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INTRACRINE AND PARACRINE REGULATION OF ESTROGEN ACTIVITY BY ESTROGEN SULFOTRANSFERASE.
Song, Wenchao1, 1
ABSTRACT- Elicitation of biological responses by estrogen in target tissues requires the presence of estrogen receptor as well as receptor-active ligand in the local microenvironment. While much attention has been devoted to the study of the receptor in estrogen target tissues, the concept is emerging that tissue estrogen sensitivity may also be regulated by ligand availability through metabolic transformation in situ. Estrogen sulfotransferase catalyzes the sulfoconjugation and inactivation of estrogen and is expressed abundantly in testicular Leydig cells. Expression of this enzyme in Leydig cells is LH- and androgen-dependent. Targeted disruption in the mouse of the estrogen sulfotransferase gene caused structural and functional lesions in the male reproductive system. Although knockout males were fertile and phenotypically normal initially, they developed age-dependent Leydig cell hypertrophy/hyperplasia and seminiferous tubule damage. Development of these lesions in the testis could be recapitulated by exogenous estradiol administration in younger knockout mice, suggesting that they arose in older knockout mice from chronic estrogen stimulation. By 18-22 months, knockout mice were found to have reduced testis and epididymis weights but increased seminal vesicle/coagulating gland weight due to tissue swelling. Furthermore, compared with age-matched wild-type mice, sperm total and forward motility of 18-22-months old knockout mice were reduced by 60% and 80%, respectively. These findings indicate that intracrine and paracrine estrogen activity can be modulated by a ligand transformation enzyme under a physiological setting. Thus, interference with the normal function of estrogen transformation enzymes such as estrogen sulfotransfearse in reproductive tissues may disturb the local steroid hormone homeostasis and lead to abnormal intracrine and paracrine estrogen stimulation.
KEY WORDS: estrogen sulfotransferase, metabolism, testis, Leydig cells
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