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 (E(2))] 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/m(2) and seven normal men with body mass indexes from 22.5-24.2 kg/m(2) underwent blood sampling at 10-min intervals for a total of 10 h before and after the iv administration of 10 and 90 microg
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 E(2) 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 E(2), 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 microg)
GnRH-stimulated conditions were similar in obese subjects and normal controls, whereas LH released by obese subjects in response to the high (90 microg)
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.