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

From the Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, and the Neuroscience Program, Medical College of Georgia, Georgia Regents University, Augusta (S.D.Q., H.-G.K., L.P.C., L.C.L.)
New England Journal of Medicine (Impact Factor: 55.87). 07/2013; 369(2):164-171. DOI: 10.1056/NEJMoa1303611
Source: PubMed


Although androgen resistance has been characterized in men with a normal chromosome complement and mutations in the androgen-receptor gene, a mutation in the gene encoding estrogen receptor α (ESR1) was previously described only in one man and not, to our knowledge, in a woman. We now describe an 18-year-old woman without breast development and with markedly elevated serum levels of estrogens and bilateral multicystic ovaries. She was found to have a homozygous loss-of-function ESR1 mutation in a completely conserved residue that interferes with estrogen signaling. Her clinical presentation was similar to that in the mouse orthologue knockout. This case shows that disruption of ESR1 causes profound estrogen resistance in women. (Funded by the National Institutes of Health.).

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    • "Pathologic, reactive hyperestrogenism may occur as a feedback mechanism against defective ER signaling.34,35 In these cases, excessive estrogen production is not a causal factor for diseases but serves as a breakthrough of blocked ER signaling mechanisms. "
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