Infertility in females with cystic fibrosis is multifactorial: evidence from mouse models

Abstract

Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men with CF has been thoroughly investigated, the infertility observed in women with CF has not been well studied. To investigate female infertility associated with CF, we used two independently derived mouse models of CF. Both of these models displayed decreased fertility characterized by a reduction in litter number and litter size. Our findings suggest that much of the reduced fertility in these mice originates from decreased fertilization due to inadequate sperm transport within the female reproductive tract. However, our data indicate that additional reproductive phenotypes in the CF female mice also contribute to the reduced fertility including small ovarian and uterine size, aberrant estrous cycles, and decreased oocyte ovulation rates. These data, along with previous work demonstrating that the gene mutated in CF, the cystic fibrosis transmembrane conductance regulator (CFTR), is normally expressed in tissues vital to reproduction, raises the possibility that CFTR may have a direct effect on fertility. If so, CFTR may also play an important role in normal female fertility within the general population.

Figure 1

Morphology and histology of ovaries, uteri, and cervix of 7-wk-old wild-type and Cftr^−/− females. A, Gross morphology of reproductive tracts of wild-type (left) and Cftr^−/− females (center and right). Bar, 500 mm. Note the overall size reduction in Cftr^−/− female tracts as well as the thinner uteri. B and C, Histology of ovaries from wild-type (B) and Cftr^−/− females (C). Bar, 500 μm. Wild-type ovaries displayed CL (marked by asterisk), whereas the markedly smaller Cftr^−/− ovaries rarely contained CLs, even though other follicle stages were present. D–F, Histology of cervices from wild-type (D) and Cftr^−/− females (E and F). Of the 15 Cftr^−/− females examined, the Cftr^−/− mouse in (F) was the only one with obvious physical blockage in the cervix (marked by arrowhead). Bar, 250 μm.

Figure 2

FSH and LH levels in wild-type and Cftr mutant female mice. FSH (A) and LH (B) levels in wild-type (open bars), ΔF508 (black bars), and S489X (striped bars) female mice. *, Significantly different from wild-type mice (P < 0.05).