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Experimental Medicine Section (A.K., S.N., A.L.N), Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892; Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital (A.C.), Oxford OX3 7LJ, United Kingdom; and Department of Human Anatomy and Genetics (J.F.M.), Oxford OX1 3QX, United Kingdom
Address all correspondence and requests for reprints to: Abner L. Notkins, M.D., National Institutes of Health, Building 30/Room 106, 30 Covent Drive, MSC 4322, Bethesda, Maryland 20892-4322. E-mail: anotkins{at}mail.nih.gov.
Female infertility is a worldwide problem affecting 10–15% of the population. The cause of the infertility in many cases is not known. In the present report, we demonstrate that alterations in two transmembrane structural proteins, IA-2 and IA-2ß, located in dense core secretory vesicles (DCV) of many endocrine and neuroendocrine cells, can result in female infertility. IA-2 and IA-2ß are best known as major autoantigens in type 1 diabetes, but their normal function has remained an enigma. Recently we showed in mice that deletion of IA-2 and/or IA-2ß results in impaired insulin secretion and glucose intolerance. We now report that double knockout (DKO), but not single knockout, female mice are essentially infertile. Vaginal smears showed a totally abnormal estrous cycle, and examination of the ovaries revealed normal-appearing oocytes but the absence of corpora lutea. The LH surge that is required for ovulation occurred in wild-type mice but not in DKO mice. Additional studies showed that the LH level in the pituitary of DKO female mice was decreased compared with wild-type mice. Treatment of DKO females with gonadotropins restored corpora lutea formation. In contrast to DKO female mice, DKO male mice were fertile and LH levels in the serum and pituitary were within the normal range. From these studies we conclude that the DCV proteins, IA-2 and IA-2ß, play an important role in LH secretion and that alterations in structural proteins of DCV can result in female infertility.
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