{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T01:24:46Z","timestamp":1775697886561,"version":"3.50.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:00:00Z","timestamp":1743724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Liver receptor homolog 1 (LRH-1; Nr5a2) and steroidogenic factor 1 (SF-1; Nr5a1) are two closely related orphan nuclear receptors that bind to the same genomic motif. Conditional depletion of either of these receptors in the ovary results in infertility, but through different mechanisms, with SF-1 being critical early in ovarian development and LRH-1 regulating ovulation. We conditionally depleted both LRH-1 and SF-1 from the ovary, using two different models of conditional depletion, generating two lines of double conditional knockout (dko) mice. In one, we used the Amhr2Cre (Amhr2-dko) mouse, where depletion is initiated in the prenatal ovary before the stage of germ cell nest breakdown. In the other, we employed Cyp19a1Cre (Cyp19a1-dko)-mediated depletion, which is initiated following formation of the follicular antrum. Both models were completely anovulatory and infertile, and no ovulation occurred following administration of exogenous gonadotropins. The Amhr2-dko mouse had dramatically reduced follicular populations at every stage of development, as well as disrupted extracellular matrix, characterized by dysregulation of collagen and laminin expression in reproductively mature mice, reduced expression of steroidogenic genes, dysregulated lipid metabolism, and inhibited granulosa cell proliferation. The latter resulted in a phenotype of reduced ovarian size in this model. The Cyp19al dko mouse displayed dysregulation of luteinizing hormone (LH) response and ovulatory mechanisms and increased activation of the activin\/inhibin signaling axis, suggesting impaired gonadotropin responsiveness. In summary, both dko models demonstrated a phenotype of complete infertility, confirming the critical importance of both LRH-1 and SF-1 in ovarian function.<\/jats:p>","DOI":"10.1093\/biolre\/ioaf079","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T17:48:42Z","timestamp":1743788922000},"page":"182-198","source":"Crossref","is-referenced-by-count":3,"title":["Double knockout of steroidogenic factor 1 (<i>NR5A1<\/i>) and liver receptor homolog 1 (<i>NR5A2<\/i>) in the mouse ovary results in infertility due to disruption of follicle development and ovulation"],"prefix":"10.1093","volume":"113","author":[{"given":"Fanny","family":"Morin","sequence":"first","affiliation":[{"name":"Centre de recherche en reproduction et fertilit\u00e9, Universit\u00e9 de Montr\u00e9al , St-Hyacinthe, Qu\u00e9bec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla H K","family":"Hughes","sequence":"additional","affiliation":[{"name":"Centre de recherche en reproduction et fertilit\u00e9, Universit\u00e9 de Montr\u00e9al , St-Hyacinthe, Qu\u00e9bec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vickie","family":"Roussel","sequence":"additional","affiliation":[{"name":"Centre de recherche en reproduction et fertilit\u00e9, Universit\u00e9 de Montr\u00e9al , St-Hyacinthe, Qu\u00e9bec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Gevry","sequence":"additional","affiliation":[{"name":"Centre de recherche en reproduction et fertilit\u00e9, Universit\u00e9 de Montr\u00e9al , St-Hyacinthe, Qu\u00e9bec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce D","family":"Murphy","sequence":"additional","affiliation":[{"name":"Centre de recherche en reproduction et fertilit\u00e9, Universit\u00e9 de Montr\u00e9al , St-Hyacinthe, Qu\u00e9bec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,4,4]]},"reference":[{"key":"2025071504314284000_ref1","doi-asserted-by":"crossref","first-page":"hoad007","DOI":"10.1093\/hropen\/hoad007","article-title":"Financial costs of assisted reproductive technology for patients in low- and middle-income countries: a systematic review","volume":"2023","author":"Njagi","year":"2023","journal-title":"Hum Reprod Open"},{"key":"2025071504314284000_ref2","doi-asserted-by":"crossref","first-page":"j138","DOI":"10.1136\/bmj.j138","article-title":"Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis","volume":"356","author":"Wang","year":"2017","journal-title":"BMJ"},{"key":"2025071504314284000_ref3","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1152\/physrev.00019.2018","article-title":"The orphan nuclear receptors steroidogenic Factor-1 and liver receptor Homolog-1: structure, regulation, and essential roles in mammalian reproduction","volume":"99","author":"Meinsohn","year":"2019","journal-title":"Physiol Rev"},{"key":"2025071504314284000_ref4","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1101\/gad.472008","article-title":"Liver receptor homolog 1 is essential for ovulation","volume":"22","author":"Duggavathi","year":"2008","journal-title":"Genes Dev"},{"key":"2025071504314284000_ref5","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1095\/biolreprod.108.069435","article-title":"Impaired follicle development and infertility in female mice lacking steroidogenic factor 1 in ovarian granulosa cells","volume":"79","author":"Pelusi","year":"2008","journal-title":"Biol Reprod"},{"key":"2025071504314284000_ref6","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41598-020-80178-4","article-title":"A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation","volume":"11","author":"Meinsohn","year":"2021","journal-title":"Sci Rep"},{"key":"2025071504314284000_ref7","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/biolre\/iox045","article-title":"Ovary-specific depletion of the nuclear receptor Nr5a2 compromises expansion of the cumulus oophorus but not fertilization by intracytoplasmic sperm injection","volume":"96","author":"Bertolin","year":"2017","journal-title":"Biol Reprod"},{"key":"2025071504314284000_ref8","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nm.3192","article-title":"Liver receptor homolog-1 is essential for pregnancy","volume":"19","author":"Zhang","year":"2013","journal-title":"Nat Med"},{"key":"2025071504314284000_ref9","doi-asserted-by":"crossref","first-page":"e2220849120","DOI":"10.1073\/pnas.2220849120","article-title":"Steroidogenic factor 1 (SF-1; 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