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Kiss1^–/– Mice Exhibit More Variable Hypogonadism than Gpr54^–/– Mice

Reproductive Endocrine Unit (R.L., J.C.P., D.Z., Y.-M.C., A.M., F.C., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Hospital for Children and Adolescents (R.L.), University of Helsinki, 00029 HUS, Finland; Division of Endocrinology (Y.-M.C.), Department of Medicine, Children’s Hospital Boston, Boston, Massachusetts 02115; and Department of Anatomy and Neurobiology (W.W.L., G.E.H.), School of Medicine, University of Maryland, Baltimore, Maryland 21209

Address all correspondence and requests for reprints to: Risto Lapatto, M.D., Ph.D., Reproductive Endocrine Unit, Bartlett Hall Extension, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: rlapatto{at}partners.org.

The G protein-coupled receptor Gpr54 and its ligand metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse metastin 43–52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.

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