The hypothalamic-pituitary-gonadal axis is central to normal reproductive function. This pathway begins with the release of
gonadotropin-releasing hormone in systematic pulses by the hypothalamus.
Gonadotropin-releasing hormone is bound by receptors on gonadotroph cells in the anterior pituitary gland and stimulates the synthesis and secretion of
luteinizing hormone and, to some extent,
follicle-stimulating hormone. Once stimulated by these
glycoprotein hormones, the gonads begin gametogenesis and the synthesis of
sex hormones. In humans, mutations of the
forkhead transcription factor, FOXP3, lead to an autoimmune disorder known as
immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. Mice with a mutation in the Foxp3 gene have a similar autoimmune syndrome and are infertile. To understand why FOXP3 is required for reproductive function, we are investigating the reproductive phenotype of Foxp3 mutant mice (Foxp3(sf/Y)). Although the gonadotroph cells appear to be intact in Foxp3(sf/Y) mice,
luteinizing hormone beta (Lhb) and
follicle-stimulating hormone beta (Fshb) expression are significantly decreased, demonstrating that these mice exhibit a
hypogonadotropic hypogonadism. Hypothalamic expression of
gonadotropin-releasing hormone is not significantly decreased in Foxp3(sf/Y) males. Treatment of Foxp3(sf/Y) males with a
gonadotropin-releasing hormone receptor agonist does not rescue expression of Lhb or Fshb. Interestingly, we do not detect Foxp3 expression in the pituitary or hypothalamus, suggesting that the
infertility seen in Foxp3(sf/Y) males is a secondary effect, possibly due to loss of FOXP3 in immune cells. Pituitary expression of
glycoprotein hormone alpha (Cga) and
prolactin (Prl) are significantly reduced in Foxp3(sf/Y) males, whereas the precursor for
adrenocorticotropic hormone,
pro-opiomelanocortin (
Pomc), is increased. Human patients diagnosed with IPEX often exhibit
thyroiditis due to destruction of the thyroid gland by autoimmune cells. We find that Foxp3(sf/Y) mice have elevated expression of
thyroid-stimulating hormone beta (Tshb), suggesting that they may suffer from
thyroiditis as well. Expression of the pituitary
transcription factors, Pitx1, Pitx2, Lhx3, and Egr1, is normal; however, expression of Foxl2 and Gata2 is elevated. These data are the first to demonstrate a defect at the pituitary level in the absence of FOXP3, which contributes to the
infertility observed in mice with Foxp3 loss of function mutations.