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Androgen Treatment in Leydig Cell Proliferation

Phase 2/Phase 3
18 Years
60 Years
Open (Enrolling)
Klinefelter Syndrome, Hypergonadotropic Hypogonadism, Hypergonadotropic Azospermia, Hypergonadotropic Cryptozoospermia

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Trial Information

Androgen Treatment in Leydig Cell Proliferation

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

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 UI (m-International-Unit/ml)

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

- negative testicular tumors markers: beta-hCG (Human chorionic gonadotropin), alpha-FP
(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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Nodule Size per Number

Outcome Description:

Percentage change of the area of the lesions multiplied by the number of the measured lesions: [(area_1 + area_2 + area_3 + ... + area_n)*n]. The latter measure account for reduction in the number of lesions (disappearence).

Outcome Time Frame:

4 month

Safety Issue:


Principal Investigator

Andrea Lenzi, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sapienza University of Rome


Italy: Ethics Committee

Study ID:




Start Date:

June 2009

Completion Date:

December 2013

Related Keywords:

  • Klinefelter Syndrome
  • Hypergonadotropic Hypogonadism
  • Hypergonadotropic Azospermia
  • Hypergonadotropic Cryptozoospermia
  • Klinefelter
  • Leydig
  • Testicular Tumor
  • LH
  • Infertility
  • Azoospermia
  • Hypogonadism
  • Klinefelter Syndrome