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Review
. 2009;56(6):729-37.
doi: 10.1507/endocrj.k09e-185. Epub 2009 Jul 17.

GnRH pulsatility, the pituitary response and reproductive dysfunction

Rie Tsutsumi  1 , Nicholas J G Webster
Affiliations
Review

GnRH pulsatility, the pituitary response and reproductive dysfunction

Rie Tsutsumi et al. Endocr J. 2009.

Abstract

GnRH plays an essential role in neuroendocrine control of reproductive function. In mammals, the pattern of gonadotropin secretion includes both pulse and surge phases, which are regulated independently. The pulsatile release of GnRH and LH plays an important role in the development of sexual function and in the normal regulation of the menstrual cycle. The importance of GnRH pulsatility was established in a series of classic studies. Fertility is impaired when GnRH pulsatility is inhibited by chronic malnutrition, excessive caloric expenditure, or aging. A number of reproductive disorders in women with including hypogonadotropic hypogonadism, hypothlamic amenorrhea, hyperprolactinemia and polycystic ovary syndrome (PCOS) are also associated with disruption of the normal pulsatile GnRH secretion. Despite these findings, the molecular mechanisms of this pulsatile GnRH regulation are not well understood. Here, we review recent studies about GnRH pulsatility, signaling and transcriptional response, and its implications for disease.

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Figures

Figure 1
Figure 1. Model for regulation of signaling by the GnRH-R in response to tonic or pulsatile GnRH
Tonic GnRH stimulation (left) causes a transient increase in Gs/cAMP signaling that rapidly returns to baseline in spite of the continued presence of GnRH. In contrast, Gq/11/DAG/Ca2+ signaling remains elevated during the entire period of GnRH stimulation. Pulsatile GnRH (right) causes matching pulses of Gs/cAMP signaling of constant amplitude over time. Gq/11/DAG/Ca2+ signaling shows an initial pulse matching the GnRH pulse but each subsequent pulse has lower amplitude until no further pulses are seen after 2 h. This may reflect a PKC or CaMK induced negative feedback loop to desensitize Gq/11 signaling.
Figure 2
Figure 2. Model for pulse regulation of the LHβ and FSHβ promoters
For the LHβ promoter (top), under a low pulse frequency, transient stimulation of Egr1 expression leads to a secondary increase in Nab2 protein. The transiently increased Egr1 level is insufficient for sustained activation of the LHβ promoter due to the repression by Nab2 and Dax1. Under high pulse frequency, high Egr1 expression is sustained, but does not lead to further increases in Nab expression. The increased Egr1 level quenches Nab2 activity, allowing increased activity of the LHβ promoter through association with transcription-activating factors. For the FSHβ promoter (bottom), under a low pulse frequency, transient stimulation of fos/jun family member expression leads to a secondary increase in FSHβ transcription but does not trigger co-repressor expression. Under high pulse frequency, TGIF/SnoN co-repressor expression is also stimulated, leading to decreased FSHβ transcription through association of co-repressors with transcription-activating factors.
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