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The Nature of the Gonadotropin-Releasing Hormone Stimulus-Luteinizing Hormone Secretory Response of Human Gonadotrophs In Vivo^*

Departments of Internal Medicine and Pharmacology, University of Virginia School of Medicine (J.D. V., M.L.J.) Charlottesville, Virginia 22908
Vincent Research Laboratories, Harvard Medical School, and the Reproductive Endocrine Unit, Massachusetts General Hospital (L.S.L.O.) Boston, Massachusetts 02114

Address requests for reprints to: Dr. Johannes Veldhuis, Box 202, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908.

To examine the stimulus-secretion response of human pituitary gonadotrophs in vivo, we applied a new multiple parameter deconvolution technique to analyze (1) exogenous GnRH-stimulated LH secretory responses in 10 men with isolated hypogonadotropic hypogonadism (IHH), and (2) endoge-nous and exogenous GnRH-stimulated LH secretory responses in 8 normal men. The GnRH-deficient men were given 4 bolus doses of synthetic GnRH (7.5, 25, 75, and 250 ng/kg) iv at 2-h intervals in randomized order after long term pulsatile GnRH administration. The normal men were studied by sampling blood at 10-min intervals for 12 h basally and after 2 consecutive 10-µg iv GnRH doses. The serum LH peaks in both groups were subjected to quantitative deconvolution to resolve underlying LH secretory and clearance rates simultaneously. Such analyses revealed that exogenous GnRH-induced LH secretory episodes in GnRH-deficient men with IHH could be modeled as algebraically Gaussian distributions of instantaneous LH secretory rates with a mean half-duration of 14 ± 2 min. The simultaneously resolved half-life of endogenous LH disappearance was 71 ± 5 min. The log dose-response relationship for GnRH dose vs. maximal LH secretory rate or vs. calculated mass of LH released per secretory burst was linear. In contrast, varying GnRH doses did not alter the duration of LH secretory bursts, the half-time of LH disappearance, or the latency of LH secretory bursts after iv GnRH injections (viz. 7.6 min). Deconvolution analysis of the spontaneous (endogenous GnRH-stimulated) LH peaks in normal men revealed a mean half-duration of secretory bursts of 9.9 ± 1.5 min, and a mean half-time of endogenous LH disappearance of 76 ± 5 min. These values were not significantly different from those in the GnRH-treated normal or GnRH-deficient men.

In summary, deconvolution analysis of LH release in men with IHH revealed a significant linear relationship between iv doses of pulsed GnRH and computer-resolved LH secretory rate and/or the mass of LH released per secretory event. In contrast, varying doses of GnRH did not alter the lag time between the GnRH stimulus and the LH secretory burst, the duration of LH secretion, or the calculated half-life of the LH released. We conclude that GnRH exerts dose-dependent effects on specific attributes of the secretory response of human gonadotrophs in vivo.

^* This work was supported in part by NIH Grant RR-00847 to the Clinical Research Center of the University of Virginia, Research Career Development Award 1-K04-HD-00634 (to J.D.V.), NIH Grants AM-30302 and GM-28928 (to M.L.J.), Diabetes and Research Training Center Grant 5-P60-AM-22125-05, and NIH-supported Clinfo Data Reduction Systems.

Received July 25, 1988.

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