Choriogonadotrophin-alpha (Cga) is one of the first molecular markers for the developing pituitary gland previously known as alpha-subunit, common to thyroid-stimulating hormone (TSH), luteinising hormone (LH) and follicle-stimulating hormone (FSH). Mice lacking Cga are hypogonadal and exhibit profound hypothyroidism and dwarfism. Light microscopy of Cga null mice has shown that pituitary thyrotrophs in the absence of thyroid function display dramatic hypertrophy, somatotrophs were reduced in number and lactotrophs absent, whereas gonadotrophs were unaffected (Kendall et al 1995 Genes Dev 9:2007). The aim of the present study was to compare pituitary ultrastructure in Cga null and control WT mice. Pituitary glands (8 week old) were collected (n=4) and prepared for quantitative electron microscopy. Immunogold labelling of pituitary cell markers was performed to identify cells. Thyrotrophs in Cga null mice have more than twice the diameter of WT cells. The cisternae of the endoplasmic reticulum (ER) in WT cells appeared normally thin and elongated, comprising only a small portion of the cytoplasm. In Cga null thyrotrophs and gonadotrophs virtually the entire cytoplasm was filled with dilated ER cisternae. Scarce secretory granules were observed in mutant thyrotrophs and gonadotrophs, probably because heterodimerization of CGA and beta subunit is required. The christae of mitochondria in thyrotrophs in Cga null mice were markedly more electron dense than in control WT mice, and were in close contact with the ER. This mitochondrial phenotype is similar to that reported following exposure to oxidative stress. Somatotroph secretory granules were significantly smaller, fewer in number and distributed to the perimeter of the cell indicating increased GH secretion to compensate for reduced somatotroph number. These findings suggest disrupted pituitary cell function in the cellular compartments responsible for energy production and protein synthesis, folding, assembly and secretion.