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A Preponderance of Circulating Basic Isoforms Is Associated with Decreased Plasma Half-Life and Biological to Immunological Ratio of Gonadotropin-Releasing Hormone-Releasable Luteinizing Hormone in Obese Men¹

Research Units in Developmental Biology (C.C.-F., A.O., D.S., J.P.M.) and Reproductive Medicine (A.U.-A.), Instituto Mexicano del Seguro Social; and Departments of Reproductive Biology (E.Z.) and Endocrinology (J.C.L.-A.), Instituto Nacional de la Nutrición SZ, Mexico D.F., Mexico; and Department of Internal Medicine, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., or Alfredo Ulloa-Aguirre M.D., D.Sc., Coordinación de Investigación Médica, Unidad de Investigación Médica en Biología del Desarrollo, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenue Cuauhtémoc 330, Apdo. Postal 73–032, Col. Doctores, 06725 México D.F., Mexico. E-mail: jpmb{at}servidor.unam.mx and aulloaa@buzon.main.conacyt.mx.

Hormonal abnormalities of the reproductive axis have been described in obesity. In men, extreme obesity is associated with low serum testosterone (T) and high estrogen [estrone and estradiol (E₂)] levels. As changes in the sex steroid milieu may profoundly affect the carbohydrate heterogeneity and thus some of the biological and physicochemical properties of the LH molecule, we analyzed the relative distribution of LH isoforms circulating under baseline conditions (endogenous GnRH drive) as well as the forms discharged by exogenous GnRH stimulation from putative acutely releasable and reserve pituitary pools in overweight men. Secondarily, we determined the impact of the changes in LH terminal glycosylation on the in vitro bioactivity and endogenous half-life of the gonadotropin. Seven obese subjects with body mass indexes ranging from 35.7–45.5 kg/m² and seven normal men with body mass indexes from 22.5–24.2 kg/m² underwent blood sampling at 10-min intervals for a total of 10 h before and after the iv administration of 10 and 90 µg GnRH. Basally released and exogenous GnRH-stimulated serum LH isoforms were separated by preparative chromatofocusing and identified by RIA of eluent fractions. Serum pools of successive samples collected across 2-h intervals (five serum pools per subject) containing LH released under baseline and exogenous GnRH-stimulated conditions were tested for bioactivity employing a homologous in vitro bioassay. Mean serum T and E₂ levels were significantly lower and higher, respectively, in the obese men than in the control group [serum T, 13.5 ± 2.4 vs. 19.4 ± 1.4 nmol/L (mean ± SEM; P = 0.01); serum E₂, 0.184 ± 0.01 vs. 0.153 ± 0.01 nmol/L (P < 0.05)]. Mean baseline serum LH levels were similar in obese subjects and normal controls (13.3 ± 1.3 and 12.2 ± 1.2 IU/L). Although multiple parameter deconvolution of the exogenous GnRH-induced LH pulses revealed that the magnitude of the pituitary response in terms of secretory burst mass, secretory amplitude, and half-duration of the LH pulses was similar in obese and control subjects, the apparent endogenous half-life of LH was significantly (P < 0.05) shorter in the obese group (98 ± 11 min) than in the normal controls (132 ± 10 min). Under all conditions studied, the relative abundance of basic isoforms (those with pH 7.0) was significantly (P < 0.05) increased in the obese subjects compared with the controls (percentages of LH immunoactivity recovered at pH 7.0: obese subjects, 34–57%; normal controls, 22–46%). The biological to immunological ratio of LH released in baseline and low dose (10 µg) GnRH-stimulated conditions were similar in obese subjects and normal controls, whereas LH released by obese subjects in response to the high (90 µg) GnRH dose exhibited significantly lower ratios than those detected in normal individuals (0.62 ± 0.07 and 0.45 ± 0.09 vs. 1.01 ± 0.10 and 0.81 ± 0.09 for LH released within 10–120 min and 130–240 min after GnRH administration in obese and controls, respectively; P < 0.05). Collectively, these results indicate that the altered sex steroid hormone milieu characteristic of extreme obesity provokes a selective increase in the release of less acidic LH isoforms, which may potentially modify the intensity and duration of the blood LH signal delivered to the gonad. Altered glycosylation of LH may therefore represent an additional mechanism modulating the hypogonadal state prevailing in morbid obesity.

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