Androgen for Leydig Cell Proliferation

NCT ID: NCT01206270

Last Updated: 2018-09-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-30
• Study Completion Date: 2018-06-30

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.

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.

Conditions

Klinefelter Syndrome; Hypergonadotropic Hypogonadism; Hypergonadotropic Azospermia; Hypergonadotropic Cryptozoospermia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Testosterone

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

Group Type: EXPERIMENTAL

Testosterone undecanoate

Intervention Type: DRUG

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

Placebo

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

Group Type: PLACEBO_COMPARATOR

Castor Oil

Intervention Type: DRUG

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

Interventions

Testosterone undecanoate

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

Intervention Type: DRUG

Castor Oil

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

Intervention Type: DRUG

Other Intervention Names

Nebido

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

University of Roma La Sapienza

OTHER

Sponsor Role: lead

Responsible Party

Andrea M. Isidori

Professor of Endocrinology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrea Lenzi, MD

Role: STUDY_CHAIR

University of Roma La Sapienza

Andrea Isidori, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Roma La Sapienza

Vincenzo Bonifacio, MD, PhD

Role: STUDY_DIRECTOR

University of Roma La Sapienza

Locations

Dipartimento di Fisiopatologia Medica

Rome, Lazio, Italy

Countries

Italy

References

Pozza C, Pofi R, Tenuta M, Tarsitano MG, Sbardella E, Fattorini G, Cantisani V, Lenzi A, Isidori AM, Gianfrilli D; TESTIS UNIT. Clinical presentation, management and follow-up of 83 patients with Leydig cell tumors of the testis: a prospective case-cohort study. Hum Reprod. 2019 Aug 1;34(8):1389-1403. doi: 10.1093/humrep/dez083.

Reference Type: DERIVED

PMID: 31532522 (View on PubMed)

Other Identifiers

160/10

Identifier Type: -

Identifier Source: org_study_id