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The Expression of Aromatase in Gonadotropes Is Regulated by Estradiol and Gonadotropin-Releasing Hormone in a Manner that Differs from the Regulation of Luteinizing Hormone

Laboratoire Estrogènes et Reproduction (G.G., S.C., M.-L.K.), Equipe d’Accueil 2608 Unité sous contrat 2006 Institut National de la Recherche Agronomique, Université de Caen Basse-Normandie; and Département Génétique et Reproduction (N.R., S.C., M.-L.K.), Unité de Formation et de Recherche de médecine Centre Hospitalier Universitaire, F-14033 Caen, France

Address all correspondence and requests for reprints to: Marie-Laure Kottler, Département Génétique et Reproduction, UFR de médecine, F-14033 Caen, France. E-mail: kottler-ml{at}chu-caen.fr.

The role of estrogens is dual: they suppress basal expression of gonadotropins and enhance GnRH responsiveness at the time of the LH surge. Estrogens are synthesized by cytochrome P450 aromatase (P450arom), encoded by the cyp19 gene. We focused on the cyp19 gene in rat and showed that it is expressed in gonadotropes through promoters PII and PI.f, using RT-PCR and dual fluorescence labeling with anti-P450arom and -LH antibodies. Real-time PCR quantification revealed that aromatase mRNA levels varied during the estrous cycle and were significantly increased after ovariectomy. This effect is prevented by estradiol (E2) as well as GnRH antagonist administration, suggesting that GnRH may mediate the steroid effect. Interestingly, the long-acting GnRH agonist that induces LH desensitization does not modify aromatase expression in ovariectomized rats. Administration of E2 in ovariectomized rats receiving either GnRH agonist or GnRH antagonist clearly demonstrated that E2 also reduces cyp19 expression at the pituitary level. The selective estrogen receptor- ligand propyl pyrazole triol and the selective estrogen receptor-ß ligand diarylpropionitrile both mimic the E2 effects. By contrast, propyl pyrazole triol reduces LHß expression whereas diarylpropionitrile does not. In addition, using transient transfection assays in an LßT2 gonadotrope cell line, we provided evidence that GnRH agonist stimulated, in a dose-dependant manner, cyp19 promoters PII and PI.f and that E2 decreased the GnRH stimulation. In conclusion, our data demonstrate that GnRH is an important signal in the regulation of cyp19 in gonadotrope cells. Both common and specific intracellular factors were responsible for dissociated variations of LHß and cyp19 expression.

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