Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.

Abstract

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...

Use of a Gonadotropin-Releasing Hormone Antagonist as a Physiologic Probe in Polycystic Ovary Syndrome: Assessment of Neuroendocrine and Androgen Dynamics1

“…levels remained significantly lower than pretreatment for up to 20 h post antagonist (P Ͻ 0.0002). Increasing the GnRH antagonist dose had no effect on either the time or the value of the FSH nadir, consistent with studies in normal women (24). The time of the FSH nadir occurred significantly later than for LH at all doses (P Ͻ 0.02).…”

“…Studies in PCOS patients were compared with previously published results in 50 regularly cycling women, 18 -40 yr old, who were studied in the early and late follicular, and early luteal phases (24,29). All controls had normal TSH and PRL levels and had ovulated in the cycle before the study, as evidenced by a midluteal phase plasma P level more than 6 ng/mL (Ͼ19 nmol/L) or a biphasic body temperature chart.…”

“…Because we have previously demonstrated no difference in the percent inhibition among these 3 cycle stages (24), the data from each dose during the different stages were combined, such that a total of 12, 23, 14, and 14 normal subjects were studied at the 5, 15, 50, and 150 g/kg doses, respectively. Although gonadotropin data are presented on all controls, androgen levels are only reported for a subset of 5 women, after administration of 150 g/kg of the antagonist, because of the limitations of sample volume.…”

“…Although monitoring of pulsatile LH and FAS secretion provides a useful insight into the frequency of GnRH secretory episodes and has been employed extensively in the study of GnRH physiology in the human (20 -23), it does not permit estimation of the overall quantity of GnRH secreted. To address this issue, we have previously used a selective GnRH antagonist to provide a semiquantitative estimate of GnRH secretion in the human (24).…”

Neuroendocrine Dysfunction in PCOS: A Critique of Recent Reviews

“…The mechanism of this effect might be related to the fact that estradiol is also thought to sensitize the pituitary to GnRH, providing part of the basis for the LH surge 36 and, at least in humans, there is also evidence for reduced production of GnRH at the time of the LH surge, placing even greater importance on such estradiol-mediated gonadotrope sensitivity to GnRH. 37 Estrogen has also been shown to increase the fraction of gonadotropes that respond to GnRH, 38 such that small GnRH pulses (normally insufficient to stimulate LH secretion) may result in discernible LH pulses. Hypothalamic uncoupling may therefore enhance this positive feedback mechanism at the pituitary level in PCOS, and indeed this has been shown in other studies to correlate with the basal levels of both estrone and 17-β-estradiol.…”