Androgen for Leydig Cell Proliferation
Condition: Klinefelter Syndrome; Hypergonadotropic Hypogonadism; Hypergonadotropic Azospermia; Hypergonadotropic Cryptozoospermia
MeSH terms: Azoospermia; Klinefelter Syndrome; Oligospermia; Hypogonadism
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Testosterone undecanoate; Castor Oil
Intervention type(s): Drug; Drug
Intervention description(s): Testosterone undecanoate 1000mg (in 4 ml of castor oil injections) at baseline (0-week), 6-week, 18-week, 30-week; 4 ml of Castor Oil injected at baseline (0-week), 6-week, 18-week, 30-week.
Other intervention name(s): Nebido
Intervention MeSH terms: Methyltestosterone; Castor Oil; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Klinefelter; Leydig; Testicular Tumor; LH; Infertility