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Division of Genetics (U.B.K., W.W.C.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Department of Obstetrics, Gynecology, and Reproductive Sciences (A.J., A.S.), University of Texas Medical School, Houston, Texas 77030
Address all correspondence and requests for reprints to: Ursula B. Kaiser, G. W. Thorn Research Building, Room 909, Brigham and Women’s Hospital, 20 Shattuck Street, Boston, Massachusetts 02115. E-mail: kaiser{at}rascal.med.harvard.edu
The hypothalamic hormone, GnRH, is released and transported to the
anterior pituitary in a pulsatile manner, where it binds to specific
high-affinity receptors and regulates gonadotropin biosynthesis and
secretion. The frequency of GnRH pulses changes under various
physiological conditions, and varying GnRH pulse frequencies have been
shown to regulate differentially the secretion of LH and FSH and the
expression of the gonadotropin 
, LHß, and FSHß subunit genes
in vivo. We demonstrate differential effects of varying
GnRH pulse frequency in vitro in superfused primary
monolayer cultures of rat pituitary cells. Cells were treated with 10
nM GnRH pulses for 24 h at a frequency of every 0.5,
1, 2, or 4 h. , LHß, and FSHß messenger RNA (mRNA) levels
were increased by GnRH at all pulse frequencies. and LHß mRNA
levels and LH secretion were stimulated to the greatest extent at a
GnRH pulse frequency of every 30 min, whereas FSHß mRNA levels and
FSH secretion were stimulated maximally at a lower GnRH pulse
frequency, every 2 h. GnRH receptor (GnRHR) mRNA levels also were
increased by GnRH at all pulse frequencies and were stimulated
maximally at a GnRH pulse frequency of every 30 min. Similar results
were obtained when the dose of each pulse of GnRH was adjusted to
maintain a constant total cumulative dose of GnRH over 24 h. These
data show that gonadotropin subunit gene expression is regulated
differentially by varying GnRH pulse frequencies in
vitro, suggesting that the differential effects of varying GnRH
pulse frequencies on gonadotropin subunit gene expression occur
directly at the level of the pituitary. The pattern of regulation of
GnRHR mRNA levels correlated with that of and LHß but was
different from that of FSHß. This suggests that and LHß mRNA
levels are maximally stimulated when GnRHR levels are relatively high,
whereas FSHß mRNA levels are maximally stimulated at lower levels of
GnRHR expression, and that the mechanism for differential regulation of
the gonadotropins by varying pulse frequencies of GnRH may involve
levels of GnRHR. Furthermore, these data suggest that the mechanisms
whereby varying GnRH pulse frequencies stimulate , LHß, and GnRHR
gene expression are similar, whereas the stimulation of FSHß mRNA
levels may be different.
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