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The central CO\n                      <jats:sub>2<\/jats:sub>\n                      chemoreflex is a critical component of this neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably the progestinic metabolite, etonogestrel (ETO), enhances CO\n                      <jats:sub>2<\/jats:sub>\n                      chemosensitivity in animal models and female patients affected by congenital central hypoventilation syndrome. However, ETO\u2018s mechanisms and sites of action remain unknown, and the experimental use of synthetic progestins has been met with mixed respiratory outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In our recent work, we demonstrated that chronic ETO treatment improved the CO\n                      <jats:sub>2<\/jats:sub>\n                      chemoreflex in female rats in which &lt;\u200980% of chemoreceptor neurons comprising the retrotrapezoid nucleus (RTN) were eliminated. Since the progesterone receptor is widely expressed in both the male and female brain, we investigated whether ETO\u2010induced CO\n                      <jats:sub>2<\/jats:sub>\n                      chemoreflex recovery can be replicated in male rats in which RTN neurons are partially eliminated by the use of substance P\u2010saporin toxin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results confirm dose\u2010dependent impairment of the CO\n                      <jats:sub>2<\/jats:sub>\n                      chemoreflex in both sexes following chemoreceptor lesion and corroborate the findings that ETO treatment restores ventilation in female rats with moderate\u2010sized lesions. Interestingly, female respiratory recovery was associated with increased expression of the pH\u2010sensing genes\n                      <jats:italic>Gpr4<\/jats:italic>\n                      and\n                      <jats:italic>Task2<\/jats:italic>\n                      in the RTN.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In contrast, male rats failed to show significant recovery with ETO treatment, suggesting a sex\u2010specific mechanism through which ETO promotes CO\n                      <jats:sub>2<\/jats:sub>\n                      chemoreflex recovery.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70194","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T12:37:11Z","timestamp":1773405431000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex Differences in the Effects of Etonogestrel on Respiratory Recovery in an In\u00a0Vivo Rat Model of Central Chemoreflex Impairment"],"prefix":"10.1111","volume":"242","author":[{"given":"Silvia","family":"Cardani","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry University of Alberta  Edmonton Alberta Canada"},{"name":"Women and Children's Health Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2824-9487","authenticated-orcid":false,"given":"Tara A.","family":"Janes","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry University of Alberta  Edmonton Alberta Canada"},{"name":"Women and Children's Health Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryaad","family":"Asif","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1482-9173","authenticated-orcid":false,"given":"Silvia","family":"Pagliardini","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry University of Alberta  Edmonton Alberta Canada"},{"name":"Women and Children's Health Research Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Neuroscience and Mental Health Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978\u20100\u2010323\u201091534\u20102.00007\u20102"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.09.002"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa0922"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.14093"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.94653"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP275866"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0386\u201023.2023"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.153163"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22\u201009\u201003755.2002"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022\u20104731(81)90171\u20100"},{"key":"e_1_2_11_12_1","volume-title":"Clinical Review Report: Etonogestrel Extended\u2010Release Subdermal Implant (Nexplanon): Merck Canada Inc. 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