In addition to the selective regulation of FSH-P mRNA levels by pituitary activin and follistatin and by testicular inhibin-B, there may be other mechanisms for the differential secretion of FSH and LH. Results from studies in rats (124) and rat pituitary cell cultures (125) revealed that the frequency of GnRH pulses regulates LH-P and FSH-P mRNA levels differently, with rapid GnRH pulse frequencies (every 15-30 min) favoring LH-P over FSH-P gene expression. This difference may be partly due to upregulation of follistatin mRNA levels by rapid GnRH pulse frequencies (125), with subsequent blockade by follistatin of activin-stimulated FSH-P gene expression. Although this mechanism is applicable to rats, its importance in men is less well established. For example, in men with congenital hypogonadotropic hypogonadism
(e.g., Kallmann syndrome) who were treated long-term with pulsatile GnRH, increasing the frequency of GnRH stimulation from every 2 h to every 30 min for 7 d increased serum LH levels threefold, but FSH levels rose by 50% (126). These findings are consistent with the greater rise in LH than in FSH secretion when normal men are administered a GnRH bolus. In a second study in a similar population of men, increasing the GnRH pulse frequency from every 1.5 h to every 0.5 h suppressed plasma FSH, but plasma LH levels were unchanged (127). In both studies, changes in testosterone, estradiol, and inhibin-B levels as a consequence of increased GnRH may have influenced the results. PACAP is a neuropeptide that stimulates a-subunit transcription and lengthens LH-P mRNA transcripts and presumably prolongs half-life but suppresses FSH-P mRNA levels by stimulating follistatin transcription (128). These observations in vitro suggest that PACAP could play a role in the differential production of FSH and LH. A third idea is that increasing the frequency of GnRH pulses modifies GnRH-receptor signaling pathways and thereby regulates FSH-P and LH-P gene expression differently (129).
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