Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins

Abstract

In the menstrual cycle, the mid-cycle surge of gonadotropins (both luteinising hormone [LH] and follicle-stimulating hormone [FSH]) signals the initiation of the periovulatory interval, during which the follicle augments progesterone production and begins to luteinise, ultimately leading to the rupture of the follicle wall and the release of an oocyte. The administration of gonadotropins in controlled ovarian stimulation (COS) leads to supraphysiological steroid concentrations of a very different profile compared with those seen during natural cycles. It has been suggested that these high steroid concentrations cause alterations in endometrial development, affecting oocyte viability in assisted reproductive technology. Furthermore, it has been proposed that elevated progesterone levels have a negative effect on the reproductive outcome of COS. This may arise from an asynchrony between embryo stage and endometrium status at the window of implantation. The regulation of progesterone production by the developing follicles during COS is a complicated interplay of hormonal systems involving the theca and granulosa cells, and the effect of the actions of both LH and FSH. The present paper reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis. Based on current evidence, it is not clear whether the high levels of progesterone produced during COS have detrimental effects on fertility.

Figure 1

Human ovarian steroidogenesis. Dashed arrows show the route of pregnenolone metabolism via the Δ5 pathway. Solid arrows show an alternative route of pregnenolone metabolism beginning with the conversion of pregnenolone to progesterone by the action of 3β-HSD. Adapted from Wickenheisser JK, et al. 2006 [12].

Figure 2

The effect of r-hFSH administration in vivo on ovarian P450c17α mRNA expression in rats. FSH values are IU/mL. PMSG: pregnant mare serum gonadotropin; FSH: follicule stimulating hormone; Gr: granulosa; Th: theca. Adapted from Smyth CD, et al. 1993 [13].

Figure 3

The follicle as a factory of steroid biosynthesis. During controlled ovarian stimulation, there is a continuum of follicular development. Source: http://en.wikipedia.org/wiki/Ovarian_follicle

Figure 4

Intrafollicular concentrations of progesterone in relation to follicular development in women during the follicular phase of the natural menstrual cycle. Filled circles show the dominant follicles and open circles show the non-dominant follicles. Adapted from Schneyer AL et al. 2000 [29].

Figure 5

Levels of progesterone and 17-OH-progesterone during the follicular phase in women stimulated with different doses of hCG. Shaded bars represent stimulation day 0, day 6 and day of hCG triggering. Graph drawn using data from Thuesen et al. 2013[40]. hCG: human chorionic gonadotropin.

Figure 6

Gonadotropic regulation of steroidogenesis at different phases of the ovarian cycle. A summary of understanding based on the currently available literature reviewed in this article. FSH: follicule stimulating hormone; hCG: human chorionic gonadotropin; LH: luteinising hormone.