Differential Regulation of Ovarian Anti-Müllerian Hormone (AMH) by Estradiol through ¦Á- and ¦Â-Estrogen Receptors

GRYNBERG, M.; PIERRE, A.; REY, R; LECLERC, A.; AROUCHE, N.; HESTERS, L.; CATTEAU-JONARD, S.; FRYDMAN, R.; PICARD, J.Y.; FANCHIN, R.; VEITIA, R.; DI CLEMENTE, N.; TAIEB, J.

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2012 vol. 97 p. 1649 - 1657

0021-972X

Background: Anti-M¨¹llerian hormone (AMH) is a member of the transforming growth factor-ß family which limits follicle maturation. Recently, serum AMH has been recognized as a useful diagnostic and prognostic tool in human reproductive endocrinology. Objective: The aim of this study was to investigate the regulation of human AMH expression by estradiol and FSH in granulosa cells (GCs). Methods: AMH mRNAs were quantified by quantitative RT-PCR in human GCs. AMH transcription was studied in KK1 GCs co-transfected with estrogen receptors (ER) ERb or ERa, and normal (hAMH-luc) or mutated AMH promoter reporter constructs. Binding sites for estradiol (1/2-ERE) and steroidogenic factor one (SF-1) were disrupted by targeted mutagenesis. The level of ERs in GCs was determined by quantitative RT-PCR and western-blotting. Results: In KK1 cells, estradiol and PPT up-regulated hAMH-luc when ERa was overexpressed, whereas estradiol and DNP inhibited it in the presence of ERb. Disruption of 1/2-ERE and/or SF-1 binding sites did not modify ERb- mediated effect of estradiol on hAMH-luc, whereas it affected that conveyed by ERa. The FSH enhancement of hAMH-luc was also abolished by estradiol in the presence of ERb. When both ERs were transfected, estradiol inhibited hAMH-luc. Estradiol repressed AMH mRNA in human GCs which express more ERa  than ERb mRNAs.  Conclusions: Our results show that AMH expression can be differentially regulated by estradiol depending on the ERs, and suggest that its decrease in GCs of growing follicles which mainly express ERb, and during controlled ovarian hyperstimulation, is due to the effect of estradiol.