Vitamin A and retinoic acid stimulate within minutes cAMP release and growth hormone secretion in human pituitary cells.

In order to gain a better understanding on the possible role of vitamin A (VA) and retinoic acid (RA) on human growth hormone (GH) secretion, we used the physiological model of pituitary cells perifusion. In perifused cells from pituitary somatotropic adenomas, RA induced within minutes a peak of GH secretion. This effect was dose dependent, maximal effect being observed with 100 nM. The GH release was associated with a discharge of cAMP delayed by 4 to 8 minutes relative to the GH surge. Similar results were obtained after VA stimulation. Our observations provide the first evidence of an action of VA and RA on cAMP production. They suggest a role of RA and VA in the regulation of human GH secretion via the cAMP dependent pathway.

Regulation of the human menstrual cycle.

Our understanding of the regulation of the menstrual cycle has recently improved with the development of various tools of investigation. The cycle is now thought to be determined mainly by the ovary itself, which sends various signals to the pituitary and the hypothalamus. The aim of the cycle is to produce a single mature oocyte each month from puberty to menopause. However, the most common evolution of a follicle is atresia, a consequence of the genetically controlled, ovarian apotosis (or "programmed cell death"). Follicular growth and maturation are mostly independent of gonadotropins, from the stage of primordial follicles to antral follicles. A complete intraovarian paracrine system is implied in this gonadotropin-independent follicular growth, and in the modulation of the actions of the gonadotropins in the ovary. FSH allows the rescue of a minority of follicles from atresia and is indispensable to only the final maturation of the preovulatory follicle. The cyclical variations of the gonadotropins are under the control of ovarian steroids (estradiol and progesterone) and peptides (inhibin). The cycle length is determined by follicular growth and by the fixed life span of the corpus luteum. The mechanism of action of gonadotropins is much better understood since the gonadotropins and their receptor cDNA have been cloned. The recent description of naturally occurring mutations has lead to a better understanding of the role of each gonadotropin, demonstrating the crucial role of FSH in the terminal maturation of the follicles. The ovarian cycle can also be monitored at the level of target tissues of steroids such as the endometrium. The cellular mechanisms of endometrial maturation, under the control of estradiol and progesterone, are better understood. The endometrial maturation is synchronized to follicular development and allows implantation of the conceptus. The genes implied in the implantation of the embryo are being identified (e.g., integrins). Last but not least, the mechanisms of endometrial shedding are being elucidated, especially the role of metalloproteases and angiogenic factors. These concepts will allow the development of new treatments for infertility, the design of new contraceptive techniques, and a better tolerance of treatments using sex steroids, particularly progestin-only pill.

Retinoic acid stimulates growth hormone synthesis in human somatotropic adenoma cells: characterization of its nuclear receptors.

In order to gain a better understanding on the possible role of retinoic acid (RA) on human GH secretion, we have characterized the expression of its nuclear receptors in somatotropic adenoma cell extracts. By immunoblotting with rabbit polyclonal antibodies directed against RAR alpha, beta, and gamma and RXR alpha and beta, we could only detect the presence of RAR alpha and RXR alpha proteins. The predominant expression of RXR alpha was confirmed at the mRNA level by Northern and slot-blot analysis. We then investigated the effect of RA on GH synthesis in cell culture of adenomatous somatotrophs. In cultured cells, RA (1 microM) stimulated GH secretion, increased intracellular GH content and GH mRNA levels within 72 h, suggesting a modulation of GH synthesis by RA.