A. Crinò¹, G. DiGiorgio¹, G. Grugni², E.Cama³, A. Anzuini³, C. Marzano³, S. Spera¹, A. Lenzi³, G. Castelli Gattinara¹, A.F. Radicioni³

Pediatric and Autoimmune Endocrine Disease Unit, Bambino Gesù Hospital, Research Institute, Palidoro (Rome) ¹; Italian Auxological Institute Foundation, Piancavallo (Verbania) ²; Dept of Medical Pathophysiology, “La Sapienza” University of Rome³

Introduction: Hypogonadism is a main feature of Prader-Willi syndrome (PWS) and is generally attributed to a hypothalamic dysfunction or to a primary gonadal defect, but data are not univocal. Inhibin B (InhB) is a glycoprotein hormone produced by Sertoli cells and represents a reliable marker of tubular function and spermatogenesis in post-pubertal age. Recently InhB has been used as a marker of gonadal function in PWS males. Furthermore, hCG test allows to analyse the response of Leydig cells.

Aim of the study: to investigate the gonadal dysfunction in male subjects with PWS.

Patients and Methods: 25 male patients with genetically confirmed PWS (methylation test and/ or FISH), aged 1.1-35.0 yrs (median age: 13.3 yrs), were admitted to the study. All subjects had a history of cryptorchidism. Eleven were pre-pubertal (G1) and 14 had spontaneously started their pubertal development, up to pubertal stage G2 (7 pts) and G3 (7 pts). A standard hCG test was performed (1000 IU i.m. <10 yrs and 2000 IU i.m. ≥10 yrs). Testosterone (T) and InhB were measured at baseline, as well as at 2, 24, 48 and 72 hours after hCG administration. According to the response to hCG test, patients were defined as responders for T (RT) and for InhB (RInhB) (increase >3 and >1.5 times compared to basal values, respectively). Basal FSH and LH levels were also measured in all subjects.

Results: In pre-pubertal group basal T was low for age in 6/11 (54.5%). Basal InhB was low for age in 9/11 (82%) and normal in 2/11 (18%). Analysing the response to hCG test, 6/11 (54.5%) were RT, and all presented a T-peak at 72h;  6/11 (54.5%) were RInhB (peak at 24h in 2, at 48h in 3 and at 72h in 1 patient). Moreover, 3 patients were both RT and RInhB.   In pubertal group basal T was low in 11/14 (78.6%) patients and basal InhB was undetectable in 9/14 (64%) and low in 5/14 (36%). Basal LH was low in 4/14 and elevated in 2 patients with G3. Basal FSH was elevated in 9/14 patients. With regard to response to hCG test, 11/14 (78.6%) were RT: 6 had pubertal stage G2 (peak at 24h in 1, at 48h in 3, at 72h in 2) and 5 had pubertal stage G3 (peak at 48h in 4 and at 72h in 1). Only 2 out of 14 (14.3%) pubertal patients were RInhB and they were also RT (pubertal stage G2 with a InhB-peak at 48h and 72h, respectively).  A positive correlation between age, pubertal stage, FSH, LH with T, and an inverse correlation of the same parameters with InhB were found.

Discussion: Leydig cells function seems to be preserved in more than 50% of prepubertal patients, as demonstrated by T response to hCG. In pubertal patients basal T levels are low in more than 75%, and T response to HCG test is normal in most of them. These findings seem to confirm that the Leydig cell maintains the ability to produce T after hCG. In some cases, the simultaneous presence of low LH and T levels could be expression of an hypogonadotropic hypogonadism of hypothalamic origin. On the other hand, a normal InhB response to hCG test is present only during pre-pubertal stage, although basal InhB levels are low in most of our cases. Meanwhile, in pubertal stage basal and stimulated InhB remain undetectable. The simultaneous presence of high FSH levels, especially in patients with G3, suggests Sertoli cell damage displaying a pattern of  hypergonadotropic hypogonadism that becomes more evident at the beginning of puberty and progresses with age.

Conclusion: Our data shows that Leydig and Sertoli cells develop independently in PWS patients, confirming that these subjects display a peculiar form of combined central and peripheral hypogonadism. Therefore, therapy with hCG could be useful in restoring Leydig cell function in producing testosterone.

Edited: 02/09/2012