[automated] update transfemscience

transfemscience.org/assets/css/hover-refs.css

@@ -0,0 +1,45 @@
+/* Hover References Popup Styling */
+
+.reference-hover-box {
+    margin-top: 5px;
+    position: absolute;
+    z-index: 9999;
+    background-color: var(--background-color, #ffffff);
+    color: var(--font-color, #333333);
+    border: 1px solid var(--code-border-color, #ccc);
+    box-shadow: 0 4px 12px rgba(0, 0, 0, 0.15), 0 8px 24px rgba(0, 0, 0, 0.1);
+    /* Deeper shadow */
+    padding: 8px;
+    border-radius: 4px;
+    max-width: 400px;
+    font-size: 0.9em;
+    line-height: 1.4;
+    pointer-events: auto;
+    /* Allow interaction with the box */
+
+    /* Ensure it handles overflow or long text gracefully */
+    word-wrap: break-word;
+}
+
+/* Dark mode support if variables are set */
+html[data-theme='dark'] .reference-hover-box {
+    background-color: var(--background-color, #222);
+    /* Fallback to dark grey */
+    border-color: var(--code-border-color, #444);
+    box-shadow: 0 4px 12px rgba(0, 0, 0, 0.4), 0 8px 24px rgba(0, 0, 0, 0.3);
+}
+
+/* Match link styles to article content links */
+.reference-hover-box a {
+    color: var(--link-color);
+    text-decoration: none;
+    background-image: linear-gradient(var(--link-underline-color) 0%, var(--link-underline-color) 100%);
+    background-repeat: repeat-x;
+    background-position: 0 100%;
+    background-size: 1px 1px;
+    word-break: break-all;
+}
+
+.reference-hover-box a:hover {
+    background-image: linear-gradient(var(--link-underline-color-hover) 0%, var(--link-underline-color-hover) 100%);
+}

transfemscience.org/assets/js/hover-refs.js

@@ -0,0 +1,373 @@
+/**
+ * Hover References Feature
+ * 
+ * Matches inline citation links with their corresponding full reference
+ * from the reference list by comparing URLs (hrefs).
+ */
+
+(function () {
+  document.addEventListener('DOMContentLoaded', function () {
+    initHoverReferences();
+  });
+
+  function initHoverReferences() {
+    // 1. Find the References section and list
+    const referencesHeader = findReferencesHeader();
+    if (!referencesHeader) return;
+
+    // Helper to normalize URLs for matching
+    // 1. Decode URI (handles %5B vs [ mismatch)
+    // 2. Lowercase
+    const normalizeRefUrl = (url) => {
+      let u = "";
+      try {
+        u = decodeURI(url).toLowerCase();
+      } catch (e) {
+        u = url.toLowerCase();
+      }
+      u = u.replace(/^(https?:)?\/\//, '').replace(/^www\./, '');
+
+      // Check for archive.org URL (e.g. web.archive.org/web/20070430161048/http://... or .../20210717084442if_/...)
+      const archiveRegex = /^web\.archive\.org\/web\/\d+(?:if_)?\//;
+      if (archiveRegex.test(u)) {
+        u = u.replace(archiveRegex, '');
+        // Re-strip protocol and www from the target URL
+        u = u.replace(/^(https?:)?\/\//, '').replace(/^www\./, '');
+      }
+
+      return u.split('#')[0].replace(/\/$/, '');
+    };
+
+    // Find all reference lists within the References section
+    // The References section might have subsections, each with their own list
+    // We need to find the container element that encompasses all References content
+
+    // Strategy: Find the parent section/container, or collect all siblings until next same-level header
+    let referenceLists = [];
+    let currentElement = referencesHeader.nextElementSibling;
+    const headerLevel = parseInt(referencesHeader.tagName.charAt(1)) || 2;
+
+    while (currentElement) {
+      // Stop if we hit another header of same or higher level (lower number)
+      if (/^H[1-6]$/.test(currentElement.tagName)) {
+        const currentLevel = parseInt(currentElement.tagName.charAt(1));
+        if (currentLevel <= headerLevel) {
+          break; // End of References section
+        }
+      }
+
+      // Collect all UL and OL elements (including nested ones in subsections)
+      if (currentElement.tagName === 'UL' || currentElement.tagName === 'OL') {
+        referenceLists.push(currentElement);
+      }
+      // Also check for lists inside divs or other container elements
+      const nestedLists = currentElement.querySelectorAll('ul, ol');
+      nestedLists.forEach(list => referenceLists.push(list));
+
+      currentElement = currentElement.nextElementSibling;
+    }
+
+    if (referenceLists.length === 0) return;
+
+    // 2. Parse all reference list items from all lists
+    // Map of "URL" -> HTML content
+    const urlMap = new Map();
+
+    referenceLists.forEach(referenceList => {
+      const listItems = referenceList.querySelectorAll(':scope > li'); // Direct children only to avoid duplicates
+
+      listItems.forEach(item => {
+        // Find all links in the reference item
+        const links = item.querySelectorAll('a');
+        links.forEach(link => {
+          const rawHref = link.getAttribute('href');
+          if (rawHref && !rawHref.startsWith('#')) { // Ignore anchor links if any
+            const href = normalizeRefUrl(rawHref); // Normalized for storage
+            // Store the item HTML for this URL
+            // If multiple refs share a URL (unlikely but possible), the last one wins, 
+            // or we could store an array. For citations, usually unique DOI/URL per ref.
+            urlMap.set(href, item.innerHTML);
+          }
+        });
+      });
+    });
+
+    // 3. Find inline citation links
+    // We look for links inside the article body
+    const articleBody = document.getElementById('article');
+    if (!articleBody) return;
+
+    const links = articleBody.querySelectorAll('a');
+
+    // Create the hover box element
+    const hoverBox = document.createElement('div');
+    hoverBox.classList.add('reference-hover-box');
+    hoverBox.style.display = 'none';
+    document.body.appendChild(hoverBox);
+
+    let hideTimeout;
+
+    // Keep box open when hovering over it
+    hoverBox.addEventListener('mouseenter', () => {
+      if (hideTimeout) clearTimeout(hideTimeout);
+    });
+
+    hoverBox.addEventListener('mouseleave', () => {
+      hideTimeout = setTimeout(() => {
+        hoverBox.style.display = 'none';
+      }, 100);
+    });
+
+    links.forEach(link => {
+      const rawHref = link.getAttribute('href');
+
+      // Skip links inside any of the reference lists
+      const isInReferenceList = referenceLists.some(list => list.contains(link));
+      if (isInReferenceList) return;
+
+      // We only care if the link HAS an href and it's in our map
+      if (rawHref && !rawHref.startsWith('#')) {
+        const exactHref = normalizeRefUrl(rawHref);
+        const baseHref = exactHref.split('#')[0];
+
+        let bestMatchHTML = urlMap.get(exactHref);
+        if (!bestMatchHTML) {
+          bestMatchHTML = urlMap.get(baseHref);
+        }
+
+        // Fallback for unmatched links (e.g. Wiki links, or refs without date/year)
+        // User requested to show just the URL, but ONLY if it looks like a ref (in parentheses)
+        if (!bestMatchHTML) {
+          // Check if the link itself contains parentheses with a year (e.g. "(2005)" or "(2005a)" or "(Aly, 2020)")
+          // We allow other text inside the parens, but it MUST contain a year-like number.
+          const yearParensRegex = /\([^)]*\b\d{4}[a-z]?\b[^)]*\)/i;
+          const textHasParens = link.textContent.includes('(') || link.textContent.includes(')');
+          const textMatchingParensYear = yearParensRegex.test(link.textContent);
+
+          // Check if enclosed in parentheses or brackets by walking siblings
+          let isEnclosed = false;
+          // We only scan if:
+          // 1. The text itself doesn't contain matching parens (if it does, we already know if it's valid or not)
+          // OR
+          // 2. The text doesn't contain parens at all (so we look for surrounding ones)
+
+          if (!textMatchingParensYear && !textHasParens) {
+            // If text has parens but didn't match yearParensRegex, it's invalid (e.g. "Kuhl (Citation)")
+            // So we only scan if text does NOT have parens.
+
+            let openParenCount = 0;
+            let openBracketCount = 0;
+            let foundOpen = false;
+
+            let curr = link.previousSibling;
+            let scans = 0;
+            const MAX_SCANS = 100; // Reasonable lookbehind limit
+
+            while (curr && scans < MAX_SCANS) {
+              if (curr.nodeType === 3) { // Text node
+                const txt = curr.textContent;
+                // Count parens from right to left
+                for (let i = txt.length - 1; i >= 0; i--) {
+                  const c = txt[i];
+                  if (c === ')') openParenCount--;
+                  else if (c === '(') openParenCount++;
+                  else if (c === ']') openBracketCount--;
+                  else if (c === '[') openBracketCount++;
+
+                  if (openParenCount > 0 || openBracketCount > 0) {
+                    foundOpen = true;
+                    break;
+                  }
+                }
+              } else if (curr.nodeType === 1) { // Element node
+                const tagName = curr.tagName;
+                // Stop at block boundaries
+                if (/^(DIV|P|BODY|MAIN|SECTION|BLOCKQUOTE|UL|OL|LI|TABLE|BR|HR|H[1-6])$/.test(tagName)) {
+                  break;
+                }
+                // Check text content of inline elements
+                const txt = curr.textContent;
+                for (let i = txt.length - 1; i >= 0; i--) {
+                  const c = txt[i];
+                  if (c === ')') openParenCount--;
+                  else if (c === '(') openParenCount++;
+                  else if (c === ']') openBracketCount--;
+                  else if (c === '[') openBracketCount++;
+
+                  if (openParenCount > 0 || openBracketCount > 0) {
+                    foundOpen = true;
+                    break;
+                  }
+                }
+              }
+
+              if (foundOpen) break;
+              curr = curr.previousSibling;
+              scans++;
+            }
+
+            if (foundOpen) {
+              isEnclosed = true;
+            }
+          }
+
+          if (textMatchingParensYear || isEnclosed) {
+            let displayUrl = rawHref;
+            if (rawHref.startsWith('/')) {
+              displayUrl = 'https://transfemscience.org' + rawHref;
+            }
+            bestMatchHTML = `<div class="fallback-url-content"><a href="${rawHref}" target="_blank">${displayUrl}</a></div>`;
+          }
+        }
+
+        if (bestMatchHTML) {
+
+          link.classList.add('reference-link');
+
+          link.addEventListener('mouseenter', (e) => {
+            // Clear any pending hide timeout
+            if (hideTimeout) clearTimeout(hideTimeout);
+
+            hoverBox.innerHTML = bestMatchHTML;
+            hoverBox.style.display = 'block';
+
+            // Use getClientRects to handle multi-line links; find the rect under the mouse
+            const rects = link.getClientRects();
+            let rect = rects.length > 0 ? rects[0] : link.getBoundingClientRect();
+
+            // Find the rect that contains the mouse Y position
+            if (rects.length > 1) {
+              let bestRect = rects[0];
+              let minDistance = Infinity;
+
+              for (let i = 0; i < rects.length; i++) {
+                const r = rects[i];
+                // Check if mouse Y is within this rect's vertical bounds
+                if (e.clientY >= r.top && e.clientY <= r.bottom) {
+                  bestRect = r;
+                  break; // Found exact line match
+                }
+
+                // Fallback: distance to vertical center
+                const centerY = r.top + (r.height / 2);
+                const dist = Math.abs(e.clientY - centerY);
+                if (dist < minDistance) {
+                  minDistance = dist;
+                  bestRect = r;
+                }
+              }
+              rect = bestRect;
+            }
+
+            // Positioning
+            let top = rect.bottom + window.scrollY; // 0px gap
+            let left = rect.left + window.scrollX;
+
+            // Boundary checks
+            if (left + hoverBox.offsetWidth > window.innerWidth) {
+              left = window.innerWidth - hoverBox.offsetWidth - 10;
+            }
+
+            hoverBox.style.top = `${top}px`;
+            hoverBox.style.left = `${left}px`;
+          });
+
+          link.addEventListener('mouseleave', () => {
+            // Set a timeout to hide the box, giving time to move into it
+            hideTimeout = setTimeout(() => {
+              hoverBox.style.display = 'none';
+            }, 100);
+
+            // Mobile Long Press Support (Touch) AND Desktop Click-and-Hold
+            let longPressTimer;
+            let isLongPress = false;
+
+            const startPress = (e) => {
+              // Only left click for mouse (button 0)
+              if (e.type === 'mousedown' && e.button !== 0) return;
+
+              isLongPress = false;
+              longPressTimer = setTimeout(() => {
+                isLongPress = true;
+
+                // Show hover box
+                if (hideTimeout) clearTimeout(hideTimeout);
+                hoverBox.innerHTML = bestMatchHTML;
+                hoverBox.style.display = 'block';
+
+                hoverBox.style.display = 'block';
+
+                const rects = link.getClientRects();
+                const rect = rects.length > 0 ? rects[0] : link.getBoundingClientRect();
+
+                let top = rect.bottom + window.scrollY;
+                let left = rect.left + window.scrollX;
+
+                if (left + hoverBox.offsetWidth > window.innerWidth) {
+                  left = window.innerWidth - hoverBox.offsetWidth - 10;
+                }
+
+                hoverBox.style.top = `${top}px`;
+                hoverBox.style.left = `${left}px`;
+
+              }, 500); // 500ms for long press
+            };
+
+            const cancelPress = () => {
+              clearTimeout(longPressTimer);
+            };
+
+            const endPress = (e) => {
+              clearTimeout(longPressTimer);
+              if (isLongPress) {
+                e.preventDefault(); // Prevent default action (click/navigate)
+                // Note for desktop: 'click' event might still fire after mouseup if we don't prevent it there too
+              }
+            };
+
+            // Touch Listeners
+            link.addEventListener('touchstart', startPress, { passive: true });
+            link.addEventListener('touchend', endPress);
+            link.addEventListener('touchmove', cancelPress);
+
+            // Mouse Listeners (Desktop)
+            link.addEventListener('mousedown', startPress);
+            link.addEventListener('mouseup', endPress);
+            link.addEventListener('mouseleave', cancelPress);
+
+            link.addEventListener('click', (e) => {
+              if (isLongPress) {
+                e.preventDefault();
+                e.stopPropagation();
+                isLongPress = false; // Reset
+              }
+            });
+
+            link.addEventListener('contextmenu', (e) => {
+              if (isLongPress) {
+                e.preventDefault(); // Prevent default context menu
+                isLongPress = false; // Reset
+              }
+            });
+          });
+        }
+      }
+    });
+  }
+
+  function findReferencesHeader() {
+    // Try by ID first
+    let header = document.getElementById('references');
+    if (header) return header;
+
+    // Try by text content
+    const headers = document.querySelectorAll('h1, h2, h3, h4, h5, h6');
+    for (const h of headers) {
+      if (h.textContent.trim().toLowerCase() === 'references') {
+        return h;
+      }
+    }
+    return null;
+  }
+
+})();

transfemscience.org/feed-posts.xml

@@ -1 +1 @@
-<?xml version="1.0" encoding="utf-8"?><feed xmlns="http://www.w3.org/2005/Atom" ><generator uri="https://jekyllrb.com/" version="3.10.0">Jekyll</generator><link href="https://transfemscience.org/feed-posts.xml" rel="self" type="application/atom+xml" /><link href="https://transfemscience.org/" rel="alternate" type="text/html" /><updated>2025-12-20T18:17:02-08:00</updated><id>https://transfemscience.org/feed-posts.xml</id><title type="html">Transfeminine Science</title><subtitle>Transfeminine Science is a site for information on hormone therapy for transfeminine people.</subtitle><author><name>Transfeminine Science</name></author></feed>
+<?xml version="1.0" encoding="utf-8"?><feed xmlns="http://www.w3.org/2005/Atom" ><generator uri="https://jekyllrb.com/" version="3.10.0">Jekyll</generator><link href="https://transfemscience.org/feed-posts.xml" rel="self" type="application/atom+xml" /><link href="https://transfemscience.org/" rel="alternate" type="text/html" /><updated>2026-02-06T16:23:17-08:00</updated><id>https://transfemscience.org/feed-posts.xml</id><title type="html">Transfeminine Science</title><subtitle>Transfeminine Science is a site for information on hormone therapy for transfeminine people.</subtitle><author><name>Transfeminine Science</name></author></feed>

transfemscience.org/feed.xml

@@ -1,4 +1,4 @@
-<?xml version="1.0" encoding="utf-8"?><feed xmlns="http://www.w3.org/2005/Atom" ><generator uri="https://jekyllrb.com/" version="3.10.0">Jekyll</generator><link href="https://transfemscience.org/feed.xml" rel="self" type="application/atom+xml" /><link href="https://transfemscience.org/" rel="alternate" type="text/html" /><updated>2025-12-20T18:17:02-08:00</updated><id>https://transfemscience.org/feed.xml</id><title type="html">Transfeminine Science | Articles</title><subtitle>Transfeminine Science is a site for information on hormone therapy for transfeminine people.</subtitle><author><name>Transfeminine Science</name></author><entry><title type="html">A Review of Pharmaceutical Interventions for Scalp Hair Loss and Implications for Transfeminine People</title><link href="https://transfemscience.org/articles/hair-loss/" rel="alternate" type="text/html" title="A Review of Pharmaceutical Interventions for Scalp Hair Loss and Implications for Transfeminine People" /><published>2025-09-08T18:00:00-07:00</published><updated>2025-09-09T00:00:00-07:00</updated><id>https://transfemscience.org/articles/hair-loss</id><content type="html" xml:base="https://transfemscience.org/articles/hair-loss/"><![CDATA[<h1 id="a-review-of-pharmaceutical-interventions-for-scalp-hair-loss-and-implications-for-transfeminine-people">A Review of Pharmaceutical Interventions for Scalp Hair Loss and Implications for Transfeminine People</h1>
+<?xml version="1.0" encoding="utf-8"?><feed xmlns="http://www.w3.org/2005/Atom" ><generator uri="https://jekyllrb.com/" version="3.10.0">Jekyll</generator><link href="https://transfemscience.org/feed.xml" rel="self" type="application/atom+xml" /><link href="https://transfemscience.org/" rel="alternate" type="text/html" /><updated>2026-02-06T16:23:17-08:00</updated><id>https://transfemscience.org/feed.xml</id><title type="html">Transfeminine Science | Articles</title><subtitle>Transfeminine Science is a site for information on hormone therapy for transfeminine people.</subtitle><author><name>Transfeminine Science</name></author><entry><title type="html">A Review of Pharmaceutical Interventions for Scalp Hair Loss and Implications for Transfeminine People</title><link href="https://transfemscience.org/articles/hair-loss/" rel="alternate" type="text/html" title="A Review of Pharmaceutical Interventions for Scalp Hair Loss and Implications for Transfeminine People" /><published>2025-09-08T18:00:00-07:00</published><updated>2025-09-09T00:00:00-07:00</updated><id>https://transfemscience.org/articles/hair-loss</id><content type="html" xml:base="https://transfemscience.org/articles/hair-loss/"><![CDATA[<h1 id="a-review-of-pharmaceutical-interventions-for-scalp-hair-loss-and-implications-for-transfeminine-people">A Review of Pharmaceutical Interventions for Scalp Hair Loss and Implications for Transfeminine People</h1>
 
 <!-- Supports up to four authors per article currently (author, author2, author3, author4) -->
 
@@ -38,7 +38,7 @@
 
 <p>In the United States, finasteride prescriptions have increased exponentially in recent years, largely driven by its use in the treatment of hair loss (<a href="https://www.americanhairloss.org/booming-demand-us-sees-200-surge-in-finasteride-prescriptions-over-7-years/">AHLA, 2024</a>). Dutasteride prescriptions are far fewer, estimated in the hundreds of thousands, but also growing due to increased use for AGA. This difference is largely due to finasteride being widely licensed for this indication throughout the world, whilst dutasteride remains off-label in most countries (<a href="https://doi.org/10.1152/physrev.00005.2024">Altendorf et al., 2025</a>). However, dutasteride is licensed for use in the treatment of AGA in South Korea, Japan and Mexico. Increasing interest is driving further adoption and research into its use.</p>
 
-<p>Despite its use for AGA being mostly off-label, dutasteride is now widely regarded as a more efficacious and hence superior 5-ARI than finasteride. Numerous studies have established that dutasteride results in greater suppression of serum DHT concentrations (i.e., about 70% with finasteride vs 90–95% with dutasteride) (<a href="https://doi.org/10.1210/jc.2003-030330">Clark et al., 2004</a>; <a href="https://doi.org/10.1016/j.jaad.2006.05.007">Olsen et al., 2006</a>; <a href="https://doi.org/10.1210/jc.2006-2203">Amory et al., 2007</a>; <a href="https://doi.org/10.1016/j.talanta.2014.07.087">Upreti et al., 2015</a>). Another study directly comparing scalp tissue concentrations found that dutasteride reduced DHT substantially more than finasteride (mean reduction of about 65% with finasteride versus 90% with dutasteride, though with wide interindividual variation). (<a href="https://doi.org/10.1016/j.cca.2023.117456">Hobo et al., 2023</a>). These differences have been primarily attributed to its broader inhibition of the 5α-reductase enzyme. More specifically, finasteride is a selective inhibitor of type II and III 5α-reductase, whereas dutasteride indiscriminately acts on all three isoforms (<a href="https://doi.org/10.1016/S0009-9236(98)90054-6">Gisleskog et al., 1998</a>; <a href="https://doi.org/10.2165/00003495-200868040-00008">Keam &amp; Scott, 2008</a>; <a href="https://doi.org/10.1515/HMBCI.2010.035">Yamana, Labrie, &amp; Luu-The, 2010</a>). Dutasteride has also been theorised to accumulate inside certain tissues, further enhancing its therapeutic effect.</p>
+<p>Despite its use for AGA being mostly off-label, dutasteride is now widely regarded as a more efficacious and hence superior 5-ARI than finasteride. Numerous studies have established that dutasteride results in greater suppression of serum DHT concentrations (i.e., about 70% with finasteride vs 90–95% with dutasteride) (<a href="https://doi.org/10.1210/jc.2003-030330">Clark et al., 2004</a>; <a href="https://doi.org/10.1016/j.jaad.2006.05.007">Olsen et al., 2006</a>; <a href="https://doi.org/10.1210/jc.2006-2203">Amory et al., 2007</a>; <a href="https://doi.org/10.1016/j.talanta.2014.07.087">Upreti et al., 2015</a>). Another study directly comparing scalp tissue concentrations found that dutasteride reduced DHT substantially more than finasteride (mean reduction of about 65% with finasteride versus 90% with dutasteride, though with wide interindividual variation) (<a href="https://doi.org/10.1016/j.cca.2023.117456">Hobo et al., 2023</a>). These differences have been primarily attributed to its broader inhibition of the 5α-reductase enzyme. More specifically, finasteride is a selective inhibitor of type II and III 5α-reductase, whereas dutasteride indiscriminately acts on all three isoforms (<a href="https://doi.org/10.1016/S0009-9236(98)90054-6">Gisleskog et al., 1998</a>; <a href="https://doi.org/10.2165/00003495-200868040-00008">Keam &amp; Scott, 2008</a>; <a href="https://doi.org/10.1515/HMBCI.2010.035">Yamana, Labrie, &amp; Luu-The, 2010</a>). Dutasteride has also been theorised to accumulate inside certain tissues, further enhancing its therapeutic effect.</p>
 
 <p>In accordance with the above, two large network meta-analysis studies found that oral dutasteride is superior to oral and topical finasteride in the treatment of male AGA in terms of both total hair density and terminal hair density (<a href="https://doi.org/10.1111/jocd.16362">Gupta et al., 2024a</a>; <a href="https://doi.org/10.1111/jocd.70320">Gupta et al., 2025a</a>). These studies also found the effects of finasteride and dutasteride to be dose-dependent. On average, there was no difference between treatment groups using oral and topical finasteride. A systematic review found that dutasteride was superior to finasteride in some studies in terms of hair thickness (<a href="https://doi.org/10.4081/dr.2024.9909">Almudimeegh et al., 2024</a>). However, in contrast to the above findings in the case of male AGA, a network meta-analysis of studies investigating different interventions for female AGA found that clinical trials assessing the effectiveness of dutasteride do not yet exist (<a href="https://doi.org/10.1111/jocd.15910">Gupta et al., 2024b</a>). Notably, oral finasteride given at a dose of 1 mg/day was not found to be effective in treating female AGA, yet oral finasteride used at a dose of 5 mg/day outperformed all other single-agent interventions. Because of the dose-dependent effects of 5-ARIs, it could well be that dutasteride might be more efficacious than finasteride in the treatment of female AGA, as in male AGA. Hopefully, future clinical trials will shed light on this.</p>
 
@@ -92,7 +92,7 @@
 
 <p>A retrospective study of users of oral minoxidil investigated the frequency of adverse effects in both men and women receiving a median dose of 1.63 mg/day (<a href="https://doi.org/10.1016/j.jaad.2021.02.054">Vañó-Galván et al., 2021</a>). The following were found to occur: <a href="https://en.wikipedia.org/wiki/Hypertrichosis">hypertrichosis</a> (excessive facial/body hair) in 15.1%, lightheadedness in 1.7%, fluid retention in 1.3%, tachycardia in 0.9%, headache in 0.4%, periorbital edema (temporary swelling around the eyes) in 0.3%, and insomnia in 0.2%. The total frequency of adverse effects was 20.4%, which prompted discontinuation in 1.2% of users, overall. Another study reported an overall hypertrichosis incidence of 24%, with the highest rates being found in the sideburns (81%), temples (73%), arms (63%), and upper lip (51%) (<a href="https://doi.org/10.1016/j.jaad.2020.08.124">Jimenez-Cauhe et al., 2021</a>). By contrast, topical minoxidil is associated with much lower overall rates of hypertrichosis. Most studies have reported incidence rates of between 0 and 5% (<a href="https://doi.org/10.1016/j.jaad.2003.06.014">Lucky et al., 2004</a>; <a href="http://jddonline.com/articles/dermatology/S1545961616P0883X">Blume-Peytavi et al., 2016</a>; <a href="https://doi.org/10.1016/j.jaad.2019.08.060">Ramos et al., 2020</a>; <a href="https://doi.org/10.1001/jamadermatol.2024.0284">Penha et al., 2024</a>; <a href="https://doi.org/10.1016/j.pdpdt.2024.103966">Yang et al., 2024</a>). These findings are consistent with a meta-analysis that reported point estimates of incidence rates for hypertrichosis of 10%, 15%, and 33% for oral minoxidil at 0.25 mg/day, 0.5 mg/day, and 1.25 mg/day, respectively, and 0% and 2% for topical minoxidil at a 2% and 5% concentration, respectively (<a href="https://doi.org/10.1016/j.jdrv.2025.02.013">Wiechert et al., 2025</a>). Despite this, the discontinuation rate across all studies was 0.49%. There also seemed to be no statistically significant difference between the rate of discontinuation for oral and topical formulations, suggesting that hypertrichosis appears to be very well tolerated.</p>
 
-<p>A concern associated with the use of oral minoxidil is its potential impact on cardiovascular health (<a href="https://doi.org/10.5070/D32946186">Ibraheim et al., 2023</a>). Since tachycardia can increase myocardial workload and lead to symptoms such as palpitations or chest discomfort, oral minoxidil should be approached cautiously, especially by individuals with underlying cardiovascular issues. Fortunately, the overall risk of severe cardiovascular complications from low-dose oral minoxidil seems to be very low in the general population (<a href="https://doi.org/10.1016/j.jaad.2020.06.1009">Randolph &amp; Tosti, 2021</a>; <a href="https://doi.org/10.1016/j.jaad.2021.02.054">Vañó-Galván et al., 2021</a>). Meanwhile, skin reactions appear to be relatively common in users of topical minoxidil. This often manifests as scalp eczema and itching, although rates of incidence vary by study (<a href="https://doi.org/10.1016/j.jaad.2003.06.014">Lucky et al., 2004</a>; <a href="https://doi.org/10.2174/187221312800166859">Rossi et al., 2012</a>; <a href="https://doi.org/10.1001/jamadermatol.2024.0284">Penha et al., 2024</a>). The culprit behind this irritating effect appears not to be minoxidil itself, but rather the ingredients in certain formulations such as propylene glycol (<a href="https://doi.org/10.2147/DDDT.S214907">Suchonwanit, Thammarucha, &amp; Leerunyakul, 2019</a>). These solvents help deliver minoxidil into the scalp, but are known to cause skin irritation in susceptible individuals. It also appears that, for most people, long-term topical minoxidil therapy may be precluded by non-compliance (<a href="https://doi.org/10.1080/09546630701383727">Ali Mapar &amp; Omidian, 2007</a>; <a href="https://doi.org/10.1007/s13555-023-00919-x">Shadi, 2023</a>).</p>
+<p>A concern associated with the use of oral minoxidil is its potential impact on cardiovascular health (<a href="https://doi.org/10.5070/D329461861">Ibraheim et al., 2023</a>). Since tachycardia can increase myocardial workload and lead to symptoms such as palpitations or chest discomfort, oral minoxidil should be approached cautiously, especially by individuals with underlying cardiovascular issues. Fortunately, the overall risk of severe cardiovascular complications from low-dose oral minoxidil seems to be very low in the general population (<a href="https://doi.org/10.1016/j.jaad.2020.06.1009">Randolph &amp; Tosti, 2021</a>; <a href="https://doi.org/10.1016/j.jaad.2021.02.054">Vañó-Galván et al., 2021</a>). Meanwhile, skin reactions appear to be relatively common in users of topical minoxidil. This often manifests as scalp eczema and itching, although rates of incidence vary by study (<a href="https://doi.org/10.1016/j.jaad.2003.06.014">Lucky et al., 2004</a>; <a href="https://doi.org/10.2174/187221312800166859">Rossi et al., 2012</a>; <a href="https://doi.org/10.1001/jamadermatol.2024.0284">Penha et al., 2024</a>). The culprit behind this irritating effect appears not to be minoxidil itself, but rather the ingredients in certain formulations such as propylene glycol (<a href="https://doi.org/10.2147/DDDT.S214907">Suchonwanit, Thammarucha, &amp; Leerunyakul, 2019</a>). These solvents help deliver minoxidil into the scalp, but are known to cause skin irritation in susceptible individuals. It also appears that, for most people, long-term topical minoxidil therapy may be precluded by non-compliance (<a href="https://doi.org/10.1080/09546630701383727">Ali Mapar &amp; Omidian, 2007</a>; <a href="https://doi.org/10.1007/s13555-023-00919-x">Shadi, 2023</a>).</p>
 
 <p>The increase in overall body hair growth (i.e., hypertrichosis) is arguably the most consequential side effects for transfeminine people found to occur with minoxidil. As noted above, hypertrichosis is much more common with oral minoxidil than with topical minoxidil. This is a result of the differences in pharmacology between these routes and the extensive systemic absorption that occurs in the case of the former (<a href="https://doi.org/10.1016/j.jdrv.2024.08.002">Desai et al., 2024</a>; <a href="https://doi.org/10.1016/j.jdrv.2025.02.013">Wiechert et al., 2025</a>). In transmasculine people, an increase in body hair growth and diameter could be beneficial. However, these effects are usually not desired by transfeminine people. Consequently, some transfeminine people may prefer to use topical minoxidil over oral minoxidil, despite possible benefits to effectiveness from the latter in some individuals.</p>
 
@@ -161,7 +161,7 @@
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@@ -599,6 +600,8 @@ Using the term desistence in this way does not imply anything about the identity
 
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+  <li>Aly. (2018). An Introduction to Hormone Therapy for Transfeminine People. <em>Transfeminine Science</em>. [<a href="/articles/transfem-intro/">URL</a>]</li>
+  <li>Aly. (2020). Approximate Comparable Dosages of Estradiol by Different Routes. <em>Transfeminine Science</em>. [<a href="/articles/e2-equivalent-doses/">URL</a>]</li>
   <li>Antoniazzi, F., Zamboni, G., Bertoldo, F., Lauriola, S., Mengarda, F., Pietrobelli, A., &amp; Tatò, L. (2003). Bone mass at final height in precocious puberty after gonadotropin-releasing hormone agonist with and without calcium supplementation. <em>The Journal of Clinical Endocrinology and Metabolism</em>, <em>88</em>(3), 1096–1101. [DOI:<a href="https://doi.org/10.1210/jc.2002-021154">10.1210/jc.2002-021154</a>]</li>
   <li>Arnoldussen, M., Steensma, T. D., Popma, A., van der Miesen, A., Twisk, J., &amp; de Vries, A. (2020). Re-evaluation of the Dutch approach: are recently referred transgender youth different compared to earlier referrals? <em>European Child &amp; Adolescent Psychiatry</em>, <em>29</em>(6), 803–811. [DOI:<a href="https://doi.org/10.1007/s00787-019-01394-6">10.1007/s00787-019-01394-6</a>]</li>
   <li>Bakwin, H. (1968). Deviant gender-role behavior in children: relation to homosexuality. <em>Pediatrics</em>, <em>41</em>(3), 620–629. [<a href="https://pubmed.ncbi.nlm.nih.gov/5641781/">PubMed</a>] [DOI:<a href="https://publications.aap.org/pediatrics/article-abstract/41/3/620/74522/DEVIANT-GENDER-ROLE-BEHAVIOR-IN-CHILDREN-RELATION">10.1542/peds.41.3.620</a>]</li>
@@ -773,6 +776,8 @@ Using the term desistence in this way does not imply anything about the identity
 
 <ul>
   <li>Abbott Laboratories. (2009). <em>Estradiol. Architect System.</em> Abbott Park, Illinois/Wiesbaden, Germany: Abbott Laboratories. [<a href="https://web.archive.org/web/20200127014925/http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf">PDF</a>]</li>
+  <li>Aly. (2020). Estrogens and Their Influences on Coagulation and Risk of Blood Clots. <em>Transfeminine Science</em>. [<a href="/articles/estrogens-blood-clots/">URL</a>]</li>
+  <li>Aly. (2021). An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations. <em>Transfeminine Science</em>. [<a href="/articles/injectable-e2-meta-analysis/">URL</a>]</li>
   <li>Behre, H. M., Abshagen, K., Oettel, M., Hubler, D., &amp; Nieschlag, E. (1999). Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. <em>European Journal of Endocrinology</em>, <em>140</em>(5), 414–419. [DOI:<a href="https://doi.org/10.1530/eje.0.1400414">10.1530/eje.0.1400414</a>]</li>
 </ul>]]></content><author><name>{&quot;first_name&quot;=&gt;&quot;Aly&quot;, &quot;last_name&quot;=&gt;&quot;W.&quot;, &quot;author-link&quot;=&gt;&quot;/about/#aly&quot;, &quot;articles-link&quot;=&gt;&quot;/articles-by-author/aly/&quot;}</name></author><category term="github" /><category term="workspace" /><summary type="html"><![CDATA[An Interactive Web Simulator for Estradiol Levels with Injectable Estradiol Esters By Aly | First published July 16, 2021 | Last modified April 12, 2023]]></summary><media:thumbnail xmlns:media="http://search.yahoo.com/mrss/" url="https://transfemscience.org/assets/images/injectable-e2/simulator-screenie.png" /><media:content medium="image" url="https://transfemscience.org/assets/images/injectable-e2/simulator-screenie.png" xmlns:media="http://search.yahoo.com/mrss/" /></entry><entry><title type="html">An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations</title><link href="https://transfemscience.org/articles/injectable-e2-meta-analysis/" rel="alternate" type="text/html" title="An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations" /><published>2021-07-16T12:00:00-07:00</published><updated>2025-05-08T00:00:00-07:00</updated><id>https://transfemscience.org/articles/injectable-e2-meta-analysis</id><content type="html" xml:base="https://transfemscience.org/articles/injectable-e2-meta-analysis/"><![CDATA[<h1 id="an-informal-meta-analysis-of-estradiol-curves-with-injectable-estradiol-preparations">An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations</h1>
 
@@ -790,7 +795,7 @@ Using the term desistence in this way does not imply anything about the identity
 
 <p>Estradiol is the main estrogen used in transfeminine hormone therapy and is available in a variety of different forms for use by different <a href="https://en.wikipedia.org/wiki/Route_of_administration">routes of administration</a>. The most commonly employed forms are <a href="https://en.wikipedia.org/wiki/Oral_estradiol">oral</a>, <a href="https://en.wikipedia.org/wiki/Sublingual_estradiol">sublingual</a>, <a href="https://en.wikipedia.org/wiki/Transdermal_estradiol">transdermal</a>, and <a href="https://en.wikipedia.org/wiki/Injectable_estradiol">injectable</a> preparations. Injectable estradiol preparations have been discontinued in many countries and hence are unavailable for use in transfeminine hormone therapy in many parts of the world, for instance in most of Europe (<a href="https://doi.org/10.1530/EJE-21-0059">Glintborg et al., 2021</a>). However, they are still used by many transfeminine people particularly in the United States and in the <a href="https://en.wikipedia.org/wiki/Self-medication">do-it-yourself</a> (DIY) community. The most commonly used forms include <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a>, <a href="https://en.wikipedia.org/wiki/Estradiol_cypionate">estradiol cypionate</a>, and <a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">estradiol enanthate</a> all in oil. Injectable estradiol preparations have certain advantages over other estradiol forms that make them a popular choice for use in transfeminine hormone therapy. These include often lower cost, capacity to easily achieve higher estradiol levels that can be useful for <a href="https://en.wikipedia.org/wiki/Pharmacodynamics_of_estradiol#Antigonadotropic_effects">testosterone suppression</a>, less frequent administration, and theoretically reduced health risks relative to oral estradiol at equivalent doses due to the lack of the <a href="https://en.wikipedia.org/wiki/First_pass_effect">first pass</a> with this route (<a href="/articles/estrogens-blood-clots/">Aly, 2020</a>). The higher estradiol levels with injections are particularly useful for estradiol monotherapy, in which an antiandrogen is not used.</p>
 
-<p>Clinically used injectable estradiol preparations are formulated not as estradiol but as <a href="https://en.wikipedia.org/wiki/Estrogen_ester">estradiol esters</a>. When <a href="https://en.wikipedia.org/wiki/Intramuscular_injection">injected into muscle</a> or <a href="https://en.wikipedia.org/wiki/Subcutaneous_injection">fat</a> in <a href="https://en.wikipedia.org/wiki/Oil_solution">oil solutions</a> or <a href="https://en.wikipedia.org/wiki/Aqueous_suspension">crystalline aqueous suspensions</a>, these estradiol esters form <a href="https://en.wikipedia.org/wiki/Depot_injection">depots</a> at the injection site from which they are slowly released. Subsequent to release, estradiol esters are rapidly <a href="https://en.wikipedia.org/wiki/Metabolism">metabolized</a> into estradiol and hence act as <a href="https://en.wikipedia.org/wiki/Prodrug">prodrugs</a>. When estradiol itself is given by intramuscular injection in an <a href="https://en.wikipedia.org/wiki/Aqueous_solution">aqueous solution</a> or oil solution, it is rapidly absorbed and has a very short duration. Due to having lipophilic <a href="https://en.wikipedia.org/wiki/Ester">esters</a>, most clinically used injectable estradiol esters are more <a href="https://en.wikipedia.org/wiki/Lipophilicity">fat-soluble</a> than estradiol (as measured by <a href="https://en.wikipedia.org/wiki/Octanol-water_partition_coefficient">oil–water partition coefficient</a> (P)) (<a href="https://en.wikipedia.org/wiki/Template:Structural_properties_of_selected_estradiol_esters">Table</a>). When these esters are administered as oil solutions by intramuscular or subcutaneous injection, their increased lipophilicity causes them to be released from the injection-site depot more slowly than estradiol and to therefore have longer durations. In the case of <a href="https://en.wikipedia.org/wiki/Fatty_acid">fatty acid</a> esters, the longer the chain length of the ester—as in e.g. <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a> (5 carbons) vs. <a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">estradiol enanthate</a> (7 carbons) vs. <a href="https://en.wikipedia.org/wiki/Estradiol_undecylate">estradiol undecylate</a> (10 carbons)—the greater the fat solubility, the slower the rate of release from the depot, and the longer the time to peak levels and duration (<a href="https://doi.org/10.1111/j.2042-7158.1959.tb10412.x">Edkins, 1959</a>; <a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://journal.pda.org/content/35/3/106.short">Chien, 1981</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://dspace.library.uu.nl/handle/1874/348465">Kalicharan, 2017</a>; <a href="https://doi.org/10.1007/978-981-13-3642-3_7">Vhora et al., 2019</a>). The durations of both injectable oil solutions and aqueous suspensions depend on the ester and its particular <a href="https://en.wiktionary.org/wiki/physicochemical">physicochemical</a> properties, but the characteristics of these preparations are different and they work in distinct ways to produce their depot effects (<a href="https://doi.org/10.1016/0039-128X(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>). The durations of oil solutions are dependent on the lipophilicity of the ester as well as oil vehicle, whereas the durations of aqueous suspensions depend on the properties of the ester <a href="https://en.wikipedia.org/wiki/Crystal_structure">crystal lattice</a> as well as <a href="https://en.wikipedia.org/wiki/Particle_size">crystal sizes</a> (<a href="https://journal.pda.org/content/35/3/106.short">Chien, 1981</a>; <a href="https://doi.org/10.1016/0039-128X(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>). The <a href="https://en.wikipedia.org/wiki/Polymer">polymeric</a> estradiol ester <a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate">polyestradiol phosphate</a> is more <a href="https://en.wikipedia.org/wiki/Hydrophilicity">hydrophilic</a> (water-soluble) than estradiol and works differently than other injectable estradiol preparations. Ιt is composed of many estradiol molecules linked together via <a href="https://en.wikipedia.org/wiki/Phosphate_ester">phosphate esters</a> (on average 13 molecules of estradiol per one molecule of polyestradiol phosphate) and has a prolonged duration due to slow <a href="https://en.wikipedia.org/wiki/Bond_cleavage">cleavage</a> into estradiol following injection. Estradiol esters are able to substantially prolong the duration of estradiol when used as injectables and these preparations have durations ranging from days to months depending on the ester and how it is formulated (<a href="https://en.wikipedia.org/w/index.php?title=Template:Potencies_and_durations_of_natural_estrogens_by_intramuscular_injection&amp;oldid=964345939">Table</a>).</p>
+<p>Clinically used injectable estradiol preparations are formulated not as estradiol but as <a href="https://en.wikipedia.org/wiki/Estrogen_ester">estradiol esters</a>. When <a href="https://en.wikipedia.org/wiki/Intramuscular_injection">injected into muscle</a> or <a href="https://en.wikipedia.org/wiki/Subcutaneous_injection">fat</a> in <a href="https://en.wikipedia.org/wiki/Oil_solution">oil solutions</a> or <a href="https://en.wikipedia.org/wiki/Aqueous_suspension">crystalline aqueous suspensions</a>, these estradiol esters form <a href="https://en.wikipedia.org/wiki/Depot_injection">depots</a> at the injection site from which they are slowly released. Subsequent to release, estradiol esters are rapidly <a href="https://en.wikipedia.org/wiki/Metabolism">metabolized</a> into estradiol and hence act as <a href="https://en.wikipedia.org/wiki/Prodrug">prodrugs</a>. When estradiol itself is given by intramuscular injection in an <a href="https://en.wikipedia.org/wiki/Aqueous_solution">aqueous solution</a> or oil solution, it is rapidly absorbed and has a very short duration. Due to having lipophilic <a href="https://en.wikipedia.org/wiki/Ester">esters</a>, most clinically used injectable estradiol esters are more <a href="https://en.wikipedia.org/wiki/Lipophilicity">fat-soluble</a> than estradiol (as measured by <a href="https://en.wikipedia.org/wiki/Octanol-water_partition_coefficient">oil–water partition coefficient</a> (P)) (<a href="https://en.wikipedia.org/wiki/Template:Structural_properties_of_selected_estradiol_esters">Table</a>). When these esters are administered as oil solutions by intramuscular or subcutaneous injection, their increased lipophilicity causes them to be released from the injection-site depot more slowly than estradiol and to therefore have longer durations. In the case of <a href="https://en.wikipedia.org/wiki/Fatty_acid">fatty acid</a> esters, the longer the chain length of the ester—as in e.g. <a href="https://en.wikipedia.org/wiki/Estradiol_valerate">estradiol valerate</a> (5 carbons) vs. <a href="https://en.wikipedia.org/wiki/Estradiol_enanthate">estradiol enanthate</a> (7 carbons) vs. <a href="https://en.wikipedia.org/wiki/Estradiol_undecylate">estradiol undecylate</a> (10 carbons)—the greater the fat solubility, the slower the rate of release from the depot, and the longer the time to peak levels and duration (<a href="https://doi.org/10.1111/j.2042-7158.1959.tb10412.x">Edkins, 1959</a>; <a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://journal.pda.org/content/35/3/106">Chien, 1981</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>; <a href="https://dspace.library.uu.nl/handle/1874/348465">Kalicharan, 2017</a>; <a href="https://doi.org/10.1007/978-981-13-3642-3_7">Vhora et al., 2019</a>). The durations of both injectable oil solutions and aqueous suspensions depend on the ester and its particular <a href="https://en.wiktionary.org/wiki/physicochemical">physicochemical</a> properties, but the characteristics of these preparations are different and they work in distinct ways to produce their depot effects (<a href="https://doi.org/10.1016/0039-128X(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>). The durations of oil solutions are dependent on the lipophilicity of the ester as well as oil vehicle, whereas the durations of aqueous suspensions depend on the properties of the ester <a href="https://en.wikipedia.org/wiki/Crystal_structure">crystal lattice</a> as well as <a href="https://en.wikipedia.org/wiki/Particle_size">crystal sizes</a> (<a href="https://journal.pda.org/content/35/3/106">Chien, 1981</a>; <a href="https://doi.org/10.1016/0039-128X(83)90109-5">Enever et al., 1983</a>; <a href="/articles/aqueous-suspensions/">Aly, 2019</a>). The <a href="https://en.wikipedia.org/wiki/Polymer">polymeric</a> estradiol ester <a href="https://en.wikipedia.org/wiki/Polyestradiol_phosphate">polyestradiol phosphate</a> is more <a href="https://en.wikipedia.org/wiki/Hydrophilicity">hydrophilic</a> (water-soluble) than estradiol and works differently than other injectable estradiol preparations. Ιt is composed of many estradiol molecules linked together via <a href="https://en.wikipedia.org/wiki/Phosphate_ester">phosphate esters</a> (on average 13 molecules of estradiol per one molecule of polyestradiol phosphate) and has a prolonged duration due to slow <a href="https://en.wikipedia.org/wiki/Bond_cleavage">cleavage</a> into estradiol following injection. Estradiol esters are able to substantially prolong the duration of estradiol when used as injectables and these preparations have durations ranging from days to months depending on the ester and how it is formulated (<a href="https://en.wikipedia.org/w/index.php?title=Template:Potencies_and_durations_of_natural_estrogens_by_intramuscular_injection&amp;oldid=964345939">Table</a>).</p>
 
 <p>There is very little in the way of research and review on the <a href="https://en.wikipedia.org/wiki/Pharmacokinetics">pharmacokinetics</a> of injectable estradiol preparations in the <a href="https://en.wikipedia.org/wiki/Transgender_health">transgender health</a> literature. Transgender hormone therapy guidelines presently offer only brief descriptions and dosing recommendations that appear to be based mainly on expert opinion for this form of estradiol (e.g., <a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016a</a>; <a href="https://doi.org/10.1210/jc.2017-01658">Hembree et al., 2017</a>). Many studies assessing the pharmacokinetics and <a href="https://en.wiktionary.org/wiki/concentration-time_curve">concentration–time profiles</a> of injectable estradiol preparations have been published but are largely confined to cisgender women and men rather than transgender people. These studies are scattered throughout the literature and have not been comprehensively reviewed or analyzed. Some review material exists on the pharmacokinetics of injectable estradiol preparations for use in <a href="https://en.wikipedia.org/wiki/Hormonal_contraception">hormonal birth control</a> and <a href="https://en.wikipedia.org/wiki/Menopausal_hormone_therapy">menopausal hormone therapy</a> in cisgender women (e.g., <a href="https://doi.org/10.1016/0378-5122(82)90064-0">Düsterberg &amp; Nishino, 1982</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/3817596/">Kuhl, 1986</a>; <a href="https://doi.org/10.1016/0378-5122(90)90003-O">Kuhl, 1990</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a>; <a href="https://doi.org/10.1080/13697130500148875">Kuhl, 2005</a>) and <a href="https://en.wikipedia.org/wiki/Androgen_deprivation_therapy">androgen deprivation therapy</a> for <a href="https://en.wikipedia.org/wiki/Prostate_cancer">prostate cancer</a> in cisgender men (e.g., <a href="https://doi.org/10.1002/pros.2990130405">Gunnarsson &amp; Norlén, 1988</a>). However, these publications discuss only small selections of the available research. Data on repeated administration of injectable estradiol preparations are more rare but have also been published (e.g., <a href="https://doi.org/10.1016/0306-4530(84)90004-0">Gooren et al., 1984</a> [<a href="https://commons.wikimedia.org/wiki/File:Hormone_levels_with_twice-daily_injectable_estradiol_benzoate_in_transgender_women.png">Graph</a>]; various others). Multi-dose <a href="https://en.wikipedia.org/wiki/Simulation">simulation</a> has been done previously for polyestradiol phosphate (<a href="https://doi.org/10.1002/(SICI)1097-0045(19990701)40:2%3C76::AID-PROS2%3E3.0.CO;2-Q">Henriksson et al., 1999</a>; <a href="https://doi.org/10.1002/1097-0045(20000615)44:1%3C26::AID-PROS4%3E3.0.CO;2-P">Johansson &amp; Gunnarsson, 2000</a>). However, it has not been explored for other injectable estradiol preparations to date. In contrast to injectable estradiol, excellent review literature and simulation exists for injectable testosterone preparations (e.g., <a href="https://doi.org/10.1007/978-3-662-00814-0_6">Behre, Oberpenning, &amp; Nieschlag, 1990</a>; <a href="https://doi.org/10.1007/978-3-642-72185-4_11">Behre &amp; Nieschlag, 1998</a>; <a href="https://doi.org/10.1017/CBO9780511545221.015">Behre et al., 2004</a>; <a href="https://doi.org/10.1007/978-3-540-78355-8_21">Nieschlag &amp; Behre, 2010</a>; <a href="https://doi.org/10.1017/CBO9781139003353.016">Nieschlag &amp; Behre, 2012</a>).</p>
 
@@ -889,7 +894,7 @@ Using the term desistence in this way does not imply anything about the identity
       <td>3</td>
       <td>Gonadectomized/postmenopausal women</td>
       <td>27.6 mg</td>
-      <td><a href="https://www.worldcat.org/title/untersuchungen-zur-pharmakokinetik-von-ostradiol-17-beta-ostradiol-benzoat-ostradiol-valerianat-und-ostradiol-undezylat-bei-der-frau-der-verlauf-der-konzentrationen-von-ostradiol-17-beta-ostron-lh-und-fsh-im-serum/oclc/311708827">Geppert (1975)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a></td>
+      <td><a href="https://www.worldcat.org/oclc/311708827">Geppert (1975)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a></td>
     </tr>
     <tr>
       <td>K75</td>
@@ -1115,7 +1120,7 @@ Using the term desistence in this way does not imply anything about the identity
       <td>3</td>
       <td>Gonadectomized/postmenopausal women</td>
       <td>26.2 mg</td>
-      <td><a href="https://www.worldcat.org/title/untersuchungen-zur-pharmakokinetik-von-ostradiol-17-beta-ostradiol-benzoat-ostradiol-valerianat-und-ostradiol-undezylat-bei-der-frau-der-verlauf-der-konzentrationen-von-ostradiol-17-beta-ostron-lh-und-fsh-im-serum/oclc/311708827">Geppert (1975)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a></td>
+      <td><a href="https://www.worldcat.org/oclc/311708827">Geppert (1975)</a>; <a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a></td>
     </tr>
     <tr>
       <td>V75a</td>
@@ -1606,7 +1611,7 @@ Using the term desistence in this way does not imply anything about the identity
       <td>3</td>
       <td>Gonadectomized/postmenopausal women</td>
       <td>32.3 mg</td>
-      <td><a href="https://www.worldcat.org/oclc/632312599">Geppert (1975)</a>/<a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_injections_of_estradiol,_estradiol_benzoate,_estradiol_valerate,_and_estradiol_undecylate_in_women.png">Graph</a>]</td>
+      <td><a href="https://www.worldcat.org/oclc/311708827">Geppert (1975)</a>/<a href="https://pubmed.ncbi.nlm.nih.gov/1150068/">Leyendecker et al. (1975)</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_injections_of_estradiol,_estradiol_benzoate,_estradiol_valerate,_and_estradiol_undecylate_in_women.png">Graph</a>]</td>
     </tr>
     <tr>
       <td>V75</td>
@@ -1988,7 +1993,7 @@ Using the term desistence in this way does not imply anything about the identity
 
 <p>Due to scarcity of data for several injectable estradiol preparations, the study selection criteria maximized data inclusion in order to allow for better curve fits at the risk of including potentially less reliable data. As examples, studies were included regardless of the status of the HPG axis of the participants, and C<sub>max</sub> data were included in the fitting if data were very limited. In the case of HPG axis state, studies with cycling women may result in greater error due to more variable levels of endogenous estradiol. Moreover, acute high levels of estradiol can induce a surge in <a href="https://en.wikipedia.org/wiki/Luteinizing_hormone">luteinizing hormone</a> levels after several days in gonadally intact women, and this may cause a delayed bump in estradiol levels (<a href="https://en.wikipedia.org/wiki/Estrogen_provocation_test">Wiki</a>). One of the more overt instances of this can be seen in a study of estradiol benzoate in such women (<a href="https://doi.org/10.1016/S0300-595X(78)80008-5">Shaw, 1978</a> [<a href="https://commons.wikimedia.org/wiki/File:Estrogen_provocation_test_and_gonadotropin_surge_with_a_single_injection_of_estradiol_benzoate_in_premenopausal_women.png">Graph</a>]). Many if not most of the included studies with estradiol benzoate involved women with intact HPG axes, whereas studies of this sort were uncommon with the other preparations. In the case of C<sub>max</sub> data, these data when C<sub>max</sub> corresponds to the mean of individual peaks are a different type of data than the peak of the mean curve of all individuals. C<sub>max</sub> levels can differ in both magnitude and timing compared to the mean curve peak (e.g., <a href="https://doi.org/10.1016/S0010-7824(80)80018-7">Oriowo et al., 1980</a> [<a href="https://commons.wikimedia.org/wiki/File:Estradiol_levels_after_a_single_5_mg_intramuscular_injection_of_estradiol_esters.png">Graph</a>]; <a href="https://doi.org/10.1016/S0010-7824(99)00086-4">Rahimy, Ryan, &amp; Hopkins, 1999</a>). This is because for instance not all individuals peak at the same time and this variability in time to peak normally serves to dilute peak levels for the mean curve when compared to individual maximal concentrations. However, C<sub>max</sub> levels are in any case generally in the vicinity of the mean curve peak. While C<sub>max</sub> levels were excluded in the fitting for most injectable estradiol preparations, they were included in the case of estradiol enanthate. This was because the available mean and individual estradiol curve data were very limited for this specific preparation, and inclusion of C<sub>max</sub> data allowed for improved fitting in spite of its limitations. Lastly, some of the included data was once-monthly multi-dose, and research with once-monthly estradiol enanthate-containing combined injectable contraceptives has found that the time to peak levels may shift with repeated long-term use (<a href="https://doi.org/10.1016/0010-7824(88)90005-4">Schiavon et al., 1988</a>; <a href="https://doi.org/10.1016/0010-7824(94)90032-9">Garza-Flores, 1994</a>).</p>
 
-<p>There was considerable variability between studies in terms of estradiol levels and concentration–time curve shapes with the same injectable estradiol preparation. The reasons for the large variability across studies are not fully clear. In any case, there are many potential factors that may contribute to this variability. These include preparation- and injection-related factors like <a href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation">formulation</a> (e.g., <a href="https://en.wikipedia.org/wiki/Excipient#Vehicles">oil vehicle</a>, other components and <a href="https://en.wikipedia.org/wiki/Excipient">excipients</a>, concentration, <a href="https://en.wikipedia.org/wiki/Particle_size">particle size</a>), injection volume, <a href="https://en.wikipedia.org/wiki/Injection_site">site of injection</a> (e.g., <a href="https://en.wikipedia.org/wiki/Gluteal_muscles">buttocks</a>, <a href="https://en.wikipedia.org/wiki/Vastus_lateralis_muscle">thigh</a>, <a href="https://en.wikipedia.org/wiki/Deltoid_muscle">upper arm</a>), injection technique (e.g., force of injection—and resulting depot droplet dimensions), and <a href="https://en.wikipedia.org/wiki/Syringe_dead_space">syringe dead space</a>. They additionally include various subject- and research-related variables like differing <a href="https://en.wikipedia.org/wiki/Analytical_technique">blood-testing methodology</a>, differing <a href="https://en.wikipedia.org/wiki/Sample_(statistics)">sample</a> characteristics (e.g., age, weight, gender, ethnicity, physical activity, HPG axis state), and <a href="https://en.wikipedia.org/wiki/Sampling_error">sampling error</a> (<a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://journal.pda.org/content/35/3/106.short">Chien, 1981</a>; <a href="https://jpet.aspetjournals.org/content/281/1/93.short">Minto et al., 1997</a>; <a href="https://doi.org/10.1208/s12248-009-9153-9">Larsen &amp; Larsen, 2009</a>; <a href="https://doi.org/10.1517/17425240903307431">Larsen et al., 2009</a>; <a href="https://books.google.com/books?id=5wcyP2OBPhoC&amp;pg=PA80">Florence, 2010</a>; <a href="https://doi.org/10.1007/978-1-4614-0554-2_7">Larsen, Thing, &amp; Larsen, 2012</a>; <a href="https://dspace.library.uu.nl/handle/1874/348465">Kalicharan, 2017</a>). Older studies, which used potentially less accurate blood tests and tended to have smaller numbers of subjects, seemed to particularly add to the variability between studies. These studies may represent less reliable data than more recent research with larger sample sizes. The exclusion criteria helped to remove <a href="https://en.wikipedia.org/wiki/Outlier">outliers</a> for the different injectable estradiol preparations however. This meta-analysis does not take into account the potential factors underlying the variability between studies. To do so would be difficult, as in many cases information on these variables is not provided in individual studies and research quantifying their precise influences and relative importances is limited.</p>
+<p>There was considerable variability between studies in terms of estradiol levels and concentration–time curve shapes with the same injectable estradiol preparation. The reasons for the large variability across studies are not fully clear. In any case, there are many potential factors that may contribute to this variability. These include preparation- and injection-related factors like <a href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation">formulation</a> (e.g., <a href="https://en.wikipedia.org/wiki/Excipient#Vehicles">oil vehicle</a>, other components and <a href="https://en.wikipedia.org/wiki/Excipient">excipients</a>, concentration, <a href="https://en.wikipedia.org/wiki/Particle_size">particle size</a>), injection volume, <a href="https://en.wikipedia.org/wiki/Injection_site">site of injection</a> (e.g., <a href="https://en.wikipedia.org/wiki/Gluteal_muscles">buttocks</a>, <a href="https://en.wikipedia.org/wiki/Vastus_lateralis_muscle">thigh</a>, <a href="https://en.wikipedia.org/wiki/Deltoid_muscle">upper arm</a>), injection technique (e.g., force of injection—and resulting depot droplet dimensions), and <a href="https://en.wikipedia.org/wiki/Syringe_dead_space">syringe dead space</a>. They additionally include various subject- and research-related variables like differing <a href="https://en.wikipedia.org/wiki/Analytical_technique">blood-testing methodology</a>, differing <a href="https://en.wikipedia.org/wiki/Sample_(statistics)">sample</a> characteristics (e.g., age, weight, gender, ethnicity, physical activity, HPG axis state), and <a href="https://en.wikipedia.org/wiki/Sampling_error">sampling error</a> (<a href="https://scholar.google.com/scholar?cluster=12842077211931556704">Sinkula, 1978</a>; <a href="https://journal.pda.org/content/35/3/106">Chien, 1981</a>; <a href="https://jpet.aspetjournals.org/content/281/1/93.short">Minto et al., 1997</a>; <a href="https://doi.org/10.1208/s12248-009-9153-9">Larsen &amp; Larsen, 2009</a>; <a href="https://doi.org/10.1517/17425240903307431">Larsen et al., 2009</a>; <a href="https://books.google.com/books?id=5wcyP2OBPhoC&amp;pg=PA80">Florence, 2010</a>; <a href="https://doi.org/10.1007/978-1-4614-0554-2_7">Larsen, Thing, &amp; Larsen, 2012</a>; <a href="https://dspace.library.uu.nl/handle/1874/348465">Kalicharan, 2017</a>). Older studies, which used potentially less accurate blood tests and tended to have smaller numbers of subjects, seemed to particularly add to the variability between studies. These studies may represent less reliable data than more recent research with larger sample sizes. The exclusion criteria helped to remove <a href="https://en.wikipedia.org/wiki/Outlier">outliers</a> for the different injectable estradiol preparations however. This meta-analysis does not take into account the potential factors underlying the variability between studies. To do so would be difficult, as in many cases information on these variables is not provided in individual studies and research quantifying their precise influences and relative importances is limited.</p>
 
 <p>It is in any case known from other studies that different oil vehicles are absorbed at different rates from the injection site (<a href="https://doi.org/10.1111/j.1600-0773.1979.tb02404.x">Svendsen &amp; Aaes‐Jørgensen, 1979</a>; <a href="https://doi.org/10.1016/S0378-5173(98)00121-5">Schultz et al., 1998</a>; <a href="https://doi.org/10.1016/S0378-5173(01)00860-2">Larsen et al., 2001</a>) and can result in different concentration–time curve shapes (<a href="https://scholar.google.com/scholar?cluster=7643602853178335452">Ballard, 1978</a> [<a href="https://archive.is/PbwqF">Excerpt</a>]; <a href="https://doi.org/10.1111/j.1600-0447.1985.tb08535.x">Knudsen, Hansen, &amp; Larsen, 1985</a>). This is thought to be due to differences in oil lipophilicity and depot release rates. <a href="https://en.wikipedia.org/wiki/Viscosity">Viscosity</a> of oils has also been hypothesized to potentially influence rate of depot escape (<a href="https://doi.org/10.5414/cp201589">Schug, Donath, &amp; Blume, 2012</a>). However, research so far has not supported this hypothesis (<a href="https://doi.org/10.1208/s12248-009-9153-9">Larsen &amp; Larsen, 2009</a>; <a href="https://doi.org/10.1007/978-1-4614-0554-2_7">Larsen, Thing, &amp; Larsen, 2012</a>). Oil vehicles can vary with injectable estradiol preparations even for the same estradiol ester. For instance, pharmaceutical estradiol valerate is formulated in <a href="https://en.wikipedia.org/wiki/Sesame_oil">sesame oil</a>, <a href="https://en.wikipedia.org/wiki/Castor_oil">castor oil</a>, or <a href="https://en.wikipedia.org/wiki/Sunflower_oil">sunflower oil</a> depending on the preparation (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>). It is notable however that these three oils have similar lipophilicities (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>). On the other hand, <a href="https://en.wiktionary.org/wiki/homebrew">homebrewed</a> injectable estradiol preparations used by DIY transfeminine people often employ <a href="https://en.wikipedia.org/wiki/Medium-chain_triglyceride">medium-chain triglyceride (MCT) oil</a> as the oil vehicle. This oil (in the proprietary form of <a href="https://en.wikipedia.org/wiki/Viscoleo">Viscoleo</a>) has notably been found to be much more rapidly absorbed than conventional oils like sesame oil and castor oil in animals (<a href="https://doi.org/10.1111/j.1600-0773.1979.tb02404.x">Svendsen &amp; Aaes‐Jørgensen, 1979</a>; <a href="https://doi.org/10.1016/S0378-5173(98)00121-5">Schultz et al., 1998</a>; <a href="https://doi.org/10.1016/S0378-5173(01)00860-2">Larsen et al., 2001</a>). In addition, although based on very limited data, MCT oil has been found to give spikier and shorter-lasting depot injectable curves in humans (<a href="https://doi.org/10.1111/j.1600-0447.1985.tb08535.x">Knudsen, Hansen, &amp; Larsen, 1985</a>). As such, injectable estradiol preparations using MCT oil as the vehicle may have differing and less favorable concentration–time curve shapes than pharmaceutical injectable estradiol products. Other excipients, like <a href="https://en.wikipedia.org/wiki/Benzyl_alcohol">benzyl alcohol</a>, as well as factors like injection site and volume, have additionally been found to influence pharmacokinetic properties with depot injectables (<a href="https://jpet.aspetjournals.org/content/281/1/93.short">Minto et al., 1997</a>; <a href="https://doi.org/10.1016/j.ejps.2015.12.011">Kalicharan, Schot, &amp; Vromans, 2016</a>). Excipients besides oil vehicle also vary by formulation (<a href="https://files.transfemscience.org/pdfs/docs/Injectable%20Estradiol%20Vehicles%20and%20Their%20Compositions%20and%20Properties.pdf">Table</a>).</p>
 
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@@ -2649,8 +2660,8 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
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+  <li>Ibrahim, S. (1996/1998). <em>Pharmakokinetische Untersuchungen mit Östradiolvalerat und Hydroxyprogesteroncaproat in Depotform nach einmaliger Applikation bei 24 postmenopausalen Frauen.</em> [<em>Pharmacokinetic studies with estradiol valerate and hydroxyprogesterone caproate in depot form after a single application in 24 postmenopausal women.</em>] (Doctoral dissertation, Dresden University of Technology.) [<a href="https://scholar.google.com/scholar?cluster=10356896144014189338">Google Scholar</a>] [<a href="https://www.worldcat.org/oclc/722383126">WorldCat</a>] [<a href="https://files.transfemscience.org/pdfs/Ibrahim%20(1996)%20-%20Pharmakokinetische%20Untersuchungen%20mit%20%C3%96stradiolvalerat%20und%20Hydroxyprogesteroncaproat%20in%20Depotform%20nach%20Einmaliger%20Applikation%20bei%2024%20Postmenopausalen%20Frauen%20[pp.%200%E2%80%9311,%2039%E2%80%9349].pdf">Partial PDF</a>]</li>
+  <li>Ittrich, G., &amp; Pots, P. (1965). Östrogenbestimmungen in Blut und Urin nach Verabreichung von Östrogenen. [Estrogen determinations in blood and urine after administration of estrogens.] In Kraatz, H. (Ed.). <em>International Symposium der Gynäkologischen Endokrinologie vom 15. bis 18. Mai 1963.</em> / <em>Abhandlungen der Deutschen Akademie der Wissenschaften zu Berlin, Klasse für Medizin</em>, 1965(1), 53–56. [ISSN:<a href="https://portal.issn.org/resource/ISSN/0568-4250">0568-4250</a>] [<a href="https://www.worldcat.org/oclc/320539552">WorldCat 1</a>] [<a href="https://www.worldcat.org/oclc/637443718">WorldCat 2</a>] [<a href="https://www.worldcat.org/oclc/263597180">WorldCat 3</a>] [<a href="https://files.transfemscience.org/pdfs/Ittrich%20&amp;%20Pots%20(1965)%20-%20%C3%96strogenbestimmungen%20in%20Blut%20und%20Urin%20Nach%20Verabreichung%20von%20%C3%96strogenen%20[Estrogen%20Determinations%20in%20Blood%20and%20Urine%20After%20Administration%20of%20Estrogens].pdf">PDF</a>] [<a href="https://files.transfemscience.org/pdfs/translations/Ittrich%20&amp;%20Pots%20(1965)%20-%20Östrogenbestimmungen%20in%20Blut%20und%20Urin%20Nach%20Verabreichung%20von%20Östrogenen.pdf">Translation</a>]</li>
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@@ -2876,7 +2887,7 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
 
 <p>The very short half-life of sublingually and buccally administered estradiol relative to other forms raises a few questions relating to its use in feminising hormone therapy. One of the most commonly asked questions on online forums is regarding which gender-affirming hormone therapy regimens might be most “effective” with respect to the feminising effects of estrogens. These include, but are not limited to, outcomes such as breast development and fat distribution.</p>
 
-<p>In contrast to oral and trandermal estradiol, limited data exist describing the extent of feminisation with the sublingual route (<a href="https://doi.org/10.1016/j.eprac.2021.12.018">Safer, 2022</a>). A non-randomised study found that self-assessed Tanner stage after 6 months of treatment did not appear to be different in users of sublingual estradiol monotherapy as compared to users of oral estradiol plus 10 mg/day cyproterone acetate (<a href="https://doi.org/10.1210/jendso/bvad114.2080">Yaish et al., 2023a</a>; <a href="https://doi.org/10.1089/trgh.2023.0022">Yaish et al., 2023b</a>). However, since breast development itself was not measured objectively, these particular data are low-quality and prevent definitive conclusions either way about the superiority or inferiority of sublingual estradiol. The same study group reported that although there were similar increases in gynoid fat in the two arms, the oral estradiol group did show an increased amount of android fat as compared to the sublingual group (<a href="https://doi.org/10.1093/jsxmed/qdaf005">Yaish et al., 2025</a>). On the other hand, a further complication of this study is the possible confounding by lack of concomitant antiandrogen therapy in the sublingual arm (<a href="https://doi.org/10.1089/trgh.2024.0048">Ruggles &amp; Cheung, 2024</a>; <a href="https://doi.org/doi/10.1089/trgh.2024.0105">Yaish et al., 2024</a>). Notably, progestogens like cyproterone acetate have been shown to be associated with weight gain (<a href="https://doi.org/10.1002/14651858.CD008815.pub4">Lopez et al., 2016</a>). This could explain the difference in android fat accumulation.</p>
+<p>In contrast to oral and trandermal estradiol, limited data exist describing the extent of feminisation with the sublingual route (<a href="https://doi.org/10.1016/j.eprac.2021.12.018">Safer, 2022</a>). A non-randomised study found that self-assessed Tanner stage after 6 months of treatment did not appear to be different in users of sublingual estradiol monotherapy as compared to users of oral estradiol plus 10 mg/day cyproterone acetate (<a href="https://doi.org/10.1210/jendso/bvad114.2080">Yaish et al., 2023a</a>; <a href="https://doi.org/10.1089/trgh.2023.0022">Yaish et al., 2023b</a>). However, since breast development itself was not measured objectively, these particular data are low-quality and prevent definitive conclusions either way about the superiority or inferiority of sublingual estradiol. The same study group reported that although there were similar increases in gynoid fat in the two arms, the oral estradiol group did show an increased amount of android fat as compared to the sublingual group (<a href="https://doi.org/10.1093/jsxmed/qdaf005">Yaish et al., 2025</a>). On the other hand, a further complication of this study is the possible confounding by lack of concomitant antiandrogen therapy in the sublingual arm (<a href="https://doi.org/10.1089/trgh.2024.0048">Ruggles &amp; Cheung, 2024</a>; <a href="https://doi.org/10.1089/trgh.2024.0105">Yaish et al., 2024</a>). Notably, progestogens like cyproterone acetate have been shown to be associated with weight gain (<a href="https://doi.org/10.1002/14651858.CD008815.pub4">Lopez et al., 2016</a>). This could explain the difference in android fat accumulation.</p>
 
 <p>Oral estradiol and other non-oral forms of estradiol (such as transdermal administration) have not been found to differ in their effects on breast development or other feminising outcomes in transfeminine people or cisgender hypogonadal girls (<a href="https://doi.org/10.1210/jc.2005-1081">Rosenfield et al., 2005</a>; <a href="https://doi.org/10.1186/1687-9856-2014-12">Shah et al., 2014</a>; <a href="https://doi.org/10.1530/EJE-17-0496">Klaver et al., 2018</a>; <a href="https://doi.org/10.1210/clinem/dgaa841">de Blok et al., 2021</a>, <a href="https://doi.org/10.1210/clinem/dgab741">Tebbens et al., 2022</a>). In consideration of this, differences in efficacy might not be expected for sublingual estradiol either. However, the use of supraphysiological doses of estrogens from the onset of therapy may stunt breast development and reduce final breast size in transfeminine people (<a href="https://doi.org/10.1210/clinem/dgae573">Boogers et al., 2025</a>). Because the use of sublingual estradiol results in estradiol concentrations that routinely achieve the supratherapeutic range, it is possible that this could have deleterious effects on breast development.</p>
 
@@ -2886,7 +2897,7 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
 
 <p>Another question that might be raised by the short half-life of sublingual estradiol is how it might compare to more conventional routes of administration in terms of its ability to suppress testosterone and other androgens.</p>
 
-<p>Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (<a href="https://cancerres.aacrjournals.org/content/1/4/293">Huggins &amp; Hodges, 1941</a>). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (<a href="https://doi.org/10.1002/(SICI)1097-0045(199605)28:5%3C307::AID-PROS6%3E3.0.CO;2-8">Stege et al., 1996</a>; <a href="https://doi.org/10.1002/cncr.21528">Kohli, 2006</a>; <a href="https://doi.org/10.1111/iju.12613">Sciarra et al., 2015</a>). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Since sublingual estradiol has never been used to treat prostatic cancer, no such data exist to show the ability of sublingual estradiol in this capacity.</p>
+<p>Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (<a href="https://aacrjournals.org/cancerres/article/1/4/293/472266/Studies-on-Prostatic-Cancer-I-The-Effect-of">Huggins &amp; Hodges, 1941</a>). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (<a href="https://doi.org/10.1002/(SICI)1097-0045(199605)28:5%3C307::AID-PROS6%3E3.0.CO;2-8">Stege et al., 1996</a>; <a href="https://doi.org/10.1002/cncr.21528">Kohli, 2006</a>; <a href="https://doi.org/10.1111/iju.12613">Sciarra et al., 2015</a>). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Since sublingual estradiol has never been used to treat prostatic cancer, no such data exist to show the ability of sublingual estradiol in this capacity.</p>
 
 <p>Some studies have found that physiologic levels of estradiol (i.e., 100–200 pg/mL [367–734 pmol/L]) or slightly higher from non-sublingual estradiol alone result in rapid and near complete, if not complete, suppression of testosterone levels to the female range in many transfeminine people (<a href="https://doi.org/10.1089/trgh.2017.0035">Leinung, Feustel, &amp; Joseph, 2018</a>; <a href="https://doi.org/10.1210/clinem/dgaa884">Pappas et al., 2020</a>; <a href="https://doi.org/10.1016/j.eprac.2025.07.002">Misakian et al., 2025</a>). Additionally, the <a href="https://en.wikipedia.org/wiki/Prostate_Adenocarcinoma:_TransCutaneous_Hormones">Prostate Adenocarcinoma TransCutaneous Hormones</a> (PATCH) study, a multicentre randomised controlled trial in the United Kingdom, showed that sustained median estradiol levels of between 215 to 250 pg/mL (789–918 pmol/L) from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (&lt;50 ng/dL [&lt;1.7 nmol/L]) (<a href="https://doi.org/10.1016/S0140-6736(21)00100-8">Langley et al., 2021</a>). However, because sublingual estradiol differs in its pharmacokinetics to other forms of estradiol, it is plausible that this route of administration might result in sub-par suppression at doses with similar concentrations of estradiol.</p>
 
@@ -2942,19 +2953,19 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
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@@ -2964,14 +2975,14 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
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   <li>Wisner, K. L., Sit, D. K., Moses-Kolko, E. L., Driscoll, K. E., Prairie, B. A., Stika, C. S., Eng, H. F., Dills, J. L., Luther, J. F., &amp; Wisniewski, S. R. (2015). Transdermal estradiol treatment for postpartum depression: a pilot randomized trial. <em>Journal of Clinical Psychopharmacology</em>, <em>35</em>(4), 389–395. [DOI:<a href="https://doi.org/10.1097/JCP.0000000000000351">10.1097/JCP.0000000000000351</a>]</li>
   <li>Wren, B. G., Day, R. O., McLachlan, A. J., &amp; Williams, K. M. (2003). Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. <em>Climacteric</em>, <em>6</em>(2), 104–111. [DOI:<a href="https://doi.org/10.1080/cmt.6.2.104.111">10.1080/cmt.6.2.104.111</a>]</li>
-  <li>Yaish, I., Gindis, G., Greenman, Y., Shefer, G., Buch, A., Arbiv, M., Moshe, Y., Sofer, Y., &amp; Tordjman, K. M. (2023). Sublingual Estradiol Only, Compared To Combined Oral Estradiol And Cyproterone Acetate,Offers No Apparent Advantage For Gender Affirming Hormone Therapy (GHAT), In Treatment Naïve Transwomen: Results Of A Prospective Pilot Study. <em>Journal of the Endocrine Society</em>, <em>7</em>(Suppl 1) [<em>ENDO 2023 Abstracts Annual Meeting of the Endocrine Society</em>], A1104–A1105 (abstract no. SAT409/bvad114.2080). [DOI:<a href="https://doi.org/10.1210/jendso/bvad114.2080">10.1210/jendso/bvad114.2080</a>] [<a href="https://academic.oup.com/jes/article-pdf/7/Supplement_1/bvad114.2080/51899408/bvad114.2080.pdf">PDF</a>]</li>
   <li>Yaish, I., Gindis, G., Greenman, Y., Moshe, Y., Arbiv, M., Buch, A., Sofer, Y., Shefer, G., &amp; Tordjman, K. (2023). Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. <em>Transgender Health</em>, <em>8</em>(6), 485–493. [DOI:<a href="https://doi.org/10.1089/trgh.2023.0022">10.1089/trgh.2023.0022</a>]</li>
-  <li>Yaish, I., Greenman, Y., Sofer, Y., &amp; Tordjman, K. M. (2024). Response to Ruggles and Cheung, Re:” Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study”. <em>Transgender Health</em>, <em>9</em>(5), 460-461. [DOI:<a href="https://doi.org/10.1089/trgh.2024.0105">10.1089/trgh.2024.0105</a>]</li>
-  <li>Yaish, I., Buch, A., Gindis, G., Sofer, Y., Arbiv, M., Moshe, Y., … &amp; Tordjman, K. (2025). Early body composition changes in trans women on low-dose estradiol: comparing oral vs sublingual administration using dual energy absorptiometry and bioelectrical impedance analysis. <em>The Journal of Sexual Medicine</em>, <em>22</em>(4), 625-635. [DOI:<a href="https://doi.org/10.1093/jsxmed/qdaf005">10.1093/jsxmed/qdaf005</a>]</li>
+  <li>Yaish, I., Gindis, G., Greenman, Y., Shefer, G., Buch, A., Arbiv, M., Moshe, Y., Sofer, Y., &amp; Tordjman, K. M. (2023). Sublingual Estradiol Only, Compared To Combined Oral Estradiol And Cyproterone Acetate,Offers No Apparent Advantage For Gender Affirming Hormone Therapy (GHAT), In Treatment Naïve Transwomen: Results Of A Prospective Pilot Study. <em>Journal of the Endocrine Society</em>, <em>7</em>(Suppl 1) [<em>ENDO 2023 Abstracts Annual Meeting of the Endocrine Society</em>], A1104–A1105 (abstract no. SAT409/bvad114.2080). [DOI:<a href="https://doi.org/10.1210/jendso/bvad114.2080">10.1210/jendso/bvad114.2080</a>] [<a href="https://academic.oup.com/jes/article-pdf/7/Supplement_1/bvad114.2080/51899408/bvad114.2080.pdf">PDF</a>]</li>
+  <li>Yaish, I., Greenman, Y., Sofer, Y., &amp; Tordjman, K. M. (2024). Response to Ruggles and Cheung, Re:” Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study”. <em>Transgender Health</em>, <em>9</em>(5), 460–461. [DOI:<a href="https://doi.org/10.1089/trgh.2024.0105">10.1089/trgh.2024.0105</a>]</li>
+  <li>Yaish, I., Buch, A., Gindis, G., Sofer, Y., Arbiv, M., Moshe, Y., Grenman, Y., &amp; Tordjman, K. (2025). Early body composition changes in trans women on low-dose estradiol: comparing oral vs sublingual administration using dual energy absorptiometry and bioelectrical impedance analysis. <em>The Journal of Sexual Medicine</em>, <em>22</em>(4), 625–635. [DOI:<a href="https://doi.org/10.1093/jsxmed/qdaf005">10.1093/jsxmed/qdaf005</a>]</li>
 </ul>]]></content><author><name>{&quot;first_name&quot;=&gt;&quot;Sam&quot;, &quot;last_name&quot;=&gt;&quot;S.&quot;, &quot;author-link&quot;=&gt;&quot;/about/#sam&quot;, &quot;articles-link&quot;=&gt;&quot;/articles-by-author/sam/&quot;}</name></author><category term="github" /><category term="workspace" /><summary type="html"><![CDATA[An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People By Sam | First published June 11, 2021 | Last modified August 14, 2025]]></summary></entry><entry><title type="html">Clinical Guidelines with Information on Transfeminine Hormone Therapy</title><link href="https://transfemscience.org/articles/transfem-hormone-guidelines/" rel="alternate" type="text/html" title="Clinical Guidelines with Information on Transfeminine Hormone Therapy" /><published>2020-11-20T10:00:00-08:00</published><updated>2024-11-17T00:00:00-08:00</updated><id>https://transfemscience.org/articles/transfem-hormone-guidelines</id><content type="html" xml:base="https://transfemscience.org/articles/transfem-hormone-guidelines/"><![CDATA[<h1 id="clinical-guidelines-with-information-on-transfeminine-hormone-therapy">Clinical Guidelines with Information on Transfeminine Hormone Therapy</h1>
 
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@@ -3039,7 +3050,7 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
 
 <p>Clinicians use <a href="https://en.wikipedia.org/wiki/Medical_guideline">clinical practice guidelines</a> (CPGs) to learn about and guide themselves in administering medical care for different indications. Clinical practice guidelines review and summarize the available scientific literature and research in a given medical area. They allow clinicians to competently administer care without necessarily having to delve into and develop their understanding via the primary scientific literature. <a href="https://en.wikipedia.org/wiki/Literature_review">Literature reviews</a> can serve a similar function. However, clinical practice guidelines are generally more substantial and are more founded in <a href="https://en.wikipedia.org/wiki/Evidence-based_medicine">evidence-based medicine</a>. They are also regularly updated. Clinical practice guidelines are developed and maintained by clinical organizations and societies, universities, government agencies, and sometimes even large medical clinics. They may be international/locationless or oftentimes region-specific.</p>
 
-<p>There are many clinical practice guidelines for transgender medicine (for review, <a href="https://dx.doi.org/10.1001%2Fjournalofethics.2016.18.11.stas1-1611">Deutsch, Radix, &amp; Reisner, 2016</a>; <a href="https://doi.org/10.1016/j.ucl.2019.07.001">Radix, 2019</a>; <a href="https://doi.org/10.1007/978-3-030-05683-4_4">Radix, 2019</a>; <a href="https://www.uptodate.com/contents/society-guideline-links-transgender-health">UpToDate</a>; <a href="https://doi.org/10.1210/jendso/bvab048.1609">Bewley et al., 2021</a>; <a href="https://doi.org/10.1136/bmjopen-2021-048943">Dahlen et al., 2021</a>; <a href="https://doi.org/10.1089/trgh.2020.0043">Ziegler, Carroll, &amp; Charnish, 2021</a>). These guidelines discuss topics such as psychotherapy, hormone therapy, voice therapy, and surgical management of transgender people, among others. In addition to educating and guiding clinicians, transgender clinical practice guidelines are useful materials for transgender people as they can help to inform them about their care.</p>
+<p>There are many clinical practice guidelines for transgender medicine (for review, <a href="https://doi.org/10.1001/journalofethics.2016.18.11.stas1-1611">Deutsch, Radix, &amp; Reisner, 2016</a>; <a href="https://doi.org/10.1016/j.ucl.2019.07.001">Radix, 2019</a>; <a href="https://doi.org/10.1007/978-3-030-05683-4_4">Radix, 2019</a>; <a href="https://www.uptodate.com/contents/society-guideline-links-transgender-health">UpToDate</a>; <a href="https://doi.org/10.1210/jendso/bvab048.1609">Bewley et al., 2021</a>; <a href="https://doi.org/10.1136/bmjopen-2021-048943">Dahlen et al., 2021</a>; <a href="https://doi.org/10.1089/trgh.2020.0043">Ziegler, Carroll, &amp; Charnish, 2021</a>). These guidelines discuss topics such as psychotherapy, hormone therapy, voice therapy, and surgical management of transgender people, among others. In addition to educating and guiding clinicians, transgender clinical practice guidelines are useful materials for transgender people as they can help to inform them about their care.</p>
 
 <p>This page is a maintained list of known English clinical guidelines throughout the world that include information specifically on the subject of transfeminine hormone therapy. The most major guidelines on transgender hormone therapy are the <a href="https://en.wikipedia.org/wiki/World_Professional_Association_for_Transgender_Health">World Professional Association for Transgender Health</a> (WPATH) <a href="https://en.wikipedia.org/wiki/Standards_of_Care_for_the_Health_of_Transsexual,_Transgender,_and_Gender_Nonconforming_People">Standards of Care for the Health of Transgender and Gender Diverse People</a> (SOC) (<a href="https://doi.org/10.1080/26895269.2022.2100644">Coleman et al., 2022</a>), the <a href="https://en.wikipedia.org/wiki/Endocrine_Society">Endocrine Society</a> guidelines (<a href="https://doi.org/10.1210/jc.2009-0345">Hembree et al., 2017</a>), and the <a href="https://en.wikipedia.org/wiki/University_of_California,_San_Francisco">University of California, San Francisco</a> (UCSF) guidelines (<a href="https://transcare.ucsf.edu/guidelines">Deutsch, 2016</a>). The WPATH SOC and the Endocrine Society guidelines are international, while the UCSF guidelines are based in the United States.</p>
 
@@ -3371,7 +3382,7 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
       <td>Online document</td>
     </tr>
     <tr>
-      <td><a href="https://doi.org/10.4103%2Fijem.IJEM_593_19">IDEA Group Consensus Statement on Medical Management of Adult Gender Incongruent Individuals Seeking Gender Reaffirmation as Female</a></td>
+      <td><a href="https://doi.org/10.4103/ijem.IJEM_593_19">IDEA Group Consensus Statement on Medical Management of Adult Gender Incongruent Individuals Seeking Gender Reaffirmation as Female</a></td>
       <td>Majumder et al. / Integrated Diabetes and Endocrine Academy (IDEA) [India]</td>
       <td>2020</td>
       <td>Published article</td>
@@ -3403,10 +3414,10 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
   <li>Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … &amp; Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. <em>International Journal of Transgender Health</em>, <em>23</em>(Suppl 1), S1–S259. [DOI:<a href="https://doi.org/10.1080/26895269.2022.2100644">10.1080/26895269.2022.2100644</a>] [<a href="https://www.wpath.org/publications/soc">URL</a>] [<a href="https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644">PDF</a>]</li>
   <li>Cundill, P., Wong, P., Cheung, A., &amp; Brownhill, A. (2020). <em>Hormone Therapy Prescribing Guide for General Practitioners working with Trans, Gender Diverse and Non-Binary Patients [Version 3.0].</em> Australia: Equinox Gender Diverse Health Centre/Thorne Harbour Health. [<a href="https://equinox.org.au/resources/">URL</a>] [<a href="https://equinoxdotorgdotau.files.wordpress.com/2021/07/ht-prescribing-guideline-v3-aug-2020.pdf">PDF</a>]</li>
   <li>Dahl, M., Feldman, J. L., Goldberg, J., &amp; Jaberi, A. (2015). <em>Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines. Physical Aspects of Transgender Endocrine Therapy.</em> Vancouver: Vancouver Coastal Health. [<a href="https://scholar.google.com/scholar?cluster=10288793516023166968">Google Scholar</a>] [<a href="http://www.phsa.ca/transcarebc/Documents/HealthProf/BC-Trans-Adult-Endocrine-Guidelines-2015.pdf">PDF</a>]</li>
-  <li>Dahlen, S., Connolly, D., Arif, I., Junejo, M. H., Bewley, S., &amp; Meads, C. (2021). International Clinical Practice Guidelines for Gender Minority/Trans People: Systematic Review and Quality Assessment. <em>BMJ Open</em>, <em>11</em>(4), e048943. [DOI:<a href="http://dx.doi.org/10.1136/bmjopen-2021-048943">10.1136/bmjopen-2021-048943</a>]</li>
+  <li>Dahlen, S., Connolly, D., Arif, I., Junejo, M. H., Bewley, S., &amp; Meads, C. (2021). International Clinical Practice Guidelines for Gender Minority/Trans People: Systematic Review and Quality Assessment. <em>BMJ Open</em>, <em>11</em>(4), e048943. [DOI:<a href="http://doi.org/10.1136/bmjopen-2021-048943">10.1136/bmjopen-2021-048943</a>]</li>
   <li>Davidson, A., Franicevich, J., Freeman, M., Lin, R., Martinez, L., Monihan, M., Porch, M., Samuel, L., Stukalin, R., Vormohr, J., &amp; Zevin, B. (2013). <em>Protocols for Hormonal Reassignment of Gender.</em> San Francisco: San Francisco Department of Public Health/Tom Waddell Health Center. [<a href="https://scholar.google.com/scholar?cluster=3995032054574212445">Google Scholar</a>] [<a href="https://www.sfdph.org/dph/comupg/oservices/medSvs/hlthCtrs/TransGendprotocols122006.pdf">PDF</a>]</li>
   <li>Deutsch, M. B. (Ed.). (2016). <em>Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition.</em> San Francisco: University of California, San Francisco/UCSF Transgender Care. [<a href="https://transcare.ucsf.edu/guidelines">URL</a>] [<a href="https://transcare.ucsf.edu/sites/transcare.ucsf.edu/files/Transgender-PGACG-6-17-16.pdf">PDF</a>]</li>
-  <li>Deutsch, M. B., Radix, A., &amp; Reisner, S. (2016). What’s in a Guideline? Developing Collaborative and Sound Research Designs that Substantiate Best Practice Recommendations for Transgender Health Care. <em>AMA Journal of Ethics</em>, <em>18</em>(11), 1098–1106. [DOI:<a href="https://dx.doi.org/10.1001%2Fjournalofethics.2016.18.11.stas1-1611">10.1001/journalofethics.2016.18.11.stas1-1611</a>]</li>
+  <li>Deutsch, M. B., Radix, A., &amp; Reisner, S. (2016). What’s in a Guideline? Developing Collaborative and Sound Research Designs that Substantiate Best Practice Recommendations for Transgender Health Care. <em>AMA Journal of Ethics</em>, <em>18</em>(11), 1098–1106. [DOI:<a href="https://doi.org/10.1001/journalofethics.2016.18.11.stas1-1611">10.1001/journalofethics.2016.18.11.stas1-1611</a>]</li>
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@@ -4243,6 +4254,13 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
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