Endocrine Abstracts

Introduction: Patients with Klinefelter Syndrome (KS) often display small, multiple, non-palpable, and typically benign testicular micro-nodules at ultrasonographic examination, representing Leydig cell hyperplasia or Leydig tumors. Increased LH levels raising from testicular damage might play a pivotal role by acting as growth factor for Leydig cells. To date, evidence on the efficacy of testosterone replacement therapy (TRT) on decreasing the micro-nodules volume are lacking.

Materials and Methods: We prospectively evaluated KS patients with classic karyotype (47, XXY) aged 15 to 50 years and naive to TRT. This evaluation included testicular ultrasound and hormone assessment. Mosaic karyotypes, previous pituitary surgery or radiotherapy or medications affecting the hypothalamus-pituitary-gonadal axis were excluded. Hypogonadal patients who received TRT were assessed after at least 6 months to evaluate the estimated volumetric change in the micro-nodules. The volume of hypoechoic lesions was calculated with the sphere formula (1/6 * π * D³). For multiple lesions, the sum of the volumes of the two dominants lesions for each testicle was considered.

Results: Seventy patients (mean age 26.4±8.7 years) were included in the study, 35 of which (Group A) displayed at least one testicular micro-nodule, while the other 35 (Group B) did not show clear lesions. Group A patients were significantly older than those in Group B (P=.010) and showed higher LH levels (P=.001) and lower Testosterone/LH ratio (P=.005), though total Testosterone (tT) levels did not differ significantly (P=.328). Testicular microlithiasis was present in 18 patients, 12 (34%) from Group A and 6 (17%) from Group B (P=.086). The tT/LH ratio effectively predicted the presence of micro-nodules (B= -1.074, OR= 0.342, 95CI= 0.123 - 0.947, P=.039) whereas the increase in age (P=.265) and concomitant microlithiasis (P=.482) did not reflect in increased lesion risk. An interim longitudinal analysis was performed on 20 of the patients who started TRT(44% gel, 56% injective). After 16.7 (11.9-31.2) months, the micro-nodules displayed significant volumetric reduction (62.9 to 22.9 mm³, P<.001) and were no longer detectable in 4 patients (20%). No difference was observed in volumetric change between TRT formulations (P=.897). Treatment duration did not correlate with the micro-nodules volumetric reduction (P=.512).

Conclusion: Our data demonstrate for the first time the efficacy of TRT in reducing the volume of testicular, non-palpable hypoechoic micro-nodules in patients with KS. These changes are likely secondary to the restoration of more physiological LH and tT/LH.