ESPE Abstracts

Introduction: Estrogens play an essential role in reproduction and their peripheral action is mediated via nuclear alfa and beta receptors (ER) as well as membrane receptors. To date, only 3 females and 2 males from 3 families with a loss of function of ERa have been reported. The phenotype in these families was strongly suggestive of an estrogen resistance with an absence of a complete puberty, a delay in epiphyseal maturation with high estradiol levels and elevated gonadotropin levels.

Goal: The objective of this study was to describe a new family in which 2 sisters displayed different levels of endocrine and ovarian defects although they carried the same homozygous rare variant in the ERa-encoding ESR1 gene.

Materials and Methods: A 36-year-old woman with a primary amenorrhea and no breast development, had elevated 17β-estradiol (1497 pg/ml), high FSH (57 IU/L) and LH (21 IU/L) plasma levels, and enlarged multifollicular ovaries (11 and 17 ml). Her 18-year-old sister did not enter puberty and had moderate increases in 17β-estradiol (204 pg/ml) with high FSH (29 IU/L) and LH (22 IU/L) plasma levels and ovaries of normal size. The parents are consanguineous.

Results: In both cases, genetic analysis identified a homozygous variant of ESR1 (c.1154A>T) leading to the substitution of the highly conserved glutamic acid at position 385 by a valine (p.Glu385Val). Both parents as well as an unaffected sister were heterozygous for the variant. The Glu385 is located in the ligand binding domain and the in-silico analysis predicted a deleterious effect on the protein function. Modeling study of the ERa-E385V variant showed a slight displacement of the H-12 helix, which plays a crucial role in signal transmission, suggesting that the Glu385Val replacement might preclude the activation of the receptor.

A functional analysis was performed by transient expression of WT-ERa or Glu385Val-ERa in HEK293A cells. Glu385Val-ERa transfected cells showed a strong decrease in transcriptional activation by 17β-estradiol of a reporter gene controlled by a standard estradiol-responsive-element as well as a milder inhibition of the KISS1 promoter when compared to WT-ERa. Immunofluorescence analysis showed lower nuclear translocation of E385V-ERa in the presence of 17β-estradiol as compared to WT-ERα.

Conclusion: These two new cases are remarkable as they are sisters and they display a different level of severity of the ovarian and hormonal phenotypes. This phenotypic discrepancy could be attributable to a mechanism that could partially compensate the ERa inactivation.