MON-244 GnRH Test Does Not Efficiently Discriminate Congenital Isolated Hypogonadotropic Hypogonadism from Constitutional Delay of Growth and Puberty in Males

Context: Delayed puberty can be due to either constitutional delay of growth and puberty (CDGP) or congenital hypogonadotropic hypogonadism (CHH). Differentiating between the two conditions either clinically or using current hormonal testing is difficult. GnRH test is currently used in many centers to differentiate CDGP from CHH but its diagnostic performance was not assessed in a significant number of CHH patients. Objective: To compare gonadotropin responses to GnRH challenge between CHH and C and to assess the diagnostic performance of this test in large cohorts of CHH and CDGP. Subjects: We included 127 men with CHH (68 Kallmann Syndrome (KS) and 69 normosmic CHH; age: 25.5±9.9 y), 74 men with CDGP (14.9±1.0 y) not treated, 31 control (C) men (25.9±5.2 y). Methods: Testicular volume (TV) was measured. Basal testosterone and inhibin B (IB, limit of detection: 3 pg/mL) were measured using sensitive immunoassays. Intravenous injection of 100 μg GnRH was performed. Serum FSH and LH were measured (at -15, 0, 15, 30, 60, and 120 min) using sensitive immunoradiometric assays with a detection limit of 0.05 IU/L for both gonadotropins. Results (mean±SD, [range]): Testosterone levels (ng/mL) were: C, 6.5±1.2 [4.2-8.7]; CHH/KS, 0.5±0.4 [0.0-2.1]; CDGP, 0.6±0.6 [0.0-2.5]. Testicular volumes (mL) were respectively in CHH/KS and CDGP: 3.1±2.8 [0.1-13.5] and 4.5±2.7 [0.7-10]. LH basal and peaks (IU/L) were: C, basal: 4.2±0.9 [2.9-6.1], peak 17.9±3.7 [11.1-26.0]; CHH/KS, basal 0.8±1.0 [0.1-4.2], peak: 6.9±7.8 [0.1-41.5]; CDGP, basal: 1.3±0.8 [0.1-3.7]; peak: 13.9±6.3 [4.0-33.4]. In 25/127 (21%) of CHH/KS, we found an overlapping in serum LH peaks levels when compared to C. Importantly, in 47% (60/127) of CHH/KS patients, GnRH-induced LH peaks overlapped with LH peak values observed in CDGP. However, none of the patients with CDGP had LH peak values below 4.0 IU/L while 68/127 (53%) of those with CHH/KS had LH peak levels below this threshold. In CHH/KS and CDGP, serum IB were respectively (58±64 [3-311] and 164±97 [35-630]). In 59% of untreated CHH/KS patients, serum IB overlapped with CDGP. In CHH, we found a significant positive correlation between LH peak and TV (r=0.41; p < 0.0001) and a stronger positive correlation between LH peak and IB (r=0.49; p< 0.0001). Conclusion: In both CHH/KS and CDGP, the ranges of GnRH induced LH peaks were very wide and a strong overlapping was found between the three groups studied. Both LH peak and IB were correlated with the severity of gonadotropin deficiency as reflected by TV. The GnRH challenge test is not efficient enough to discriminate CHH/KS from CDGP but very weak LH responses (4 IU/L) were specifically observed in CHH/KS. Diagnosis efficiency of serum IB will also be discussed.