Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice

Steroidogenic acute regulatory protein (SMR) is essential for adrenal and g onadal steroidogenesis, stimulating the translocation of cholesterol to the inner mitochondrial membrane where steroidogenesis commences. StAR mutatio ns in humans cause congenital lipoid adrenal hyperplasia (lipoid CAH), an a utosomal recessive condition with severe deficiencies of all classes of ste roid hormones. We previously described StAR knockout mice that mimic many f eatures of lipoid CAH patients. By keeping StAR knockout mice alive with co rticosteroid replacement, we now examine the temporal effects of StAR defic iency on the structure and function of steroidogenic tissues. The adrenal g lands, affected most severely at birth, exhibited progressive increases in lipid deposits with aging. The testes of newborn StAR knockout mice contain ed scattered lipid deposits in the interstitial region, presumably in remna nts of fetal Leydig cells. By 8 weeks of age, the interstitial lipid deposi ts worsened considerably and were associated with Leydig cell hyperplasia. Despite these changes, germ cells in the seminiferous tubules appeared inta ct histologically, suggesting that the StAR knockout mice retained some cap acity for androgen biosynthesis. Sperm maturation was delayed, and the germ cells exhibited histological features of apoptosis, consistent with subopt imal androgen production. Immediately after birth, the ovaries of StAR knoc kout mice appeared normal. After the time of normal puberty, however, promi nent lipid deposits accumulated in the interstitial region, accompanied by marked luteinization of stromal cells and incomplete follicular maturation that ultimately culminated in premature ovarian failure. These studies prov ide the first systematic evaluation of the developmental consequences of St AR deficiency in the various steroidogenic organs.