title: Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model.
abstract: Liver receptor homologue-1 (LRH-1) is an orphan nuclear receptor that has been implicated in steroid hormone biosynthesis and fertility. Herein we describe a transgenic inducible short hairpin (sh) RNA mouse model that was used to study the effect of transient LRH-1 knockdown in vivo. Induction of expression of the shRNA directed against LRH-1 for 2-6 weeks resulted in 80% knockdown of LRH-1 protein in the ovary and complete infertility. Gonadotropin hyperstimulation could not rescue the observed defects in ovulation and corpus luteum formation in LRH-1-knockdown mice. The infertility phenotype was fully reversible because LRH-1-knockdown females became pregnant and delivered normal size litters and healthy pups after cessation of LRH-1 shRNA expression. Timed ovarian microarray analysis showed that, in line with the observed decrease in plasma progesterone levels, key steroid biosynthesis genes, namely Star, Cyp11a1, Hsd3b and Scarb1, were downregulated in LRH-1-knockdown ovaries. In contrast with what has been described previously, no clear effect was observed on oestrogenic activity in LRH-1-knockdown mice. Only Sult1e1 and, surprisingly, Hsd17b7 expression was modulated with potentially opposite effects on oestradiol bioavailability. In conclusion, the fully reversible infertility phenotype of LRH-1-knockdown mice shows the feasibility of an LRH-1 antagonist as new contraceptive therapy with a mechanism of action that most prominently affects cholesterol availability and progesterone production.
authors: Merck Sharp and Dohme Research Laboratories, Women's Health Department, Molenstraat 110, 5342 CC, Oss, The Netherlands. Corresponding author. Email: han.gerrits@merck.com.
authors: Han
authors: H
authors: Gerrits
authors: Merck Sharp and Dohme Research Laboratories, Women's Health Department, Molenstraat 110, 5342 CC, Oss, The Netherlands.
authors: Marc C B C
authors: MC
authors: Paradé
authors: Merck Sharp and Dohme Research Laboratories, Women's Health Department, Molenstraat 110, 5342 CC, Oss, The Netherlands.
authors: Annemie M C B
authors: AM
authors: Koonen-Reemst
authors: Merck Sharp and Dohme Research Laboratories, Women's Health Department, Molenstraat 110, 5342 CC, Oss, The Netherlands.
authors: Nicole E C
authors: NE
authors: Bakker
authors: Merck Sharp and Dohme Research Laboratories, Women's Health Department, Molenstraat 110, 5342 CC, Oss, The Netherlands.
authors: Lenita
authors: L
authors: Timmer-Hellings
authors: Merck Sharp and Dohme Research Laboratories, Molecular Design and Informatics, Molenstraat 110, 5342 CC, Oss, The Netherlands.
authors: Maarten D
authors: MD
authors: Sollewijn Gelpke
authors: Merck Sharp and Dohme Research Laboratories, Women's Health Department, Molenstraat 110, 5342 CC, Oss, The Netherlands.
authors: Jan A
authors: JA
authors: Gossen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005298:Fertility; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D005838:Genotype; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010053:Ovary / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: C431936:Nr5a2 protein, mouse; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D011374:Progesterone; D004958:Estradiol; D002784:Cholesterol