Estrogen insensitivity syndrome

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The estrogen insensitivity syndrome (EIS) or estrogen resistance is a form of congenital estrogen deficiency[1] caused by a defective estrogen receptor (ER). Thus, estrogens cannot be recognized and initiate their biological action.[2]

In humans, the condition is very rare and only one case has been described. A reported male with EIS was tall as estrogens were unable to act to close the epiphyseal line, at risk for osteoporosis, and sterile (suggesting that in humans estrogens are necessary for reproduction).[3]

ERKO mice

Estrogen insensitivity syndrome of can be experimentally induced in animals, typically mice, by knocking out the estrogen receptor. In so-called ERKO mice different estrogens receptors can be disabled allowing to study the role of such receptors.[4] ERKO mice show development of the respective female or male reproductive systems, and male and female alpha ERKO mice are infertile, beta ERKO males are fertile while females are subfertile, male and female double alpha and beta ERKO mice are sterile. The hypoplastic (underdeveloped) uterus does not respond to exogenous stimulation by estrogens. Males are infertile with atrophy (reduction in function and size) in the testes. Bones age is delayed and bones are more brittle. Variations in these patterns can be achieved by selectively disabling the alpha or beta ERs.


In contrast to EIS, the androgen insensitivity syndrome (AIS) where the androgen receptor is defective is relatively common. This can be explained by the genetics of each syndrome. AIS is a X-linked recessive condition and thus carried over into future generations. EIS is not compatible with reproduction, thus each occurrence in humans would have to be a de-novo mutation and is not transmitted to offspring.

Congenital estrogen deficiency can also be caused by a defect in the aromatizing enzyme.[5]


  1. Rochira V, Balestrieri A, Madeo B, et al. (June 2001). "Congenital estrogen deficiency: in search of the estrogen role in human male reproduction". Mol. Cell. Endocrinol. 178 (1-2): 107–15. doi:10.1016/S0303-7207(01)00432-4. PMID 11403900.
  2. Smith, E.P., Boyd, J., Frank G.R., Takahashi, H., Cohen, R.M., Specker, B., Williams, T.C., Lubahn, D. B., Korach, K. S. Estrogen insensitivity syndrome in an adult man caused by homozygous nonsense mutation of the estrogen receptor gene. New England J. Med. 331: 1056-1061, 1994.
  3. Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, Kimbro KS, Eddy EM, Migliaccio S, Snedeker SM, Lubahn DB, Schomberg DW, Smith EP. Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Recent Prog Horm Res. 1996;51:159-86 PMID 8701078
  4. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999 Jun;20(3):358-417 PMID 10368776
  5. Rochira V, Balestrieri A, Madeo B, Spaggiari A, Carani C. Congenital estrogen deficiency in men: a new syndrome with different phenotypes; clinical and therapeutic implications in men. Mol Cell Endocrinol. 2002;193(1-2):19-28. PMID 12160998


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