Increased exposure to estrogens disturbs maturation, steroidogenesis, and cholesterol homeostasis via estrogen receptor alpha in adult mouse Leydig cells

Endocrinology. 2009 Jun;150(6):2865-72. doi: 10.1210/en.2008-1311. Epub 2009 Feb 5.


Deteriorated male reproductive health has been connected to overexposure to estrogens or to imbalanced androgen-estrogen ratio. Transgenic male mice expressing human aromatase (AROM(+) mice) serve as an apt model for the study of the consequences of an altered androgen-estrogen ratio. Our previous studies with AROM(+) mice showed that low androgen levels together with high estrogen levels result in cryptorchidism and infertility. In the present study, the AROM(+) mice were shown to have severe abnormalities in the structure and function of Leydig cells before the appearance of spermatogenic failure. Decreased expression of adult-type Leydig cell markers (Ptgds, Vcam1, Insl3, Klk21, -24 and -27, Star, Cyp17a1, and Hsd17b3) indicated an immature developmental stage of the Leydig cells, which appears to be the first estrogen-dependent alteration. Genes involved in steroidogenesis (Star, Cyp17a1, and Hsd17b3) were suppressed despite normal LH levels. The low expression level of kallikreins 21, 24, and 27 potentially further inhibited Leydig cell function via remodeling extracellular matrix composition. In connection with disrupted steroidogenesis, Leydig cells showed enlarged mitochondria, a reduced amount of smooth endoplasmic reticulum, and an accumulation of cholesterol and precursors for cholesterol synthesis. The results of studies with AROM(+) mice crossed with estrogen receptor alpha or beta (ERalpha and ERbeta, respectively) knockout mice lead to the conclusion that the structural and functional disorders caused by estrogen exposure were mediated via ERalpha, whereas ERbeta was not involved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aromatase / genetics
  • Aromatase / metabolism
  • Cholesterol / metabolism*
  • Estradiol Dehydrogenases / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Estrogens / metabolism*
  • Estrogens / pharmacology
  • Follicle Stimulating Hormone / blood
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • Leydig Cells / drug effects
  • Leydig Cells / metabolism*
  • Luteinizing Hormone / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Animal
  • Phosphoproteins / metabolism
  • Sexual Maturation / drug effects
  • Sexual Maturation / physiology*
  • Steroid 17-alpha-Hydroxylase / metabolism
  • Steroids / metabolism*
  • Testosterone / metabolism


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • Phosphoproteins
  • Steroids
  • steroidogenic acute regulatory protein
  • Testosterone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone
  • Cholesterol
  • Estradiol Dehydrogenases
  • Aromatase
  • Steroid 17-alpha-Hydroxylase