfard F, Jamilian M, Bahmani F, et al. : Calcium plus vitamin D supplementation influences biomarkers of inflammation and oxidative stress in overweight and vitamin D-deficient women with polycystic ovary syndrome: A randomized double-blind placebo-controlled clinical trial. Clin Endocrinol (Oxf). 2015; 83 (6): 888–94. PubMed Abstract | Publisher Full Text 31. Irani M, Seifer DB, Grazi RV, et al. : Vitamin D Supplementation Decreases TGF-β1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial. J Clin Endocrinol Metab. 2015; 100 (11): 4307–14. PubMed Abstract | Publisher Full Text 32. Martins WP, Kollmann M, Raine-Fenning N: Counting ovarian follicles: updated threshold for diagnosis of hyperandrogenic anovulation. Ultrasound Obstet Gynecol. 2014; 44 (2): 131–4. PubMed Abstract | Publisher Full Text 33. Dewailly D, Lujan ME, Carmina E, et al. : Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2014; 20 (3): 334–52. PubMed Abstract | Publisher Full Text 34. Fraissinet A, Robin G, Pigny P, et al. : Use of the serum anti-Müllerian hormone assay as a surrogate for polycystic ovarian morphology: impact on diagnosis and phenotypic classification of polycystic ovary syndrome. Hum Reprod. 2017; 32 (8): 1716–22. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 35. Bellver J, Rodríguez-Tabernero L, Robles A, et al. : Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet. 2018; 35 (1): 25–39. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 36. Witchel SF, Oberfield S, Rosenfield RL, et al. : The Diagnosis of Polycystic Ovary Syndrome during Adolescence. Horm Res Paediatr. 2015; 83 : 376–389. PubMed Abstract | Publisher Full Text 37. Fitzgerald S, DiVasta A, Gooding H: An update on PCOS in adolescents. Curr Opin Pediatr. 2018; 30 (4): 459–465. PubMed Abstract 38. Shah D, Bansal S: Polycystic ovaries - beyond menopause. Climacteric. 2014; 17 (2): 109–15. PubMed Abstract | Publisher Full Text 39. Luque-Ramírez M, Nattero-Chávez L, Ortiz Flores AE, et al. : Combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2018; 24 : 225–41. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 40. Balen AH, Morley LC, Misso M, et al. : The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update. 2016; 22 (6): 687–708. PubMed Abstract | Publisher Full Text 41. Yang PK, Hsu CY, Chen MJ, et al. : The Efficacy of 24-Month Metformin for Improving Menses, Hormones, and Metabolic Profiles in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2018; 103 (3): 890–9. PubMed Abstract | Publisher Full Text 42. Morley LC, Tang T, Yasmin E, et al. : Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017; 11 : CD003053. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 43. Pedersen AJT, Stage TB, Glintborg D, et al. : The Pharmacogenetics of Metformin in Women with Polycystic Ovary Syndrome: A Randomized Trial. Basic Clin Pharmacol Toxicol. 2018; 122 (2): 239–44. PubMed Abstract | Publisher Full Text 44. Saini N, Sodhi RK, Bajaj L, et al. : Intravaginal administration of metformin hydrochloride loaded cationic niosomes amalgamated with thermosensitive gel for the treatment of polycystic ovary syndrome: In vitro and in vivo studies. Colloids Surf B Biointerfaces. 2016; 144 : 161–9. PubMed Abstract | Publisher Full Text 45. Jensterle M, Kravos NA, Pfeifer M, et al. : A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome. HHormones (Athens). 2015; 14 (1): 81–90. PubMed Abstract | Publisher Full Text 46. Graff SK, Mario FM, Ziegelmann P, et al. : Effects of orlistat vs. metformin on weight loss-related clinical variables in women with PCOS: systematic review and meta-analysis. Int J Clin Pract. 2016; 70 (6): 450–61. PubMed Abstract | Publisher Full Text 47. Monastra G, Unfer V, Harrath AH, et al. : Combining treatment with myo-inositol and D-chiro-inositol (40:1) is effective in restoring ovary function and metabolic balance in PCOS patients. Gynecol Endocrinol. 2017; 33 (1): 1–9. PubMed Abstract | Publisher Full Text 48. Bevilacqua A, Dragotto J, Giuliani A, et al. : Myo-inositol and D-chiro-inositol (40:1) reverse histological and functional features of polycystic ovary syndrome in a mouse model. J Cell Physiol. 2019; 234 (6): 9387–9398. PubMed Abstract | Publisher Full Text 49. Nordio M, Proietti E: The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci. 2012; 16 (5): 575–81. PubMed Abstract 50. Colazingari S, Treglia M, Najjar R, et al. : The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial. Arch Gynecol Obstet. 2013; 288 (6): 1405–11. PubMed Abstract | Publisher Full Text 51. Mendoza N, Pérez L, Simoncini T, et al. : Inositol supplementation in women with polycystic ovary syndrome undergoing intracytoplasmic sperm injection: a systematic review and meta-analysis of randomized controlled trials. Reprod Biomed Online. 2017; 35 (5): 529–35. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 52. Jamilian M, Farhat P, Foroozanfard F, et al. : Comparison of myo-inositol and metformin on clinical, metabolic and genetic parameters in polycystic ovary syndrome: A randomized controlled clinical trial. Clin Endocrinol (Oxf). 2017; 87 (2): 194–200. PubMed Abstract | Publisher Full Text 53. Tagliaferri V, Romualdi D, Immediata V, et al. : Metformin vs myoinositol: which is better in obese polycystic ovary syndrome patients? A randomized controlled crossover study. Clin Endocrinol (Oxf). 2017; 86 (5): 725–30. PubMed Abstract | Publisher Full Text 54. Fruzzetti F, Perini D, Russo M, et al. : Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2016; 33 (1): 39–42. PubMed Abstract | Publisher Full Text 55. Eggers S, Kirchengast S: The polycystic ovary syndrome--a medical condition but also an important psychosocial problem. Coll Antropol. 2001; 25 (2): 673–85. PubMed Abstract 56. Coffey S, Bano G, Mason HD: Health-related quality of life in women with polycystic ovary syndrome: a comparison with the general population using the Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36). Gynecol Endocrinol. 2006; 22 (2): 80–6. PubMed Abstract | Publisher Full Text 57. Dokras A, Clifton S, Futterweit W, et al. : Increased risk for abnormal depression scores in women with polycystic ovary syndrome: a systematic review and meta-analysis. Obstet Gynecol. 2011; 117 (1): 145–52. PubMed Abstract | Publisher Full Text 58. Dokras A: Mood and anxiety disorders in women with PCOS. Steroids. 2012; 77 (4): 338–41. PubMed Abstract | Publisher Full Text 59. Practice Committee of the American Society for Reproductive Medicine: Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril. 2017; 108 (3): 426–41. PubMed Abstract | Publisher Full Text 60. Wang R, Kim BV, van Wely M, et al. : Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis. BMJ. 2017; 356 : j138. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 61. Legro RS: Ovulation induction in polycystic ovary syndrome: Current options. Best Pract Res Clin Obstet Gynaecol. 2016; 37 : 152–9. PubMed Abstract | Publisher Full Text 62. Bordewijk EM, Nahuis M, Costello MF, et al. : Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev. 2017; 1 : CD009090. PubMed Abstract | Publisher Full Text | Free Full Text 63. Hanem LGE, Stridsklev S, Júlíusson PB, et al. : Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs. J Clin Endocrinol Metab. 2018; 103 (4): 1612–21. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 64. Franik S, Eltrop SM, Kremer JA, et al. : Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018; 5 : CD010287. PubMed Abstract | Publisher Full Text 65. Rezk M, Shaheen AE, Saif El-Nasr I: Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: a randomized clinical trial. Gynecol Endocrinol. 2018; 34 (4): 298–300. PubMed Abstract | Publisher Full Text 66. Kalem MN, Kalem Z, Gurgan T: Effect of metformin and oral contraceptives on polycystic ovary syndrome and IVF cycles. J Endocrinol Invest. 2017; 40 (7): 745–52. PubMed Abstract | Publisher Full Text 67. Salamun V, Jensterle M, Janez A, et al. : Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol. 2018; 179 (1): 1–11. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 68. Palomba S, de Wilde MA, Falbo A, et al. : Pregnancy complications in women with polycystic ovary syndrome. Hum Reprod Update. 2015; 21 (5): 575–92. PubMed Abstract | Publisher Full Text 69. Yu HF, Chen HS, Rao DP, et al. : Association between polycystic ovary syndrome and the risk of pregnancy complications: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2016; 95 (51): e4863. PubMed Abstract | Publisher Full Text | Free Full Text 70. Rocha ALL, Campos RR, Miranda MMS, et al. : Safety of hormonal contraception for obese women. Expert Opin Drug Saf. 2017; 16 (12): 1387–93. PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 26 Apr 2019 ADD YOUR COMMENT Comment Author details Author details 1 Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 2 Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 3 Department of Clinical and Toxicological Analysis, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Ana L. Rocha Roles: Conceptualization, Data Curation, Writing – Original Draft Preparation Flávia R. Oliveira Roles: Data Curation, Writing – Original Draft Preparation Rosana C. Azevedo Roles: Conceptualization, Data Curation, Writing – Review & Editing Virginia A. Silva Roles: Data Curation, Writing – Original Draft Preparation Thais M. Peres Roles: Data Curation, Writing – Original Draft Preparation Ana L. Candido Roles: Project Administration, Supervision, Writing – Review & Editing Karina B. Gomes Roles: Conceptualization, Supervision, Writing – Review & Editing Fernando M. Reis Roles: Conceptualization, Data Curation, Methodology, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 26 Apr 2019, 8:565 https://doi.org/10.12688/f1000research.15318.1 Copyright © 2019 Rocha AL et al . 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 Rocha AL, Oliveira FR, Azevedo RC et al. Recent advances in the understanding and management of polycystic ovary syndrome [version 1; peer review: 3 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):565 ( https://doi.org/10.12688/f1000research.15318.1 ) 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 Joop Laven , Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus University Medical Center (Erasmus MC), The Netherlands Competing interests: No competing interests were declared. (for version 1) Mariano Bizzarri , Department of Experimental Medicine, Systems Biology Group, University La Sapienza, Italy Competing interests: No competing interests were declared. (for version 1) Harpal Randeva , Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, UK Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 26 Apr 2019 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 26 Apr 19 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. Joop Laven , Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus University Medical Center (Erasmus MC), The Netherlands Competing interests: No competing interests were declared. View more View less Mariano Bizzarri , Department of Experimental Medicine, Systems Biology Group, University La Sapienza, Italy Competing interests: No competing interests were declared. View more View less Harpal Randeva , Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, UK 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 = "Recent advances in the understanding and...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/8-565/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/8-565/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/8-565/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Rocha AL et al.'); 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/8-565/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/8-565", templates : { twitter : "Recent advances in the understanding and management of polycystic.... Rocha AL et al., published by " + "@F1000Research" + ", https://f1000research.com/articles/8-565/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/15318/16688") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("faculty-reviews", "article", "16688"); $(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 = { "47591": 1, "47592": 0, "47593": 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 = "b8efd201-8fd4-445d-a1de-21771b98f017"; 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(",","/")); } }); });