Modulation of the steroidogenesis of cultured human granulosa-lutein cells by gonadotropin-releasing hormone analogs.

Abstract

GnRH analogs are widely used in reproductive medicine to create a hypogonadotropic hypogonadism. However, numerous animal studies have demonstrated a direct regulation of the gonadal function by GnRH. To ascertain this direct ovarian effect in humans, the steroidogenesis of cultured human granulosa cells was studied with or without GnRH and five of its agonists. Buserelin (D-Ser(But)6, desGly10) GnRH ethylamide, leuprorelin (D-Leu6, desGly10) GnRH ethylamide, H4055 (desGly10) GnRH ethylamide, and H4065 (D-Trp6, desGly10) GnRH ethylamide significantly enhanced estradiol secretion. In addition, buserelin induced a significant cell surface decrease that seemed to be mediated by cytoskeleton modifications. The two other molecules, GnRH and triptorelin (D-Trp6) GnRH), had no effect on estrogen secretion at any of the studied concentrations. Thus, despite similar pituitary effects, these agonists did not exhibit the same ovarian action. This may be accounted for by the differences found between pituitary and ovarian receptors. These results suggest that some GnRH analogs can modulate human granulosa cell steroidogenesis at least in the preovulatory period.

Can GnRH agonists act directly on the ovary and contribute to cyst formation?

“…This hypothesis is primarily based on two premises: (i) reports on the presence of GnRH pituitary desensitization took longer in this woman. However, as the values of FSH and LH were very low, it is more likely receptors on the ovary (Latouche et al, 1989;Namiki et al, 1990); and (ii) reports of GnRH agonist-induced steroidogen-that this case along with earlier reports (Liu et al 1991;Weissman et al, 1998) supports the hypothesis that GnRH esis by cultured human granulosa cells (Parinaud et al, 1992;Bussenot et al, 1993).…”

“…of progesterone to decrease gonadotrophin release in response There have been several reports on the presence of ovarian to GnRH agonist (Araki et al, 1985), therefore the initial cysts while the women are still undergoing treatment with transient 'flare-up effect' of GnRH agonist becomes subdued GnRH agonists (Feldberg et al, 1989;Ron-El et al, 1989; and subsequently the formation of cysts. This hypothesis Sampaio et al, 1991;Jenkins et al, 1992;Parinaud et al, explains the presence or formation of ovarian cysts after GnRH 1992; Stewart et al, 1992;Jenkins et al, 1993;Tarlatzis et al, agonist administration, but fails to explain how these 'cysts' 1994; Keltz et al, 1995;Weissman et al, 1998). The elevated continue growing and secreting oestradiol in the absence of concentrations of serum oestradiol and the high concentration any endogenous or exogenous gonadotrophin stimulation for of oestradiol in the fluids aspirated from these cysts indicate a prolonged period of time.…”

“…It is pituitary desensitization, the ovaries were active as indicated by the increase in the diameter of the follicular cyst (1-2.5 probable that the circulating gonadotrophin concentrations may not have dropped down to that of a 'hypophysectomized stage'. cm), the number of follicles (there was only one follicle, Ͼ0.5 cm, at the time of starting the GnRH agonist but after 14 days This also explains why in some women, continuation of GnRH agonist for a few more days prior to starting stimulation brings there were three more follicles with a diameter of 0.9 cm); serum oestradiol concentrations after 14 days were 146 pg/ml; about both a drop in the serum oestradiol concentrations and the size of the cysts (Sampaio et al, 1991;Parinaud et and the thickness of the endometrium increased from 0.5 mm on the day of starting GnRH agonist to 1.05 cm after 14 days. al., 1992).…”

Is there a difference in the function of granulosaluteal cells in patients undergoing in-vitro fertilization either with gonadotrophin-releasing hormone agonist or gonadotrophin-releasing hormone antagonist?

“…Similar direct GnRH effects have been considered for the human ovary, but the results have been contradictory (e.g. Casper et al, 1982;Tureck et al, 1982;Bussenot et al, 1993). Since we examined the effect of cetrorelix and buserelin exposure in vitro, it is impossible to draw conclusions regarding any direct effects on the granulosa cells in vivo.…”

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“…However, there is debate concerning the effect of GnRH agonists on granulosa cell function because studies on the actions of GnRH analogues on steroidogenesis in granulosa lutein-cells in vitro revealed contradictory effects (7,(9)(10)(11)(12)(13). Moreover, little is known about any direct action of GnRH antagonists on ovarian steroidogenesis (3).…”