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J Clin Endocrinol Metab. 2017 Jan 1;102(1):93-99. doi: 10.1210/jc.2016-2749.

Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation.

Author information

INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
Service de Pédiatrie, Hôpital Nafissa Hamoud, Alger, 16040 Algeria.
Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, and.
Laboratoire d'Hormonologie, Pôle de Biologie Médicale et Pathologie, site Saint-Antoine, Hôpitaux Universitaires Est Parisien, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France.
Service de Pédiatrie, Hôpital de Bab El Oued, Alger, 16040 Algeria.
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina 27709.
Service d'Endocrinologie et Maladies de la Reproduction, Centre Hospitalier Universitaire de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France.
Service d'Endocrinologie et Maladies de la Reproduction, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France; and.
INSERM 933, Université Pierre et Marie Curie, 75011 Paris, France.



Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) α and β, encoded by ESR1 and ESR2 genes, respectively.


The study's aim was to describe a family in which 3 members presented with estrogen insensitivity.

Design and Setting:

Clinical evaluation and genetic and mutational analysis were performed in an academic medical center.

Patients and Interventions:

An ESR1 mutation was identified in 2 sisters and 1 brother, originating from a consanguineous Algerian family, who did not enter puberty and presented with delayed bone maturation consistent with estrogen insensitivity. The 2 sisters had enlarged multicystic ovaries. Hormonal evaluation as well as genetic and mutational analysis were performed.


Hormonal evaluation revealed extremely high plasma 17β-estradiol (>50-fold normal range) associated with elevated gonadotropin levels (greater than threefold normal range), highly suggestive of estrogen resistance. The 3 affected patients carried a homozygous mutation of a highly conserved arginine 394 for which histidine was substituted through an autosomal recessive mode of transmission. Structural and functional analysis of the mutant ERα revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ERα. A group of other potential ER activating ligands were tested, but none overcame the estrogen insensitivity in these patients.


Description and analysis of this family of patients with mutant ERα provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition.

[Indexed for MEDLINE]
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