Hormones in synergy: regulation of the pituitary gonadotropin genes

Abstract

The precise interplay of hormonal influences that governs gonadotropin hormone production by the pituitary includes endocrine, paracrine and autocrine actions of hypothalamic gonadotropin-releasing hormone (GnRH), activin and steroids. However, most studies of hormonal regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the pituitary gonadotrope have been limited to analyses of the isolated actions of individual hormones. LHbeta and FSHbeta subunits have distinct patterns of expression during the menstrual/estrous cycle as a result of the integration of activin, GnRH, and steroid hormone action. In this review, we focus on studies that delineate the interplay among these hormones in the regulation of LHbeta and FSHbeta gene expression in gonadotrope cells and discuss how signaling cross-talk contributes to differential expression. We also discuss how recent technological advances will help identify additional factors involved in the differential hormonal regulation of LH and FSH.

Fig. 1

Transcription factors and associated binding sites involved in hormonal induction of the rat LHβ and mouse FSHβ promoters. Binding sites for factors involved in basal expression, which interact with factors or sites involved in hormonal regulation, are illustrated with circles or ovals. Squares indicate sites involved in GnRH induction. Hexagons indicate sites involved in steroid hormone regulation, and are labeled as hormone response elements (HREs) if they play a role in regulation by 3-keto steroid hormones or as a negative progesterone response element (nPRE). Rounded rectangles indicate activin responsive elements (AREs). Smad transcription factors bind some of these elements (−116 in LHβ and −267 in FSHβ), while others bind different factors (i.e. Pbx and Prep at −120 in the FSHβ promoter), which may interact with Smads and help stabilize Smad-DNA interactions.

Fig. 2

Activin synergizes with GnRH (A–B) or progesterone (C–D) to induce FSHβ gene expression. A luciferase reporter containing 1 kb of the mouse FSHβ promoter was transiently transfected into LβT2 cells. After overnight starvation in serum-free media, the cells were treated with vehicle control (C), 10 ng/μl activin (A), 10 nM GnRH (G), 100 nM R5020 (a synthetic progestin; P), activin and GnRH co-treatment (AG) or activin and progestin (AP), as indicated. The asterisks indicate significant differences from the vehicle-treated control, while pound signs indicate a synergistic interaction as defined by a two-way ANOVA (p<0.05). The dashed line in A and C represents the level at which the hormone co-treatment is additive rather than synergistic. In B and D, synergy is demonstrated graphically as described in Slinker et al. (Slinker, 1998). If the lines diverge, there is synergy, whereas if the lines remain parallel, there is no interaction. The circles represent control and GnRH (B) or progestin (D) treatment alone. The squares represent activin treatment, both alone and with GnRH (B) or progestin (D).

Fig. 3

A model of hormonal regulation of differential LH and FSH synthesis in pituitary gonadotrope cells. There are multiple ways that peptide and steroid hormones can influence gonadotropin transcription. On the morning of proestrus, activin signaling is minimized due to high levels of the inhibitory molecules, follistatin (FS) and inhibin (1). GnRH signaling is also muted, resulting in low levels of both LHβ and FSHβ mRNA (2). On the afternoon of proestrus, GnRH pulsatility and amplitude increase dramatically prior to ovulation leading to increased transcription of LHβ and FSHβ (3). Estrogen may also play a direct role in inducing LHβ gene expression (4). During estrus, the levels of bio-available activin increase due to a reduction in follistatin and inhibin levels, resulting in increased levels of FSHβ mRNA (5). Concurrently, GnRH pulses become slower, which may favor FSHβ transcription directly and indirectly via reduced induction of follistatin (6). Moreover, progesterone action leads to induction of FSHβ but suppression of LHβ gene expression (7). Finally, synergy between activin and GnRH or progesterone signaling pathways enhances the positive action of these hormones on FSHβ transcription (8) and, thus, may help regulate the secondary FSH surge.