To investigate the contribution of hypothalamic gonadotropin-releasing hormone (GnRH) secretion to the midcyde gonadotropin surge in the human, the response of luteniZing hormone (LH) to competitive GnRH receptor blockade achieved by administration of a range of doses of a pure GnRH antagonist was used to provide a semiquantitative estimate of endogenous GnRH secretion. The LH response to 5, 15, 50, and 150 iag/kg s.c. of the NAL-GLU GnRH antagonist ',D-4CIPhe2,D-Pal3,Arg5,D-4-p-methoxybenzoyl-2-aminobutyric acid'6,D-Ala1O'GnRH, where 2Nal is 2-naphthylalanine, 4CIPhe is 4-chlorophenylalanine, and 3Pal is 3-pyridylabnine) was measured in normal women in the early and late follicular phases of the menstrual cycle, at the time of the midcycle LH surge and in the early luteal phase. LH decreased in a dose-response fashion after administration of the GnRH antagonist in aUi cycle phases (P < 0.0001 Direct measurements of GnRH in pituitary portal blood indicate that a surge of GnRH secretion is generally associated with spontaneous and sex steroid-induced gonadotropin surges in sheep (4-6). GnRH levels also appear to increase at the time of the proestrus surge in rats (7) and rhesus monkeys (8, 9). These direct techniques of accessing information regarding the hypothalamic component of the preovulatory surge are clearly not feasible in the human and measurements of GnRH in the peripheral circulation do not accurately reflect hypothalamic GnRH secretion ifat all (10). Therefore, an understanding of the physiology of GnRH secretion and pituitary responsiveness to this releasing hormone in the human can only be achieved by combining a number of indirect approaches. Monitoring of pulsatile LH secretion can provide insight into the frequency of GnRH secretory episodes (11) but does not permit estimates to be made ofthe amount of GnRH secreted. The dose of exogenous pulsatile GnRH required to mimic normal menstrual cycles and a normal midcycle surge in GnRH-deficient women (3) has been determined empirically, by comparison with "target"or reference ranges derived from studies in normal women, but does not provide information about potential changes in the actual quantity of endogenous GnRH secreted under various physiologic conditions in the intact human.A competitive receptor antagonist can be used to assess the relative amount of an unmeasurable endogenous ligand by determining the susceptibility of a marker of its action to specific blockade. This principle derives from quantitative theories of drug action (12) and has proven extremely useful in determination of opioid tone using the opiate receptor blocker, naloxone (13,14). We have applied an analogous approach to the assessment of the overall amount of GnRH secreted by using a GnRH antagonist that competitively blocks the GnRH receptor and LH secretion as the marker of GnRH action. The underlying assumption is that the amount ofGnRH present at a given time is directly proportional to the dose of GnRH antagonist required to inhibit LH secretion. 2Nal is 2-napht...