Androgen for Leydig Cell Proliferation
Androgen for Leydig Cell Proliferation
Patients with infertility often presents alterations at ultrasonographic examination of the
 testis. These alterations include a much higher incidence of small, multiple, non-palpable
 hypoechoic micro-nodules that can show internal vascularization. This finding often create
 alarm and anxiety, because it has to be placed in a differential diagnosis versus low-stage
 malignant germ cell tumors. Nevertheless, explorative surgery reveal that a consistent number
 of these lesion are benign, due to Leydig cell hyperplasia or Leydig cell tumours. The
 purpose of this study is to evaluate the effects of androgen therapy on the size and number
 of non-palpable hypoechoic micro-nodules in patients with elevated gonadotropin levels.
Patients with the testicular dysgenesis syndrome, that comprises a variable spectrum of
 clinical manifestations, such as infertility, cryptorchidism, hypospadias, impaired
 spermatogenesis and testicular germ cell neoplasms, often develop alterations in the Leydig
 cell compartment. These alterations range from abnormal localization and clustering to
 hyperplasia or tumorous formation.

 Leydig cell tumors (LCTs), although uncommon in the general population, are the most frequent
 non-germ cell testicular neoplasms, and their incidence has been reported increasingly
 growing, especially in infertile patients. Given that the focal areas of Leydig cell
 hyperplasia are nowadays easily detectable at ultrasonography of the testis (US), as small
 non-palpable hypoechoic micro-nodules that can show internal vascularization, their finding
 create a diagnostic challenge versus low-stage malignant germ cell tumors.

 Patients with testicular dysgenesis syndrome in general exhibit an elevation of
 Follicle-Stimulating Hormone (FSH), but in these patients, very frequently, even Luteinizing
 Hormone (LH) is above the reference range. The latter can work as a growth factor for Leydig
 cells. Since exogenous testosterone can suppress LH levels, it could be that androgen therapy
 could revert the LH-induced growth stimulation of Leydig cell compartment.

 The purpose of this study is to evaluate the effects of androgen therapy on the size and
 number of non-palpable hypoechoic micro-nodules in patients with elevated gonadotropin
 levels.

 The purpose of this study is also to evaluate whether the behavior (UltraSonographic
 appearance, US) of the non-palpable hypoechoic micro-nodules during a 4-month trial of
 testosterone therapy can offer a novel diagnostic tool in the differential diagnosis of
 benign versus malignant testicular nodules.

 The trial will be open only for patients with multiple non-palpable hypoechoic micro-nodules
 that have an elevation of both FSH and LH and that are not seeking conception.

 Participants in the study will be randomized to one of two treatment groups, receiving either
 testosterone undecanoate (low-dose androgen) or placebo, for two 6 months. All participants
 will be evaluated for safety at the beginning of the study and at 2, 4, and 6 months with
 careful history, physical examination, blood sampling and testicular ultrasonography.
 Patients will also be offered the possibility to perform Magnetic Resonance Imaging (MRI) of
 the testis at baseline and after treatment, and/or surgical enucleation of the lesions.
Inclusion Criteria:

 -  Non-palpable Multiple hypoechoic testicular nodules (with the largest having a
 diameter > 2 mm and < 12 mm)

 -  Serum Follicle-stimulating hormone (FSH) > 7 mIU/ml (m-International-Unit/ml)

 -  Serum Luteinizing hormone (LH) > 7 IU (International-Unit/ml)

 -  Infertility: Klinefelter Syndrome, Hypergonadotropic Hypogonadism, Hypergonadotropic
 Azospermia, Hypergonadotropic Cryptozoospermia

 -  negative testicular tumors markers: beta-hCG (Human chorionic gonadotropin), alpha-FP
 (alpha-Feto-Protein), CEA (Carcinoembryonic antigen), LDH (Lactate dehydrogenase),
 ferritin, PLAP (Placental Alkaline Phosphatase).

 Exclusion Criteria:

 -  Hypogonadotropic Hypogonadism

 -  FSH o LH < 7 UI

 -  non-homogeneous testicular lesion > 12 mm

 -  positive testicular tumors markers: beta-hCG, alpha-FP, CEA, LDH, ferritin, PLAP

 -  patients with contraindication to testosterone therapy: prostate cancer, PSA>4 ng/ml,
 severe hepatic or renal insufficiency, Hb>17, Htc>52%, severe urinary retention

 -  desire to conceive

 -  history of germ-cell testicular neoplasia