Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant

This article describes a young woman with marked estrogen resistance owing to a homozygous loss-of-function mutation in ESR1, which encodes estrogen receptor α. This case shows that disruption of ESR1 causes profound estrogen resistance in women. Mutations in the androgen-receptor gene have been shown to cause androgen resistance in 46,XY humans 1 , 2 and in murine models, 3 but estrogen-receptor mutations are rare. The action of estrogen in peripheral tissues is mediated through a receptor 4 that is predominantly nuclear in location. 5 After the cloning of this receptor, termed estrogen receptor α, 6 , 7 in 1985, a second receptor (estrogen receptor β) was identified in 1996. 8 – 10 Nonnuclear estrogen signaling has also been suggested. The action of estradiol influences breast development, and feedback from estradiol on the hypothalamus and pituitary involves estrogen receptor α. 11 In mice, the ablation of both . . .