Thyroid Hormone Is Essential for Pituitary Somatotropes and Lactotropes *

Mice homozygous for a disruption in the a-subunit essential for TSH, LH, and FSH activity (aGsu) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in aGsu mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in aGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in aGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5and 1.5-fold, respectively). In addition, T4 replacement therapy of aGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not a-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in aGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types. (Endocrinology 140: 1884–1892, 1999) T MAJOR cell types of the anterior pituitary are distinguished by the hormones that they produce. TSH and the gonadotropins, LH and FSH, are heterodimeric glycoprotein hormones composed of a common a-subunit and unique b-subunits that confer specificity and bioactivity. Two functions of TSH are stimulation of the thyroid gland and thyroid folliculogenesis in the fetus. Likewise, LH and FSH play an integral role in gonadal differentiation in neonates (1) and are also regulators of sperm and ovarian development (2, 3). The gonadotropins and TSH are under feedback control by gonadal steroids and thyroid hormone, respectively. Feedback occurs both at the level of the hypothalamus and the pituitary gland. Targeted disruption of the glycoprotein hormone a-subunit (aGsu or Cga) gene through homologous recombination in mouse embryonic stem cells was used to analyze the role of a-subunit, TSH, LH, and FSH in vivo (1). aGsu mice are normal and fertile, whereas aGsu mice exhibit hypothyroidism, hypogonadism, infertility, and severe growth deficiency. Although the aGsu mice have a normal lobular pituitary structure, there is a profound reduction in number of somatotropes and lactotropes as well as evidence of hyperplasia and hypertrophy of thyrotropes. Although the thyrotrope hyperplasia was expected, the near absence of lactotropes was not. Hypothyroidism usually leads to elevation of TRH, which results in stimulation of PRL production (4, 5). One plausible explanation is that lactotrope differentiation is impaired due to the lack of secreted a-subunit monomers. This hypothesis is based on the observation that a-subunit stimulates PRL production in fetal pituitary cell cultures (6). Alternatively, reduced PRL and GH production in response to the lack of steroid hormones and thyroid hormone, respectively, could be responsible. Finally, if thyrotropes, somatotropes, and lactotropes are derived from a common precursor, the hyperplasia of thyrotropes may deplete the precursor pool available for differentiation of the other cell