A preponderance of circulating basic isoforms is associated with decreasedplasma half-life and biological to immunological ratio of gonadotropin-releasing hormone-releasable luteinizing hormone obese men

Hormonal abnormalities of the reproductive axis have been described in obes ity. In men, extreme obesity is associated with low serum testosterone (T) and high estrogen [estrone and estradiol (E-2)] levels. As changes in the s ex steroid milieu may profoundly affect the carbohydrate heterogeneity and thus some of the biological and physicochemical properties of the LH molecu le, 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 o f the changes in LH terminal glycosylation on the in vitro bioactivity and endogenous half-life of the gonadotropin. Seven obese subjects with body ma ss indexes ranging from 35.7-45.5 kg/m(2) and seven normal men with body ma ss indexes from 22.5-24.2 kg/m(2) underwent blood sampling at 10- min inter vals for a total of 10 h before and after the iv administration of 10 and 9 0 mug GnRH. Basally released and exogenous GnRH-stimulated serum LH isoform s were separated by preparative chromatofocusing and identified by RIA of e luent fractions. Serum pools of successive samples collected across 2-h int ervals (five serum pools per subject) containing LH released under baseline and exogenous GnRH-stimulated conditions were tested for bioactivity emplo ying a homologous in vitro bioassay. Mean serum T and E-2 levels were signi ficantly lower and higher, respectively, in the obese men than in the contr ol group [serum T, 13.5 +/- 2.4 vs. 19.4 +/- 1.4 nmol/L (mean +/- SEM; P = 0.01); serum E-2, 0.184 +/- 0.01 vs. 0.153 +/- 0.01 nmol/L (P < 0.05)]. Mea n baseline serum LH levels were similar in obese subjects and normal contro ls (13.3 +/- 1.3 and 12.2 +/- 12 IU/L). Although multiple parameter deconvo lution of the exogenous GnRH-induced LH pulses revealed that the magnitude of the pituitary response in terms of secretory burst mass, secretory ampli tude, and half-duration of the LH pulses was similar in obese and control s ubjects, the apparent endogenous half-life of LH was significantly (P < 0.0 5) shorter in the obese group (98 +/- 11 min) than in the normal controls ( 132 +/- 10 min). Under all conditions studied, the relative abundance of ba sic isoforms (those with pH greater than or equal to 7.0) was significantly (P < 0.05) increased in the obese subjects compared with the controls (per centages of LH immunoactivity recovered at pH <greater than or equal to>7.0 : obese subjects, 34-57%; normal controls, 22-46%). The biological to immun ological ratio of LH released in baseline and low dose (10 mug) GnRH-stimul ated conditions were similar in obese subjects and normal controls, whereas LH released by obese subjects in response to the high (90 mug) GnRH dose e xhibited significantly lower ratios than those detected in normal individua ls (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 i ndicate that the altered sex steroid hormone milieu characteristic of extre me obesity provokes a selective increase in the release of less acidic LH i soforms, which may potentially modify the intensity and duration of the blo od LH signal delivered to the gonad. Altered glycosylation of LH may theref ore represent an additional mechanism modulating the hypogonadal state prev ailing in morbid obesity.