ALCeP: Androgen for Leydig Cell Proliferation

Sponsor

University of Roma La Sapienza (Other)

Overall Status

Completed

CT.gov ID

NCT01206270

Collaborator

(none)

Enrollment

Location

Arms

108

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Klinefelter Syndrome Hypergonadotropic Hypogonadism Hypergonadotropic Azospermia Hypergonadotropic Cryptozoospermia	Drug: Testosterone undecanoate Drug: Castor Oil	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

56 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Androgen Treatment in Leydig Cell Proliferation

Study Start Date :

Jun 1, 2009

Actual Primary Completion Date :

Jun 1, 2017

Actual Study Completion Date :

Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Testosterone Testosterone undecanoate 1000mg injection at baseline (0-week), 6-week, 18-week, 30-week	Drug: Testosterone undecanoate Testosterone undecanoate 1000mg (in 4 ml of castor oil injections) at baseline (0-week), 6-week, 18-week, 30-week Other Names: Nebido
Placebo Comparator: Placebo Injection 4 ml of castor oil at baseline (week-0), week-6, week-18, week-30	Drug: Castor Oil 4 ml of Castor Oil injected at baseline (0-week), 6-week, 18-week, 30-week.

Arm

Intervention/Treatment

Experimental: Testosterone

Testosterone undecanoate 1000mg injection at baseline (0-week), 6-week, 18-week, 30-week

Drug: Testosterone undecanoate

Testosterone undecanoate 1000mg (in 4 ml of castor oil injections) at baseline (0-week), 6-week, 18-week, 30-week

Other Names:

Nebido

Placebo Comparator: Placebo

Injection 4 ml of castor oil at baseline (week-0), week-6, week-18, week-30

Drug: Castor Oil

4 ml of Castor Oil injected at baseline (0-week), 6-week, 18-week, 30-week.

Outcome Measures

Primary Outcome Measures

Nodule Size per Number [4 month]
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 (disappearance).

Secondary Outcome Measures

Nodule Size [4 month]
Percentage change in the area of the lesion (measured with computer assisted graphics).
Luteinizing Hormone (LH) [2 month]
Reduction of the serum Luteinizing Hormone (LH) levels during testosterone therapy
Spermatogenesis [8 month (follow-up)]
Evaluation of sperm cell production after testosterone withdrawal.
Testicular US echo-texture [36 month (follow-up)]
Changes in the number of areas / nodules / lesions in the long-term safety assessment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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