Interplay between dose and frequency of GnRH administration in determining pituitary gonadotropin responsiveness.
OBJECTIVE
The dose, frequency and contour of GnRH stimulation of the pituitary gonadotrope have been shown to be independent variables influencing pituitary LH secretion. The dynamic interaction between these variables during physiological and pathophysiological states has yet to be examined.


METHODS
Twelve men with GnRH deficiency and idiopathic hypogonadotropic hypogonadism undergoing GnRH therapy participated in a series of studies in which 2 log orders of GnRH doses (2.5-250 ng/kg) were administered at frequencies varying from 0.5 to 8 hourly. Pituitary responses were characterized by pulse amplitudes and nadirs. The relative sensitivity of the gonadotrope to GnRH was defined as that dose of GnRH capable of eliciting an LH pulse amplitude equal to the mean LH amplitude in normal men.


RESULTS
As GnRH stimulation of the gonadotrope slowed from 0.5 to 8 hourly, pulse amplitudes of LH increased whereas mean nadirs decreased (p < 0.05). Unique, curvilinear dose-response curves were found for each frequency that demonstrated an increasing slope (p < 0.03) as the frequency of GnRH stimulation slowed. Thus, the relative sensitivity of the gonadotrope increased as the frequency of GnRH stimulation decreased over the range of physiological frequencies tested.


CONCLUSIONS
We conclude that a delicate interplay exists between the dose and frequency of GnRH stimulation of the gonadotrope that determines pituitary LH gonadotropin responsiveness in the human. Slower frequencies favor increased LH release largely due to decreasing LH nadirs and improved sensitivity of the gonadotropes to GnRH stimulation.
Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Mass. 02114 USA.
Virginia A
VA
Hughes
Paul A
PA
Boepple
William F
WF
Crowley
Stephanie B
SB
Seminara
D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage*; D006062:Gonadotropins / Q000097:blood*; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000188:drug therapy; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism*
D006062:Gonadotropins; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone