Excess in Vitro Secretion of the Free α-Subunit of the Glycoprotein Hormones by Pituitary Cells from Chronically Uremic Rats*

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Abstract
In an attempt to develop an animal model of uremic hypogonadism, various parameters of in vivo and in vitro pituitary-Leydig cell function were examined in control, chronically uremic (4 weeks after 5/6th nephrectomy), and acutely uremic (2 days after bilateral ureteral ligation) adult male Sprague-Dawley rats. Levels of serum urea nitrogen (SUN) were 12.6 ± 0.4, 46.3 ± 2.9, and 233.4± 9.9 mg/dl (mean ± SEM) in control, chronically uremic, and acutely uremic rats, respectively, while the corresponding serum testosterone (T) values were 446.6± 85.2, 177.3 ± 52.0, and 45.8 ± 4.0 ng/dl. There was a significant inverse correlation between levels of SUN and those of T (r = -0.508; P < 0.05). Despite the decreased levels of serum T in uremic rats, there were significant reductions in serum levels of LH (P < 0.01) and FSH (P < 0.05) in both chronically uremic and acutely uremic rats. However, there were significant elevatios (P < 0.01) of PRL and a positive correlation between PRL and SUN values (r= 0.366; P < 0.05) in the sera of uremic rats. The release of LH, FSH, and the free α-subunit of the glycoprotein hormones was measured in primary cultures of dispersed anterior pituitary cells from the three groups of rats. During 48 h of incubation, the basal secretion rates (nanograms per 106 cells/h) of the glycoproteins from cells of control, chronically uremic, and acutely uremic rats were, respectively, 0.03, 0.12, and 0.03 for LH, 0.13, 0.43, and 0.13 for FSH, and 0.53, 4.82, and 0.39 for a. After LHRH (10-8 M) stimulation, the absolute increment in the secretion of each of the glycoproteins was greater from cells of chronically uremic rats than from cells of control or acutely uremic rats. Under baseline conditions, the molar ratio of α to LH plus FSH secreted by cells from chronically uremic rats was 2.7-fold greater than that by cells from control rats and 3.9-fold greater than that by cells from acutely uremic rats. Excess glycoprotein secretion by cells from chronically uremic rats was also evident after stimulaion with variable doses of LHRH (10-1010-7 M); molar ratios of a to LH plus FSH released by cells from chronically uremic rats varied from 5.4-8.6, while the corresponding ratios released by cells from control rats ranged from 1.2-2.2. In contrast to the in vitro findings, the molar ratios of a to LH plus FSH were similar in pituitary extracts from control (0.21), chronically uremic (0.23), and acutely uremic (0.25) rats. The immunochemical properties of α-subunit in media and pituitary extracts from control and uremic rats were similar to those of purified rat pituitary α However, by Sephadex G-100 chromatography, media a from cells of chronically uremic rats eluted as species of slightly larger apparent molecular size than purified rat pituitary α, but of a size similar to that of other eutopic and ectopic secreted forms of α These data suggest that hyperprolactinemia and hypogonadotropic hypogonadism are concomitants of both moderate and severe renal dysfunction in the male rat. Moreover, the finding of a disproportionate excess in the in vitro secretion of free a-subunits, ompared with LH and FSH, by pituitary cells from chronically uremic rats together with previously reported data indicating discordant elevation of serum a levels in uremic humans suggest that uremia is associated with major derangements in normally coordinated α- and β-subunit synthesis and/or secretion.