Gonadotropin and α-subunit secretion during long term pituitary suppression by D-Trp⁶-luteinizing hormone-releasing hormone microcapsules as treatment of precocious puberty

Short term treatment with GnRH agonists has been reported to increase plasma gonadotropin α-subunit (Gnα) levels while decreasing plasma immunoreactive LH (IR-LH) levels. In this study we examined the effect of D-Trp⁶-LHRH (LHRH-A) in microcapsules (60 μg/kg, im, every 28 days for 1 yr) in 13 girls suffering from precocious puberty. Plasma IR-Gnα was measured by RIA; plasma IR-LH and IR-FSH were measured by both polyclonal RIAs and monoclonal immunoradiometric assays (IRMA). Before treatment, basal IR-LH and IR-FSH levels and peak responses to LHRH measured by both RIA and IRMA were similar, and the Gnα response paralleled that of LH. After the first injection of LHRH-A, RIA-LH levels were significantly higher than pretreatment levels until day 21, while IRMA LH levels transiently increased, but returned to pretreatment levels by day 7 and became lower thereafter (P < 0.005). Plasma IR-Gnα levels increased from days 3-21 (P < 0.05). After 1.5 months of treatment, basal RIA LH levels remained detectable and not different from pretreatment levels; IRMA LH levels were very low. The mean RIA and IRMA LH responses to LHRH were decreased at 1.5 and 12 months (P <0.01). Basal plasma RIA and IRMA FSH levels were similar during treatment (P > 0.05) and significantly lower than pretreatment values (P < 0.01). The mean RIA and IRMA FSH responses to LHRH decreased significantly at 1.5 months (P < 0.001). After 12 months, both RIA and IRMA FSH responses were increased, but IRMA values were significantly lower than RIA values. A sustained increase in basal Gnα values occurred, but there was a tendency for the peak levels after LHRH treatment to decrease, becoming significantly lower than pretreatment peak levels after 1 yr. The chromatographic analysis on Sephadex G-100 of a pool of plasma samples collected during a LHRH test in three children treated for 6 months indicated that IR-Gnα coeluted with [¹²⁵I]Gnα. The large discrepancy between RIA and IRMA LH values suggests the secretion of unusual LH molecules which are recognized by RIA but not by IRMA. The sustained release of large amounts of IR-Gnα indicates dissociated effects of LHRH-A on α- and β-subunit secretion by the gonadotrophs. The sustained response of Gnα to LHRH demonstrates that gonadotroph cell LHRH receptors are still responsive to LHRH during treatment with a LHRH agonist.