Jacques Drouin

Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene

Previous studies defined a DNA element necessary for glucocorticoid repression of the pro‐opiomelanocortin (POMC) gene. The glucocorticoid receptor (GR) binds this negative glucocorticoid response element (nGRE) with an in vitro affinity similar to that of GR for positive GREs. However, whereas GR binds GREs as homodimers, a novel GR complex which forms with nGRE appears to contain three GR molecules. Biochemical characterization of this complex as well as equilibrium binding studies suggest that it is formed by sequential binding of a GR homodimer followed by binding of a GR monomer on the opposite side of the double helix. The DNA‐binding domain (DBD) of GR is sufficient for differential binding of GRE and nGRE, as bacterially‐expressed DBD formed unique nGRE complexes that contain three GR polypeptides. Thus, the POMC nGRE provides the first example of an interaction between GR and DNA in which GR binds otherwise than as a homodimer. Despite its high affinity for GR, the nGRE differs significantly from GREs in that it does not activate transcription in any context. As the nGRE appears insufficient on its own to confer hormone responsiveness, other POMC promoter elements are likely to be required to mediate glucocorticoid repression.

Specificity of the stimulatory effect of prostaglandins on hormone release in rat anterior pituitary cells in culture

Specificity of the effect of prostaglandins (PGs) on hormone release by the anterior pituitary gland was studied using cells in primary culture. Growth hormone (GH) release is stimulated by all eight PGs studied, PGE1 and E2 being 1000-fold more potent than the corresponding PGFs. The release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) remains unchanged upon addition of PGEs. While the basal release of thyrotropin (TSH) is only slightly stimulated by concentrations of PGEs above 10(-6)M, an important potentiation of the stimulatory effect of thyrotropin-releasing hormone on TSH release is observed. The release of GH, TSH and LH is stimulated equally well by PGAs and PGBs at concentrations higher than 10(-6)M, 3 X 10(-6)M, and 10(-5)M, respectively. PGFs do not affect the release of any of the measured pituitary hormones at concentrations below 10(-4)M. The stimulation of GH release by PGE2 can be inhibited by the PG antagonist 7-oxa-13-prostynoic acid, a half-maximal inhibition being found at a concentration of 4 X 10(-5)M of the antagonist in the presence of 10(-6)M PGE2. In the presence of somatostatin 10(-8)M, the inhibition of GH release cannot be reversed by PGE2 at concentrations up to 10(-4)M. 8-bromo-cyclic AMP-induced GH release is additive with that produced by PGE2. The present data show that 1) of the five pituitary hormones measured, only GH release is stimulated by prostaglandins at relatively low concentrations, 2) the PGE-induced GH release can be competitively inhibited by 7-oxa-13-prostynoic acid, 3) the inhibition of GH release by somatostatin cannot be reversed by PGE2 and 4) the PGEs increase the responsiveness of the thyrotrophs to TRH.

Role of Sex Steroids on LH and FSH Secretion in the Rat

Elucidation of the structure of LH-RH (Matsuo et al., 1971; Burgus et al., 1971) has opened new possibilities for studies of the factors involved in the control of LH and FSH secretion. This presentation will attempt to summarize the data describing the role of estrogens and androgens as specific and important modulators of gonadotropin secretion. Using the rat as model, evidence vill be presented of a specific action of these steroids at the hypothalamic and pituitary levels.

Site of the in vivo stimulatory effect of prostaglandins on LH release

A possible direct effect of prostaglandins E1 and E2 (PGE1 and PGE2) on luteinizing hormone (LH) release at the pituitary level was studied in vitro using anterior pituitary cells in primary culture, a system approximately 10-fold more sensitive to stimulation of LH release than previously used hemipituitaries. No effect of PGE1 or PGE2 could be detected on the time course of basal or LH-RH-stimulated LH release or on the LH responsiveness to LH-RH. This absence of a direct effect of PGEs at the pituitary level on LH release was confirmed by in vivo experiments using female rats under Surital anesthesia in the afternoon of proestrus. After intravenous injection, under these conditions, 15(S)-15-methyl PGE2 was 3-5 times more potent than PGE2 to increase plasma LH levels while PGE1 had about 50% the potency of PGE2. Injection of sheep anti-LH-RH serum one hour before PGE1 or PGE2 injection not only lowered basal plasma LH levels but prevented the rise induced by PGEs. These data indicate clearly that the increased plasma LH levels observed after in vivo PGE injection are secondary to a stimulation of LH-RH release while PGEs do not appear to have a significant effect on LH release at the pituitary level.

Interactions of TRH, LH-RH, and Somatostatin in the Anterior Pituitary Gland

Publisher Summary This chapter focuses on the interactions of TRH, LH-RH, and somatostatin in the anterior pituitary gland. The secretory activity of anterior pituitary cells is controlled by specific hypothalamic hormones and the feedback action of gonadal, adrenal, and thyroid hormones. The neurohormones are released from the nerve endings containing these peptides in the median eminence and transported to their site of action by a small vascular portal system, growth hormone (GH) prolactin (PRL), adrenocorticotropin (ACTH), and thyrotropin (TSH) are secreted by different cell types, while there is evidence that luteinizing hormone (LH) and follicle-stimulating hormone (FSH) could originate from the same cell. The influence of the hypothalamus on LH, FSH, and ACTH secretion appears to be only positive, while the best available evidence indicates that both positive and negative effects are exerted on GH, TSH, and PRL secretion. The secretory activity of anterior pituitary cells is controlled by the specific hypothalamic hormones and the feedback action of gonadal, adrenal, and thyroid hormones. The neurohormones are released from the nerve endings containing these peptides in the median eminence and transported to their site of action by a small vascular portal system. The observed effects on the spontaneous proestrus plasma LH surge and ovulation support the possibility of developing a contraceptive method based on inhibitory L H-R H analogs.