Impaired Regulation of Gonadotropins Leads to the Atrophy of the Female Reproductive System in klotho-Deficient Mice

Abstract

klotho-Deficient mice exhibit a syndrome resembling human premature ageing, with multiple pathological phenotypes in tissues including reproductive organs. It was proposed that Klotho might possess the hormonal effects on many organs. In this study, the female reproductive system of klotho mice was examined to reveal the mechanism that brought the female sterility by histological and molecular approaches. We observed cessation of ovarian follicular maturation at the preantral stage and the presence of numerous atretic ovarian follicles and atrophic uteri. In situ hybridization analysis revealed that LH receptor and aromatase P450 were not expressed in the ovaries. These results suggest the impairment of gonadal development during the antral transition process. We next addressed the responsible organs for the failure of antral transition. Transplantation of klotho ovaries to wild-type mice resulted in the ability to bear offspring. Administration of FSH or GnRH induced advanced maturation of ovaries and uteri in klotho mice. These results indicate that the female reproductive organs in klotho mice are potentially functional and that klotho gene deficiency leads to the atrophy of reproductive organs via impairment of the hypothalamic-pituitary axis. Absence of the estrus cycle and constant low trends of both FSH and LH levels were found in female klotho mice. Immunohistochemical analysis revealed that the production of both FSH and LH were decreased in pituitary gland. Taken together, our findings suggest the involvement of klotho in the regulatory control of pituitary hormones.

Different effects on bone strength and cell differentiation in pre pubertal caloric restriction versus hypothalamic suppression

“…Decreased serum estrogen is associated with significant decreases in trabecular architecture in both the vertebra and femur. Suppressed levels of the hormone estradiol have been reported following GnRH-a injection protocols [38,57,58] with similar uterine and ovarian tissue atrophies [38,59]. Suppressed leptin levels following energy restriction may provide an explanation for the differing vertebral bone volumes.…”

Klotho, the Key to Healthy Brain Aging?

“…Although the CNS component of the hypothalamic-pituitary-adrenal (HPA) axis does not express KL [ 113 ], KL-deficient mice show HPA axis dysfunction causing a wide range of peripheral problems beyond the scope of this review. However, KL mRNA is detected in the pituitary gland and KL-deficient mouse pituitary cells responsible for hormone secretion are abnormally small [ 1 ].…”

A phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease

“…The transgene insertion caused extensive hypermethylation around the insertion site and silenced expression of the transgene and the neighboring klotho gene. 10 As a result, mice homozygous for the transgene ( kl/kl mice) lack Klotho expression and develop complex phenotypes resembling human aging around 4 weeks of age, including growth arrest, cognition impairment, 11 hearing loss, 12 hypogonadotropic hypogonadism, 13 vascular calcification, cardiac hypertrophy, 14 emphysematous lung, 15 osteopenia, 16 ectopic calcification in soft tissues, atrophy of thymus, fat, skin, and skeletal muscle, resulting in premature death around 9 weeks of age. 9 They also exhibit a marked increase in blood phosphate, calcium, and calcitriol levels.…”