title: Congenital hypothyroid female pax8-deficient mice are infertile despite thyroid hormone replacement therapy.
abstract: Absence of the Pax8 gene results in congenital hypothyroidism in mice, and mutations of the Pax8 gene have been associated with thyroid hypoplasia in humans. As in humans, treatment of congenital hypothyroid Pax8 null mice with thyroxine normalizes the known deficits. However, we report here that thyroxine-substituted female Pax8(-/-) mice are infertile because they lack a functional uterus revealing only remnants of myometrial tissue. In addition, the vaginal opening is absent. Interestingly, oviduct, cervix, and upper parts of the vagina are not affected, although Pax8 expression has been described in the entire Müllerian duct before. Because the natural outflow of the oviduct is impaired, a hydrosalpinx develops frequently. Folliculogenesis, ovarian hormone production, and transcription of pituitary hormones are in a normal range. Thus, infertility in Pax8(-/-) mice seems to be due to a defect in development of the Müllerian duct rather than to hormonal imbalance, pointing to a direct morphogenic role for Pax8 in uterine development. Because we demonstrated Pax8 expression not only in the uterine epithelium of mice but also in the human endometrium, it remains to be elucidated whether adequate development of the uterus may also be affected in congenital hypothyroid female patients with mutations in the Pax8 gene.
authors.affiliation: University Hospital Essen, Institute of Anatomy, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Mittag
authors.forename: Elke
authors.initials: E
authors.lastname: Winterhager
authors.forename: Karl
authors.initials: K
authors.lastname: Bauer
authors.forename: Ruth
authors.initials: R
authors.lastname: Grümmer
mesh_terms: D000818:Animals; D003409:Congenital Hypothyroidism / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005836:Genitalia, Female / Q000473:pathology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D020249:Hormone Replacement Therapy; D006801:Humans; D007247:Infertility, Female / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010907:Pituitary Hormones / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013974:Thyroxine / Q000627:therapeutic use*; D014599:Uterus / Q000378:metabolism / Q000503:physiopathology
chemical_list: D012739:Gonadal Steroid Hormones; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D010907:Pituitary Hormones; D012333:RNA, Messenger; D013974:Thyroxine